The Singularity of Nature: A Convergence of Biology, Chemistry and Physics [1 ed.] 1788017978, 9781788017978

Table of contents :
Hlaf Title
Title
Copyright
Preface
Contents
Chapter 1 The Singularity of Nature
1.1 Introduction
1.1.1 Prologue
1.2 On the Mechanisms of Biologic Evolution
1.3 Cell–Cell Interactions and Embryonic Pattern Formation
1.4 In the Beginning
1.5 The Driving Force Behind Biology Is Ambiguity
1.6 Evolutionary Biology Is Scale-free, Physics Is Not
1.7 The Role of Deception in Biology
1.8 Terminal Addition as Evidence of the Singularity
1.9 Proximate and Ultimate Causation – a Myth
1.10 Cell–Cell Signaling Perspective as Common Ground for Physiologic Evolution
1.11 Epigenetic Inheritance and the Primacy of the Unicellular State
1.12 Pauli's Exclusion Principle and the First Principles of Physiology
1.13 Non-localization in Physics and Biology
1.14 A Fractal View of Life
1.15 Consciousness, the Epitome of the Continuum from Inanimate to Animate
1.16 Discussion
1.17 Conclusion
References
Chapter 2 Bohm Meets Bacon
2.1 Introduction
2.2 Bohm's Explicate and Implicate Orders Meet the Arts
2.3 Einstein's Relativity Is Necessary to Think This Way
2.4 Conclusions
References
Chapter 3 The Cell, Evolution and Occam's Razor
3.1 Introduction
3.2 On the Consequences of Descriptive Biology
3.3 Revising the Standard Synthesis
3.4 The Primacy of the Unicellular State
3.5 Phenotype Is a Verb, Not a Noun
3.6 New Validity to Terminal Addition
3.7 Neoteny/Heterochrony in a New Frame
3.8 The Life Cycle Rethought
3.9 Discussion
3.9.1 Descriptive versus Cellular–Molecular Biology and Occam's Razor
3.9.2 Heliocentrism, the Age of Reason and Beyond
3.9.3 Consequences for Biomedical Research
3.10 Conclusion
References
Chapter 4 C.P. Snow's “Two Cultures” Condition Is Resolved by the Singularity
4.1 Empiricism as the Path from the Explicate to the Implicate Order: Common Ground for Science and the Arts
4.2 Einstein's Relativity Is Necessary to Think This Way
4.3 Conclusions
References
Chapter 5 The Heart Is Not Just a Pump; the Brain Is Not Your Only “Mind”
5.1 Holland's Skin-brain Hypothesis
5.2 Nicotine's Effect on N-acetylcholine Receptors Homology Between Lung and Brain
5.3 Pleiotropic Defensins Reveal Deep Physiologic Relationship Between Lung and Skin
5.4 Symmorphosis Experience as Corollary to Deep Physiology
5.5 The Brain Is Not the Mind
5.6 The Body Is Not Who We Are
References
Chapter 6 Why You Must Transcend Space-time in Order to Understand Consciousness
6.1 Predictive Value of Consciousness as a Fractal of the Cosmos
References
Chapter 7 The Evolutionary Significance of Homeostasis
7.1 Homeostasis Is Not Stasis
7.2 Bernard to Cannon
7.3 Dyshomeostasis
7.4 Waddington's Diachronic Perspective
7.5 Downward Causation
7.6 Diachronic Signaling Mechanisms Link Development, Homeostasis and Regeneration
7.7 Homeostasis, Agent for Change in the Vertebrate Water-land Transition as Emergence
7.8 Homeostasis as the Consequence of Developmental Mechanisms
7.9 Parathyroid Hormone-related Protein Regulation of Physiologic Stress
7.10 Parathyroid Hormone-related Protein Expression in Adrenal Corticoid Synthesis
7.11 Diachronic Regulation of Homeostasis
7.12 Allostasis as Integrated Homeostasis
7.13 Conclusions
References
Chapter 8 Networking from the Cell to Quantum Mechanics as Consciousness
References
Chapter 9 On Cellular Cooperativity as the Basis for Moral Behavior
9.1 Introduction
9.2 Our Physiology, Ourselves
9.3 Morality as the Unicell Ascribing to the Laws of Nature
9.4 Metabolic Cooperativity as the Basis for Biologic Morality
9.5 So Why Is There Immorality?
9.6 Morality in the Anthropocene
9.7 Altruistic Behavior in Bacteria
9.8 Discussion
9.9 Conclusion
References
Chapter 10 Aging, Senescence and Death as a Systematic Breakdown in Cell–Cell Communication
10.1 Introduction
10.2 Why We Age
10.3 Dying and the Microbiome
10.4 Phenotype as Agent
10.5 The Red Queen and the Singularity
10.6 Epigenetic Inheritance and Aging
10.7 Physiology as Niche Construction
10.8 Insight to Aging in the Context of Cell–Cell Signaling
10.9 Empiric Evidence for Aging as Loss of Cell–Cell Signaling
10.10 Gender Differences as Proof of Principle for Aging as Loss of Cell–Cell Signaling
10.11 Loss of Homeostatic Control Is Marked by Increased Wingless/Int Expression
10.12 Discussion
References
Chapter 11 A Holistic Perspective on Consciousness
11.1 Introduction
11.2 Evolution, From Its Origin
11.3 Why Do We See “Red” in Association with Pain?
11.4 Restoring Cellular Homeostasis
11.5 The Hard Problem, No Longer
11.6 The Integration of Consciousness and the Ecosystem
11.7 Human Consciousness as Cell–Cell Communication
11.8 Consciousness Revealed by Cartesian Coordinates
11.9 Consequences of the Hypothesis and Discussion
References
Chapter 12 Cell Division Seen as the Symmetry Breaking of the Singularity/Big Bang
12.1 Introduction
12.2 Homeostasis Is the Common Ground Between Physics and Biology
12.3 Are We in the Cosmos or of the Cosmos?
12.4 Epigenetic Inheritance
12.5 The Systematic Error in Seeing the Phenotype as Object, Not Agent
12.5.1 Yeast/Lung/Bone/Gravity
12.5.2 Turritopsis dohrnii
12.5.3 Slime Mold, or Dictyostelium discoideum
12.5.4 Nutrient Restriction Model of Metabolic Syndrome
12.5.5 Piaget's Perspective on Human Development
12.6 Discussion
12.6.1 Cell Division as the Singularity/Big Bang: Reductio Ad Absurdum of Holistic Cosmology?
12.6.2 Space-time is an Artifact
References
Chapter 13 Minding the Gap, or the Unicell Fills the Gap Between Proximate and Ultimate Causation
13.1 The Unicell as Resolution of the Mayr's Proximate and Ultimate Causation in Evolution
References
Chapter 14 The Big Bang: The Vectoral Origin of the Periodic Table and Evolution
14.1 Introduction
14.2 The Periodic Table of Elements and You
14.3 The Environment Gave Rise to Endothermy
14.4 Diachronic Vectors of the Big Bang
14.5 Information Theory Meets Informatics
14.6 Truth Be Told
14.7 There Is Only Space, There Is No Time
14.8 A Novel Prediction of Consciousness as the Singularity
14.9 The Vertical Integration of Gravity, Chemistry and Biology as Consciousness
14.10 Biology and Chemistry as Vectors of the Big Bang
14.11 Conclusions
References
Chapter 15 The Physiological and Evolutionary Significance of Deuterostomy
15.1 Early Embryologic Developmental Differences Between Protostomes and Deuterostomes
15.2 Evolution of Endothermy as Positive Selection for Bipedalism and Specialization of Forelimbs: Universal Consciousness as Past/Present/Future
15.3 Plasticity of the Foregut
15.4 The Phylogeny of the Thyroid
15.5 An Evolutionary Vertical Integration of the Phylogeny and Ontogeny of the Thyroid
15.6 Plasticity of the Vagus
15.7 Acquisition of Epigenetic Marks Overlayed on the above Makes for a Highly Robust Form of Consciousness
15.8 “From Horizontal to Vertical”, or the Grand Synthesis
15.9 Ontogeny Recapitulates Phylogeny – Ernst Haeckel Was Right
15.10 Gravity Is the “Stretching” of the Fabric of Space-Time; So Too Is the Stretching of the Swim Bladder or Lung
15.11 Gastrulation, Epigenetic Inheritance, Formation of the Coelomic Membrane Covering the Reptilian/Bird Lung
15.12 On the Endocrine System and Vertebrate Evolution
15.13 The Commutative Principle as the Basis for the “Kaleidoscope” of Physiologic Adaptation
15.14 Discussion
References
Chapter 16 We Are All Denizens of Gaia
16.1 Gaia Is Us
16.2 Phenotypic Variation as Agency for Epigenetic Inheritance
16.3 On the Evolution of Metazoans
16.4 Consciousness as the Product of Gaia – Why We Inherently Care About Mother Earth
16.5 Morality as Gaia
16.6 Climate Change, Gaia and Us
References
Chapter 17 Cell–Cell Signaling, the Energy Flow from the Big Bang to Civilization
References
Chapter 18 The Physics of Biology Conforms to the Singularity
References
Chapter 19 Foundational Physicochemical Principles Drive Human Economics
19.1 Basic Principles of Cellular Cooperation
19.2 Cellular Principles Drive Human Economics
19.3 Cellular Principles, Trading and Behavioral Economics
19.4 Conclusion
References
Chapter 20 Singularity, Life and Mind: New Wave Organicism
20.1 Introduction
20.2 Singularity and Nature
20.3 On the Causal-processual Mechanisms of Biological Evolution
20.4 Biology as a Continuum
20.5 Conscious Mind and Its Emergence in the Continuum from Inanimate to Animate
20.6 Mind is a Form of Life 1: Solving the Mind–Body Problem
20.7 Dynamic Systems Theory and the Dynamic World Picture
20.8 Mind is a Form of Life 2: Solving the Free Will Problem
20.9 Thoreau and the Transcendence of the Cell–Cell Communication Approach to Evolution
20.10 The First Waves of Organicist Philosophy, Organicist Science, and Organicist Modernism; and What Went Wrong Between Philosophy and Science after 1950
20.11 The Second Waves of Organicist Philosophy, Organicist Science, and Organicist Modernism
20.12 Conclusion
References
Chapter 21 Conclusion: The Singularity Unites the Cosmos
Subject Index

Citation preview

The Singularity of Nature A Convergence of Biology, Chemistry and Physics

The Singularity of Nature A Convergence of Biology, Chemistry and Physics By John S. Torday UCLA Evolutionary Medicine, USA Email: [email protected]

and

William B. Miller Jr Banner Health Systems, USA Email: [email protected]

Print ISBN: 978-1-78801-797-8 PDF ISBN: 978-1-83916-224-4 EPUB ISBN: 978-1-83916-225-1 A catalogue record for this book is available from the British Library © John S. Torday and William B. Miller Jr 2021 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. Whilst this material has been produced with all due care, The Royal Society of Chemistry cannot be held responsible or liable for its accuracy and completeness, nor for any consequences arising from any errors or the use of the information contained in this publication. The publication of advertisements does not constitute any endorsement by The Royal Society of Chemistry or Authors of any products advertised. The views and opinions advanced by contributors do not necessarily reflect those of The Royal Society of Chemistry which shall not be liable for any resulting loss or damage arising as a result of reliance upon this material. The Royal Society of Chemistry is a charity, registered in England and Wales, Number 207890, and a company incorporated in England by Royal Charter (Registered No. RC000524), registered office: Burlington House, Piccadilly, London W1J 0BA, UK, Telephone: +44 (0) 20 7437 8656. Visit our website at www.rsc.org/books Printed in the United Kingdom by CPI Group (UK) Ltd, Croydon, CR0 4YY, UK

Preface The subject of this book was originally outlined in a journal article with the same title by J.S. Torday. The general presenting concept was that because cosmology and biology originated from the Singularity/Big Bang, they share numerous homologies at the quantum mechanical and cellular levels. Such homologies are implemented by chemical, physical and biologic reactions that account for balanced physical reactions as physiologic cellular homeostasis. Although these reactions are all exercised at the level of individual cells, their aggregation through multicellularity permits our perceptions of “reality” instead of perpetual chaos. A key determinant in this volume is that the Big Bang produced an “equal and opposite” reaction based on Newton's third law of motion. This forced relationship represents the foundation of cellular homeostasis by establishing the intracellular negentropic state. In chemistry and physics, reaction sets express combinations of mass and energy on either side of an “equals” sign. Therein lies the fundamental difference between these sciences and biology. In the case of chemistry and physics, the product of the reaction is stable and predictable. In the case of a biological reactions, the product remains “unstable” and is never an absolute equality. This dynamic relates to the presence of the two conflicting imperatives of the living state. The definitional negentropic status of the internal cell that must be maintained, yet, this dynamic must be achieved despite consequential conditional ambiguities that define the living circumstance. The basic cell resolves this conflict to maintain internal relative negentropy through the continuous dynamics of chemiosmosis and homeostasis. Together, these three vital living components form the first principles of physiology (negentropy, chemiosmosis and homeostasis). In living systems, stasis is tantamount to extinction. Biology copes through products of biologic reactions as adaptive offspring, molded by their environment through epigenetic inheritance. Nonetheless, the animate and inanimate must both adhere to the same laws of nature, each reconciling the dualities of the Big Bang in their own manner. From this well-grounded base, a novel cellular-molecular approach to the evolution of physiology based on developmental biology emerges as a continuum from the Singularity forward over universal space-time. The Royal Society of Chemistry has been dedicated to the advancement of excellence in the chemical sciences since 1841, over twenty years before Mendeleev's periodic table was first published, merging chemistry and physics using atomic number as a “normalizing” factor. Similarly, the approach to evolution using cell-cell signaling has merged ontogeny and phylogeny into one continuous process. The further recognition that the atom and the cell are both homologues of quantum mechanics has merged physics, chemistry and biology into a justifiable Singularity. The hypothetical deployment of lipids to form the first cell is predicated on micelles spontaneously forming primitive cells with semipermeable membranes provided the requisite physicochemical separation between the cellular interior and the outward environment upon which life depends. The ability of such structures to deform when warmed by the sun, and reform at night conferred the required “memory” for evolution to take place. The recognition of chemiosmosis as one of only three first principles of physiology places chemistry squarely in the center of the evolution of life. The

alignment of ions with positive or negative charges on either side of an internal membrane to generate electron flow for bioenergy was essential for the maintenance of negative entropy; the pact with the devil that life has struck for remaining viable. John S. Torday and William B. Miller Jr

Contents Chapter 1 The Singularity of Nature 1.1

Introduction 1.1.1 Prologue

1.2

On the Mechanisms of Biologic Evolution

1.3

Cell–Cell Interactions and Embryonic Pattern Formation

1.4

In the Beginning

1.5

The Driving Force Behind Biology Is Ambiguity

1.6

Evolutionary Biology Is Scale-free, Physics Is Not

1.7

The Role of Deception in Biology

1.8

Terminal Addition as Evidence of the Singularity

1.9

Proximate and Ultimate Causation – a Myth

1.10 Cell–Cell Signaling Perspective as Common Ground for Physiologic Evolution 1.11 Epigenetic Inheritance and the Primacy of the Unicellular State 1.12 Pauli's Exclusion Principle and the First Principles of Physiology 1.13 Non-localization in Physics and Biology 1.14 A Fractal View of Life 1.15 Consciousness, the Epitome of the Continuum from Inanimate to Animate 1.16 Discussion 1.17 Conclusion References Chapter 2 Bohm Meets Bacon 2.1

Introduction

2.2

Bohm's Explicate and Implicate Orders Meet the Arts

2.3

Einstein's Relativity Is Necessary to Think This Way

2.4

Conclusions References

Chapter 3 The Cell, Evolution and Occam's Razor 3.1

Introduction

3.2

On the Consequences of Descriptive Biology

3.3

Revising the Standard Synthesis

3.4

The Primacy of the Unicellular State

3.5

Phenotype Is a Verb, Not a Noun

3.6

New Validity to Terminal Addition

3.7

Neoteny/Heterochrony in a New Frame

3.8

The Life Cycle Rethought

3.9

Discussion 3.9.1 Descriptive versus Cellular–Molecular Biology and Occam's Razor 3.9.2 Heliocentrism, the Age of Reason and Beyond 3.9.3 Consequences for Biomedical Research

3.10 Conclusion References Chapter 4 C.P. Snow's “Two Cultures” Condition Is Resolved by the Singularity 4.1

Empiricism as the Path from the Explicate to the Implicate Order: Common Ground for Science and the Arts

4.2

Einstein's Relativity Is Necessary to Think This Way

4.3

Conclusions References

Chapter 5 The Heart Is Not Just a Pump; the Brain Is Not Your Only “Mind” 5.1

Holland's Skin-brain Hypothesis

5.2

Nicotine's Effect on N-acetylcholine Receptors Homology Between Lung and Brain

5.3

Pleiotropic Defensins Reveal Deep Physiologic Relationship Between Lung and Skin

5.4

Symmorphosis Experience as Corollary to Deep Physiology

5.5

The Brain Is Not the Mind

5.6

The Body Is Not Who We Are References

Chapter 6 Why You Must Transcend Space-time in Order to Understand Consciousness 6.1

Predictive Value of Consciousness as a Fractal of the Cosmos References

Chapter 7 The Evolutionary Significance of Homeostasis 7.1

Homeostasis Is Not Stasis

7.2

Bernard to Cannon

7.3

Dyshomeostasis

7.4

Waddington's Diachronic Perspective

7.5

Downward Causation

7.6

Diachronic Signaling Mechanisms Link Development, Homeostasis and Regeneration

7.7

Homeostasis, Agent for Change in the Vertebrate Water-land Transition as Emergence

7.8

Homeostasis as the Consequence of Developmental Mechanisms

7.9

Parathyroid Hormone-related Protein Regulation of Physiologic Stress

7.10 Parathyroid Hormone-related Protein Expression in Adrenal Corticoid Synthesis 7.11 Diachronic Regulation of Homeostasis 7.12 Allostasis as Integrated Homeostasis 7.13 Conclusions References Chapter 8 Networking from the Cell to Quantum Mechanics as Consciousness References Chapter 9 On Cellular Cooperativity as the Basis for Moral Behavior 9.1

Introduction

9.2

Our Physiology, Ourselves

9.3

Morality as the Unicell Ascribing to the Laws of Nature

9.4

Metabolic Cooperativity as the Basis for Biologic Morality

9.5

So Why Is There Immorality?

9.6

Morality in the Anthropocene

9.7

Altruistic Behavior in Bacteria

9.8

Discussion

9.9

Conclusion References

Chapter 10 Aging, Senescence and Death as a Systematic Breakdown in Cell–Cell Communication

10.1 Introduction 10.2 Why We Age 10.3 Dying and the Microbiome 10.4 Phenotype as Agent 10.5 The Red Queen and the Singularity 10.6 Epigenetic Inheritance and Aging 10.7 Physiology as Niche Construction 10.8 Insight to Aging in the Context of Cell–Cell Signaling 10.9 Empiric Evidence for Aging as Loss of Cell–Cell Signaling 10.10 Gender Differences as Proof of Principle for Aging as Loss of Cell– Cell Signaling 10.11 Loss of Homeostatic Control Is Marked by Increased Wingless/Int Expression 10.12 Discussion References Chapter 11 A Holistic Perspective on Consciousness 11.1 Introduction 11.2 Evolution, From Its Origin 11.3 Why Do We See “Red” in Association with Pain? 11.4 Restoring Cellular Homeostasis 11.5 The Hard Problem, No Longer 11.6 The Integration of Consciousness and the Ecosystem 11.7 Human Consciousness as Cell–Cell Communication 11.8 Consciousness Revealed by Cartesian Coordinates 11.9 Consequences of the Hypothesis and Discussion References Chapter 12 Cell Division Seen as the Symmetry Breaking of the Singularity/Big Bang 12.1 Introduction 12.2 Homeostasis Is the Common Ground Between Physics and Biology 12.3 Are We in the Cosmos or of the Cosmos? 12.4 Epigenetic Inheritance 12.5 The Systematic Error in Seeing the Phenotype as Object, Not Agent 12.5.1 Yeast/Lung/Bone/Gravity 12.5.2 Turritopsis dohrnii

12.5.3 Slime Mold, or Dictyostelium discoideum 12.5.4 Nutrient Restriction Model of Metabolic Syndrome 12.5.5 Piaget's Perspective on Human Development 12.6 Discussion 12.6.1 Cell Division as the Singularity/Big Bang: Reductio Ad Absurdum of Holistic Cosmology? 12.6.2 Space-time is an Artifact References Chapter 13 Minding the Gap, or the Unicell Fills the Gap Between Proximate and Ultimate Causation 13.1 The Unicell as Resolution of the Mayr's Proximate and Ultimate Causation in Evolution References Chapter 14 The Big Bang: The Vectoral Origin of the Periodic Table and Evolution 14.1 Introduction 14.2 The Periodic Table of Elements and You 14.3 The Environment Gave Rise to Endothermy 14.4 Diachronic Vectors of the Big Bang 14.5 Information Theory Meets Informatics 14.6 Truth Be Told 14.7 There Is Only Space, There Is No Time 14.8 A Novel Prediction of Consciousness as the Singularity 14.9 The Vertical Integration of Gravity, Chemistry and Biology as Consciousness 14.10 Biology and Chemistry as Vectors of the Big Bang 14.11 Conclusions References Chapter 15 The Physiological and Evolutionary Significance of Deuterostomy 15.1 Early Embryologic Developmental Differences Between Protostomes and Deuterostomes 15.2 Evolution of Endothermy as Positive Selection for Bipedalism and Specialization of Forelimbs: Universal Consciousness as Past/Present/Future 15.3 Plasticity of the Foregut 15.4 The Phylogeny of the Thyroid

15.5 An Evolutionary Vertical Integration of the Phylogeny and Ontogeny of the Thyroid 15.6 Plasticity of the Vagus 15.7 Acquisition of Epigenetic Marks Overlayed on the above Makes for a Highly Robust Form of Consciousness 15.8 “From Horizontal to Vertical”, or the Grand Synthesis 15.9 Ontogeny Recapitulates Phylogeny – Ernst Haeckel Was Right 15.10 Gravity Is the “Stretching” of the Fabric of Space-Time; So Too Is the Stretching of the Swim Bladder or Lung 15.11 Gastrulation, Epigenetic Inheritance, Formation of the Coelomic Membrane Covering the Reptilian/Bird Lung 15.12 On the Endocrine System and Vertebrate Evolution 15.13 The Commutative Principle as the Basis for the “Kaleidoscope” of Physiologic Adaptation 15.14 Discussion References Chapter 16 We Are All Denizens of Gaia 16.1 Gaia Is Us 16.2 Phenotypic Variation as Agency for Epigenetic Inheritance 16.3 On the Evolution of Metazoans 16.4 Consciousness as the Product of Gaia – Why We Inherently Care About Mother Earth 16.5 Morality as Gaia 16.6 Climate Change, Gaia and Us References Chapter 17 Cell–Cell Signaling, the Energy Flow from the Big Bang to Civilization References Chapter 18 The Physics of Biology Conforms to the Singularity References Chapter 19 Foundational Physicochemical Principles Drive Human Economics 19.1 Basic Principles of Cellular Cooperation 19.2 Cellular Principles Drive Human Economics 19.3 Cellular Principles, Trading and Behavioral Economics

19.4 Conclusion References Chapter 20 Singularity, Life and Mind: New Wave Organicism 20.1 Introduction 20.2 Singularity and Nature 20.3 On the Causal-processual Mechanisms of Biological Evolution 20.4 Biology as a Continuum 20.5 Conscious Mind and Its Emergence in the Continuum from Inanimate to Animate 20.6 Mind is a Form of Life 1: Solving the Mind–Body Problem 20.7 Dynamic Systems Theory and the Dynamic World Picture 20.8 Mind is a Form of Life 2: Solving the Free Will Problem 20.9 Thoreau and the Transcendence of the Cell–Cell Communication Approach to Evolution 20.10 The First Waves of Organicist Philosophy, Organicist Science, and Organicist Modernism; and What Went Wrong Between Philosophy and Science after 1950 20.11 The Second Waves of Organicist Philosophy, Organicist Science, and Organicist Modernism 20.12 Conclusion References Chapter 21 Conclusion: The Singularity Unites the Cosmos Subject Index

CHAPTER 1

The Singularity of Nature 1.1

Introduction “When one man has reduced a fact of the imagination to be a fact to his understanding, I foresee that all men will at length establish their lives on that basis” – Henry David Thoreau, Walden

1.1.1

Prologue

The following is not an exercise in sophistry. We are at a watershed in human history, in which humans are affecting global climate, considering delegating our intelligence to machines, and genetically modifying ourselves. All of this is happening without an understanding of our origins and evolution, Darwin notwithstanding. In light of that, we offer the following insights for your consideration. Did you ever wonder why there is never a bad color combination in nature? Contemplating that realization has been an enduring focus of our thoughts from the pre-Socratic Greek philosophers, across the breadth of the Aristotelian vitalistic concepts of entelechy, extending to E.O. Wilson's contemporary book, Consilience (1998). Wilson proposed that all knowledge could exist in one common database by reducing it to binary 1s and 0s. Others have struggled to build on that belief, in science (Smolin, 1997), metaphysics (Lipton, 2016; Sheldrake, 2017) and philosophy (Whitehead, 2010). Prior to Einstein's formulation of the equivalency of energy and mass (E=mc2), it was commonplace to dismiss such ideas as if they were one of Kipling's Just So Stories. However, that monumental equation changed our thoughts by radically equating energy and matter. Through this simple equation, the entire gamut of existence was circumscribed, the more surprising since this aweinspiring breakthrough occurred to Einstein in a dream when he was sixteen years old (Isaacson, 2007). Just as physics was unsettled by this illuminating brilliance, that equation also challenges us to determine how biology conforms to this allencompassing perspective. Biology is unlike physics. As a history of continuous dynamic changes, biology has long been presumed to exist without an underpinning of eternal laws. Nonetheless, one belief has become central to biology. As Dobzhansky (1973) memorably pronounced: “Nothing in biology makes sense except in the light of evolution.” Any attempt at reconciling chemistry and physics must therefore explain how basic chemical and physical laws can seamlessly yield the biological forms that populate our planet. In order to properly begin the process, it can be pointed out that the equivalency of energy and mass in Einstein's equation equally permeates all of the sciences, encompassing physics, chemistry and biology. Fundamentally, they are all characterized by the relationship between energy and mass. When this is properly

considered, a facile exchange of concepts between the competing sciences of chemistry, physics and biology is worth encouraging. A continued challenge has been finding the correct means of placing biology alongside physics and chemistry, insofar as both of the latter have their own forms of exactitude. In this book, we will examine how biology can be placed within an equivalent template of predictive rigor. That path travels through the unicellular domains that cooperate to enable multicellular collaborative life. A window into this complex process can best be appreciated through the process of embryologic development, in which primordial germ cells communicate with one another through signaling mechanisms that determine the growth and differentiation of the developing fetus. Those processes are mediated by high-energy phosphates, as second messengers, which change the genetic readout of the cell. When seen as a series of linked energy and information transfers, from cell to cell, and from generation to generation, ontogeny and phylogeny can stand alongside physics and chemistry as being based within understandable and reiterative rules that govern life on the planet, and then might equally apply to any other life in our universe. The Big Bang was the point source of the universe, radiating out the origin of the cosmos as microwaves that began our existence (Singh, 2005). Biology, too, has its own homologous point source, which has been identified as the unicellular origin of life (Torday and Miller, 2016a). This is not by analogy or expressed as a metaphor. Single-celled living organisms formed on Earth 3.8 billion years ago and dominate to this day. The evolution of eukaryotes that enable our type of multicellular life was perpetuated by the synthesis and insertion of cholesterol into the cell membrane (Bloch, 1992). As a result, it facilitated the coordination of vertebrate metabolism, locomotion and respiration as the three foundational traits of vertebrate evolution (Perry and Carrier, 2006). Physico-chemically, the cell membrane became more fluid, enabling endo- and exocytosis, allowing for the internalization of environmental factors that periodically posed an existential threat – heavy metals, ions and gases – instead compartmentalizing them within endomembranes, making them useful for physiologic functions (Torday and Rehan, 2012). This concept is referred to as the endosymbiosis theory (Gray, 2017). The reduction of physiologic evolution to cell–cell communications has led to the realization that contemporary biology remains descriptive (Torday, 2015a) rather than being mechanistic (Nicholson, 2012; Moss 2012). Over the last several hundred years, physics and chemistry have matured into predictive “hard sciences.” Instead, biologists continue to amass observational data instead of formulating founding principles. To correct this problem, a “Central Theory of Biology” was formulated (Torday, 2015a), providing a basis for common ground between biology, physics and chemistry. By superimposing the mechanisms of embryologic development on the phylogenetic “history” of organisms, a cellular–molecular common denominator for evolution was discovered (Torday and Rehan, 2017). Those interrelationships become particularly relevant when the interrelationships between the cellular– molecular mechanisms of physiologic development, phylogeny, homeostasis and dyshomeostasis (pathology) are further expanded (Torday and Rehan, 2007). That reduction allows for a deep understanding of what had been merely descriptive biology, and now moves it in a forward direction. Beginning with the fundamental unicell, multicellular physiology can now be logically understood (Torday and Rehan, 2017), rather than through retrospective rationalizations that are dogmatic, teleological and tautological. By understanding our cellular selves at

this fundamental level, our place in the great scheme of nature as individuals, social beings and as a species among species can be better understood. This might even lead to the creation of a periodic table of biology (Torday, 2004), integrating all of the natural sciences into one functionally predictive search engine, finally realizing the unity of science (Cat, 2017). Ever since the works of the natural philosophers of Greece, the atomistic idea of the “Singularity” has subliminally occupied our thoughts. This ancient and alluring concept has extended from Anaxagoras to Anaximenes, and then to Parmenides, Heraclitus and Aristotle (entelechy). In our contemporary era, there have been those who have furthered that possibility of a fundamental universal unity across nature, such as L.L. Whyte (1949) and E.O. Wilson, in his book Consilience (1998). Whyte intuited that there must be inherent common principles that form a basis for the Singularity. In our computer age, Wilson proposed that since the world's knowledge is being reduced to 1s and 0s, there should be a common groundwork for a universal explanation of all knowledge as a universal database. As is always a certainty, not all agree. Unifying ideas for physics, chemistry and biology have been decidedly countered by Prigogine (1984) and Polanyi (1968), both preeminent physicist-polymaths, who concluded that biology was too complicated to be understood by this means. Their philosophical mantle was reinforced by biologists and physicians, such as Bruce Lipton, Richard Sheldrake and Richard Moss, who all defaulted to mysticism in order to explain the nature of life. Over time, one of the systematic errors in any attempt to discern a universal unity from the Singularity forward has been the assumption that a solution could be found through the study of logic (Bohm, 1980). Instead, it is insisted that finding the proper connections rests in experimentation. The key to understanding The Singularity lies in the first principles of physiology as that singular unity (Torday and Rehan, 2012). That idea emerged from superimposing the cell–cell communication mechanisms of embryologic ontogeny on phylogeny, which are derived from the physical environment (Deamer, 2017). It is by this means that life can be fully understood, emerging from non-life on the basis of discoverable scientific principles, which lead backward in a step-wise manner to the Singularity of Nature.

1.2

On the Mechanisms of Biologic Evolution

Daniel Nicholson (2012) defines biologic mechanisms in three ways: “It may refer to a philosophical thesis about the nature of life and biology (‘mechanicism’), to the internal workings of a machine-like structure (‘machine mechanism’), or to the causal explanation of a particular phenomenon (‘causal mechanism’).” In a series of publications, biologically operative mechanisms have been addressed by examining evolution, starting from its unicellular origins (Torday and Rehan, 2012; Torday and Miller, 2016a; Torday and Rehan, 2017). It is proposed that this yields a novel predictive form of evolutionary etiology. Starting from the origin of life, which is based on cellular–molecular principles of ontogeny applied to phylogeny, the biological mechanisms for successfully coping with environmental stresses can be elucidated (Torday, 2015b). It can be correctly asserted that the first principles of physiology – negentropy, chemiosmosis and homeostasis – provide the initial conditions for evolution and homeostasis (Torday and Rehan, 2012), providing insight to how and why organisms have evolved. Through developmental physiology, it can be appreciated that there is a

reiterative pattern between the initiating conditions of the Singularity and the life cycle of the organism, extending from the unicellular state to the multicellular form. It is extremely pertinent that this process is bidirectional. In multicellular eukaryotic life, it extends back again through our obligatory recapitulation through the unicellular zygotic stage that enables one life cycle to the next. Up until recently, it was assumed that the organism was obligated to go through all of the stages of the life cycle in order to replenish members of the species that were either lost through attrition or were successful in evolutionary adaptations (Darwin, 1859). But formulating our conception of the cell as the first niche construction (Torday, 2016a) that permits cellular knowledge about its surroundings and authorizes epigenetic phenotypic agency (Torday and Miller, 2016c), the function of the life cycle could now be seen as an active process, rather than as an end in itself (Torday and Miller, 2016a; Torday, 2016b). It had long been assumed that the epigenetic marks obtained over the course of the life cycle were “erased” during meiosis. However, it is now known that there is a specific mechanism for sorting and selecting such marks during meiosis (Schaefer and Nadeau, 2015), embryogenesis (Cheedipudi et al., 2014) and the life cycle itself (Zhang and Ho, 2011). Indeed, it is now accepted that the life cycle is thoroughly affected by epigenetics. For example, the crucial endocrine system is under the influence of epigenetics (Anway and Skinner, 2008), determining the duration and depth of any given stage of the life cycle, including maternal bonding, crawling, toddling, adolescence, teen-hood, adulthood and senescence/aging. This view of the life cycle is a departure from the past, as it represents an ongoing, active reciprocity with the environment through the process of niche construction (Torday, 2016a). Wide acceptance of epigenetic inheritance has changed our perspective on the life cycle. For example, exposure of the fetus and newborn to cigarette smoke has been identified as being strongly associated with childhood asthma (Zacharasiewicz, 2016). This relationship regained prominent attention when the “freeway” epidemiology group at the University of Southern California reported the finding that whether or not your grandmother smoked was the biggest risk factor for childhood asthma (Gilliland et al., 2000), inferring a transgenerational effect of cigarette smoke on the upper airway of either the fetus or developing infant (Gilliland et al., 2001). Rehan and Torday studied the heritable effects of nicotine, one of the 3000 constituents of cigarette smoke, because it is absorbed into the circulation, crosses the placenta, and is stored in fatty tissue in the fetus (McEvoy and Spindel, 2017). That research indicates that treating pregnant rats with nicotine causes asthma in the offspring for multiple generations (Rehan et al., 2013). Epigenetic marks chemically change DNA transcription through methylation, ribosylation or multiple processes of ubiquitination. Nicotine causes the appearance of such marks in the upper airways of rat offspring; more importantly, it induces the same marks in the DNA of the sperm and egg, which is how the nicotine effect is passed from one generation to the next.

1.3

Cell–Cell Interactions and Embryonic Pattern Formation

Our insights into the fundament of physiology (Torday and Rehan, 2012), exclusively derived from experimental evidence, began with the realization that the effect of cortisol on lung surfactant production was paracrine in nature (Smith,

1979). The glucocorticoid receptor was identified in the interstitial fibroblasts of the alveolar wall, accelerating the maturation of connective tissue fibroblasts to produce fibroblast pneumocyte factor (Smith, 1979). This empiric discovery ran contrary to the conventional wisdom that the hormonal effect would be directly on the alveolar type II pneumocyte, the site of lung surfactant production (Goss et al., 2013). The principle that lung development was dependent on cell-cell communication was consistent with Grobstein's earlier discovery that the process is mediated by low molecular weight soluble growth factors (1953). Furthermore, when lung epithelial cells (Lwebuga-Mukasa et al., 1986) or liver hepatocytes (Michalopoulos et al., 1979) were cultured, they lost their differentiated function and structure unless provided with soluble factors from their connective tissue environment, providing clues to the fundamental nature of their development, homeostasis and repair (Warburton et al., 2010). Subsequently, the paracrine regulation of many tissues and organs has been elucidated, starting with the cross-talk between the animal and vegetal poles of the zygote (Gurdon et al., 1997). The lesson learned from this experience was that the smallest functional unit of biology is the cell (Torday and Rehan, 2012), which Schleiden and Schwann had concluded in the mid-nineteenth century (Tavassoli, 1980). The reason for the long lapse between the top-down and bottom-up approaches to development was due to the prevailing “machine” concept of the organism (Nicholson, 2012; Moss 2012), i.e. that the whole is equal to the sum of its parts. That concept persists to this day, DNA–RNA–protein being the “central dogma” for both molecular biology and the modern evolutionary synthesis (Crick, 1970). The cellular evolutionary principle is predictive (Torday, 2015c), whereas the molecular biologic approach is not. For example, the cell–cell communication model predicts the process of lung maturation after a cortisol challenge (Torday and Rehan, 2007), whereas the molecular model can only state that there is an association or correlation with a specific disease (Ioannidis, 2005). Prior to the publication of the human genome, it was speculated that hominins would have at least 100 000 genes based on the analogy with simpler organisms. Yet humans have fewer genes than a carrot (19 000 vs. 40 000). One would expect this to challenge the existing paradigm, but there have been no repercussions to date.

1.4

In the Beginning

When the lipids in the primordial oceans generated micelles, they spontaneously separated the internal environment of the cell from the external environment (Deamer, 2017). That gave rise to intracellular negative entropy (Schrodinger, 1944), circumventing the second law of thermodynamics, energized by chemiosmosis and regulated by homeostasis. These are the first principles of physiology (FPP) (Torday and Rehan, 2012). The organism complies with these FPP by monitoring the environment based on the principle of homeostasis. There is a range of conditions that homeostasis can tolerate, beyond which remodeling of the cellular niches formed by developmental mechanisms occur (Storr et al., 2013). Such auto-engineering underpins evolution (Varela et al., 1974; Shapiro, 2011; Torday and Rehan, 2012; Miller, 2016; Torday and Rehan, 2017; Miller et al., 2019). The organism must ascribe to the FPP to survive, making it deterministic. Conversely, homeostasis monitors the environment, providing freedom for the internal environment to vary around its set-point. If the limits of homeostatic

control are violated, the organism will remodel itself by reverting to its previous phylogenetically determined set-point to maintain homeostasis (Torday, 2015d).

1.5

The Driving Force Behind Biology Is Ambiguity

The differential between the internal cellular negentropy and the external environmental entropy generated an ambiguity (Torday and Miller, 2017) that has propelled organisms to solve the problems presented by an ever-changing environment. We humans instinctively recognize that ambiguity as “original sin” in the Judeo-Christian tradition, or karma in Hinduism, as the life force biologically, or the conscious processes of self-doubt from which all anxieties derive. It is the result of the Faustian pact that life has made with the laws of physics, circumventing the second law of thermodynamics. We have coped with that ambiguity using religion, myth, art, music and literature. But over the course of the last five hundred years, we have employed science to systematically push back the shroud of fear created by the ambiguity, progressively gaining insight to our origins and how we have evolved. Darwin (1859) liberated us from the Great Chain of Being, but did not offer a means for doing testable and refutable science. Instead, he invoked natural selection as the metaphoric “mechanism” of evolution. The cellular–molecular approach to evolution categorically differs by providing Popperian (2002) testables and refutables to biology that finally extend biology beyond its descriptive limits.

1.6

Evolutionary Biology Is Scale-free, Physics Is Not

Biology and evolution are scale-free, whereas physics is scalar. For example, special relativity does not resolve general relativity, indicating a fundamental difference between them. The reason is biologic self-reference and self-organization that deploy physical principles for their own purposes (Varela et al., 1974; Miller, 2016; Miller, 2017; Miller et al., 2019). Biology has authored its own first principles that permit the internalization of the environment, thereby authoring physiology (Torday and Rehan, 2012), and functioning between the boundaries of determinism and free will. It is autonomous, but still compliant with the laws of physics. The intimate relationship between biology and physics has been made possible by internalizing physical factors such as heavy metals, ions and gases, in service to the perpetuation of negentropy. The difference between the inanimate physical realm and living biology is stark. Biology continuously reinvents itself in response to environmental stresses. The inanimate realm does not. This process of perpetual problem-solving leads to our complex biological selves which then, as a continuing echo of its fundamental principles, further reiterate, through our human hands as simple and compound machines, aerodynamic foils and gravity-fed toilets.

1.7

The Role of Deception in Biology

Ever since Schrödinger's much-vaunted insight to the negentropic nature of cellular life, it has been acknowledged that the cell is able to circumvent the second law of thermodynamics. The active basis for this deception is now plain. It is due to the first principles of physiology. All of life is rife with deceptions. We mislead ourselves and deceive others (Trivers, 2011). That supervenes to maintain homeostatic status even as life is confronted with a constant barrage of ambiguous

information (Miller, 2017). Cells cope with this constant flow of environmental information through epigenetic accommodations (Cheedipudi et al., 2014) and niche construction (Torday, 2016a). It is through these mechanisms that organisms generate their own immediate environment. Therefore, cellular responses to metabolic demands and external environmental stresses through self-organizing, self-referential adaptations are the crux of evolutionary development. Within this perspective, many otherwise dogmatic aspects of selection-biased evolution can now be understood to be a continuum of self-referential, self-organizing cells solving external environmental problems by remodeling their internal milieus (Miller, 2016). Flexible temporary adjustments to transient stresses notwithstanding, the eukaryotic cellular form remains ensconced in cellular first principles projecting ever-forward without substantial deviation from its unicellular origins (Torday and Rehan, 2012; Torday and Miller, 2016b).

1.8

Terminal Addition as Evidence of the Singularity

One characteristic of biological systems over evolutionary space–time is that, as new traits emerge, they are added to the ends of evolutionary sequences. This phylogenetic and developmental mechanism is referred to as terminal addition. When regarded as a manifestation of communication between cells for embryologic development, homeostasis, phylogeny and evolution (Torday and Rehan, 2012), the presence of the Singularity is revealed. The water–land transition best exemplifies such interrelationships (Torday and Insel, 2013). Three receptor genes duplicated, or amplified, during that era – the parathyroid hormone-related protein (PTHrP) receptor, the β-adrenergic receptor, and the glucocorticoid receptor. That all three duplications were for receptors, rather than their ligands is not coincidental; it is providential because the receptor-mediated pathways evolved by terminal addition. The down-stream ligand-receptor-mediated cell–cell interactions evolved to provide homeostatic stability as an iterative process over the course of phylogeny and ontogeny. It is far more bioenergetically efficient to amplify the receptor than the ligand because the receptor has an inherent multiplier effect, rendering it more efficient in increasing the signal than amplifying the ligand. The structural expression of these signaling pathways is what is conventionally focused on in describing terminal addition. However, it is actually the underlying cellular– molecular components that are evolving. The ligands are elaborated by one celltype, the receptors are elaborated by a neighboring cell-type of a different embryonic germ layer. The receptor then produces a “second messenger” that ultimately communicates with the nucleus through a cascade of intermediate steps, binding to DNA polymerase to synthesize RNA, stimulating the biosynthesis of a peptide that facilitates the metabolic function of the pathway involved, for example. It is informative to analyze the consequences of the actual receptor gene duplications that occurred during the water–land transition in comparison to the type IV collagen isotype involved in Goodpasture syndrome (MacDonald et al., 2006). The type IV collagen isotype in Goodpasture syndrome prevents water and electrolyte loss across the alveolar and glomerular barriers because it has several amino acid substitutions that are hydrophobic, making the barrier water-resistant as a result. The other relevant comparison is with the isotypes of hemoglobin (Natarajan et al., 2016) that facilitated oxygen-carrying capacity over evolutionary time. In the case of the receptor duplications, there is minimal evidence for them causing

disease (Dorn, 2010). However, the Goodpasture syndrome type IV collagen isotype causes respiratory and kidney failure, potentially resulting in death (Greco et al., 2015); the hemoglobin polymorphisms are well known to cause specific genetic diseases (Smith and Orkin, 2016). The difference between the adaptive receptor mutations and those of the type IV collagen and hemoglobin is that, in the case of the former, they were terminal additions that were in evolutionary conformity with the up-stream metabolic signaling cascades, whereas in the latter case, they were ad hoc measures that did not comply with atavistic evolutionary constraints.

1.9

Proximate and Ultimate Causation – a Myth

Ernst Mayr published his landmark position paper in 1961, stating that there was a fundamental difference between the biologic traits underpinning evolution and the mechanism of evolution itself, which he referred to as the proximate and ultimate aspects of the overall process of evolution (1961). He used the example of bird migration. In the interim, we have learned a great deal about the reproductive physiology of birds, how the wavelength of ambient atmospheric light affects the pineal gland and controls behavior (Nishiwaki-Ohkawa and Yoshimura, 2016). Such data offer a step-wise continuum from environmental light to the reproductive physiology of birds, accounting for the mechanisms and reasons for bird migration. Many other cellular–molecular physiologic properties of vertebrates offer a similar mechanistic understanding of evolution, ranging from the lung to the kidney, skin and brain.

1.10 Cell–Cell Signaling Perspective as Common Ground for Physiologic Evolution By reducing vertebrate evolution down to the cellular–molecular level, interfacing biology with the physical environment becomes practical (Torday and Miller, 2016a). Though there is no direct evidence for the exact molecular origins of life, the subsequent steps in vertebrate evolution are well documented and based on the evolutionary principle of pre-adaptation or exaptation. This pre-adaptive perspective offers an opportunity to “back calculate” the initial steps in vertebrate evolution. For example, Konrad Bloch (1992) hypothesized that cholesterol was a “molecular fossil,” since it took 11 atoms of oxygen to synthesize one molecule of cholesterol. Cholesterol formed the structure for lipid rafts, the physico-chemical basis for cell surface receptors for cell–cell signaling (Head et al., 2014). Accumulation of carbon dioxide in the atmosphere during the early phase of unicellular vertebrate evolution led to increased calcium in the water due to the formation of carbonic acid. The excess calcium caused endoplasmic reticulum stress, which was met by the evolution of the peroxisome (De Duve, 1969). The carbon dioxide-driven atmospheric “greenhouse” resulted in rising temperatures, drying up bodies of water (Romer, 1949), driving some vertebrates out of water onto land. The vertebrate skeletal changes mediating the adaptation to land are well documented and widely acknowledged (Clack, 2012), but the effect on visceral organs has literally been ignored. But the experimental deletion of the PTHrP gene in embryonic mice highlighted the role of this bone calcium regulatory hormone in lung (Rubin et al., 2004), kidney (Hochane et al., 2013), skin (Philbrick, 1998) and brain (Gu et al., 2012) development. In combination with evidence that the PTHrP

receptor gene duplicated during the water–land transition, an opportunity opens to invoke an evolutionary mechanism (Pinheiro et al., 2012). The physiologic consequences of the adaptation to land can be seen in the effect of physiologic stress on cell–cell communication in a wide variety of organs – lungs, kidneys, skin, bone, brain – allowing for the concerted cell–molecular changes that mediated these tissue-level adaptations for land. The direct effects of such environmental factors as oxygen (Berner et al., 2007) and gravity (Torday, 2003) on morphologic changes allowed for connections between the physical and biologic environments that constituted evolution. This is the first time that evolutionary changes have been directly attributed to well-documented sequential geophysical and geochemical changes in the environment (Torday and Rehan, 2011).

1.11 Epigenetic Inheritance and the Primacy of the Unicellular State Lamarck's theory of the transmissibility of acquired phenotypic characteristics to offspring, now understood as epigenetic inheritance, failed in his time because he was unable to provide scientific evidence to support his concept. It is only recently that the direct inheritance of epigenetic “marks” from the environment has been scientifically proven (Skinner, 2015). Such “marks” appear in the sperm of males and eggs of females, and are passed on to their offspring during reproduction. During meiosis and the early stages of embryological development, mechanisms exist that determine which epigenetic marks are retained and which are discarded (Schaefer and Nadeau, 2015). The evidence is that the gametes determine the epigenetic imprint on their offspring, in contradiction to the Darwinian presumption that the central genome of adults is the only operative factor.

1.12 Pauli's Exclusion Principle and the First Principles of Physiology Mendeleev was successful in formulating a periodic table of elements because he used atomic numbers as a “common denominator” to normalize the data in his algorithm. Although unknown at the time of its formulation, it was quantum mechanics that provided the explanation for this phenomenon. As expressed by Harold Morowitz in his book The Emergence of Everything (2004), when the primordium generated by the Big Bang finally cooled, some energy became positively charged protons and negatively charged electrons as matter emerged. The determining factor is that electrons interact with an atomic nucleus in specific quantum states designated as orbits. The interaction of an electron with its atomic nucleus is calculated using four quantum numbers: n, the principal quantum number; ℓ, the angular momentum quantum number; mℓ, the magnetic quantum number; and ms, the spin quantum number. The quantum mechanical solutions yield probability distributions for the electrons orbiting around the nucleus. The Pauli exclusion principle stipulates that no two electrons in an atom or molecule can have the same four quantum numbers; three in space, and one in time. The arrangement of electrons and nuclei that constitute the periodic table of the elements, chemical bonding and the different states of matter are determined by the Pauli exclusion principle (PEP). These properties of matter begin to explain how and why the whole is not equal to the sum of its parts, given that the PEP dictates

the behavior of two or more electrons, not one electron in isolation. And the fact that the quantum state of the first electron determines that of the second electron confers a “knowing” or noetic character, i.e. logic to the universe. Pleiotropy (Torday, 2015c) reflects evolutionary novelty holistically by expressing the same gene in different tissues and organs, forming “electrochemical fields.” More explicitly, pleiotropic genes in different tissues and organs throughout the body have the potential to synchronize calcium flows within and between cells, both at baseline and when activated by stress. The net effect of such organized flows would be electrochemical fields (Torday, 2018).

1.13 Non-localization in Physics and Biology Non-localization highlights the fact that, based on quantum theory, a system cannot be analyzed as parts whose basic properties do not depend on the state of the whole system. Bohm and Hiley (1975) show that this approach implies a new universal type of description in which the standard form is always ordered as supersystem/system/subsystem, leading to the radically new notion of unbroken wholeness of the entire universe. Biology conforms to the same set of principles, but it is not apparent when seen from a synchronic, descriptive vantage-point. However, when understood from a diachronic perspective, transcending space and time, it can be understood in the terms used by Bohm and Hiley (1975) for quantum physics. This way of thinking about biology cellularly–molecularly is exemplified by a re-examination of pleiotropy (Torday, 2015). In contrast to the conventional way of thinking about pleiotropy as the random expression of a gene throughout the organism to generate more than one distinct phenotypic trait, it is actually a deterministic consequence of the evolution of complex physiology based on the FPP in the unicellular state. Pleiotropy emerges through recombinations and permutations of cell–cell communication established during meiosis based on the developmental and phylogenetic history of the organism in service to the future existential needs of the organism. Functional homologies ranging from the lung to the kidney, skin, brain, thyroid and pituitary typify the evolutionary strategy of pleiotropy. The power of this perspective is revealed by the understanding of evolutionary gradualism (Darwin, 1859) and punctuated equilibrium (Eldredge and Gould, 1972) in much the same way that Niels Bohr resolved the paradoxical wave-particle duality of light as complementarity (Selleri, 2012). Seen in this way, biology and physics are both non-localized, acting at all scales to form and maintain their integrated entirety.

1.14 A Fractal View of Life A salient principle of biological development is its reiterative character across all living scales. This can be likened to the well-known concept of fractal reiteration in physical systems that are believed to characterize nature. Although there is a common metaphor in physics that this phenomenon should be viewed in a reductive manner as “turtles all the way down,” biology must be conceived in a fundamentally different manner. Biology is better understood as the perpetual adherence to the FPP, as perpetual reiterations that stem from an identifiable set of elemental principles. Starting with unicellular organisms, all the way up to complex physiology (Torday and Rehan, 2012), the FPP determine structure and function.

This conception of the evolution of physiology across scales drives how it is believed that our bodies respond through cell–cell communication, ultimately governing the physiological regulation of genes in response to the signals provided by the environment (Torday, 2016b). This entire process can be appreciated as exemplifying the fractal nature of physiology expressed through the ubiquity of the basic cellular form (Torday and Rehan, 2017). Basic cells have facilitated oxygenation, metabolism and locomotion as traits that originate from the insertion of cholesterol into the semi-permeable cell membrane (Bloch, 1992). The scale-free self-similarity of physiology is central because it demonstrates the universality of the underlying self-referential, self-organizing structure that undergirds the FPP. The discovery of deep homologies in the physiological systems of widely disparate taxa highlights the fractal nature of physiological processes. To start, a fractal is a mathematical pattern – it is the math that underlies the dynamics of natural systems – and it drives the evolution of phenomena via a basic function that repeats itself across all scales of time and space, producing self-similarity at every level. The self-similarity of ontogeny and phylogeny is not being claimed to have resulted from selection acting independently on different processes (development of a trait versus the evolution of traits). Rather, it is being claimed that the processes of ontogeny and phylogeny are one and the same, operating at different time scales. Upon inspection of molecular traits, ontogenetically and phylogenetically, they appear in specific sequences in both time frames. The genes expressed earliest in ontogeny are those that are phylogenetically most ancient. Genes expressed late in development are those that have evolved more recently, having a much tighter phylogenetic distribution (Roux and Robinson-Rechavi, 2008). When molecular traits are “stressed” they follow the same trajectory in the reverse direction of ontogeny/phylogeny, suggesting that there is a common origin for all traits, going back to the unicellular state. That means that the dynamics at the molecular level are self-similar to those at the cellular level, which ratchet up to produce both organ and organ system level interactions that culminate holistically as physiology. These fractal interrelationships reflect the evolution of the internal environment, or physiology, in adaptation to the external environment (Torday and Rehan, 2012). The external environment was fashioned by the Big Bang (Singh, 2005), which we now know because the background radiation referred to as the redshift emanates from the deep history of the universe. Physiology mimics the external universe to form its own internal “universe,” homeostasis being its iterative self-referential, self-organizing framework (Torday and Rehan, 2011; Torday and Rehan, 2012; Miller, 2016; Torday and Rehan, 2017). This patterning is shared by all living beings. For example, Davidson (2007) has shown that the stem cells of the heart in the tunicate, Ciona intestinalis, are derived from the tail, suggesting that the beating of the tail for locomotion has been exapted for the beating of the heart. Since unicellular organisms do not require a heart or a circulatory system, this phenomenon suggests that the heart evolved in support of fundamental biologic traits like respiration, metabolism and locomotion in multicellular organisms. The heart is a derivative. Exaptations such as the evolution of the middle ear bones in vertebrates from the jaw bones of early fishes, have provided powerful clues to the ancestry of structures, and reveal the iterative process of evolution through innovation from pre-existing conditions (Tucker et al., 2004; Downs et al., 2008). Homologously, the brain may have a history in response to the demand for central control of the evolving viscera (organ systems for respiration, digestion, barrier function and movement) (Bronner and LeDouarin,

2012; Obermayr et al., 2013). The evolution of semi-permeable cell membranes provides an informative example of how fractal processes influence modern day human beings’ nutritional needs. The following may help in considering the relationship of fractal physiology and nutrition. Biology was able to entrain energy using semi-permeable membranes, promoting the reduction in entropy that is the “metabolic dynamism” for evolution (Torday and Rehan, 2012). For example, the incorporation of cholesterol in the plasma membrane made it more compliant, facilitating both endocytosis and exocytosis by eukaryotes, and enhancing aerobic respiration by thinning out the membrane, making it more permeable for gas exchange. Another process in this ab initio context is chemiosmosis, the forming of semi-permeable membranes within the cell that allowed for the generation of ionic gradients fundamental for generating the “vital force” of life. The entropic and chemiosmosis mechanisms are complementary in their mutual dependence on the presence of a cellular semi-permeable membrane. As these processes evolved, they had to cope with thermodynamics hierarchically. Cholesterol subsequently exapted to facilitate the formation of lipid rafts, the structural basis for cell–cell signaling, culminating in the synthesis of steroid hormones to form the endocrine system, in part. That interrelationship was serially reiterated in evolution as vertebrates emerged from water to land (Bridgham et al., 2006; Torday and Rehan, 2011), tracing a repetitive physiologic arc of evolution that seamlessly extends from unicellular to multicellular organisms, and from simple to complex physiology.

1.15 Consciousness, the Epitome of the Continuum from Inanimate to Animate A case can be made for the interrelationship between the physical and biologic realms based on the “logic” of each. Consciousness can be considered to be the interface between the two (Torday and Miller, 2016d), forming a conduit for the flow of information between the inanimate and animate. This is what is referred to in the consciousness literature as the “hard” problem, which attempts to separate the mystery of experiential consciousness from those processes that seem to have a direct biochemical and anatomic basis. By providing a level playing field between the atom and the cell (Torday and Miller, 2016a, 2016b), in combination with such quantum concepts as non-locality, the bigger venue of consciousness becomes soluble as reiterative cell–cell communication. It follows that solutions at one cellular level can be carried and adjusted within the context of the next, just as physiologic properties are serial pre-adaptations. Seeing “red” when you whack your thumb with a hammer might easily reduce to an atavistic “remembrance of things past” (Proust, 1982), which is, in this instance, a recollection of a prior pattern of cellular responses at a different level than our form of experiential consciousness.

1.16 Discussion Recognizing biology as a continuum is long overdue. It must become a predictive science, comparable with chemistry and physics (Birks, 1962) in order to effectively utilize all of the “omics” now available to biology and medicine. The constraint toward this goal has largely been historic, due to the usurping of cell biology by genetics (Smocovitis, 1996). Even with the recognition of the relevance

of developmental biology to evolution, or evo-devo (Hall, 2003), a further appreciation of a central requirement to recognize cell biology as the fundament of embryology (Slack, 2014), biological development and evolution has been lacking. With the realization of the central role of cell–cell communication in evolution (Torday and Rehan, 2007; Torday and Rehan, 2012; Torday and Rehan, 2017), many biologic dogmas have been redefined mechanistically (Torday, 2015a; Torday, 2015b; Torday, 2015c; Torday, 2016c). This offers a new-found transparency for biology that had remained opaque in the descriptive mode, which has consistently dominated biology. As a result, the language of biology changes, resulting in a paradigm shift (Kuhn, 1962). This enlightened view of biology has led to the novel recognition of the first principles of biology (Torday and Rehan, 2012), and to a central theory of biology (Torday, 2015a), predicting the advent of endothermy based on developmental and phylogenetic physiologic principles instead of ex post facto rationalization (Bennett and Ruben, 1979). Such insights are on par with heliocentrism: the recognition that the sun is the center of the solar system. Similarly, the displacement of humans from the center of the biosphere would offer a new vista for understanding our place in the biologic universe. That realization is critically important to consideration of climate change, artificial intelligence and genetic engineering (CRISPR). There is great danger in misjudging the significance in the case of the former, and a risk of misapplication in the case of the latter two at this critical juncture in human history, now being referred to as the Anthropocene (Steffen et al., 2011; Edwards, 2015). Moreover, by understanding the principles of biology, we can formulate ways of affecting the arc of our evolution based on congruent ethical principles, rather than blindly invoking technological change, and then having to correct it after the fact.

1.17 Conclusion The works of Plato, Whyte (1949), Morowitz (2004) and Capra (2016) redirected our thinking about nature by attempting to account for all that we see – from rocks, to life; from flora, to fauna – into a single consistent system. All throughout human history, many have encouraged us to think in this manner, for example, by equating mass and energy, or by merging all knowledge as consilience (Wilson, 1998). Yet the great polymath Polanyi (1968), and the physicist Prigogine (1984) both concluded that the relationship between physics and biology is too complicated to be easily encompassed. The truth lies elsewhere. In the past, when scientists have been confronted with the complexities of science, some have defaulted to mysticism and metaphysics. But the key to the scientific approach is arrestingly different. For example, Mendeleev configured his version of the periodic table by identifying atomic number as the “lowest common denominator.” Others had attempted this feat, but failed to imagine the organizing principle behind the elements. By analogy, in a review article on the cellular–molecular perspective on evolution (Torday and Miller, 2016a), it was proposed that there are homologies between the atom and the cell that provide a unifying common denominator. In this way, the unicell communicates with its surroundings, both inanimate and animate, (Torday and Miller, 2016a, 2016b), fulfilling the vision of the “One” seen by the Greek atomists such as Heraclitus and Anaximander. The power of this concept is in its empiric foundations (Torday and Rehan, 2012; Torday and Rehan, 2017), offering a solely scientific means of exploiting the information explosion occurring all around us.

References Anway M. D. and Skinner M. K., Epigenetic programming of the germ line: effects of endocrine disruptors on the development of transgenerational disease, Reprod. Biomed. Online, 2008, 16, 23–25. Bennett A. F. and Ruben J. A., Endothermy and activity in vertebrates, Science, 1979, 206, 649–654. Berner R. A., Vandenbrooks J. M. and Ward P. D., Evolution. Oxygen and evolution, Science, 2007, 316, 557–558. Birks J. B., (1962, ), Rutherford at Manchester, London: Heywood. Bloch K., Sterol molecule: structure, biosynthesis, and function, Steroids, 1992, 57, 378–383. Bohm D., (1980, ), Wholeness and the Implicate Order, London: Routledge & Kegan Paul. Bohm D. J. and Hiley B. J., On the Intuitive Understanding of Nonlocality as Implied by Quantum Theory, Found Phys., 1975, 5, 93–109. Bridgham J. T., Carroll S. M. and Thornton J. W., Evolution of hormone-receptor complexity by molecular exploitation, Science, 2006, 312, 97–101. Bronner M. E. and LeDouarin N. M., Development and evolution of the neural crest: an overview, Dev. Biol., 2012, 366, 2–9. Capra F., (2016, ), The Systems View of Life: A Unifying vision, Cambridge: Cambridge University Press. Cat J., (2017, ), The Unity of Science, in Zalta E. N., (ed.), The Stanford Encyclopedia of Philosophy, [online], Available from: https://plato.stanford.edu/archives/fall2017/entries/scientific-unity. Cheedipudi S., Genolet O. and Dobreva G., Epigenetic inheritance of cell fates during embryonic development, Front. Genet., 2014, 5, 19. Clack J. A., (2012, ), Gaining Ground, Bloomington : Indiana University Press. Crick F., Central dogma of molecular biology, Nature, 1970, 227, 561–563. Darwin C., (1859, ), On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life, London : John Murray. Davidson B., Ciona intestinalis as a model for cardiac development, Semin. Cell Dev. Biol., 2007, 18, 16–26. De Duve C., Evolution of the peroxisome, Ann. N. Y. Acad. Sci., 1969, 168, 369– 381. Deamer D., The Role of Lipid Membranes in Life's Origin, Life, 2017, 7(1), 5. Dobzhansky T., Nothing in biology makes sense except in the light of evolution, Am. Biol. Teach., 1973, 35, 125–129. Dorn G. W., Adrenergic signaling polymorphisms and their impact on cardiovascular disease, Physiol. Rev., 2010, 90, 1013–1062. Downs J. P., Daeschler E. B., Jenkins Jr. F. A. and Shubin N. H., The cranial endoskeleton of dreaming, Front. Psychol., 2008, 5, 1133. Edwards L. E., What is the Anthropocene?, EOS, 2015, 97(2), 6–7. Eldredge N. and Gould S. J., (1972, ), Punctuated equilibria: an alternative to phyletic gradualism, Models in Paleobiology, San Francisco: Freeman Cooper. Gilliland F. D., Berhane K., McConnell R., Gauderman W. J., Vora H., Rappaport E. B., Avol E. and Peters J. M., Maternal smoking during pregnancy, environmental tobacco smoke exposure and childhood lung function, Thorax, 2000, 55, 271–276.

Gilliland F. D., Li Y. F. and Peters J. M., Effects of maternal smoking during pregnancy and environmental tobacco smoke on asthma and wheezing in children, Am. J. Respir. Crit. Care Med., 2001, 163, 429–436. Goss V., Hunt A. N. and Postle A. D., Regulation of lung surfactant phospholipid synthesis and metabolism, Biochim. Biophys. Acta, 2013, 1831, 448–458. Gray M. W., Lynn Margulis and the endosymbiont hypothesis: 50 years later, Mol. Biol. Cell, 2017, 28, 1285–1287. Greco A., Rizzo M. I., De Virgilio A., Gallo A., Fusconi M., Pagliuca G., Martellucci S., Turchetta R., Longo L. and De Vincentiis M., Goodpasture's syndrome: a clinical update, Autoimmun. Rev., 2015, 14, 246–253. Grobstein C., Inductive epitheliomesenchymal interaction in cultured organ rudiments of the mouse, Science, 1953, 118, 52–55. Gu Z., Liu Y., Zhang Y., Jin S., Chen Q., Goltzman D., Karaplis A. and Miao D., Absence of PTHrP nuclear localization and carboxyl terminus sequences leads to abnormal brain development and function, PLoS One, 2012, 7, e41542. Gurdon J. B., Ryan K., Stennard F., McDowell N., Zorn A. M., Crease D. J. and Dyson S., Cell response to different concentrations of a morphogen: activin effects on Xenopus animal caps, Cold Spring Harbor Symp. Quant. Biol., 1997, 62, 151–158. Hall B. K., Evo-Devo: evolutionary developmental mechanisms, Int. J. Dev. Biol., 2003, 47, 491–495. Head B. P., Patel H. H. and Insel P. A., Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling, Biochim. Biophys. Acta, 2014, 1838, 532–545. Hochane M., Raison D., Coquard C., Imhoff O., Massfelder T., Moulin B., Helwig J. J. and Barthelmebs M., Parathyroid hormone-related protein is a mitogenic and a survival factor of mesangial cells from male mice: role of intracrine and paracrine pathways, Endocrinology, 2013, 154, 853–864. Ioannidis J. P., Why most published research findings are false, PLoS Med., 2005, 2, e124. Isaacson W., (2007, ), Einstein, New York: Simon & Schuster. Kuhn T., (1962, ), The Structure of Scientific Revolutions, Chicago: The University of Chicago Press. Lipton B., (2016, ), The Biology of Belief, Carlsbad: Hay House, (Sheldrake 2018). Lwebuga-Mukasa J. S., Ingbar D. H. and Madri J. A., Repopulation of a human alveolar matrix by adult rat type II pneumocytes in vitro. A novel system for type II pneumocyte culture, Exp. Cell Res., 1986, 162, 423–435. MacDonald B. A., Sund M., Grant M. A., Pfaff K. L., Holthaus K., Zon L. I. and Kalluri R., Zebrafish to humans: evolution of the alpha3-chain of type IV collagen and emergence of the autoimmune epitopes associated with Goodpasture syndrome, Blood, 2006, 107, 1908–1915. McEvoy C. T. and Spindel E. R., Pulmonary Effects of Maternal Smoking on the Fetus and Child: Effects on Lung Development, Respiratory Morbidities, and Life Long Lung Health, Paediatr. Respir. Rev., 2017, 21, 27–33. Michalopoulos G., Russell F. and Biles C., Primary cultures of hepatocytes on human fibroblasts, In Vitro, 1979, 15, 796–806. Miller Jr. W. B., Cognition, Information Fields and Hologenomic Entanglement: Evolution in Light and Shadow, Biology, 2016, 5, 21.

Miller Jr. W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Miller Jr. W. B., Torday J. S. and Baluška F., Biological evolution as the defense of ‘self’, Prog. Biophys. Mol. Biol., 2019, 142, 54–74. Morowitz H., (2004, ), The Emergence of Everything, Oxford: Oxford University Press. Moss L., Is the philosophy of mechanism philosophy enough?, Stud. Hist. Philos. Biol. Biomed. Sci., 2012, 43, 164–172. Natarajan C., Hoffmann F. G., Weber R. E., Fago A., Witt C. C. and Storz J. F., Predictable convergence in hemoglobin function has unpredictable molecular underpinnings, Science, 2016, 354, 336–339. Nicholson D. J., The concept of mechanism in biology, Stud. Hist. Philos. Biol. Biomed. Sci., 2012, 43, 152–163. Nishiwaki-Ohkawa T. and Yoshimura T., Molecular basis for regulating seasonal reproduction in vertebrates, J. Endocrinol., 2016, 229, R117–R127. Obermayr F., Hotta R., Enomoto H. and Young H. M., Development and developmental disorders of the enteric nervous system, Nat. Rev. Gastroenterol. Hepatol., 2013, 10, 43–57. Perry S. F. and Carrier D. R., The coupled evolution of breathing and locomotion as a game of leapfrog, Physiol. Biochem. Zool., 2006, 79, 997–999. Philbrick W. M., Parathyroid hormone-related protein is a developmental regulatory molecule, Eur. J. Oral. Sci., 1998, 106, 32–37. Pinheiro P. L., Cardoso J. C., Power D. M. and Canário A. V., Functional characterization and evolution of PTH/PTHrP receptors: insights from the chicken, BMC Evol. Biol., 2012, 12, 110. Polanyi M., Life's irreducible structure. Live mechanisms and information in DNA are boundary conditions with a sequence of boundaries above them, Science, 1968, 160, 1308–1312. Popper K., (2002, ), The Logic of Scientific Discovery, London: Routledge. Prigogene I. and Stengers I., (1984, ), Order Out of Chaos, London: Bantam. Proust M., (1982, ), Remembrance of Things Past, New York: Vintage. Rehan V. K., Liu J., Sakurai R. and Torday J. S., Perinatal nicotine-induced transgenerational asthma, Am. J. Physiol.: Lung Cell. Mol. Physiol., 2013, 305, L501–L507. Romer A. S., (1949, ), The Vertebrate Story, Chicago: University of Chicago Press. Roux J. and Robinson-Rechavi M., Developmental constraints on vertebrate genome evolution, PLoS Genet., 2008, 4, e1000311. Rubin L. P., Kovacs C. S., De Paepe M. E., Tsai S. W., Torday J. S. and Kronenberg H. M., Arrested pulmonary alveolar cytodifferentiation and defective surfactant synthesis in mice missing the gene for parathyroid hormone-related protein, Dev. Dyn., 2004, 230(2), 278–289. Schaefer S. and Nadeau J. H., The genetics of epigenetic inheritance: modes, molecules, and mechanisms, Q. Rev. Biol., 2015, 90, 381–415. Schrodinger E., (1944, ), What is Life?, Cambridge: Cambridge University Press. Selleri F., (2012, ), Wave-Particle Duality, New York : Springer. Shapiro J. A., (2011, ), Evolution: A View from the 21st Century, Upper Saddle River: FT Press. Sheldrake R., (2017, ), Science and Spiritual Practices, London: Coronet. Singh S., (2005, ), Big Bang: The Origin of the Universe, New York: Harper

Collins. Skinner M. K., Environmental Epigenetics and a Unified Theory of the Molecular Aspects of Evolution: A Neo-Lamarckian Concept that Facilitates NeoDarwinian Evolution, Genome Biol. Evol., 2015, 7, 1296–1302. Slack J., Establishment of spatial pattern, WIREs Dev. Biol., 2014, 3(6), 379–388. Smith B. T., Lung maturation in the fetal rat: acceleration by injection of fibroblast-pneumonocyte factor, Science, 1979, 204, 1094–1095. Smith E. C. and Orkin S. H., Hemoglobin genetics: recent contributions of GWAS and gene editing, Hum. Mol. Genet., 2016, 25, R99–R105. Smocovitis V., (1996, ), Unifying Biology, Princeton: Princeton University Press. Smolin L., (1997, ), The Life of the Cosmos, Oxford: Oxford University Press. Steffen W., Grinevald J., Crutzen P. and McNeill J., The Anthropocene: conceptual and historical perspectives, Philos. Trans. R. Soc., A, 2011, 369, 843. Storr S. J., Woolston C. M., Zhang Y. and Martin S. G., Redox environment, free radical, and oxidative DNA damage, Antioxid. Redox Signaling, 2013, 18, 2399–23408. Tavassoli M., The cell theory: a foundation to the edifice of biology, Am. J. Pathol., 1980, 98, 44. Torday J. and Rehan V., Neutral lipid trafficking regulates alveolar type II cell surfactant phospholipid and surfactant protein expression, Exp. Lung Res., 2011, 37, 376–386. Torday J., A periodic table for biology, Scientist, 2004, 18, 32–33. Torday J. S., Parathyroid hormone-related protein is a gravisensor in lung and bone cell biology, Adv. Space Res., 2003, 32, 1569–1576. Torday J. S., Pleiotropy as the Mechanism for Evolving Novelty: Same Signal, Different Result, Biology, 2015, 4(2), 443–459. Torday J. S., A central theory of biology, Med. Hypotheses, 2015a, 85, 49–57. Torday J. S., Homeostasis as the Mechanism of Evolution, Biology, 2015b, 4, 573–590. Torday J. S., The cell as the mechanistic basis for evolution, Wiley Interdiscip. Rev.: Syst. Biol. Med., 2015c, 7, 275–284. Torday J. S., Homeostasis as the Mechanism of Evolution, Biology, 2015d, 4(3), 573–590. Torday J. S., Heterochrony as Diachronically Modified Cell-Cell Interactions, Biology, 2016a, 5(1), 4. Torday J. S., Life Is Simple—Biologic Complexity Is an Epiphenomenon, Biology, 2016b, 5(2), 17. Torday J. S., The Cell as the First Niche Construction, Biology, 2016c, 5(2), 19. Torday J. S., Quantum Mechanics predicts evolutionary biology, Prog. Biophys. Mol. Biol., 2018, 135, 11–15. Torday J. S. and Insel P. A., AJP-Cell Physiology begins a Theme series on Evolution and Cell Physiology, Am. J. Physiol.: Cell Physiol., 2013, 305, C681. Torday J. S. and Miller W. B., Biologic relativity: Who is the observer and what is observed?, Prog. Biophys. Mol. Biol., 2016a, 121, 29–34. Torday J. S. and Miller Jr. W. B., On the Evolution of the Mammalian Brain, Front. Syst. Neurosci., 2016b, 10, 31. Torday J. S. and Miller W. B., Phenotype as Agent for Epigenetic Inheritance, Biology, 2016c, 5(3), 30.

Torday J. S. and Miller Jr. W. B., On the Evolution of the Mammalian Brain, Front. Syst. Neurosci., 2016d, 10, 31. Torday J. S. and Miller Jr. W. B., The resolution of ambiguity as the basis for life: A cellular bridge between Western reductionism and Eastern holism, Prog. Biophys. Mol. Biol., 2017, 131, 288–297. Torday J. S. and Rehan V. K., The evolutionary continuum from lung development to homeostasis and repair, Am. J. Physiol.: Lung Cell. Mol. Physiol., 2007, 292, L608–L611, (Torday 2004) . Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology: Cell–Cell Communication, and Complex Disease, Hoboken: Wiley. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, Hoboken: Wiley. Trivers R., (2011, ), The Folly of Fools, New York: Basic Books. Tucker A. S., Watson R. P., Lettice L. A., Yamada G. and Hill R. E., Bapx1 regulates patterning in the middle ear: altered regulatory role in the transition from the proximal jaw during vertebrate evolution, Development, 2004, 131, 1235–1245. Varela F. G., Maturana H. R. and Uribe R., Autopoiesis: the organization of living systems, its characterization and a model, Curr. Mod. Biol., 1974, 5, 187–196. Warburton D., El-Hashash A., Carraro G., Tiozzo C., Sala F., Rogers O., De Langhe S., Kemp P. J., Riccardi D., Torday J., Bellusci S., Shi W., Lubkin S. R. and Jesudason E., Lung organogenesis, Curr. Top. Dev. Biol., 2010, 90, 73– 158. Whitehead A. N., (2010, ), Process and Reality, New York : Free Press. Whyte L. L., (1949, ), The Unitary Principle in Physics and Biology, London : Cresset Press. Wilson E. O., (1998, ), Consilience: The Unity of Knowledge, New York : Vintage. Zacharasiewicz A., Maternal smoking in pregnancy and its influence on childhood asthma, ERJ Open Res., 2016, 29, 2. Zhang X. and Ho S. M., Epigenetics meets endocrinology, J. Mol. Endocrinol., 2011, 46, R11–R32.

CHAPTER 2

Bohm Meets Bacon 2.1

Introduction

The title of this chapter refers to the physicist David Bohm, who emphasized the importance of empiricism as the means of escaping our subjective perception of reality; and Roger Bacon, who realized that his empiric data differed from Aristotle's four causes (Ackerman, 1978). In his book, Wholeness and the Implicate Order (1980), David Bohm used a stretchable matrix with ink dots on it to explain the transition from the Explicate to the Implicate Order as a thought experiment, the former being how our subjective, evolved senses have interpreted reality for us, the latter being what actually exists in the cosmos (Bohm, 1980). In a larger context, the notion that there is a continuum from the Explicate to the Implicate Order can also be seen as the basis for scientific experimentation (Thurs, 2011), providing a systematic means for transcending the Explicate and progressively entering the Implicate Order. For example, in his book entitled The Periodic Table: Its Story and Its Significance, Eric Scerri (2006) explains that Mendeleev used both atomic number and chemical reactivity as characteristics for positioning the elements in his version of the periodic table, effectively taking into account both the synchronic (atomic mass) and diachronic (chemical reactivity) traits of the elements. From Scerri (2006): “Mendeleev avoided using Cannizzaro's atomic weight of 120 for uranium […] If uranium had an atomic weight of 120, it would need to be placed between tin {118} and antimony {122}. These two elements show valences of 4 and 3, respectively, and so the inclusion of uranium between them would have violated the gradual decrease in valence on moving across the elements in group IV through group VII. In addition, the placement of both tin and antimony appeared quite secure and in little doubt. Tin was in the same group as silicon and lead, both of which show valences of 4, and antimony was in the same group as phosphorous, arsenic, and bismuth, all of which show valences of 3. In an early manuscript table, Mendeleev designated uranium as “U 120” and listed it outside the table at the foot of the page. Later he crossed this out and replaced it with “U 116?” placed in the main body of the table between cadmium and tin. This place should have been filled by the element indium, but Mendeleev also initially misplaced this element because he wrongly assumed that its atomic weight was 75.6. In the spring of 1869, Mendeleev personally undertook the experimental study of the atomic volume of uranium with the object

of resolving the uranium problem. He decided that the element did not in fact fit between cadmium and tin, and considered that Cannizzaro's value of 120 might indeed be correct. […] he proposed that the value should be doubled because the high density of uranium {18.4} was typical of heavy-atomic-weight elements such as platinum {197}, osmium {199}, and iridium {198}. He then set his assistant Bohuslav Brauner the task of measuring the specific heat of uranium, but since the results were somewhat inconclusive, Mendeleev announced the atomic weight modification without the support of experimental evidence. In late 1870, Mendeleev actually placed “U=240” for the first time in the periodic table. Experimental support for the corrected atomic weight of uranium came later, in 1874, from Henry Roscoe in England. It took its place as a higher chemical analogue of chromium, molybdenum, and tungsten, where it remained throughout the rest of Mendeleev's life and indeed until the middle of the twentieth century. […] Glenn Seaborg's discovery of the actinide series prompted a major readjustment of the periodic table, which included the repositioning of uranium.” Similarly, using the cell-cell interactions that generate patterns during embryologic development, as presented in Torday and Rehan's Evolutionary Biology, the Logic of Biology (2012), as it applies to phylogeny, provides a way of using experimental data to determine biologic form and function. For example, it had long been thought that the gills of fish were the evolutionary origin of the lung, reasoning by analogy that both organs functionally oxygenate blood, instead of by homology, based upon the evolutionary transition from water to land, during which the swim bladder gives rise to the lung. Etienne Roux has stated that basing physiology on function is teleologic (Roux, 2014), leaving open the question as to what physiologic evolution is based on? When seen from its origins in the unicellular state, forming the basis for the first principles of physiology, the ab initio mechanisms for the evolution of structure and function can be seen (Torday and Rehan, 2012; Torday and Rehan, 2017). For example, when the swim bladder and lung are recognized as homologous, based on the utility of cholesterol acting to facilitate gas exchange (Daniels et al., 2004) their common origin in the unicell can be fully appreciated. Moreover, the causal relationship between cholesterol and lung alveolar evolution is evidenced by the effect of deleting a key gene in cholesterol synthesis in the alveolar type II cell, Scap-1, resulting in compensation by over-expression of lipofibroblasts (Besnard et al., 2009). Furthermore, basing the homology between the swim bladder and the lung on surfactant chemistry and physiology reveals that interrelationship as different adaptations for gas exchange (Daniels and Orgeig; Torday and Rehan, 2012). The molecular genetics of the developing swim bladder have been found to be consistent with its foundation for lung development (Zheng et al., 2011). Other such examples of homologies based on molecular signaling mechanisms instead of descriptive phenotypic functions are the thyroid having evolved from the endostyle of elasmobranchs (Torday and Rehan, 2012), the middle ear ossicles having evolved from the jaws of boney fish (Torday and Rehan, 2012), endothermy having evolved from the reaction of the hypothalamic-pituitary-adrenal axis to physiologic stress (Torday, 2015), and the central nervous system having evolved

from the skin (Holland, 2003). In each instance, the data for these homologies are based on experimental evidence, not inductive reasoning. Both the chemical and evolutionary “reactions” are characteristically based on the conversion of one form of energy and matter into another as an equivalency, as reflected by the “equals sign” between them. These reactions are evidence for the transition from the Explicate Order to the Implicate Order (Bohm, 1980). In the case of the Explicate Order, the interrelationships are in the same synchronic space and time, as descriptions of the elements based on atomic number, or the thyroid gland as the organ for the production of thyroid hormone. In the case of the Implicate Order, the chemistry of the elements helps to further calibrate where they belong in the table, and the cell-cell interactions inform the underlying nature of the biologic structures and functions, emanating from regressively earlier and earlier forms over the course of evolution. By way of explanation, in conducting a scientific experiment, we “control” it using the convention of the scientific method to take into account any extraneous changes in conditions that might inadvertently have occurred to support the hypothesis erroneously. Or so it would seem. In actuality, controls are used to accommodate the pseudo-existence of the Explicate Order, tacitly acknowledging the subjectivity of our perception of reality (Torday and Baluska, 2019). So controls provide reference points within the subjective Explicate Order to reduce the likelihood of spurious findings and, for example, witness the true Implicate Order that exists just beyond our perception, as in Bohm's stretchable matrix experiment referred to above (Bohm, 1980). It is for this reason, for example, that evolutionary changes are characterized as “emergent,” as if appearing out of nowhere, like prestidigitation, when in fact they derive from pre-adaptations previously utilized in some other context over the course of the evolutionary history of the organism. Both wound healing and evolution represent the regaining of cellular homeostasis, though in the case of the former, it is to re-establish cellular homeostasis, whereas in the case of the latter, it is to remodel structure and function in adaptation to environmental changes.

2.2

Bohm's Explicate and Implicate Orders Meet the Arts

Applying this concept to music – jazz, for example – is also a form of experimentation that is conducive to the transition from the Explicate to the Implicate Order. The conventional playing of a standard piece of music, referred to as the “head”, followed by jazz improvisation, finishing with the conventional head again is analogous to controlling a scientific experiment, bracketed by the heads acting in that capacity. That perspective is particularly true when compared and contrasted with classical music, which remains true to the composer's written composition, without improvisation, reinforcing the existing Explicate Order. The Explicate Order is consistent with Newton's physics and his “clockwork world” before the advent of relativity theory. In the post-relativity world, the force of gravity was redefined by Einstein as the warping of the fabric of space-time. So jazz improvisation is more in keeping with quantum mechanical principles such as the Heisenberg uncertainty principle, Pauli's exclusion principle, non-localization and coherence. There are elements of these principles in classical music too, but they are not improvised. Another example of how art can encourage us to think about the Explicate and Implicate Orders is a Henry Moore sculpture – a monolithic piece of

representational art made from granite or bronze – but with a large hole in it representing negative space. This form asks the viewer to decide which aspect of the piece is representative of “reality,” the solid portion of the sculpture, or the hole? That duality provokes ambiguity that can either lead to resolution in the mind of the observer, or leave him/her in limbo, the latter encouraging the observer to ponder the “experiment.” In either case, the experience culminates in a spatial and temporal transition to another frame of mind contingent upon the psyche of the observer, their foreknowledge of art, philosophy, history, life experience, worldview etc. In short, this encounter fulfills the purpose of art to entice, provoke and illuminate, challenging us to think beyond the mundane. In short, our reach should always exceed our grasp. Literature can have a similar effect. For example, the stream of consciousness in Proust's Remembrance of Things Past encourages the reader to see life as a continuum rather than as independently linked events; or James Joyce's Ulysses, a complete lifetime collapsed into one twenty-four-hour period of time, inferring the ambiguity of the way in which we perceive our very being. Even in playing sports, there is a spatio-temporal aspect. In a tennis match, when player A hits a shot to his/her opponent, he/she is asking player B if he/she has an “answer” to his/her “question.” Or in a game of billiards, looking at the way the balls are distributed on the felt, the player thinks about whether he/she “knows” this scenario, and what shot to take based on past experience. In that sense he/she is transcending space-time, their billiard knowledge evolving through experimentation.

2.3

Einstein's Relativity Is Necessary to Think This Way

This way of thinking about the Explicate and Implicate Orders was made possible by Einstein's theory of relativity and its aftermath at the turn of the twentieth century. Prior to that, Newtonian physics was all about the “clockwork” nature of the universe. But with the advent of relativity theory, the conception of things being fixed in space and time was challenged by physics and mathematics, followed culturally by the arts. Einstein published three seminal papers in the Journal Physical Letters in 1905, referred to as his wunder jahre, or wonder year. The first paper in the sequence explained Brownian movement as the random collision of molecules in water; the second described the photoelectric effect; and the third was about special relativity. According to Walter Isaacson's biography of Einstein (2007), the scientist dreamt that he was travelling in tandem with a beam of light when he was sixteen years old. He was essentially traversing the space-time of the universe, seeing it from a privileged vantage-point as the Implicate Order, free of the cultural myths and Kipling Just So Stories (1902) formulated in the Explicate Order. That experience gave Einstein license to think outside of the box, unifying the prevailing concepts of electromagnetism and light through relativity theory. The Modern art movement, for example, was made feasible by thinking outside of conventional reality, as with the kinetic representation of movement in “Nude Descending a Staircase” (Duchamp), the three-dimensional faces portrayed in two dimensions (Picasso), dripping paint on large canvases (Pollack), and soup cans as art (Warhol). Similarly, music made a quantum leap with the first performance of Rhapsody in Blue in 1924. It departed from classical music, as if creating itself, like the Big

Bang, there being no precedent in that form – as conducted by Paul Whiteman – having movements rather than being improvised like jazz. It took another 50 years for this way of thinking to penetrate biology, as recounted above. Prior to the publication of The Evolutionary Continuum from Lung Development to Homeostasis and Repair (Torday and Rehan, 2012), biology was enmired in description, literally unaware or resistant to admitting that, like Rutherford's accusation that biology was “stamp collecting” (Birks, 1962), the discipline was stuck in the mode of Linnaeus's binomial nomenclature, reflecting associations and correlations, not mechanistic origins and causation (Nicholson, 2012). Hopefully, the cellular-molecular approach to evolution will not take as long to catch on as did Copernicus's empirically derived conception of the sun as the center of the solar system.

2.4

Conclusions

The scientific method is a formalized way of making confirmatory and reproducible observations. Such activities are critical if we are to make the transition from the Explicate Order of self-deceptions like Just So Stories, mythology and after-the-fact reasoning, as in the case of Darwinian evolution, to the Implicate Order, where the true representation of the cosmos lies. Such deceptions account for why we humans are the only species that would systematically destroy our planet. Einstein said that doing the same thing over and over again and expecting a different outcome is the functional definition of insanity. Only through introspection, science and reason can we rectify our current state of being. Every form of art is capable of reinterpretation by every individual observer. Some art forms, like jazz and abstract art, are explicit and deliberate attempts to encourage a variety of idiosyncratic and personal sensations and reactions. Only science is able to reveal the true essences of nature. To that end, the integrity of the scientific method must always be protected or we all suffer the consequences. When we actively seek those basic principles that underscore our existence and which extend beyond nominal explicates to include an appropriate interrogation of those implicates that are actual circumstances, then permanent rewards accrue. The cellcell communication/signaling principle of evolution, which supplants an outdated and restrictive Darwinian narrative, offers such an opportunity.

References Ackerman J. S., Leonardo's Eye, J Warburg Courtauld Inst., 1978, 41, 108–146. Besnard V., Wert S. E., Stahlman M. T., Postle A. D., Xu Y., Ikegami M. and Whitsett J. A., Deletion of Scap in alveolar type II cells influences lung lipid homeostasis and identifies a compensatory role for pulmonary lipofibroblasts, J. Biol. Chem., 2009, 284, 4018–4030. Birks J. B., (1962, ), Rutherford at Manchester, London: Heywood. Bohm D., (1980, ), Wholeness and the Implicate Order, London: Routledge & Kegan. Daniels C. B., Orgeig S., Sullivan L. C., Ling N., Bennett M. B., Schürch S., Val A. L. and Brauner C. J., The origin and evolution of the surfactant system in fish: insights into the evolution of lungs and swim bladders, Physiol. Biochem. Zool., 2004, 77, 732–749. Holland N. D., Early central nervous system evolution: an era of skin brains?,

Nat. Rev. Neurosci., 2003, 4, 617–627. Isaacson W., (2007, ), Einstein, New York: Simon & Schuster. Kipling R., (1902, ), Just So Stories, Toronto: George S. Morang & Co. Nicholson D. J., The concept of mechanism in biology, Stud. Hist. Philos. Sci. C, 2012, 43, 152–163. Roux E., The concept of function in modern physiology, J. Physiol., 2014, 592, 2245–2249. Scerri E., (2006, ), The Periodic Table: Its Discovery and Significance, Oxford: Oxford University Press. Thurs D., (2011, ), Scientific Methods, Chicago: University of Chicago Press. Torday J. S., A central theory of biology, Med. Hypotheses, 2015, 85, 49–57. Torday J. S. and Baluska F., Why Control an Experiment?, EMBO Rep., 2019, 20, e49110. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology: Cell–Cell Communication, and Complex Disease, Hoboken: Wiley. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, Hoboken: Wiley. Zheng W., Wang Z., Collins J. E., Andrews R. M., Stemple D. and Gong Z., Comparative transcriptome analyses indicate molecular homology of zebrafish swimbladder and mammalian lung, PLoS One, 2011, 6, e24019.

CHAPTER 3

The Cell, Evolution and Occam's Razor 3.1

Introduction

All science began as description, skewed through our subjective senses (Bohm, 1980). Physics, chemistry and biology all began within these same circumstances. However, the two former disciplines have ultimately become “hard” mechanistic sciences by being thoroughly grounded within prediction; that is, testable and refutable. Despite its so-called mechanisms, only biology has remained descriptive (Moss, 2012; Nicholson, 2012). The problem for biology has been that there are fundamental ontogenetic and epistemological problems that hinder the advancement of the biological sciences (Torday, 2013). As a result, biology remains post-dictive rather than predictive; showing associations and correlations, rather than being illuminated through fundamental causal relationships. This problem stems from the absence of a central theory in biology (Torday, 2015a). Certainly, there have been attempts in that direction, such as Crick's notable dictum of the unilateral transcription and translation of DNA, now known to be incorrect (Shapiro, 2009). Yet no central principles stand for biology in the same manner as basic physical laws. Of all the biological sciences, this non-predictive footing is nowhere more evident than within the field of evolutionary biology. On the one hand, Darwin liberated us from The Great Chain of Being by hypothesizing that evolution occurs by natural selection, descent with modification and survival of the fittest (Darwin, 1859). But these are all metaphors rather than mechanisms, at best acting as placeholders until the actual mechanisms of evolution can be determined. Dobzhansky (1973) put it best when he stated that “evolution is all of biology,” thereby setting an initiating bar for the determination of any underlying integrating mechanism of biology. Yet, within the field, there is no experimental evidence for genetic and phenotypic change consistent with phylogeny, i.e. how fish mechanistically evolved into amphibians, reptiles, mammals and birds. Instead of a fundamental understanding of the underlying mechanisms that determine such changes, “family trees” are described (Schuh and Brower, 2009), inferring causality without providing testable evidence. The reticence to provide such data is plain. Neo-Darwinism considers evolution “solved” through random mutations and natural selection. That belief system and its ingrained investiture discourages the evaluation of any emergent and contingent serial changes that might be in contradistinction to that. Therefore, creationism/intelligent design can lay claim to the process of evolution just as well as the modern synthesis, since both the former and the latter are based on belief systems, rather than on experimentally derived science. However, through an overlap of biophysics and molecular biology, a novel approach to evolution that is mechanistic and predictive can be offered. By focusing on the cellular–molecular processes that underpin vertebrate embryogenesis based on cell–cell communication, mediated by ligand-receptor interactions, the

development, homeostatic control and regeneration of organisms can be determined (Torday and Rehan, 2012). Moreover, this path reveals a close relationship between cellular–molecular changes and major epochs in the Earth's geochemistry (Torday and Rehan, 2011). The product is an integration within biology that can be considered as a set of principles with universal applicability that unites biology across space–time. As it is based on only a few assumptions that are validated by experimental evidence, its direct simplicity is in adherence to Occam's razor, or the principle of parsimony, i.e. the simplest answer is usually the best.

3.2

On the Consequences of Descriptive Biology

It can be considered that the prevailing reason why biology remains descriptive is its allegiance to Linnaean binomial nomenclature. Instead of determining any rigorous underlying organizing principle, natural selection has been widely regarded as that cohering precept as a default. However, selection and fitness are entirely descriptive concepts. In consequence, it is not surprising that Ernest Rutherford (Birks, 1962) had stated that “All science is either Physics or stamp collecting.” That attitude reveals the crux of the issue. With respect to the biological sciences, and evolution in particular, progress can only be made when naturally intuitive and comfortable associations are displaced by firm scientific evidence, even if it contradicts accumulated dogma. It may even be necessary for biology to teach a “new” physics, just as quantum mechanics revealed previously unknown interstices of Newtonian mechanics. Only then will biology no longer be a mere stepchild to the quantifiable domains of chemistry and physics (Hunter, 2010). Yet, at this moment, although the mechanisms for essential properties of biology such as mitosis and meiosis have been described down to the molecular level, the means by which such processes have actually manifested have not been elucidated. Instead of a systematic understanding of biology (Torday and Miller, 2017), there has only been an inventorying of parts. Clearly, then, there is a need to seek a central theory for biology, from which testable and refutable experiments might devolve.

3.3

Revising the Standard Synthesis

In the absence of an acknowledged testable central theory of biology, numerous fallacies have become ingrained within descriptive biology, beginning with the hierarchical relationship between the cell and the organism. Darwin (1859) focused on the adult phenotype as the observable means towards evolutionary change. He assumed that the variations among adult organisms provided the substrate for differential reproduction and selection. With the discovery of genes, the source of that heritable variation became ensconced within neo-Darwinism as random genetic mutations and gene frequencies. However, contemporary knowledge of molecular embryology and genomics empowers a fundamental revision of what has previously been dogmatically accepted as the only valid evolutionary path. Exploration of several examples is offered in support, each of which differs substantially from conventional associations.

3.4

The Primacy of the Unicellular State

The cardinal aspect of any novel reconsideration of an evolutionary narrative must

begin with the understanding that, not only is the cell the basic organic form, but that the entire process of evolutionary development exists in a frame of the continuous primacy of the unicellular state over space–time (Torday and Miller, 2016a). That perpetuation is mediated by soluble growth factors and their ligands. Thus, the entire arc of embryogenesis and the subsequent developmental biology can be understood as a continuum (Warburton et al., 2010; Combes et al., 2015; Itoh, 2016; Miller and Torday, 2018). This alternative perspective on morphogenesis offers a comprehensive understanding of the nature of structure and function at its source. Biology can be deconstructed in reverse in both time and space back to its unicellular origins, and then continued forward from generation to generation as evolution, both ontogenetically and phylogenetically (Torday and Rehan, 2012). Given that evolution has been described as serial pre-adaptations or exaptations (Gould and Vrba, 1982), this way of viewing biology allows for an understanding of how and why specific genes have been re-purposed over the course of evolution by deconstructing the traits into which they have evolved. Such insights derive from the commonalities among the development, phylogeny and regeneration of those traits over evolutionary space-time (Torday and Rehan, 2009a). The reason given for the linear nature of terminal addition is because it is formed through cell–cell signaling, mediated by growth factors and their receptors residing of cells of different origins (endodermal, mesodermal, ectodermal) (Torday and Miller, 2018). Briefly, when a growth factor binds to its receptor it triggers a downstream cascade of second messengers such as cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), ultimately binding to DNA and affecting the expression of the cell phenotype. The interaction between the cells is determined by both genetic and epigenetic mechanisms (Warburton et al., 2010). An understanding of the primacy of the unicellular state offers significant further insights into previously ill-understood biological observations. For example, the obligatory return of all multicellular eukaryotes to the unicellular zygotic form can now be coherently justified. In an evolutionary schema in which a macro-organic entirety is achieved through an adherence to a requisite cellular inherency, the obligatory reproductive recapitulation is a measuring and ratifying phase of epigenetic marks through its originating “oneness.” The success of the perpetuating unicellular form lies within its flexible adjustment to both short-term environmental stresses in such a manner as to not compromise its survival in the face of long-term environmental vicissitudes. Therefore, it is no longer surprising that the unicellular zygotic phase is one in which there is considerable adjudication of acquired epigenetic marks (Monk, 2015; Zheng et al., 2016).

3.5

Phenotype Is a Verb, Not a Noun

The conventional view of phenotype is that it is an epiphenomenon directly driven by selection. Instead, it has been shown that any phenotype is a means towards optimally obtaining genetic marks from the environment, rather than just being the result of a reproductive strategy (Torday and Miller, 2016b). By focusing on an evolutionary imperative of strategically deriving and sorting epigenetic marks from the environment, the centrality of the process distances itself from the adult phenotype and its momentary fitness, or even that of its immediate offspring. As is often the case, transgenerational effects are not necessarily immediately expressed (Wang et al., 2017). Although the actual identity of the mechanism that determines

the distribution of the epigenetic marks from germ cells to somatic cells is not completely known, it is clear that the unicellular recapitulation has a substantial impact (Wang et al., 2017; Gapp and Bohacek, 2018). When this distance from standard Darwinism is acknowledged, pleiotropy (Torday, 2015c), heterochrony (Torday, 2016a), neoteny (Skulachev et al., 2017), and pedomorphosis (Godfrey and Sutherland, 1996) can each be understood as mechanisms through which epigenetic inheritance might be facilitated. This novel perspective becomes a salient change in our understanding of such processes directed towards a comprehensive understanding of evolution (Torday, 2015a). Further yet, by using this approach, the evolution of complicated phenotypic traits like the lung, kidney, skeleton, skin and brain has been elucidated from their origins in the cell membrane of the unicellular eukaryote (Torday and Rehan, 2017). Based on this approach, the commonalities between such disparate physiologic principles as respiration and micturition, integument and brain, skeletal and visceral organs (Torday and Rehan, 2017) can be understood logically and made useful to diagnose and treat pathology as predictive medicine (Torday and Rehan, 2012).

3.6

New Validity to Terminal Addition

Terminal addition has been described dogmatically as the phenomenon by which new biologic traits are added on to the end of any given phenotype. Yet, when it is better considered in terms of cell–cell signaling as the basis for phenotypic evolution, the addition of a step to any given morphogenetic pathway would be added at the end of any developmental sequence in service to its direct evolutionary use, rather than inserting it within the pathway, where it would be inefficient at best, and potentially disruptive at worst.

3.7

Neoteny/Heterochrony in a New Frame

The processes of neoteny (retention of a juvenile feature in an adult) and heterochrony (developmental change in the timing or rate of events, leading to changes in size and shape) are vital steps in organismal development that have been misunderstood in prior terms restricted to Darwinian selection. Mechanistically, they offer the opportunity to cope with environmental changes by exploiting earlier stages in evolution that had proven to be successful adaptations in a progenitor context. As a pertinent example of this new cellular perspective, the hydrozoan Turritopsis dohrnii, can change from its jellyfish phenotype to its developmentally immature polyp form under environmentally stressful conditions. This latter phenomenon is conventionally assessed as an example of “reverse development” or “immortality” based on an apparent reversion to an earlier stage of the jellyfish life cycle (Schmich et al., 2007). A better explanation can be offered as a reversion to an atavistic phenotype for the commensurate collection of epigenetic marks relevant to an ever-changing environment (Torday and Miller, 2016b; Torday and Miller, 2017). Therefore, it can be asserted that the jellyfish Turitopsis reverts to its immature stage under physiologic stress as the form that optimally allows for the most advantageous assessment of adverse environmental cues.

3.8

The Life Cycle Rethought

The life cycle is dogmatically understood as the sequence of life stages that an organism undergoes from birth to reproduction and the generation of offspring. However, since the endocrine system determines the length and depth of these stages, and each is under epigenetic control, the life cycle should be reconsidered as a means by which the phenotype optimally engages with its environmental niche to collect epigenetic marks in a stage-specific manner. For example, it has been suggested that human primates have a protracted childhood to accommodate the growth and differentiation of our large brains. This is the perspective that the developmental psychologist Piaget advocated (Gruber and Voneche, 1977). Yet, this strategy could alternatively be considered as a prolonged passage through the developmental sequence; from infancy, to crawling, toddling, adolescence, puberty and adulthood as the requisite stages for the collection of condition-related epigenetic marks, including its microbiome. The result is a human organism that is better prepared to deal with its full range of environmental stresses when it is no longer under parental protective care (Miller, 2016a, 2016b). Continuing within the life cycle construct, senescence is conventionally pictured in terms of end-of-life events such as loss of function due to deterioration and disease. However, seen from the perspective of development, homeostasis and regeneration as a continuum of cell–cell signaling, senescence can alternatively be considered as the natural consequence of finite bioenergetics (Hayflick, 2007) causing failure of cellular communication (Torday and Rehan, 2012).

3.9 3.9.1

Discussion Descriptive versus Cellular–Molecular Biology and Occam's Razor

Based upon a differing frame of biology as continuously rooted within unicellular requisites, evolutionary biology changes from a purely descriptive exercise to a predictive science. The uniting feature is cell–cell signaling and its cognate receptors from this frame, a truer nature of many aspects of biology is revealed that might otherwise remain reflexive dogma, such as the life cycle (Torday, 2016b), life span (Torday and Rehan, 2012), heterochrony (Torday, 2016c), pleiotropy (Torday, 2015c), homeostasis (Torday, 2015b) and phenotype (Torday and Miller, 2016b). All can be conjoined as aspects of basically reiterating biological principles. In the Middle Ages, William of Occam formulated an enduring principle that has consistently been applied towards problem-solving in a wide variety of fields. His direct aim had been to criticize scholastic philosophy in which theories were growing ever more elaborate, but never more predictive (Domingos, 1999). His lasting pronouncement has been loosely translated as “Entities should not be multiplied beyond necessity” (Domingos, 1999). It could be argued that there is no problem-solving circumstance in which that expression is more apt than in its application to biological development and evolution. The Darwinian concentration on macro-organic form is both complex and non-predictive. Based on the principle of “Occam's razor,” which emphasizes that the simplest explanation is usually the best choice as it is the easiest to test and refute, a direct reduction towards

simplicity is offered. The unicellular state has continuous primacy. Its macroscopic elaboration proceeds in continuous fidelity to its long-term needs. In consequence, epigenetic inheritance derived from the existing environment stands alongside the genome as a concurrent means of sustaining organismal–environmental complementarity. It is a simple construct, no more complex than any reproductive strategy rooted within Darwinian inheritance (Torday, 2016b). It could be argued that any misunderstanding of causation in evolution has farreaching consequences. Consider the fact that there have been no major advances in medicine since the publication of the human genome, despite the prediction that all of the ills of humanity would be ameliorated by such knowledge (DeLisi, 1988). Prior theory has proved spectacularly off mark. Based on Darwinian theory, the human genome was predicted to contain at least 100 000 genes. Contemporary data have indicated that humans have fewer than 19 000 protein-encoding genes (Ezkurdia et al., 2014). That earlier prediction was based on the descriptive perception that biologic complexity is the direct result of the number of genes in the genome. By contrast, the cellular–molecular approach that is offered herein appreciates that that evolution and genomic size are functions of cell–cell interactions and an emergent regulatory apparatus rather than raw genetic frequencies (Torday and Rehan, 2012).

3.9.2

Heliocentrism, the Age of Reason and Beyond

Any challenge to dogma should expect resistance. It is daunting to change our natural assumption of the importance of our own macroscopic form to the acceptance of the imperative of unicellular life in our life, with all the rest due to epiphenomena (Torday and Miller, 2016a). Yet, just such a paradigm shift was required when the sun displaced the Earth as the center of the solar system, giving rise to the Age of Reason and the Enlightenment (Koestler, 1989). Yet, it should be fully considered that in our contemporary circumstances, in which man has such a disparate impact on our planet compared to all other creatures, the displacement of humans from the center of the biosphere might be expected to have a salutary impact on our planet that might be viewed in concert with Gaia theory (Lovelock, 1995). It might then be hoped that a realization of our proper relationship to all of our companion creatures might result. Minimally, it offers a way to understand how and why organisms interact with their environments to obtain epigenetic marks (Torday and Miller, 2016a, 2016b). Maximally, it merges evolution theory with ecology. As a result, the readily assumed concepts of random mutation, mate selection and natural selection that characterize neo-Darwinism might be displaced (Torday, 2016c) towards a position of biologic ecological stewardship (Miller, 2016a; Miller and Torday, 2018). This centers on a new understanding of evolution in which it is seen as more than the mere merging of two gene pools towards variation and novelty, but as a continuous environmental balance in which epigenetic inheritance provides consistent cues referring back the primary unicellular form.

3.9.3

Consequences for Biomedical Research

Currently, biomedical research is in crisis. This situation has been attributed to lack of funding, poor training of scientists, and general dysfunction of the field (Alberts et al., 2014). However, the problems are more systemic. Biology remains

descriptive rather than mechanistic and predictive. How might biomedical research flourish when instead it is deprived of basic principles that should be the substrate for their experimentation, validation and refutation? Ioannidis (2005) has asked, “Why most published research findings are false,” and points out the flaws in biological methodology. Others such as Richard Strohman (1993) and Ken Weiss et al. (2011) have recognized that there are inherent flaws in biology, but have failed to specify that there is a lack of investigation into fundamental mechanisms consistent with evolution. It is philosophers such as Nicholson (2012) and Moss (2012) who have identified the crux: the absence of fundamental mechanistic principles behind biology is a fatal flaw. The barriers to that coherent set of principles has been considered by some to be insurmountable. Based upon the evidence then at hand, even Prigogene and Stengers (1984), and Polanyi (1968) had decided that biology was too complicated to reduce to a simplified set of cohering principles. In apposition, a differing stance can be validated. In a series of papers, it has been presented that a coherent mechanism of biological development and all of its biological intermediates can be based on cell–cell communication, mediated by soluble growth factors and their receptors (Stone and Bhimji, 2017). It is argued that this is our evolutionary “Occam's razor.” Furthermore, since phylogeny is predicated on ontogeny, the combination of these two perpetual properties of life as the enacted short-term and long-term histories of the organism communicating to maintain homeostasis, can be understood as evolution (Torday and Rehan, 2007; Torday and Rehan, 2009a, 2009b; Miller, 2016a; Miller, 2017). The reward for such a cohering stance extends beyond a refined understanding of biological development and evolution. It has a direct impact on medical science. Biology is the basic science of medicine. By remaining descriptive, biology fails to be predictive; and as a result, medicine remains mired in associations and correlations, rather than more certain outcomes that can positively affect patient care and the quality of our lives.

3.10 Conclusion If there is to be any substantive progress in evolutionary biology, the field must be able to stand on par with its brethren sciences. Such an imperative requires a formal systematization that permits its scrutiny through rigorous testing and refutation. For this goal to be achieved, an identifiable set of fundamental principles must be identified that can become the basis of direct interrogation. That centralized core set of biological principles can only be realized through challenging established orthodoxy and a willing consideration of valid alternatives. In our current moment, contemporary research permits that formulation of a coherent biological alternative whose parsimonious components can be apposed to standard Darwinian precepts. Biology and its evolution are continuously rooted in the unicellular state. It elaborates through cell–cell communication mediated by ligand-receptor interactions and a vast array of cell–cell signaling mechanisms. Through this reciprocating means, homeostatic mechanisms are sustained at reiterating macroorganic scales. Thus, evolution can be interrogated as the successive layering of cell–cell signaling pathways accumulated over evolutionary space–time. It is this process, in continuous organismal–environmental complementarity, that has permitted both the faithful regeneration of organisms and their spectacular variations.

References Alberts B., Kirschner M. W., Tilghman S. and Varmus H., Rescuing US biomedical research from its systemic flaws, Proc. Natl. Acad. Sci. U. S. A., 2014, 111, 5773–5777. Birks J. B., (1962, ), Rutherford at Manchester, London: Heywood. Bohm D., (1980, ), Wholeness and the Implicate Order, London: Routledge & Kegan. Combes A. N., Davies J. A. and Little M. H., Cell-cell interactions driving kidney morphogenesis, Curr. Top. Dev. Biol., 2015, 112, 467–508. Darwin C., (1859, ), On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life, London: John Murray. DeLisi C., The Human Genome Project, Am. Sci., 1988, 76, 488. Dobzhansky T., Nothing in biology makes sense except in the light of evolution, Am. Biol. Teach., 1973, 35, 125–129. Domingos P., The role of Occam's razor in knowledge discovery, Data Min. Knowl. Discovery, 1999, 3, 409–425. Ezkurdia I., Juan D., Rodriguez J. M., Frankish A., Diekhans M., Harrow J., Vazquez J., Valencia A. and Tress M. L., Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes, Hum. Mol. Genet., 2014, 23, 5866–5878. Gapp K. and Bohacek J., Epigenetic germline inheritance in mammals: looking to the past to understand the future, Genes, Brain Behav., 2018, 17, e12407. Godfrey L. R. and Sutherland M. R., Paradox of peramorphic paedomorphosis: heterochrony and human evolution, Am. J. Phys. Anthropol., 1996, 99(1), 17– 42. Gould S. J. and Vrba E. S., Exaptation—a missing term in the science of form, Paleobiology, 1982, 8, 4–15. Gruber H. E. and Voneche J. J., (1977, ), The Essential Piaget, New York: Basic Books. Hayflick L., Biological aging is no longer an unsolved problem, Ann. N. Y. Acad. Sci., 2007, 1100, 1–13. Hunter P., Biology is the new physics, EMBO Rep., 2010, 11, 350–352. Ioannidis J. P., Why most published research findings are false, PLoS Med., 2005, 2, e124. Itoh N., FGF10: A multifunctional mesenchymal-epithelial signaling growth factor in development, health, and disease, Cytokine Growth Factor Rev., 2016, 28, 63–69. Koestler A., (1989, ), The Sleepwalkers, London: Penguin. Lovelock J., (1995, ), The Ages of Gaia: A Biography of Our Living Earth, New York: W. W. Norton & Co. Miller W. B., Cognition, information fields and hologenomic entanglement: evolution in light and shadow, Biology, 2016a, 5, 21. Miller W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016b, 4, 96. Miller W. B. and Torday J. S., Four Domains: The Fundamental Unicell and PostDarwinian Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2018, 140, 49–73. Miller W. L., Steroidogenesis: Unanswered Questions, Trends Endocrinol.

Metab., 2017, 28, 771–793. Monk D., Germline-derived DNA methylation and early embryo epigenetic reprogramming: The selected survival of imprints, Int. J. Biochem. Cell Biol., 2015, 67, 128–138. Moss L., Is the philosophy of mechanism philosophy enough?, Stud. Hist. Philos. Biol. Biomed. Sci., 2012, 43, 164–172. Nicholson D. J., The concept of mechanism in biology, Stud. Hist. Philos. Biol. Biomed. Sci., 2012, 43, 152–163. Polanyi M., Life's irreducible structure. Live mechanisms and information in DNA are boundary conditions with a sequence of boundaries above them, Science, 1968, 160, 1308–1312. Prigogene I. and Stengers I., (1984, ), Order Out of Chaos, London: Bantam. Schmich J., Kraus Y., De Vito D., Graziussi D., Boero F. and Piraino S., Induction of reverse development in two marine Hydrozoans, Int. J. Dev. Biol., 2007, 51, 45–56. Schuh R. T. and Brower A. V. Z., (2009, ), Biological Systematics: Principles and Applications, Ithaca: Cornel University Press. Shapiro, Revisiting the central dogma in the 21st century, Ann. N. Y. Acad. Sci., 2009, 1178, 6–28. Skulachev V. P., Holtze S., Vyssokikh M. Y., Bakeeva L. E., Skulachev M. V., Markov A. V., Hildebrandt T. B. and Sadovnichii V. A., Neoteny, Prolongation of Youth: From Naked Mole Rats to “Naked Apes” (Humans), Physiol. Rev., 2017, 97, 699–720. Stone W. L. and Bhimji S. S., (2017, ), Physiology, Growth Factor, Florida: StatPearls Publishing. Strohman R. C., Ancient genomes, wise bodies, unhealthy people: limits of a genetic paradigm in biology and medicine, Perspect. Biol. Med., 1993, 37, 112–145. Torday J. and Rehan V., Neutral lipid trafficking regulates alveolar type II cell surfactant phospholipid and surfactant protein expression, Exp. Lung Res., 2011, 37, 376–386. Torday J. S., Evolutionary biology redux, Perspect. Biol. Med., 2013, 56, 455– 484. Torday J. S., A central theory of biology, Med. Hypotheses, 2015a, 85, 49–57. Torday J. S., Homeostasis as the Mechanism of Evolution, Biology, 2015b, 4, 573–590. Torday J. S., The cell as the mechanistic basis for evolution, Wiley Interdiscip. Rev.: Syst. Biol. Med., 2015c, 7, 275–284. Torday J. S., Heterochrony as Diachronically Modified Cell-Cell Interactions, Biology, 2016a, 5(1), 4. Torday J. S., Life Is Simple—Biologic Complexity Is an Epiphenomenon, Biology, 2016b, 5(2), 17. Torday J. S., The Cell as the First Niche Construction, Biology, 2016c, 5(2), 19. Torday J. S. and Miller W. B., Biologic relativity: Who is the observer and what is observed?, Prog. Biophys. Mol. Biol., 2016a, 121, 29–34. Torday J. S. and Miller W. B., The Unicellular State as a Point Source in a Quantum Biological System, Biology, 2016b, 5(2), 25. Torday J. S. and Miller W. B., The resolution of ambiguity as the basis for life: A cellular bridge between Western reductionism and Eastern holism, Prog. Biophys. Mol. Biol., 2017, 131, 288–297.

Torday J. S. and Miller W. B., Terminal addition in a cellular world, Prog. Biophys. Mol. Biol., 2018, 135, 1–10. Torday J. S. and Rehan V. K., Developmental cell/molecular biologic approach to the etiology and treatment of bronchopulmonary dysplasia, Pediatr. Res., 2007, 62, 2–7. Torday J. S. and Rehan V. K., Lung evolution as a cipher for physiology, Physiol. Genomics, 2009a, 38, 1–6. Torday J. S. and Rehan V. K., The Evolution of Cell Communication: The Road not Taken, Cell Commun. Insights, 2009b, 2, 17–25. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology, Cell–Cell Communication and Complex Disease, Hoboken: Wiley. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, Hoboken: Wiley. Wang Y., Liu H. and Sun Z., Lamarck rises from his grave: parental environmentinduced epigenetic inheritance in model organisms and humans, Biol. Rev. Cambridge Philos. Soc., 2017, 92, 2084–2111. Warburton D., El-Hashash A., Carraro G., Tiozzo C., Sala F., Rogers O., De Langhe S., Kemp P. J., Riccardi D., Torday J., Bellusci S., Shi W., Lubkin S. R. and Jesudason E., Lung organogenesis, Curr. Top. Dev. Biol., 2010, 90, 73– 158. Weiss K. M., Buchanan A. V. and Lambert B. W., The Red Queen and her king: cooperation at all levels of life, Am. J. Phys. Anthropol., 2011, 53, 3–18. Zheng H., Huang B., Zhang B., Xiang Y., Du Z., Xu Q., Li Y., Wang Q., Ma J., Peng X., Xu F. and Xie W., Resetting Epigenetic Memory by Reprogramming of Histone Modifications in Mammals, Mol. Cell, 2016, 63, 1066–1079.

CHAPTER 4

C.P. Snow's “Two Cultures” Condition Is Resolved by the Singularity In his famous lecture, “The Two Cultures,” C.P. Snow (Snow, 1959) expressed his dismay at the schism between science and the arts. That schism has not only persisted, but the gap has gotten wider and wider with the specialization of the sciences, so much so that even scientists cannot easily communicate their findings in their own fields to scientists in different disciplines. This fragmentation of knowledge is largely due to the overly reductionist mission of cutting-edge science, requiring that the student dedicate him/herself to a narrow and focused discipline, to the exclusion of any rounded exposure to the arts. That compartmentalization of thought is unfortunate, because we have yet to understand the origin and causation of living organisms, let alone the nature of consciousness. Given that life is greater than the sum of its parts, it will require more than just technology to ascertain these enigmatic features of life. That is because the terms of inquiry into nature and life by the ancient Greeks was as instructive then as it is today. Our current systematic error is our attempt to discern the essence of nature and the “how and why” of life through futile means. There is a better way. The cellular approach to evolutionary biology offers a novel and fruitful perspective on the history of life, which is consonant with our actual living conditions. Clearly, the way in which we examine life, which is intimately related to our own self-image, “colors” our way of thinking about its nature. The classic example is the anthropic principle; that is, the notion that we are the universal object, since all of our perceptions about the universe are filtered by the fact that in order for us to observe it, the universe must conform to our consciousness and our living faculties. We may be in this “universe” by chance, and it is fortunate that prevailing conditions are “just right” for our habitation. But still, no observable universe could be any other way. That is in contradistinction to endosymbiosis theory – that is, that we are literally made of stardust – as Carl Sagan taught us, as a product of innumerable linkages that together have made us what we are. One school of thought along these lines is that the lipids embedded in the snowball-like asteroids that pelted the atmosphere-less Earth formed the origins of life. Lipids immersed in water spontaneously form micelles – spheres enwrapped in semi-permeable membranes – allowing things in the environment to enter and exit the internal space of the protocell. Importantly, lipids exhibit hysteresis, or memory. If they are deformed, they remember how to reform. When micelles were heated by the sun in daylight, they liquified, but then reformed at night when the environment cooled. This primitive memory was critically important for evolution, which relies upon such recall in order to efficiently re-purpose traits in their evolutionary repertoire, referred to as serial pre-adaptations, or exaptations. The use of DNA as memory was a later adaptation.

4.1

Empiricism as the Path from the Explicate to the Implicate Order: Common Ground for Science and the Arts

In Wholeness and the Implicate Order (Bohm, 1980), David Bohm used a stretchable matrix with ink dots on it for a “thought experiment,” to explain the transition from the Explicate to the Implicate Order; the former being how our subjective, evolved senses have interpreted reality for us, the latter being what actually exists in the cosmos. The notion that there is a continuum from the Explicate to the Implicate Order can also be seen as the basis for scientific experimentation, providing a systematic means for gradually transcending the Explicate and gradually entering the Implicate Order. For example, in his book, The Periodic Table: Its story and Its Significance (2019), Eric Scerri explains that Mendeleev used both atomic number and chemical reaction characteristics to position the elements in his table, taking into account both the synchronic (atomic mass) and diachronic (chemical reactivity) traits of the elements. Similarly, using the cell–cell interactions that generate structure and function during embryologic development as presented in Torday and Rehan's Evolutionary Biology, the Logic of Biology (2017) as it applies to phylogeny provides a way of using experimental data to determine biologic form and function. In either case, the conversion of one form of energy and matter into another as an equivalency is evidence for the transition from the descriptions of the Explicate Order to the mechanisms of the Implicate Order. By way of explanation, in conducting a scientific experiment, we “control” it operationally to take into account any extraneous changes in conditions that might inadvertently support the hypothesis erroneously. Or so it would seem. In actuality, controls are used to recognize the pseudo-existence of the Explicate Order, tacitly acknowledging the subjectivity of our perception of reality. So the controls provide reference points within that subjective realm in order to reduce the likelihood of spurious findings and, for example, witness the true Implicate Order that exists just beyond our perception, as in Bohm's stretchable matrix scenario. It is for this reason, for example, that evolutionary changes are characterized as “emergent,” as if coming out of nowhere, like prestidigitation, when in fact they derive from preadaptations utilized over the course of their evolutionary history. Both wound healing and evolution represent the regaining of cellular homeostasis, though in the case of the former, it is to re-establish cellular homeostasis, whereas in the case of the latter it is to remodel structure and function in adaptation to environmental constraints.

4.2

Einstein's Relativity Is Necessary to Think This Way

The ability to think about the Explicate and Implicate Orders was made possible by Einstein's theory of relativity and its aftermath at the turn of the twentieth century. Prior to that, Newtonian physics was all about the Newtonian “clockwork” nature of the universe. But the advent of relativity theory – which conceived of things being unfixed in space and time – initially challenged physics and mathematics. It did not take long for the cultural arts to follow. As mentioned earlier in Chapter 2, the Modern art movement, for example, was made possible by thinking outside of conventional standards. Each expressive

movement was an active attempt to grasp how Einstein had unmoored our casual perceptions of reality. Similarly, music made a series of quantum leaps with a fresh sense of experimentation with new musical forms, rhythms and idioms, also mentioned earlier in Chapter 2. Of all the scientific disciplines, biology has been the most resistant to this liberating perspective. Prior to the publication of “The Evolutionary Continuum from Lung Development to Homeostasis and Repair” (Torday and Rehan, 2007), biology was enmired in description, literally unaware or resistant to admitting that, like Rutherford's accusation that it was “stamp collecting,” the discipline was stuck in the mode of Linnaeus's binomial nomenclature, reflecting associations and correlations, not mechanistic origins and causation. Hopefully, it will not take as long for this concept to take hold as it did Copernicus's empirically derived conception of the sun as the center of the solar system.

4.3

Conclusions

The scientific method is a formalized way of making duplicatable and reproducible observations. Such activities are critical if there is going to be an insightful transition from our appraisal of the Explicate Order of self-deceptions, or the afterthe-fact reasoning of Darwinian evolution to the Implicate Order, where the true representation of the cosmos lies.

References Bohm D., (1980, ), Wholeness and the Implicate Order, London: Routledge & Kegan. Scerri E., (2019, ), The Periodic Table: Its Story and Its Significance, 2nd edn, Oxford: Oxford University Press. Snow C. P., Two Cultures, Science, 1959, 130, 419. Torday J. S. and Rehan V. K., The evolutionary continuum from lung development to homeostasis and repair, Am. J. Physiol. Lung Cell Mol. Physiol., 2007, 292(3), L608–L611. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, Hoboken: Wiley.

CHAPTER 5

The Heart Is Not Just a Pump; the Brain Is Not Your Only “Mind” Etienne Roux (2014) has stipulated that defining physiology based on function is teleology. That leaves us in a quandary with respect to how to define physiologic traits. The approach taken in this book, exploiting cell–cell communication based on growth factor/growth factor receptor signaling can identify physiologic traits based on genetics. For example, the first organ that functioned like a heart is thought to have appeared over 500 million years ago among our ancestral bilaterians. It was similar to the simple tubular vessel-like organs of amphioxi and tunicates, which contain a myoepithelial cell layer, without defined chambers or valves. The heart of Drosophila, referred to as the dorsal vessel, also functions as a linear peristaltic pump but, in contrast to the hearts of tunicates and amphioxi, it ends in a closed cardiac compartment and contains a cardio-aortic valve that separates a posterior lumen and an anterior aorta-like structure. Nematodes do not possess a heart per se, but their pharynx contracts like a heart, and the muscle cells that line its walls exhibit electrical activity similar to that of mammalian cardiomyocytes. The hearts of fish contain a single atrial chamber connected directly to a ventricle; amphibians have two atria separated by a septum and a single ventricle; terrestrial vertebrates have divided hearts in which septae separate the oxygenated and deoxygenated blood within the pulmonary and systemic circulations. The hearts of fish and amphibians lack a right ventricle but contain a rudimentary outflow tract, a structure derived from the secondary heart field in mammals. The reptilian heart, although evolved to function physiologically under conditions particular to reptilian life, is an evolutionary intermediate between amphibian and avian/crocodilian hearts in its ventricular development. The pump function of the heart was first questioned by Rudy Steiner, and more recently by Cowan (2016), who points out that only half of heart failure patients have overt loss of cardiac contractility as primary pump failure. There are other ways that cardiac failure can manifest, such as valvular disease, hypertension or restrictive cardiac processes. The heart is one component of the circulatory system, and it is the blood vessels that cause the flow of blood through it (Cowan, 2016). Blood flow and blood pressure are a complex overlapping product of spiral vascular streaming, vascular resistance and cardiac pulsation. It has long been known that the heart, in and of itself, is incapable of sustaining blood circulation (Marinelli et al., 1995). The heart serves many purposes that extend beyond its muscular contractility. In addition to that crucial role, it is a well-recognized endocrine organ (Chiba et al., 2018). Cardiomyocytes secrete critical hormones, including atrial natriuretic peptide and brain natriuretic peptides that target remote organs to regulate cardiovascular homeostasis, systemic metabolism and modulate

inflammatory states. Viewing physiology from a functional perspective distracts from the evolutionary origin of such properties that refer back to the first principles of physiology. For example, it has long been assumed that the lung evolved from the gill, reasoning by analogy that since both are gas exchangers and fish came earlier in vertebrate phylogeny, that gills were the origin of lungs. However, we now know that there are strong molecular homologies between the swim bladder of fish and the lungs of amphibians, reptiles, birds and mammals. Based on their shared adaptation to gravity, and the molecular role of surfactant to maintain the gas exchange surface in both organs, the course of lung evolution from the swim bladder is much clearer than that based on the gill. This paradox points out the fallacy in reasoning backwards from existing organisms to understand evolution in general. In a series of articles, Torday et al. have shown that the deconvolution of lung evolution facilitates tracing gas exchange back to the unicellular state, the cell membrane acting like a “lung.” The link to the vertebrate lung becomes more evident when cholesterol is introduced into the cell membrane, acting to thin the membrane, increasing gas exchange, enhancing metabolism and locomotion, the three primary principles of vertebrate evolution. Here again, Konrad Bloch, the discoverer of the cholesterol biosynthetic pathway, had rationalized that, since it takes 11 atoms of oxygen to synthesize one molecule of cholesterol, that there had to be enough oxygen in the atmosphere to do so, enabling the determination of approximately when in vertebrate phylogeny that occurred (1992). But was the latter necessary or sufficient for cholesterol biosynthesis in response to elevated oxygen? Since evolution is the result of serial pre-adaptations, that raises the question as to what adaptation was coopted for the use of lipids to protect against oxygen? It has been proposed that the polycyclic hydrocarbons that populated the snowball-like asteroids that pelted the Earth to form the oceans spontaneously formed micelles when submersed in water, generating the first “cells” on the planet, consisting of spheres bounded by semipermeable membranes. That way of thinking is consistent with the arc of vertebrate evolution, leading from such lipid-based spheres to primitive “memory” due to hysteresis, memory being essential for the process of evolution (Torday, 2019). In contrast to that, rationalizing that oxygen was necessary for cholesterol synthesis is a teleologic dead-end to understanding evolution as a continuum. For example, when the SCAP gene was experimentally deleted from the lungs of embryonic mice, preventing synthesis of cholesterol by the alveolar type II cells, the lungs compensated for the increased surface tension by generating more lipofibroblasts (Besnard et al., 2009). The latter are connective tissue fibroblasts that initially evolved to use lipids as antioxidants. Subsequently, they evolved to actively “traffic” neutral lipids for the on-demand production of lung surfactant in response to distension of the alveolar wall (Torday and Rehan, 2011), acquiring Adipocyte Differentiation Related Protein (ADRP) (Schultz et al., 2002), which increased the uptake and storage of neutral lipid from the circulation in response to leptin secretion by the alveolar type II cells for neutral lipid trafficking. The observation that without cholesterol the alveoli compensate by increasing the number of lipofibroblasts would have remained anecdotal, like much of biology, without the context of cell–cell signaling for serial adaptations. Conversely, the cell–cell signaling mechanism as the basis for physiologic evolution ascribes to Occam's razor or parsimony, since it is a simpler, cohesive, continuous process from the unicell to seemingly complex physiologic traits, hypothetically explaining

why we return to the unicellular state over the course of the life cycle. The cellcentric perspective offers mechanistic insights into physiology and its evolutionary course, compared with descriptive biology based solely on function. For example, it has been reported that the stem cells for the formation of the heart in Ciona intestinalis originate in the tail (Davidson and Levine, 2003), offering a hypothetical continuum from the beating of the tail to the beating of the heart.

5.1

Holland's Skin-brain Hypothesis

Reasoning by analogy instead of by homology caused a gap in determining the evolution of the vertebrate brain from invertebrates, given that invertebrates do not have a central nervous system. But Nick Holland reasoned that, since worms have their nervous systems in their skin, that that was where the higher-order brains evolved from (2003). There are cellular-molecular homologies between the skin and brain such as the use of lipids to form “barriers,” mediated by the neuregulin epidermal growth factor pathway. Moreover, there are skin lesions associated with neurodegenerative diseases such as Nieman-Pick, Gauche's Disease, and TaySachs, further attesting to the commonalities between these structures pathophysiologically.

5.2

Nicotine's Effect on N-acetylcholine Receptors Homology Between Lung and Brain

The study of the epigenetic effect of cigarette smoke on childhood asthma has revealed even deeper, counterintuitive homologies in physiology. Because there are 3000 components in cigarette smoke, nicotine was chosen as a proxy to experimentally mimic the hypothesized effect of smoking on asthma. It was found that the nicotine caused the formation of DNA methylation of N-acetylcholine receptors 3 alpha and 7 alpha in the upper airway smooth muscle of the offspring, enhancing calcium flux upon stimulation by cold air, which constitutes asthma. Such methylated DNA was further found to appear in the egg, sperm and zygote, accounting for the epigenetic inheritance of asthma for at least three generations (Rehan et al., 2013). Nicotine also increases the same N-acetylcholine receptor isotypes in the brain, where it homologously enhances short-term memory by increasing calcium flow in response to neuronal stimulation.

5.3

Pleiotropic Defensins Reveal Deep Physiologic Relationship Between Lung and Skin

There is overlap between the lung and skin as barriers, both of which have packaged lipids together with defensins for host defense. Through cellular exaptations, these telescope to neocortical myelination, as shown above. And as predicted, they also translate into disease. For example, patients with asthma often have the skin disease atopic dermatitis. These molecular phenotypes have been mechanistically linked through a common molecular defect in defensin, which mediates innate host defense in both skin and lung (Torday and Rehan, 2012). In dogs, defensins have been shown to determine coat color, which serves a multitude of adaptive advantages, ranging from protective coloration to reproductive strategies. Defensin CD103 has also been shown to cause atopic dermatitis in dogs, and possibly asthma, since it is found in dog airway epithelial

cells.

5.4

Symmorphosis Experience as Corollary to Deep Physiology

Euwald Weibel and associates (2015) set out to test the hypothesis that physiology evolved to adapt to the environment “economically,” referring to the concept as “symmorphosis.” Their major conclusion was that the lung was over-engineered, having more capacity than required. Since lung adaptation to terrestrial life was existential, having been attempted at least five times (Clack, 2012), clearly there were physiologic limitations to “gaining ground.” This raises the question as to what the basis for lung evolution was that would account for the excess capacity. Here again, the founding of lung evolution on the swim bladder, which, in turn, was driven by adaptation to gravity, would be consistent with Weibel et al.'s findings, particularly when compared to the analogy with the gills, which superficially accounts for the sourcing of oxygen without intermediary steps in its evolution. On the other hand, the juxtaposition of an organ of gas exchange for buoyancy in water in adaptation to gravity (read “efficiency of feeding for optimal metabolism”) with an organ of gas exchange on land for oxygenation, mediated by cell–cell interactions that “remodeled” the swim bladder by forming smaller and smaller gas exchange units to optimize oxygen uptake is a continuum consistent with the role of physiologic stress acting locally on structure and function due to the generation of radical oxygen species causing gene duplications within the constraints of the existing organ (Torday and Rehan, 2012). The preceding offers a perspective on how and why the parathyroid hormonerelated protein (PTHrP) receptor duplicated during the water-land transition, since it was existential for the formation of alveoli in the lung. The effective amplification of the PTHrP signaling pathway gave rise to the harder skeleton, the glomerulus of the kidney, the skin barrier and the brain, for adaptation to terrestrial life overall. But suffice it to say that, in order for all of those adaptations to have occurred, the subset of boney fish that were able to make that transition from water to land were selected due to their PTHrP receptor being more “amplifiable,” i.e. ubiquitous. That is, it was only the physostomous boney fish swim bladder that was the bauplan for the lung, not the physoclistous swim bladder. The remodeling of the swim bladder was predicated on the existence of a pneumatic duct between the esophagus and bladder, unlike the physoclistous bladder, which obtains gases from the circulation directly from the microcirculation. In other words, there were specific attributes that were made use of for exaptations – gravity and anatomy – that offered the possibility of remodeling based on atavistic traits. That robust signaling capacity is likely why Weibel et al. found the lung to have been “over-engineered.” From this, it can be understood that the lung may be over-engineered for its terrestrial purpose, but is, on an evolutionary basis, a product of a set of phenotypic and physiologic exaptations and adaptations that originated for reasons other than terrestrial air-exchange. Lung “over-engineering” is the residue of this evolutionary path rather than merely being a selective end-point of terrestrial adaptations.

5.5

The Brain Is Not the Mind

Descartes's “mind-body” dichotomy raised the question as to where the mind is localized. That question becomes particularly relevant when the primacy of the

unicell is discussed. Miller (2017) had emphasized that cognition is a cell-centered phenomenon experienced as an aggregate by multicelluar organisms. In his book, First Minds, Arthur Reber (2018) also expressed the idea that the mind is the aggregate of our physiologic evolution, given that even unicellular organisms are conscious. There is empiric evidence for this in the work of Mashour and Alkire (2013), who have documented the phylogenetic path of consciousness when patients recover from general anesthesia, given that vertebrate phylogeny can be traced back to unicellular organisms, raising the question as to whether consciousness might be invested in sub-cellular entities.

5.6

The Body Is Not Who We Are

Conventionally, we are our bodies and minds. Yet it has been estimated that our obligatory microbial cellular fraction might exceed our own personal eukaryotic cells by as many as ten to one (Miller, 2016). The question arises as to what our soma actually constitutes, particularly since it has also been proposed that our phenotype is not merely the sum of our traits, but is the agent for collecting epigenetic marks from the environment. Given that, consider the observation that when we are buried and decompose, our microbiome leaves a “footprint,” referred to as the necrobiome, which remains intact. That leaves the possibility that our microbiome could enter the soil, the aquafer and thus plants and animals, offering the option of immortality if ingested and assimilated by other living entities. Cellular-molecular studies disclose a much richer and insightful analysis of every facet of our living experience than can be derived through purely functional analysis. Our organs are only superficially measured through their overt tasks. They are both more and less than surmised by that means. Certainly, our brain is a critical structure, but our “minds” and our rich bodily sensations are the product of decentralized cellular experiences that summate as a cohesive entirety. From this, a vital lesson can be learned. An accurate comprehension of our own biology and our actual evolutionary path cannot be achieved through merely descriptive means. True insight can only be attained through meticulous cellular-molecular deconstructions of all of our physiologic and metabolic pathways and their linkages to cellular homologies.

References Besnard V., Wert S. E., Stahlman M. T., Postle A. D., Xu Y., Ikegami M. and Whitsett J. A., Deletion of Scap in alveolar type II cells influences lung lipid homeostasis and identifies a compensatory role for pulmonary lipofibroblasts, J. Biol. Chem., 2009, 284, 4018–4030. Bloch K., Sterol molecule: structure, biosynthesis, and function, Steroids, 1992, 57, 378–383. Chiba A., Watanabe-Takano H., Miyazaki T. and Mochizuki N., Cardiomyokines from the heart, Cell. Mol. Life Sci., 2018, 75, 1349–1362. Clack J. A., (2012, ), Gaining Ground, Bloomington: Indiana University Press. Cowan T., (2016, ), Human Heart, Cosmic Heart, Vermont: Chelsea Green Publishing. Davidson B. and Levine M., Evolutionary origins of the vertebrate heart: Specification of the cardiac lineage in Ciona intestinalis, Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 11469–11473.

Holland N. D., Early central nervous system evolution: an era of skin brains?, Nat. Neurosci. Rev., 2003, 4, 617–627. Marinelli R., Fuerst B., van der Zee H., McGinn A. and Marinelli W., The heart is not a pump: A refutation of the pressure propulsion premise of heart function, Front. Perspect., 1995, 5, 15–24. Mashour G. A. and Alkire M. T., Evolution of consciousness: phylogeny, ontogeny, and emergence from general anesthesia, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 10357–10364. Miller Jr. W. B., Cognition, information fields and hologenomic entanglement: evolution in light and shadow, Biology, 2016, 5, 21. Miller Jr. W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Reber A., (2018, ), The First Minds, Oxford University Press, Oxford. Rehan V. K., Liu J., Sakurai R. and Torday J. S., Perinatal nicotine-induced transgenerational asthma, Am. J. Physiol. Lung Cell Mol. Physiol., 2013, 305, L501–L507. Roux E., The concept of function in modern physiology, J. Physiol., 2014, 592, 2245–2249. Schultz C. J., Torres E., Londos C. and Torday J. S., Role of adipocyte differentiation-related protein in surfactant phospholipid synthesis by type II cells, Am. J. Physiol. Lung Cell Mol. Physiol., 2002, 283(2), L288–L296. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S. and Rehan V. K., A cell-molecular approach predicts vertebrate evolution, Mol. Biol. Evol., 2011, 28, 2973–2981. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology: Cell–Cell Communication, and Complex Disease, Hoboken: Wiley. Weibel E., Taylor C. R. and Bolis L., (2015, ), Principles of Animal Design, Cambridge: Cambridge University Press.

CHAPTER 6

Why You Must Transcend Space-time in Order to Understand Consciousness The nature of consciousness has been debated without resolution for centuries of recorded history, beginning with the ancient Greek philosophers. Over the centuries, fresh concepts have been presented and old analyses have been challenged. In our contemporary moment, David Chalmers (1995) separated the issue of conscious into two differing aliquots. In his terms, there is an “easy” part, which includes those hard-wired responses to stimuli through which our brain instructs our reactions. These can be interrogated by modern scientific techniques. On the other hand, there is a class of consciousness, termed the “hard problem,” which are our experiences as phenomenal consciousness. For example, getting extremely angry and “seeing red.” This latter type of phenomenon, termed qualia, is much more difficult to explain than the former. Andy Clark approached this perpetual question by postulating an “extended mind” hypothesis (Clark and Chalmers, 1998). This concept proposes an “active externalism” by which the environment has an active role in driving the cognitive (conscious) processes of any individual. This question of the true nature of consciousness is more than academic speculation; it defines who and what we are as human beings. The concept of two differing sorts of “mind” has a long history, originating long before Descartes’ well-known expositions on mind-body duality, which are regarded as a watershed in human thought. Basically, Descartes proposed that the “mind” exerts control over the brain. In effect, the “mind” was his thinking “self” (his soul), which is distinct from the brain but necessarily influenced it (Mohammed, 2012). The epicenter of that control was deemed to be the pineal gland. After a long and rich history of intriguing hypotheticals, modern scientific research is offering new insights into how and why consciousness is experienced. Much of this new evidence contradicts the musings of our non-scientific forebears. For example, there is substantial evidence that even unicellular organisms are conscious (Ford, 2004; Shapiro, 2011; Lyon, 2015; Miller, 2016; Ford, 2017; Reber, 2018; Miller et al., 2019a, 2019b). From this cellular vantage point, the concept of consciousness as a phenomenon of cellular aggregation is gaining traction. Yet, even if this controversial position is considered valid, the specifics of the relationship between cognitive cells and how experiential humans function looms large. The celebrated philosopher, Schopenhauer, had stated that “Consciousness is the mind's idea of the body,” essentially implying a holistic way of understanding the mind that transcends the mechanistic testing that will be required to completely understand consciousness. If it is supposed that consciousness is an endowment of all cells then how might it aggregate to reach the level of our conscious perceptions? It might extend along

the same paths that permitted multicellular physiology to evolve from the unicellular form. The strongest scientific evidence supporting this type of path centers on the documented evolution of the lung, skeleton and kidney based on cell–cell signaling mediated by soluble growth factors. This pathway indicates how the evolution of the nervous system and the brain was integral to the development of the visceral organs (Torday and Rehan, 2012). A breakthrough in understanding brain evolution was the insight that invertebrates have their central nervous systems in their skin, giving rise to the “skin-brain” hypothesis. That was conceptually significant because there are both phylogenetic and molecular connections between the skin and brain. Phylogenetically, the skin is the homologue of the unicellular cell membrane as the structure that forms the boundary between the organism and its environment. Functionally, there are molecular homologies between the skin and the brain. For example, the lipid barrier between the dermis and epidermis is generated by epithelial cells that package lipids mediated by neuregulin (NRG). In the brain, neuregulin mediates the myelinization of neurons by Schwann Cells (Birchmeier and Bennett, 2016). As a consequence, all of the neurodegenerative diseases have skin homologues, implicating NRG in the evolution of the skin and brain from a structure-function perspective. Genetically, this phenomenon is recognized as pleiotropy, the utilization of the same gene for different functions and/or structures. Beyond the relationship between the skin and brain, NRG also connects the molecular interrelationships between the lung, skin and brain. The lung surfactant lipid-protein complex is composed in part by surfactant proteins A and D, which are defensins, or host-defense peptides. Defensins are also components of those lipid complexes that NRG mobilizes for the lipid barrier of the dermis. NRG is also involved in the secretion of surfactant by the epithelial type II cells that line the alveoli along with epithelial type I cells. The interconnection between these mechanisms is highlighted by mutations in defensins in the lung that cause asthma; whereas, in the skin they affect coat color in dogs, which also develop asthma, i.e. reproductive strategy and protective coloration. From the foregoing, it follows that these interconnections between physiologic properties bridge their evolution alongside axonal connections in the brain, providing the functional connection between physiology and the mind. Of course, it is known that there is such a physical connection, deriving from the peripheral nervous system and even the gut, with signaling to the central nervous system. That interrelationship is mediated through cell–cell communications in support of homeostasis, which itself refers back to the first principles of physiology that originated in the unicellular state. Cell–cell communications are critical pre-adaptations, or exaptations, which also form the basis for evolution. When challenged by an existential threat, an organism reuses earlier adaptations by reaching into its genetic cellular toolkit to mitigate its current environmental threat, as a form of continuous cellular problem-solving (Miller, 2017; Torday and Miller, 2018a, 2018b). One of the great unknowns in science is why cells formed in the first place. One perspective is to regard it as an echo of the unity of the Singularity that existed prior to the Big Bang (Hawking, 1998). The explosive disruption of the Singularity would have given rise to an “equal and opposite reaction” sequence based on Newton's third law (Torday and Miller, 2018a, 2018b). The opposite of expansion, with its consequent increasing entropy was localized “pools” of relative negentropy as localized opposing reactions. This becomes the origin of homeostasis, just as it might have been similarly the origin of all forces of material attraction that make up

all celestial bodies. Furthermore, if chemistry and physics are characterized by concurring equations that mediate the transition from one set of energy-mass variables to another, then homeostasis becomes the biological expression of its means of satisfying that mathematical requirement. From within this perspective, further insight into evolutionary processes can be attained, which unites all of existence, inorganic and organic alike, into a common process. The key to understanding organic evolution is that it is constituted by the endogenization of factors in the environment that pose an existential threat to the living state. By compartmentalizing such factors, the organism internalizes them as its physiology. In that way, the living state achieves its equipoise by always being in direct concert with its outward environment, which is its own form of satisfying the energy-mass equality. Therefore, life complies with the same natural laws, just as the inorganic states do within the cosmos. Thus, even the evolutionary process complies with the Singularity as a reciprocal vector, reacting to the expanding universe by endogenizing it when threatened through the continual process of adaptation. When viewed in this manner, the cellular form can now be understood as being a fractal of the cosmos, with each of its adaptations rooted within basic physical forces representing an instance of reiteration. This goes beyond the theoretical. It can be shown experimentally through the effects of microgravity on cell physiology. As noted, there are physiologic interrelationships between lung, kidney, skin, bone and brain at the cell-molecular level. Those connections are made evident when the parathyroid hormone-related protein (PTHrP) gene is deleted in developing mice. All of those organs are affected in ways that are consistent with their evolution. Because of the mechanotransductive physiologic role of stretch on lung, kidney and bone, the effect of microgravity on PTHrP can be studied. When lung and bone cells are exposed to microgravity, PTHrP gene messenger RNA expression levels decrease, and can be restored to normal when the cells are placed back in unit gravity conditions again (Torday, 2003). This loss of PTHrP messenger RNA expression is indicative of its roles in the integrated physiology of its critical target organs (lung, kidney, skin, bone and brain). Importantly, when yeast are subjected to microgravity (Purevdorj-Gage et al., 2006), their ability to bud, i.e. to reproduce and to polarize, is diminished. Since maintaining calcium flux is critical to this reproductive process, it can be considered that this repeats as a fractal homolog that underpins our consciousness. In microgravity, yeast react as if they are in a relative state of suspended animation, cut off from their typical orientation to the physical world. These data indicate the fundamental relationships of organisms with gravity and the complex interrelated pathways that connect every aspect of physiology. As mentioned in the previous chapter, in his book, The First Minds, Arthur Reber made the case for unicellular consciousness. Every cell reacts to its environment, receives information, interprets and communicates it, deploys solutions to problems, and learns (Miller et al., 2019a, 2019b). Pertinently, when stimulated, unicells exhibit a calcium flux just like the neurons in our brains. Such unicellular organisms may not be able to do calculus or write poetry, but their basic sentience is demonstrable, according to their scope and scale, exhibiting the same basic physicochemical reactions to their environments that humans do.

6.1

Predictive Value of Consciousness as a Fractal of the

Cosmos Many have pondered Chalmers’ “hard problem,” for example, why we see “red” when we whack our thumb with a hammer. Yet, on the one hand, physiology began with the unicell, and on the other it is the aggregate of what we think of as the mind. Given that, perhaps qualia are atavistic memories of earlier stages in physiologic evolution? And as for Clark's extended mind, if mind is a fractal of the cosmos, by definition, mind extends beyond our bodies. That is particularly arguable when the unicell is properly considered as the first niche construction, as one living way station of the fractal reiteration of the basic evolutionary principle of all organisms endogenizing their environments. In this type of framework, the “phenotype as agent” scenario, may also be considered a manifestation of the extended mind. Phenotypes are cellular ecologies whose purpose in multicellular organisms is to support physiology and metabolism and, in doing so, gain environmental experiences. In this way, phenotypes can be seen as extensions of the organism for obtaining epigenetic marks. These are returned to the primary unicellular stage through adult reproduction. The zygote is somehow “aware” of the overall physiology of the organism, and also somehow seems to have a long-term sense of environmental history. This critical sensibility can be equated with mind, hence the proposal that phenotypic agency is an aspect of Clark's extended mind. This view of the “phenotype as agent” (Torday and Miller, 2016) is consistent with the overall concept that life is the perpetual flow of energy. As conceived in Alfred North Whitehead's process theory, all of existence is governed by a perpetuating identity between energy and matter. The communication of information between cells is always an energy transfer and it is that communication that is the active means by which life is sustained. The essential process of cell-cell communication began with the very first primordial cells. It still persists robustly at that level today and, by a long evolutionary arc of fractal reiterations, has become all the visible forms of complex multicellular life that eventually became our own sort of human consciousness. It is in this way that physiology unites with “mind” to form our own, very human, idiosyncratic behaviors and faculties.

References Birchmeier C. and Bennett D. L., Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair, Curr. Top. Dev. Biol., 2016, 116, 45–64. Chalmers D., Facing up to the problem of consciousness, J. Conscious. Stud., 1995, 2, 2002–2019. Clark A. and Chalmers D. J., The extended mind, Analysis, 1998, 58, 7–19. Ford B. J., (2004, ). Ford B. J., Cellular intelligence: microphenomenology and the realities of being, Prog. Biophys. Mol. Biol., 2017, 131, 273–287. Hawking S., (1998, ), A Brief History of Time, Bantam, New York. Lyon P., The cognitive cell: bacterial behavior reconsidered, Front. Microbiol., 2015, 6, 264. Miller W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016, 4, 96. Miller W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26.

Miller W. B., Torday J. S. and Baluška F., Biological evolution as the defense of ‘self’, Prog. Biophys. Mol. Biol., 2019a, 142, 54–74. Miller W. B., Torday J. S. and Baluška F., The N-Space Episenome Unifies Cellular Information Space-Time within Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2019b, 150, 111–139. Mohammed A. A., A Critique of Descartes’ Mind-Bogy Dualism, Kritike, 2012, 6, 1. Purevdorj-Gage B., Sheehan K. B. and Hyman L. E., Effects of low-shear modeled microgravity on cell function, gene expression, and phenotype in Saccharomyces cerevisiae, Appl. Environ. Microbiol., 2006, 72, 4569–4575. Reber A., (2018, ), The First Minds, Oxford University Press: Oxford. Shapiro J. A., (2011, ), Evolution: A View from the 21st Century, FT Press: Upper Saddle River. Torday J. S., Parathyroid hormone-related protein is a gravisensor in lung and bone cell biology, Adv. Space Res., 2003, 32, 1569–1576. Torday J. S. and Miller W. B., Biologic relativity: Who is the observer and what is observed?, Prog. Biophys. Mol. Biol., 2016, 121, 29–34. Torday J. S. and Miller W. B., A systems approach to physiologic evolution: From micelles to consciousness, J. Cell. Physiol., 2018a, 233, 162–167. Torday J. S. and Miller W. B., The Cosmologic Continuum From Physics to Consciousness, Prog. Biophys. Mol. Biol., 2018b, 140, 41–48. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology, Cell-Cell Communication and Complex Disease, Wiley: Hoboken.

CHAPTER 7

The Evolutionary Significance of Homeostasis Homeostasis is typically considered a mechanism for maintaining balance between fixed set-points, like a home heating system. However, cellular homeostasis is different at both the level of individual cells and for the cellular ecologies that support our physiology. Homeostasis in the living circumstance denotes a flexible dynamic in which the relevant set-points are being continuously adjusted within limits, in accordance with environmental circumstances. The origin of living homeostasis is not known, but it has been previously argued that it represents a type of “equal and opposite reaction” to the Big Bang, based on Newton's third law of motion. Physics and chemistry are both characterized as disciplines rooted within sets of basic equations that are fundamental to each, and denominate balanced reaction sets. Energy and/or mass on one side of an equation can be set off by “equals” signs, through which reactants become products. In every instance, products of the reactants can be predicted with certainty if the measurements are accurate enough. Biology is different. There are never any equivalent equals signs, only active dynamic interrelationships that can yield generally concordant results. Those relationships do not yield identities, only varying degrees of similarities. Nowhere is that demonstrated more clearly than in the role of phenotype as agent, seeking novelties in the ever-changing environment and reporting them back to the parent organism for the protection of the soon-to-be offspring. This registers from somatic cells to egg and sperm as heritable epigenetic adjustments (Torday and Miller, 2016b; Miller and Torday, 2018). These germ cells retain those acquired epigenetic marks and transfer them during the process of meiosis. Then, when the egg is fertilized, those epigenetic marks that were retained are adjusted to fit longterm environmental proscriptions to modify the offspring in order to adapt to the on-coming environment (Torday and Miller, 2016b). Of equal importance to maintaining equipoise, homeostasis comes into play when the organism must evolve. Under stress, cells will generate radical oxygen species (ROS) that can cause gene mutations and duplications. Under such conditions, the cells responsible for the structure and function of specific tissues will re-establish homeostasis by modifying their signals; this usually is due to an increase in receptors, which is the most efficient way to change such a signaling mechanism, since the latter are “professional” amplifiers. Once the new set-point for homeostasis is established, the tissue can resume its prior functions, having been altered to a new level of functionality. This is a mechanistic explanation for how and why evolution occurs. When correctly appraised through the cellular-molecular perspective, homeostasis is the mechanistic fundament of biology, beginning with the first protocell. It follows that medicine and all of biology should be based on

ontologic and epistemologic principles rooted in these types of perpetual principles. That goal was previously unachievable due to the dominance of Darwinian evolution, which is metaphoric; that is, it describes a mechanism, but does not actually determine its fundamental characteristics. Teleology has facilitated our understanding of biologic pathways, but it has constrained our thinking about mechanistic origins as traits that have evolved from permutations and combinations of pre-existing genetic motifs. Jacob characterized this process as “tinkering” (1977), but in doing so he trivialized the underlying mechanisms involved at the cellular-molecular level. This stance largely discouraged novel inquiries since a bedrock assumption of Darwinism has been that the driving mechanism of evolution is random mutations. Yet, it is now known that specific gene duplications and mutations occurred during the vertebrate transition from water to land; that of the parathyroid hormone-related protein receptor, and the β-adrenergic receptor, and the mutation of the mineralocorticoid receptor to form the glucocorticoid receptor. All three of these genetic changes were key to the physiologic adaptations necessary for land life: skeletal, pulmonary, kidney, skin and vascular. The reconfiguring of these genes was the consequence of past conditions rejuvenated for existential change, allowing the seeming emergence of novel biologic traits through ontogeny and phylogeny. An innovative mechanistic cellular approach to the processes of eukaryotic evolution based on the unicellular state of the life cycle as the principal level of organismal adaptation has been previously proposed (Torday and Miller, 2016a; Miller and Torday, 2018). To frame the historic conditions of the past that led up to these events, an ontogenetic-phylogenetic perspective can be exploited. Cells originated from lipid-based micelles that provided a privileged internal space in which chemiosmosis fueled a reduction in entropy, maintained and perpetuated by homeostasis. This view of the origin and evolution of life offers an across-spacetime understanding of the past, present and future of the organism. Rather than the usual static view of homeostasis maintaining equilibrium, now the exaptive mechanisms that permit its continued successes are revealed.

7.1

Homeostasis Is Not Stasis

Biologists traditionally pull animals and plants apart, describing their structure and function. However, a critical empiric observation revealed that epithelial cells cultured in isolation from their connective tissue fibroblasts lost their ability to remain differentiated. When those epithelial cells were again combined with their respective fibroblasts, that ability was revived, explaining why intact embryonic tissue, which is inherently pluripotential, continues to develop along its normal trajectory in culture. Combining epigenetic inheritance with an understanding of the fetal origins of adult disease (Carpinello et al., 2018) as a loss of cell–cell signaling becomes a powerful integration of homeostasis between generations. Such fundamental observations have led to a mechanistic understanding of evolution based on cellular communication. It has been suggested that evolution must be seen holistically as the organism's merged ontogenetic and phylogenetic history. The distinction between descriptive and mechanistic evolution is epitomized by homeostasis being seen as either static or dynamic. Homeostasis is the latter, constantly vacillating about reference-points, always poised to reset itself if necessary for survival in an ever-changing environment. This dynamic perspective of homeostasis is exemplified within

developmental physiology. For example, when the normal homeostatic mechanisms are interrupted in preterm infants, the growth factor signaling mechanisms of development, regeneration and repair become dysfunctional. Robert G.B. Reid highlights the interrelationship between homeostasis and evolution in his book, Evolutionary Theory – The Unfinished Synthesis (1985), but without invoking the necessary developmental dimension. The different phases of the life cycle are described without the underlying mechanistic interrelationships that underpin them, which is a direct systematic error.

7.2

Bernard to Cannon

From this, it can be seen that homeostasis is the way that functional variation is controlled within a constraining bandwidth. For example, homeostasis regulates body temperature and the balance of pH in bodily fluids, maintaining an internal physiologic environment in response to fluctuations in external environmental conditions. Beginning in 1854, Claude Bernard was the first to characterize physiologic control as the milieu interieur in Introduction to the Study of Experimental Medicine (2012). The term “homeostasis” was formally applied by Cannon in his book, The Wisdom of the Body (1963). The term “homeostasis” has been applied to many machine mechanisms as autonomous control systems, ranging from cruise control to astral bodies. For these, homeostatic control needs a sensor for detecting changes in the process to be regulated, an effector mechanism that can control that condition and a negative feedback mechanism. Living organisms depend on complex sets of integrated, interacting metabolic chemical reactions. Internal metabolic processes function to maintain conditions within closely regulated and controlled constraints. That ensures that these reactions can proceed from unicellular organisms to complex plants and animals. As such, homeostasis functions at the level of cells, cellular ecologies as tissue types, each organ, and at the level of the entire organism. At this latter aggregated level, that reciprocating cellular homeostasis is referred to as “allostasis.” Three interactive components are necessary for biologic homeostatic control. A receptor senses, monitors and responds to changes in the environment, and if the receptor is stimulated, it signals to the nucleus and the entire sensory apparatus of the cell, which determines the range in which the variable is maintained. The entire cell determines an appropriate response to the stimulus. It sends signals to effector molecules; that is, other cells, tissues, organs or structures. They all might receive signals for the purpose of homeostatic control, and each may be part of a reciprocal response. Negative feedback buffers the output or gain of any organ or system. For example, in the case of blood pressure regulation, blood vessels sense the resistance to blood flow when blood pressure increases. The blood vessels act as receptors, relaying the message to the brain. The brain then sends a message to the heart and blood vessels, which are both effectors. As a result, the heart rate will decrease as the blood vessels increase in diameter (vasodilation). This change causes the blood pressure to decrease to within its normal range. The opposite occurs when blood pressure decreases, causing coordinate increased heart rate and vasoconstriction. Another important example is seen when the body is starved of food. In response, the body will lower the set-point for metabolic activity, allowing the body to continue to function at a slower metabolic rate, even though the body is starving.

Therefore, people depriving themselves of food while trying to lose weight find it easy to shed weight initially, but it becomes much harder to lose more thereafter, due to the body automatically readjusting itself to a lower metabolic set-point to allow it to survive with its lower supply of energy. Exercise can alter this effect by increasing the metabolic demand. Another negative feedback mechanism is body temperature control. The hypothalamus determines body temperature, and is capable of sensing the smallest changes in body temperature. Variations in temperature can stimulate sweat glands, reducing body temperature, or signal muscles to shiver in order to increase body temperature.

7.3

Dyshomeostasis

Diseases can cause disturbances in homeostasis. For instance, during the aging process, the control of homeostatic systems declines due to the loss of receptor capacities. These cumulative inefficiencies gradually result in an unstable internal environment that increases the risk of illness, leading to the physical changes associated with aging. Specific homeostatic imbalances, like elevated core body temperature, or high concentrations of ions in the blood, or low concentrations of oxygen, can produce physiologic reactions such as warmth, thirst or breathlessness, which provoke adaptive behaviors for restoring homeostasis.

7.4

Waddington's Diachronic Perspective

“It is not enough to see the horse pulling a cart past the window as the good working horse it is today; the picture must also include the minute fertilized egg, the embryo in its mother's womb, and the broken-down old nag it will eventually become.” Conrad Hal Waddington, in The Strategy of the Genes (1957). There is an inherent problem in Darwinian evolutionary theory: its perspective on the life cycle. As Waddington has intimated in the quote above, the entire process of life must be seen as a continuum in order to understand the underlying evolutionary principles that are involved. In contrast, when the cellular approach reduced both lung evolution and physiology of vertebrates to its cellular, mechanistic level, meaningful purchase was gained toward understanding embryonic development and phylogeny across space and time as one continuous diachronic mechanism. This is an important breakthrough perspective because it demonstrates the fallacy in looking at ontogeny and phylogeny as independent of one another, as would seem to be the case when looked at from the perspective of their embryologic and adult anatomic forms. This differing frame led to a reconsideration of Haeckel's biogenetic law that ontogeny recapitulates phylogeny in a new light (Torday and Miller, 2018). The properties of the cell have allowed vertebrates to adapt to the ever-changing environment for eons, orchestrated by the modulating effects of the unicellular zygotic stage and embryogenesis on acquired epigenetic characteristics. The further recapitulation of phylogeny through terminal addition may act to constrain evolutionary changes to maintain internal consistency of homeostatic control at key stages of embryologic development. In their book, The Plausibility of Life (2005), Kirschner and Gerhart cite the effects of polyploidy on newt development, the embryos having fewer, but larger,

cells, which had no effect on tissue or body size. For example, kidney duct size remained unaffected by the reduced number of epithelial cells surrounding it. This finding stymied even the great Einstein, prompting him to state that: “It looks as if the importance of the cell as ruling element of the whole had been overestimated previously. What the real determinant of form and organization is seems obscure.” However, since homeostasis remains the basis for solute exchange by the renal tubules, the absence of overall structural change can be reconciled as being always based on the cellular reception of environmental cues and cell–cell communication. The importance of this reconsideration of biology and evolutionary development is that it places it within a frame of cellular problem-solving at each scale to maintain homeostasis as the controlling element (Miller and Torday, 2018). In so doing, genes can assume their proper place as tools of the cell. And the cell can be rightly assessed as the “common denominator” in evolutionary theory.

7.5

Downward Causation

The concept of downward causation is a systematic error that has been made in biology due to a teleological assumption that the living narrative is directed toward a culminating adult state. That view contrasts to Waddington's “cart and horse” imagery in Strategy of the Genes, encouraging thinking beyond the present circumstance to the continuum of life, including the next generation (the fertilized egg in the mother's womb). Yet, even Waddington had not completely separated from the concept of downward causation. Noble (2008) thought differently and concluded, through a systems biology approach, that there is no privileged level of causation in biology. However, even as there is no privileged level of causation in reciprocating and dynamic biological systems, there is still a central focus of biological determinism. All multicellular life returns to the unicellular state, which is the perpetual living form (Miller and Torday, 2018). In that transient moment, the epigenetic “marks” acquired over the course of the life of the organism are adjudicated, with some remaining heritable and biologically active. For example, maternal nicotine exposure causes transgenerational inheritance of the asthma phenotype. Nicotine induces specific epigenetic changes in the gonads and upper airway of the offspring for at least three generations. This is the first experimental evidence for true epigenetic transgenerational inheritance. The theory of Downward Causation attempts to establish the primacy of developmental control from the top-down, albeit with retained influences from the bottom-up, or from the “middle-out.” The former mechanism coincides with Darwinian evolution, whereas the latter mechanisms transcend spatio-temporal ontogeny and phylogeny in concert with the effects of environmental forces. As a vector of such forces, evolution would advance both horizontally and vertically from generation to generation, constantly gaining information from the environment in the process, as both epigenetics and terminal addition. Organisms go through their life cycles acquiring relevant epigenetic information from their surroundings, preparing the offspring to adapt to an ever-changing environment. Ontogeny and phylogeny provide the short-term and long-term “histories” of the organism, in conjunction with the unicellular zygote, as expressed during early embryogenesis, as a means of monitoring the homeostatic relevance of the acquired epigenetic “marks.”

7.6

Diachronic Signaling Mechanisms Link Development, Homeostasis and Regeneration

Growth and development during embryogenesis are mediated by paracrine growth factor-receptor signaling. Such signaling mechanisms generate the patterns for the form and function of tissues and organs. These data are best known for the lung because its development is existential for survival at the time of birth. In order to form an efficient, diffusible surface for gas exchange, the lung grows and differentiates, forming the conducting airways and alveoli, respectively; matched with a complementary vascular system. The key genes involved in lung development are highly conserved across phylogeny, at least as far back as the swim bladder of physostomous fish. Signaling by such “messengers” as the insulinlike growth factor, epidermal growth factor and transforming growth factor-β/bone morphogenetic protein pathways, extracellular matrix components and integrins all direct lung morphogenesis. The soluble growth factors secreted by lung mesoderm comprehensively induce lung morphogenesis, a phenomenon first reported by Clifford Grobstein.

7.7

Homeostasis, Agent for Change in the Vertebrate Water-land Transition as Emergence

Specific genes doubled during the vertebrate water-land transition, specifically the parathyroid hormone-related protein receptor, the β-adrenergic receptor and the glucocorticoid receptor. These amplified genes facilitated adaptation to land, giving rise to the respiratory, skeletal, kidney and skin functions that are necessary for terrestrial life. The doubling of these specific genes was not a merely random occurrence, as Darwinists have insisted. They were essential for survival to accommodate adaptation to land. When viewed in this context, particularly when genes are acknowledged as tools of the cell to maintain their homeostatic requirements, their appearance can be properly understood. Critical cellular structural and functional homeostasis was mediated during the water-land transition by cell–cell interactions causing microvascular shear stress generating radical oxygen species that caused the remodeling of specific tissues and organs, permitting the successful emergence of species from water to land.

7.8

Homeostasis as the Consequence of Developmental Mechanisms

Pre-adaptations, or exaptations, are frequently mentioned in the evolution literature. Typically, though, their use is applied from their ends, rather than through their actual means. The concept of exaptations, actually reduced by logical extension to the unicellular form as the origin of metazoans, is founded on perpetual ontogenetic and phylogenetic principles. With this insight, it can be reinforced that there is a continuum from the unicell to complex evolved traits. The primary impulse for such exaptations is the cellular drive to continuously adapt to an ever-changing environment as a perpetual process for the internalization of the environment that characterizes all of biology. These causal relationships have been robustly elucidated through previously documented stages of lung evolution. Through a regression of the operative genes that determine structure and function

during lung ontogeny and phylogeny against major epochs in the environment, the cellular adaptive mechanisms that can be directly attributed to physical forces can be identified. Such physical forces are mediated by physiologic stress, starting with the advent of the peroxisome as balancing selection for calcium dyshomeostasis. The lung is the optimal example of evolutionary changes in vertebrate visceral physiology during the water-land transition. In a water-dominated environment, there would have been no seeming alternatives to gill breathing. Yet, the swim bladder of physostomous fish was adaptive for gas exchange, albeit for buoyancy; and the lining cells of the bladder secrete cholesterol, the most primitive of all surfactants, which was necessary for the evolution of the alveoli of the lung. Hence, each of these prior adaptations extending forward from the unicell could be exapted for gas exchange. The specific implications of the three gene duplications that occurred during that transition permit a lesson to be learned, given that the vertebrate skeleton evolved at least five times, according to the fossil record. Such substantial structural modifications necessitated the co-evolution of the visceral organs needed for land adaptation. The glucocorticoid and β-adrenergic receptors likely duplicated in support of the latter since deletion of the parathyroid hormone-related protein gene results in defects of the lung (no alveoli), bone (failure to calcify) and skin (immature barrier). Thus, genetic modifications should be considered at the cellular level within their context of environmental stresses, provoking cellular solutions to cellular homeostatic problems. These are interactive solutions, not the product of random Darwinian point mutations. The physiologic stresses in transition from water to land were enormous. The concomitant microvascular shear force would have been greatest within the specific microvascular beds on which that transition was most dependent; that is, lung, bone and kidney. Vascular wall shear stress generates radical oxygen species that cause gene mutations and duplications in response to environmental stresses. Therefore, these can be categorized as “epigenetic” modifications. Necessarily, any such conditional epigenetic variations would either have allowed for adaptation, or the organism would have become extinct. Genetic remodeling of the alveolus for stretch-regulated parathyroid hormonerelated protein signaling had dual physiologically adaptational advantages: it off-set the stress of alveolar insufficiency by stimulating alveolar surfactant production; increased production of regulated parathyroid hormone-related protein produced more alveoli and alveolar capillaries. Duplication of the gene for the β-adrenergic receptor also occurred during the vertebrate water-land transition. That allowed for the independent regulation of alveolar capillary blood pressure, separately from systemic blood pressure. The advent of that physiologic trait may have resulted from the co-evolution of parathyroid hormone-related protein signaling in both the anterior pituitary and the adrenal cortex, increasing adrenocorticotropic hormone and glucocorticoid production, respectively. As a result, increased responsiveness to physiologic stress by the pituitary-adrenal axis (PAA) amplified adrenalin production, since the corticoids produced in the adrenal cortex pass through the adrenal medulla, where they physiologically stimulate the rate-limiting step in adrenalin production as phenylethanolamine-N-methyltransferase (PNMT). That adaptation to hypoxia was further ramified by the contemporaneous fluctuations in atmospheric oxygen over the course of the last 500 million years, ranging between 15% and 35%. The resulting increase in the amount of parathyroid hormone-related protein flowing

through the medulla would have promoted the formation of more vascular arcades in the mammalian adrenal medulla, further amplifying the adrenalin response to stress since parathyroid hormone-related protein is angiogenic. Over-expression of adrenalin transiently alleviated the limitation of the alveolus to oxygenate by increasing surfactant secretion, lowering alveolar surface tension, in combination with transiently increased blood flow due to parathyroid hormonerelated protein's potent vasodilatory effect. All of these pre-adapted physiologic traits were enlisted to optimize air breathing in the consistent maintenance of cellular homeostasis, as experienced at each concurring cellular level. The purpose of this coordination can be identified. It is the perpetual attempt by every cell to sustain its homeostatic equipoise. The duplication of the β-adrenergic receptor increased its frequency of expression and activity within the pulmonary circulation. That adaptation accommodated the evolving metabolic demand for an increase in lung surface area to facilitate gas exchange based on systemic allostatic mechanisms. The mineralocorticoid receptor evolved into the glucocorticoid receptor during this same epoch due to two gene mutations. That relieved the maladaptive elevation in blood pressure caused by the increased force of gravity on land, and constrained the evolution of the lung's surface area, as indicated above. Glucocorticoids are stimulators of beta-adrenergic receptors, which therefore express in synergy with the evolution of local alveolar blood pressure regulation and facilitated oxygen uptake. Validating the relevance of β-adrenergic receptors to land adaptation, blocking βadrenergic receptor signaling during embryonic mouse development inhibits normal heart development. Given that the lung evolved in parallel with the heart, from the one chamber in worms, to four in mammals, the expansion of lung surface area should not be surprising, since it had to accommodate increasing blood flow. Coordinated evolution of the lungs and heart by parathyroid hormone-related protein and β-adrenergic receptor gene duplications would have facilitated land habitation and led to further evolutionary adaptation through increases in gasexchange and improved blood pressure regulation under physiologic stress conditions. The evolution of the glomerulus from the primitive fish kidney glomus, having a primitive capillary system, was the consequence of the interactions between parathyroid hormone-related protein and the associated beta-receptor. Remodeling of the glomus resulted in homeostatic parathyroid hormone-related protein regulation of water and fluid balance by the mesangium, with the beta-adrenergic receptors regulating urinary output under stress.

7.9

Parathyroid Hormone-related Protein Regulation of Physiologic Stress

Parathyroid hormone-related protein plays an essential role in normal lung development. The deletion of parathyroid hormone-related protein from the embryonic mouse impairs lung alveolar formation. Similarly, any insult to the lung resulting in loss of alveoli correlates with decreased parathyroid hormone-related protein. Premature infants can develop chronic lung disease, termed bronchopulmonary dysplasia. This critical impairment of respiratory exchange can be related to a deficiency in parathyroid hormone-related protein, as measured in

lung fluid.

7.10 Parathyroid Hormone-related Protein Expression in Adrenal Corticoid Synthesis Parathyroid hormone-related protein is known to be expressed in the pituitary gland and stimulates cortisol in the adrenal cortex, which then stimulates adrenalin production by the adrenal medulla. This pathway may have evolved as a result of the water-land transition, whereby the lung would periodically have been unable to provide enough oxygen, causing hypoxia, which is the most potent physiologic agonist known. Stimulating adrenalin production increases surfactant secretion by the alveoli, transiently alleviating the stress on the lung. Such a mechanism may reference the Cenozoic era, when our rodent-like ancestors had to be agile and wary in order to avoid being eaten by predators. The aggregate stress on the microvasculature of the lung, pituitary and adrenal cortex may have caused the “remodeling” of all of these structures, including the adrenal medulla. The adrenal medulla evolved a complex arcade of blood vessels in mammals, amplifying adrenalin production in response to stress.

7.11 Diachronic Regulation of Homeostasis The key to understanding the evolutionary interrelationship between homeostasis and embryogenesis lies in their diachronic relationships across space-time. Growth factor signaling mediated the formation of structure and function during embryogenesis, culminating in the establishment of relative and adjustable homeostatic set-points. When these set-points have been challenged postnatally, the same signaling principles, emanating from their initiating context in embryogenesis, concurrently maintain homeostasis. Challenging the limits of homeostasis can result in growth factor signaling variations that can reference ancestral forms. This is the common biological pathway to fibrosis. Although this cellular response is commonly seen medically as pathology, it is better understood as a type of cellular adaptation to current environmental stresses by reaching backwards into the organism's evolutionary tool-kit (Miller and Torday, 2017; Torday and Miller, 2018). Under such conditions, organisms can adapt to less-than-favorable physiologic conditions. Those adaptive members of the species best suited for such harsh conditions pass their genes on to their offspring as successful cellular solutions to environmental stresses. When successful in populations, new, stable, heritable phenotypes are fixed in a genetic sense and can continue forward as the species phenotype. As a result, the relationship between embryogenesis and homeostasis, and phenotypic and phylogenetic change are all underpinned by a cellular-molecular continuum, mediated by growth factor signaling properties that are mechanistically common to all. In this way, the capacities of primitive cells to generate a sustainable internal environment using the cell membrane and endomembrane systems could be compartmentalized through evolutionary space-time as the basis of multicellular physiology. Translation of environmental stress into cellular remodeling based on the first principles of physiology – that is, negentropy, chemiosmosis and homeostasis – epitomizes the function of the cell. The recapitulation of this process from generation to generation, and the acquiring of new “knowledge” through

epigenetics, perpetuates each cellular domain in perpetuity (Miller and Torday, 2018).

7.12 Allostasis as Integrated Homeostasis The correct conceptualization of allostasis permits an understanding of homeostasis in its fullest form as a diachronic process that underlies all of biology. McEwen and Wingfield (2003) define allostasis as a process that supports homeostasis, through organism-wide “set-points” within boundaries of control that must dynamically change for physiologic and/or life history stages to achieve stability. That homeostasis is essential for the life of individual cells, which aggregate as allostasis to maintain these individual systems in organism-wide balance. Importantly, homeostasis began with the first cells, just as it defines the unicellular realm today. The persistent Darwinian concept of downward causation is based on a fallacy that it is the adult form that dominates. Instead, evolution can only be understood as a continuum that emanates from the unicellular state. At each ensuing cellular level within complex multicellular organisms, homeostasis is maintained through repetitive reiterations of cellular capacities that enable multicellular life at the successive living levels of cellular ecologies, organs, and entire organisms. Each has its independent functions and all are parts of a coordinated whole. At all times, those properties that we ourselves ascribe to allostasis are higher-level expressions of the same homeostatic principles expressed at the cellular, tissue and organ levels. Seen in light of life as a continuum of cell–cell signaling, allostasis takes on a very different set of characteristics from its conventional appraisal. As opposed to contented equilibrium, stress can have short-term effects that might be physiologically beneficial for the health of an organism or its reproductive strategy. Necessarily, the opposite can also be the case. For example, small-for-gestation birth causes accelerated morbidity in longitudinal studies (Giapros et al., 2012). It has been postulated that precocious aging and death occur after premature birth because of an interruption of normal cellular development and an impairment in cell–cell signaling (Smith et al., 2010). Our vantage point of evolutionary development and allostasis is further skewed by focusing on the pathology of allostasis. As an example, the role of the production of androgens by the adrenal cortex is not understood, nor is its exact relationship to phenomena such as premature adrenarche as precocious puberty. It is known that there is a significant association of this phenomenon to intrauterine growth retardation (IUGR). Counter intuitively, this can lead, in later life, to overweight children, even though it is defined by being underweight for chronological age. Those mechanisms that yield an early reaction in puberty to low food abundance during gestation are unknown. Nonetheless, it can be supposed that as a biologically relevant response, it is rooted in adaptation. It may be that from a cellular perspective, early sexual maturation of the offspring makes it possible for the offspring in the next generation to move to an environment of greater food abundance as the environment inevitably cycles.

7.13 Conclusions The still-dominant narrative of evolution based on selection has shown little interest in the first principles of physiology. Yet, a deep understanding of these elemental forces is of critical importance to our effective utilization of genomic information.

The limitations of science have been well pointed out by both Duhem and W.O.V. Quine. Quine commented that “knowledge is a man-made fabric which impinges on experience only along the edges,” and that “a conflict with experience at the periphery occasions readjustments in the interior of the field.” The cellularmolecular approach to biological development and evolution permits a robust interrogation of that “interior” field. Cellular life is centered within perpetual stipulations to maintain its homeostatic equipoise, despite any and all environmental threats through common eternal connections to the Singularity.

References Bernard C., (2012, ), Introduction to the Study of Experimental Medicine, Mineola: Dover. Cannon W. B., (1963, ), The Wisdom of the Body, New York: WW Norton. Carpinello O. J., DeCherney A. H. and Hill M. J., Developmental Origins of Health and Disease: The History of the Barker Hypothesis and Assisted Reproductive Technology, Semin. Reprod. Med., 2018, 36, 177–182. Giapros V., Drougia A., Krallis N., Theocharis P. and Andronikou S., Morbidity and mortality patterns in small-for-gestational age infants born preterm, J. Matern.-Fetal Neonat. Med., 2012, 25, 153–157. Jacob F., Evolution and tinkering, Science, 1977, 196, 1161–1166. Kirschner M. W. and Gerhart J. C., (2005, ), The Plausibility of Life, New Haven: Yale University Press. McEwen B. S. and Wingfield J. C., The concept of allostasis in biology and biomedicine, Horm. Behav., 2003, 43, 2–15. Miller Jr W. B. and Torday J. S., Four Domains: The Fundamental Unicell and Post-Darwinian Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2018, 140, 49–73. Noble D., (2008, ), The Music of Life, Oxford: OUP Oxford. Reid R. G. B., (1985, ), Evolutionary Theory—The Unfinished Synthesis, New York: Springer. Smith L. J., McKay K. O., van Asperen P. P., Selvadurai H. and Fitzgerald D. A., Normal development of the lung and premature birth, Paediatr. Respir. Rev., 2010, 11, 135–142. Torday J. S. and Miller W. B., Biologic relativity: Who is the observer and what is observed?, Prog. Biophys. Mol. Biol., 2016a, 121, 29–34. Torday J. S. and Miller Jr W. B., Phenotype as Agent for Epigenetic Inheritance, Biology, 2016b, 5(3), 30. Torday J. S. and Miller Jr W. B., The resolution of ambiguity as the basis for life: A cellular bridge between Western reductionism and Eastern holism, Prog. Biophys. Mol. Biol., 2017, 131, 288–297. Torday J. S. and Miller W. B., A systems approach to physiologic evolution: From micelles to consciousness, J. Cell. Physiol., 2018, 233, 162–167. Waddington C. H., (1957, ), The Strategy of the Genes, London: Routledge.

CHAPTER 8

Networking from the Cell to Quantum Mechanics as Consciousness A series of peer-reviewed journal articles (Torday and Rehan, 2007; Torday, 2013; Torday, 2015a, 2015b, 2015c; Torday, 2018) and monographs (Torday and Rehan, 2012; Torday and Rehan, 2017) has illustrated how cell–cell signaling for form and function during embryologic development can be exploited to determine the evolution of such processes. This is most particularly the case when the mechanisms of development are identified as the source of phylogenetic changes in physiologic traits such as the lung, kidney, skin and bone. This diachronic, or transcendent-across-space–time way of deconvoluting evolution, made it possible to trace the changes in the gas-exchanger (Maina, 2002) back to the unicellular state by identifying the advent of cholesterol as the mechanism for protecting the cell against rising levels of oxygen in the environment (Torday and Rehan, 2016). The principle of pre-adaptation, or exaptation (Gould and Vrba, 1982) can then be applied to interpret the process further. Doing so emphasizes the crucial role of lipids in forming the first protocell to generate micelles (Deamer, 2017) as the means toward the instantiation of life as an essential pre-condition for the living state. Nor is it the sole requirement. The living state begins with the self-referential state (Igamberdiev, 2004; Shapiro, 2011; Miller, 2016; Miller, 2017; Miller and Torday, 2019; Miller et al., 2019) and selforganization (Jantsch, 1980). Yet, although acknowledged, there has been no mechanistic way of expressing the “how and why” of those properties. One explanation has been to consider self-reference as a physical recoil, due to Newton's third law of motion, as a consequence of the Singularity/Big Bang. It is absolutely established that for every action there is an equal and opposite reaction (School Mathematics Project, 1993). If so, then an argument can be advanced that the essential qualities of self-reference and self-organization were founded from within the Singularity as its instantiating point of reference (Hawking, 1998). It may be helpful at this point to contrast the diachronic approach to consciousness being advocated herein with a well-known alternative, the concept put forward by Hameroff and Penrose. They have written extensively about the nature and origin of consciousness (Hameroff and Penrose, 2014). Knowing full well that consciousness is more than just the sum of its parts, their perception is that this state is exerted from within synchronic calcium fluxes that mediate neuronal transmission. Given that even unicellular organisms can be deemed cognitive (Lyon, 2015; Miller, 2016; Miller, 2017; Reber, 2018), the process must be more than just neuronal transduction, as the pre-eminent neurophysiologist Sherrington pointed out. Penrose (Penrose, 2001) has hypothesized that the organizational principle of the brain is based on cytoskeletal microtubules acting to coordinate the data being processed. Yet, the cells of the visceral organs also possess cytoskeletons

with microtubules, so given that, there is every reason to think that there is crosstalk between the body and mind during consciousness, the more so since all cells have their own form of self-awareness (Miller, 2016). Therefore, it can be considered that consciousness is the aggregate of our physiology according to the following pathway. If it is assumed that there is a continuum from contemporary physiology that extends back to the Singularity/Big Bang, then a parallel opportunity opens for a novel mechanistic understanding of the relationship between evolutionary biology and the Singularity/Big Bang as consciousness (see Figure 8.1).

Figure 8.1

The Singularity/Big Bang, the cosmos and consciousness. The Singularity/Big Bang gave rise to the cosmos (top). Subsequently, endogenization of physical factors gave rise to physiology. The aggregate of physiology is what we recognize as consciousness.

This alternative narrative transcends the conventional way in which consciousness is presumed as merely perception or awareness of one's surroundings. Instead, based on physiological mechanisms, an alternative holistic view of consciousness can be advanced as its being at the foundation of the planetary consciousness that might further relate to a universal cosmic consciousness (Bucke, 2007). The advantage of this viewpoint is that it allows for a comprehensive view that both physiology and consciousness are more than just the sum of their parts (Weibel, 2000), transcending space and time by a continuous referencing of the Singularity/Big Bang. If consciousness is thought of in cosmologic terms, it can be considered as the combination of physics, chemistry and biology. This potentially answers the socalled “hard problem” of how and why we conceive of things in the ways that we do (Chalmers, 1995). Chalmers distinguishes two elements within consciousness: (a) an “easy” problem that represents some ability or the performance of some function or behavior based on the bioactive molecules that permit those faculties that are subject to direct interrogation through conventional anatomic and physiological studies; and (b) a separate “hard” problem, which is the mystery of

why and how sensory information can be experienced to form our self-referential appreciation of its abstractness. It is this ineffable “qualia,” or intrinsic selfreferential quality of consciousness that can be satisfied by extending consciousness back to the Singularity/Big Bang as a comprehensive state of being. Therefore, a panpsychic perspective in which both animate and inanimate are “conscious” can, at least theoretically, be entertained. It is argued that such an integrated, holistic way of approaching consciousness as the awareness of an encompassing realm of existence would be intellectually selfsatisfying. However, without the opportunity to test the hypothesis, it could remain highly speculative and easily categorized and rejected as a tautology. In actuality, this conceptualization has serendipitously been experimentally tested to some degree. When yeast are exposed to microgravity, their ability to polarize is diminished, with a loss of orientation that, at least initially, leads to a decrease in their ability to bud or reproduce. The loss of such functions renders the organism less responsive to normal stimuli, or in a relative form of suspended animation, which is believed to be due to a decreased ability to mediate calcium fluxes. It is possible that this is a critical component of our conscious being. When lung or bone cells are put into a microgravitational environment, they lose their capacity for the cell–cell signaling that maintains homeostatic control because their parathyroid hormone-related protein (PTHrP) expression declines. PTHrP is necessary for the specific maintenance of both lung and bone phenotypes (Torday and Rehan, 2003). It is likely that these terrestrial traits were instituted during the vertebrate water–land transition, brought about by the “greenhouse effect” of rising carbon dioxide levels in the atmosphere, since the PTHrP signaling pathway was duplicated or amplified, during this period (Pinheiro et al., 2012). This affected a host of existential land-adaptive functions, such as the skeleton, lungs, kidneys and skin. The cause-effect nature of these properties is shown by the experimental deletion of the PTHrP gene in embryonic mice, affecting all of these physiologic traits in a way that is comparable to their developmental and phylogenetic evolution (Philbrick, 1998; Karaplis and Goltzman, 2000; Rubin et al., 2004; Hochane et al., 2013). Other gene duplications such as the β-adrenergic receptor and glucocorticoid receptor also occurred during that same period, playing a critical role in the mitigation of physiologic stress in the adaptation of vertebrates to land during that epoch, as has been previously attested. The orchestration of such complex physiology could not have occurred merely by random mutations based on the observation that, under stress, the process of evolution is “reversible” (Guex, 2016). This runs counter to neo-Darwinian evolutionary theory, which is based on random mutations. If evolutionary variations were indeed random, there would be fluid pathway to permit an evolutionary reversal to gain access to beneficial exaptations (Guex et al., 2020). The monitoring of such integrated physiology for stability and change is ascribed to homeostasis at the level of an individual cell and, at the level of aggregated cells, as allostasis as an organism-wide phenomenon. Yet, there must be some underlying mechanism to account for such control. This mechanism has been identified as the first principles of physiology (i.e. negentropy, chemiosmosis and homeostasis). In concerted action, these act as a fundamental reference point for the integration and organization of all cellular processes. The cytoskeleton participates in the reproductive phenotypic status of the cell, crucial to homeostatic, mitotic or meiotic processes. The target of rapamycin (TOR)

gene is physically connected to the cytoskeleton, making it responsive to physical perturbations. TOR controls all physiologic aspects of cell function – metabolism, ion concentrations, mechanotransduction and oxidants – providing a mechanistic explanation for TOR's global role in the state of the cell. The TOR gene is widely expressed in a variety of species, such as yeast (Zhang et al., 2018), Dictyostelium (Rosel et al., 2012), Drosophila (Zhang et al., 2006) and mammals (Dobashi et al., 2011). Because of its central role in integrating both an organism's external and internal environments, it can be productively argued that the cytoskeleton/TOR complex acts as one aspect of the cell's consciousness in being a comprehensive sensing mechanism. It can then be further considered that this becomes an interactive physical sensor, and through its crucial role in reacting to gravity, extends its relationship beyond physiology to cosmology as a theoretical source of consciousness. A pathway exists from TOR to homeostasis at the level of individual cells, to allostasis at the level of local tissue ecologies, to an entire organism. Allostatic homeostasis can thus be considered a process that relates to a perceptual consciousness of the whole organism itself. At least in part, this might be mediated by evolved pleiotropic (when one gene influences two or more seemingly unrelated phenotypic traits) relationships within and between the visceral organs, and between the viscera and central nervous system (Torday, 2015a; Torday, 2018). It is now posited that networked genes can form electrochemical fields through which they share information; as such, this provides a mechanistic pathway towards the type of communal consciousness that describes human social systems as described by Christakis's group theories (2010). When these same types of interactions summate, it can be proposed that this same mechanism provides those further connections that blanket the Earth as niche constructions, ultimately adding up to Gaia and, beyond that, to the cosmos as a homology with consciousness (Bucke, 2007, Goswami, 1990, Swimme, Freke, Frankl) due to self-referential, self-organizing consciousness, which is enabled through the first principles of physiology (see Figure 8.2).

Figure 8.2

From first principles of physiology (FPPs) to the cosmos. Starting from the FPPs (at the far left), the first cell formed a niche construction that was the basis for ecosystems that then formed Gaia, and ultimately the cosmos as a homology with consciousness.

Miller et al. (2019) have furthered this concept. They postulated that there is a unifying referential information-space that enables the varied species that constitute a holobiont to effectively measure environmental cues. In this way, all living organisms represent this type of summation. It has been rightly argued that the physiologic properties of the cell are the product of the continuous endogenization of the external environment (Bloom,

Evans and Mouritsen, 1991; Gray, 2017; Gabaldon and Pittis, 2015; Torday and Rehan, 2012; Miller, 2016). If so, this would be the means by which quantum mechanics becomes biological action. Such properties as the Pauli exclusion principle, Heisenberg's uncertainty principle, non-localization, coherence, entanglement and electrochemical fields show homology with biologic properties. It has been difficult to identify such homologies until now, but the reduction of biology and evolution to cell networks formed during embryonic development offers the opportunity to interconnect it with the interactive aspects of quantum mechanics (QM) in much the same manner as Lee Smolin has described homologies between cosmology and Darwinism (Smolin, 1997). Consciousness is conventionally thought of as the process of being aware of ourselves and our surroundings. Yet there is also the awareness of something “greater than ourselves” that drives us to be and do more than just exist (Frankl, Bucke, 2007, De Chardin, Gurdjieff, Swimme, Freke, Goswami 1990). That sense may come from the above integration of quantum mechanics and cellular physiology as the origins of life through self-reference. Others have alluded to such a continuum, but have not offered a mechanistic way of understanding it in terms that are scientifically testable and refutable as would be required if it is to be evidence-based. Our physiologic evolution offers another way to re-envision our path to consciousness. The emergence of endothermy/homeothermy has been reconceptualized as the consequence of the physiologic stress experienced during the water-land transition (Torday, 2015a). The evolution of endothermy facilitated bipedalism since it requires more energy to stand on two legs. That in turn freed the forelimbs for specializations such as flight in birds, and tool-making in humans. The convergence of lung evolution and endothermy is consistent with the phylogenetic appearance of key intermediates in this cascade, such as PTHrP signaling in both the anterior pituitary and adrenal cortex, with increased vascularization of the adrenal medulla (Wurtman, 2002), and step-wise concomitant changes in the composition of lung surfactant, rendering it more physiologically bio-active at 41 °C than at 25 °C (Daniels et al., 1998). This conjecture is strengthened by realizing that decreased cholinergic regulation during hibernation or meditation can be considered the physiological inverse of the fight or flight mechanism, which directly reciprocates with consciousness (Torday, 2015a). If so, this provides a physiological link between the evolution of endothermy and consciousness. It can, therefore, be proposed that the vertically integrated physiologic changes that evolved endothermy are functionally linked to consciousness through Hobson and Friston's concept of “brain cooling” as the mechanism by which experiences are internalized (2012). Hobson and Friston have found that there is a need to suspend homeothermy during rapid eye movement sleep, and have speculated that “sleep is an optimization process that is disclosed by the nightly removal of sensory perturbations; in other words, the brain can take itself off-line with impunity, so that synaptic plasticity and homoeostasis” (Gilestro et al., 2009) can reduce the complexity it has accrued during wakefulness. Similarly, in tandem with the phylogenetic evolution of endothermy, Porges has hypothesized the polyvagal theory (1995), which recounts the phylogenetic progression from the vegetal to the fully functional vagus. In this way, behavioral changes rising up from the gut to the brain are mediated phylogenetically by the myelination of the vagus. Thus, the evolution of the autonomic nervous system intersects mechanistically with the evolution of endothermy via the expression of PTHrP in Schwann cells, stimulating neuregulin, which is the only documented

mechanism for myelination. Viktor Frankl's logotherapy expresses the need for us to believe that there is something bigger than ourselves, and being “conscious” of something greater than ourselves, as expressed by such authors as Swimme, Freke, Goswammi, Bucke, De Chardin, and Gurdjieff. This is typically framed in religious terms, but perhaps religion is a subset of what “something bigger than one's self” really means. By connecting the consciousness of perception with being conscious of the cosmos through physiologic evolution as the internalization of the external environment and its functional utilization, we gain insight to what being “conscious” means. In effect, as cellular beings, we are continually internalizing the exterior environment through homeostasis and adaptation. Although the actual process is occurring at the level of individual cells, we still experience it as complete beings as part of organism-wide allostasis. This becomes, at least in theory, a subjective connection, channeled through our human type of abstraction, to a “sense of oneness with something greater,” as a reiterative connection to the cosmos as its own form of endogenization. This deep understanding of the interrelationship between physiology and consciousness becomes tangible when it is realized that there are first principles of physiology that are the bioactive means by which quantum mechanics is actualized through the cell. And it must be emphasized that this interrelationship between cosmology, physics and physiology cannot be understood until the conventional synchronic way of thinking about physiology is superseded by a diachronic perspective that factors out the artifact of time from the process. It has been previously argued that evolution is the process of sustaining the unicellular form in perpetuity (Miller and Torday, 2018). Thus, the unicell is the epitomic process, and what we think of as “biologic diversification” is merely the result of “the phenotype as agent,” coping with an ever-changing environment. As “proof of principle,” it can be argued that this is this reason why there is an obligatory return to the unicellular state over the course of the eukaryotic life cycle. As disturbing as it might seem, it can be argued that, in fact, we never actually leave it. Like the Red Queen in Alice in Wonderland, we are running as fast as we can to remain in place in order to abide by the first principles of physiology. These are consistently reinforced through the experiences of the macro-organism through its extension into the environment through its phenotypic complement. When all this is taken together, epigenetic experiences that accumulate and express in an organism, whether immediately or in successive generations, can be viewed as attempts to internalize the environment in order to remain consilient with a greater cosmic consciousness. When biology is reduced to a network of cell–cell signaling among selfreferential agents, evolution can be traced as a continuum. Perhaps it began with the cytoskeleton of the unicell, and then progressed to the homeostatic and allostatic physiologic interrelationships between cells that are generated during embryogenesis. From there, it might have proceeded to communal networks like those described by Nicholas Christakis, who theorized that this is due to his “contagion theory.” From there, it can be enlarged towards the Darwinian interrelationships between cosmic phenomena like black holes and stellar evolution, formulated by Lee Smolin (Smolin, 1997). Yet, even this progression is still lacking. Instead, a new beginning must be envisioned: all interrelationships are due to the common derivation of the physical and the biological from the Singularity (Torday, 2019). Seen from the conventional perspective, consciousness is an enigmatic entity,

independent of other physiologic functions, just as Descartes had stated it as the mind-body duality several centuries ago. But now, in the twenty-first century, with the knowledge of physiology from its developmental and phylogenetic evolutionary origins, consciousness can be understood to be integral to physiology, the nervous system and the visceral organs. All have co-evolved under the aegis of consciousness (Miller et al., 2019). When consciousness is understood to be life's initiating factor, holistic physiology is more than just the synchronic sum of its parts. Instead, it transcends space and time with a perpetual attachment to the Singularity. There is more to this than an evolutionary perspective. This is practical knowledge since this informed optic energizes novel thoughts about human disease, and opens new pathways to their treatment and the alleviation of suffering. And it also offers something even more profound. From this enlightened perspective, our perpetual individual links to the cosmos are revealed, and our place among Earth's creatures is refined – with humans as interfaces, not overlords – as a fellow traveler in an environmental continuum that enforces elemental equality among all planetary creatures in a potential universal narrative of cosmic consciousness.

References Bloom M., Evans E. and Mouritsen O., Physical properties of the fluid lipidbilayer component of cell membranes: A perspective, Q. Rev. Biophys., 1991, 24(3), 293–397. Bucke R. M., (2007, ), Cosmic Consciousness, New York: Cosimo Classics. Chalmers D., Facing up to the problem of consciousness, J. Conscious. Stud., 1995, 2, 2002–2019. Daniels C. B., Lopatko O. V. and Orgeig S., Evolution of surface activity related functions of vertebrate pulmonary surfactant, Clin. Exp. Pharmacol. Physiol., 1998, 25, 716–721. Deamer D., The Role of Lipid Membranes in Life's Origin, Life, 2017, 7(1), 5. De Chardin T., (1999, ), The Human Phenomenon, Brighton: Sussex Academic Press. Dobashi Y., Watanabe Y., Miwa C., Suzuki S. and Koyama S., Mammalian target of rapamycin: a central node of complex signaling cascades, Int. J. Clin. Exp. Pathol., 2011, 4, 476–495. Frankl V., (2006, ), Man's Search for Meaning, Boston: Beacon Press. Freke T., (2017, ), Soul Story, London: Watkins Publishing. Gabaldón T. and Pittis A. A., Origin and evolution of metabolic sub-cellular compartmentalization in eukaryotes, Biochimie, 2015, 119, 262–268. Gilestro G. F., Tononi G. and Cirelli C., Widespread changes in synaptic markers as a function of sleep and wakefulness in Drosophila, Science, 2009, 324, 109– 112. Goswami A., Consciousness in quantum physics and the mind-body problem, J. Mind Behav., 1990, 11, 75–96. Gould S. J. and Vrba E. S., Exaptation—a missing term in the science of form, Paleobiology, 1982, 8, 4–15. Gray M. W., Lynn Margulis and the endosymbiont hypothesis: 50 years later, Mol. Biol. Cell, 2017, 28, 1285–1287. Guex J., (2016, ), Retrograde Evolution During Major Extinction Crises, New York: Springer.

Guex J., Torday J. S. and Miller Jr. W. B., (2020, ), Morphogenesis, Environmental Stress and Reverse Evolution, New York : Springer, (in press). Needleman J. and Baker G., (2004, ), Gurdjieff, New York: Continuum. Hameroff S. and Penrose R., Consciousness in the universe: a review of the ‘Orch OR’ theory, Phys. Life Rev., 2014, 11, 39–78. Hawking S., (1998, ), A Brief History of Time, New York: Bantam. Hochane M., Raison D., Coquard C., Imhoff O., Massfelder T., Moulin B., Helwig J. J. and Barthelmebs M., Parathyroid hormone-related protein is a mitogenic and a survival factor of mesangial cells from male mice: role of intracrine and paracrine pathways, Endocrinology, 2013, 154, 853–864. Igamberdiev A. U., Quantum computation, non-demolition measurements, and reflective control in living systems, BioSystems, 2004, 77, 47–56. Jantsch E., (1980, ), The Self-Organizing Universe, Oxford: Pergamon. Karaplis A. C. and Goltzman D., PTH and PTHrP effects on the skeleton, Rev. Endocr. Metab. Disord., 2000, 1, 331–335341. Lyon P., The cognitive cell: bacterial behavior reconsidered, Front. Microbiol., 2015, 6, 264. Maina J. N., Fundamental structural aspects and features in the bioengineering of the gas exchangers: comparative perspectives, Adv. Anat., Embryol. Cell Biol., 2002, 163, 1–108. Miller Jr. W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016, 4, 96. Miller Jr. W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Miller Jr. W. B. and Torday J. S., Four Domains: The Fundamental Unicell and Post-Darwinian Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2018, 140, 49–73. Miller Jr. W. B. and Torday J. S., Reappraising the exteriorization of the mammalian testes through evolutionary physiology, Commun. Integr. Biol., 2019, 12, 38–54. Miller Jr. W. B., Torday J. S. and Baluška F., Biological evolution as the defense of ‘self’, Prog. Biophys. Mol. Biol., 2019, 142, 54–74. Penrose R., Consciousness, the brain, and spacetime geometry: an addendum. Some new developments on the Orch OR model for consciousness, Ann. N. Y. Acad. Sci., 2001, 929, 105–110. Philbrick W. M., Parathyroid hormone-related protein is a developmental regulatory molecule, Eur. J. Oral Sci., 1998, 106, 32–37. Pinheiro P. L., Cardoso J. C., Power D. M. and Canário A. V., Functional characterization and evolution of PTH/PTHrP receptors: insights from the chicken, BMC Evol. Biol., 2012, 12, 110. Porges S. W., Orienting in a defensive world: mammalian modifications of our evolutionary heritage. A Polyvagal Theory, Psychophysiology, 1995, 32, 301– 318. Reber A., (2018, ), The First Minds, Oxford: Oxford University Press. Rosel D., Khurana T., Majithia A., Huang X., Bhandari R. and Kimmel A. R., TOR complex 2 (TORC2) in Dictyostelium suppresses phagocytic nutrient capture independently of TORC1-mediated nutrient sensing, J. Cell Sci., 2012, 125, 37–48. Rubin L. P., Kovacs C. S., De Paepe M. E., Tsai S. W., Torday J. S. and Kronenberg H. M., Arrested pulmonary alveolar cytodifferentiation and

defective surfactant synthesis in mice missing the gene for parathyroid hormone-related protein, Dev. Dyn., 2004, 230, 278–289. Shapiro J. A., (2011, ), Evolution: A View from the 21st Century, Upper Saddle River: FT Press. Smolin L., (1997, ), The Life of the Cosmos, Oxford: Oxford University Press. Swimme B. T., (2019, ), Hidden heart of the Cosmos, New York: Orbis. Torday J. S., Evolutionary biology redux, Perspect. Biol. Med., 2013, 56, 455– 484. Torday J. S., A central theory of biology, Med. Hypotheses, 2015a, 85, 49–57. Torday J. S., Homeostasis as the Mechanism of Evolution, Biology, 2015b, 4, 573–590. Torday J. S., Pleiotropy as the Mechanism for Evolving Novelty: Same Signal, Different Result, Biology, 2015c, 4, 443–459. Torday J. S., Quantum Mechanics predicts evolutionary biology, Prog. Biophys. Mol. Biol., 2018, 135, 11–15. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S. and Rehan V. K., Mechanotransduction determines the structure and function of lung and bone: a theoretical model for the pathophysiology of chronic disease, Cell Biochem. Biophys., 2003, 37, 235–246. Torday J. S. and Rehan V. K., The evolutionary continuum from lung development to homeostasis and repair, Am. J. Physiol.: Lung Cell. Mol. Physiol., 2007, 292, L608–L611. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology: Cell–Cell Communication, and Complex Disease, Hoboken: Wiley. Torday J. S. and Rehan V. K., On the evolution of the pulmonary alveolar lipofibroblast, Exp. Cell Res., 2016, 340, 215–219. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, Hoboken: Wiley. Weibel E. R., (2000, ), Symmorphosis, Cambridge: Harvard University Press. Wurtman R. J., Stress and the adrenocortical control of epinephrine synthesis, Metabolism, 2002, 51(6), 11–14. Zhang Y., Billington Jr. C. J., Pan D. and Neufeld T. P., Drosophila target of rapamycin kinase functions as a multimer, Genetics, 2006, 172, 355–362. Zhang Y., Chen G., Gu Z., Sun H., Karaplis A., Goltzman D. and Miao D., DNA damage checkpoint pathway modulates the regulation of skeletal growth and osteoblastic bone formation by parathyroid hormone-related peptide, Int. J. Biol. Sci., 2018, 14, 508–517.

CHAPTER 9

On Cellular Cooperativity as the Basis for Moral Behavior 9.1

Introduction

There is an integral relationship between physics, chemistry and biology, beginning with the formation of the first cell, derived from the lipids delivered by snowballlike asteroids during the formation of earth's oceans. Lipids naturally form cell-like structures, referred to as micelles, when they are immersed in water. Such semipermeable, membrane-bound spheres generate bioenergy through chemiosmosis, maintaining a reduced state of entropy within themselves, which Schrodinger (1944) referred to as negentropy. This negentropic internal state is more ordered than the outer environment, and is controlled by the dynamic of homeostasis. The origin of the cell is not known, but it can be considered to be a natural consequence of the Singularity (Torday, 2019). According to Newton's third law, every action imposes an equal and opposite force. In reaction to the Big Bang, a countervailing reaction would be expected as a response to the increase of entropy by universal inflation. This reaction might be considered to be the origin of intracellular negentropy. This state would then be reinforced through the continuous influence of the initiating first principles of physiology (FPPs) (i.e. negentropy, chemiosmosis and homeostasis). Since homeostasis is a dynamic process around relative setpoints, and is not itself fixed, it can be supposed that this could be the very beginning of free will, which becomes its own form in human expression. Physics, too, has its own dynamical relationship that can be considered relevant to the mystery of free will. Based on the Pauli exclusion principle, no two electrons in a poly-electron atom can have the same values for their four quantum numbers; the first three quantum numbers are deterministic, whereas the fourth is probabilistic. Thus, there are fundamental roots that extend from the Singularity that can be considered as foundational for our own idiosyncratic human behaviors, which necessarily impact on our moral stances. The premise of this chapter is that moral behavior is founded in the fundamental principles of our cellular origin and the way in which we perpetuate ourselves through evolutionary mechanisms. The British philosopher Derek Parfit was featured in a biographical Profile in the New Yorker magazine in 2011 (MacFarquhar). The article was entitled “How to be Good.” Parfit expressed his frustration with trying to reconcile Darwinism and empathy – how do you countenance “survival of the fittest” and behave decently at the same time? This lack of moral consequence is also encountered in the Robert Trivers’ idea that life is full of deceptions, both of the self and of others. In The Better Angels of Our Nature, Steven Pinker (2011) attempts a different answer, ascribing it to the difference between an innate understanding of “right and wrong,” which is consistently challenged through confrontation with our individual interpretations of morality. Yet, any of these seeming paradoxes can be ascribed to

our lack of understanding of the exact conditions of our origins, and the means we have devised to cope with those ambiguous beginnings. From this cellular perspective, the answer to the question of the basis of morality emerges. It is a derivative of multicellular metabolic cooperativity.

9.2

Our Physiology, Ourselves

Unicellular organisms dominated the Earth for the first 3.3 billion years. Billions of years ago, unicellular prokaryotes began forming biofilms, as vast complex aggregates of cooperative cells linked through abundant communication pathways as quorum sensing. These biofilms were not homogenous cell-types. Most biofilms were cooperative matrices of co-dependent microbes of varying species derived from each of the three cellular domains (Prokaryota, Archaea, Eukaryota), just as they are now. Beginning about half a billion years ago, true eukaryotic multicellularity developed. Through increasingly sophisticated cell–cell signaling mechanisms, linked sub-specialized cellular ecologies formed the reciprocating physiologic systems of metabolism, respiration and locomotion, as well as the differing types of conscious behaviors typical of individual types of plants and animals (Miller, 2016; Miller et al., 2019). It follows that all of our physiological capacities are the result of highly developed cellular systems of cooperation. Their combined purpose is the protection of their individual self-identities, which is best accomplished in the multicellular form, and consistently maintained through the active endogenization of the external environment to assure continued survival (Miller et al., 2019). From within these roots, our human manifestations of mind, which are intimately linked to our physiology, travel through pathways of cell–cell communication to emerge as our specific type of cognitive abilities, which also encompasses our moral sensibilities. If this can be granted, what then are those fundamental cellular roots? Certainly, in that hierarchy, the requirement to maintain homeostatic equipoise is an absolute living cellular constraint. It can be supposed that this has an equivalence at our entire human level to be a part of a human moral sensibility, which imposes its own form of self-restraint. To better understand this, it should be reinforced that, within a cognitive frame, homeostasis should be considered a preferential state, even at the level of individual cells (Miller, 2013). This position can be justified since homeostasis is quite directly the defense of self-referential integrity. In can then be generalized that this same sensibility, which is plainly evident at the level of individual cells, can aggregate to an organism-wide level as preferential allostasis that reflects a positive discriminatory status for the entirety. With that as background, when our own human intellectual gifts are superimposed, including our particular faculty for abstraction, it can be defended that this allostatic preferential sense becomes a social compact among like-minded organisms, which can be likened to “Extended Mind.” It follows that this issue of cellular homeostasis naturally intersects with free will. Again, homeostasis is not a fixed level, but a dynamical variation around relative set-points. There are absolute limits, but considerable conditional variability is an obvious feature of any homeostatic dynamic. Indeed, this cellular feature again matches our human moral proclivities, which include some areas of strict moral authority, and other areas in which morality is conditional. In this way, basic cellular dynamics link to human choices along physiological pathways. From this base, then, it would no longer seem surprising that for individuals, and even societies, morality has its ambiguities. For

example, what we as individuals might do in war would not be deemed moral in peace-time. At all times, our own human sense of morality matches a natural order that determines the conditional circumstances of our cellular constituents. It begins with the reality that all biological information is ambiguous and requires interpretation. Obviously, such is the case for all environmental cues. But even further, the physical world, too, has its own innate ambiguities. These can be expressed by the basics of quantum theory, such as the Heisenberg uncertainty principle. From these inviolable influences, human morality might be considered a fractal form of cosmic homology.

9.3

Morality as the Unicell Ascribing to the Laws of Nature

Memory is necessary for evolution, providing pre-adaptive or exaptive options under environmental stress, always with reference to the first principles of physiology as the fundament of the cell. When micelles as protocells first formed, they established elemental relationships between thermoregulation, memory and evolution. These micelles formed from the lipids present on the asteroids that helped form the Earth's primordial ocean. Such micelles would have been warmed by the sun, causing them to liquify and deform; conversely, at night, absent heat, they would have solidified, re-establishing their original form due to hysteresis, or “molecular memory.” Any evolutionary process must therefore reflect this initiating, reciprocating path between thermoregulation and memory, which then became essential to all cellular life. There is no doubt that this pathway is always at work. Hobson et al. (2014) have found that there is a phenomenon of “brain cooling” during rapid eye movement sleep. Any “higher” consciousness, including our human moral stances, therefore must have deep roots within the most primitive aspects of cellular physiology, all of which, in turn, ultimately reference the Singularity. It defaults that those initiating governing relationships form essential components of moral order, sensed by us or not. Having established a set of initiating rules to establish the cellular form, the cell was able to achieve enduring complexity by being the first niche construction (Torday, 2016). It was in this manner that the base cell established the fundamental evolutionary pattern of assimilating environmental factors that might pose an existential threat. By doing so, they were rendered useful as physiologic properties. This process, which began with the first cells, has reiterated over evolutionary space-time. It thus provides a mechanistic explanation for the integration of individual cellular physiology to entire ecologic connections. It is through this type of interface between individual cells and cooperative groups as reiterating instances of mutualizing niche construction that a pathway towards a consonant sense of a moral code can travel, transcending the individual to become a collective biological imperative. It is this transcendent quality of the most elemental cellular principles, always remaining consonant with the basic physical laws of quantum mechanics (Torday, 2018, Torday and Miller, 2016) that can be envisioned as the first stepping stones towards human moral behavior, if theological considerations are put aside. Murray Bookchin, a social philosopher, devised the concept of social ecology, appealing to our sense of oneness with the world, giving rise to the environmental green movement (Light, 1998). This is a direct appeal to our innate sense of responsibility for ourselves, our environment and the planet. A cell-based approach provides a robust scientific rationale for Bookchin's intuition. Elemental cellular rules, established billions of years ago, provide discernible pathways from the

Singularity to human behavior (Torday, 2019).

9.4

Metabolic Cooperativity as the Basis for Biologic Morality

In response to existential threats, multicellular eukaryotes devised complex cell–cell communication, implementing soluble growth factors and their cell-surface receptors to transfer the energy generated by such communications. Ligand-receptor interactions produce so-called “second messengers” composed of high-energy phosphates, like cyclic adenosine monophosphate and inositol phosphate, which generate pathways that culminate in changes in the DNA readout for growth and differentiation of the affected cell. The programmatic cell–cell signaling of the embryo gives rise to the offspring (Perrimon et al., 2012). In addition, epigenetic “marks” acquired from the environment modify the genome, providing advanced notice to the parent organism of changes in the environment (Nilsson et al., 2018). Acquiring such “marks” is directed by the phenotypic behavior of the offspring in its environment as a consequence of iterative cycles of epigenetic inheritance. Epigenetic marks are assimilated by the egg and sperm of the parents, modifying DNA “readout” as RNA and protein in the embryo. Such modifications affect the behavior of the offspring, considering that the mesoderm, which confers “plasticity,” is under epigenetic control. For example, Lewis Wolpert, the British developmental biologist, has famously said that the most important thing you will do over the course of your life is “not birth, marriage or death, but gastrulation which is truly the most important time in your life.” Gastrulation is the phase of early embryo formation when the mesoderm appears between the endoderm and ectoderm. Moreover, the mesoderm is under hormonal control, and the endocrine system is under epigenetic control. So, on the whole, there is a highly interactive relationship between the environment and the behavior of the organism, which is, therefore, partly under epigenetic control. By implication then, moral behaviors are themselves influenced by epigenetic impacts. This should not be in the least controversial. Aside from a few moral absolutes, most moral issues are “shades of gray” to differing individuals. Indeed, this is the great quandary of human morality. Often, there is little concrete agreement.

9.5

So Why Is There Immorality?

If life arose through cooperation, why is there immorality? As stated earlier, life began as an ambiguity of energetic statuses, negative entropy within the cell, positive entropy in the surrounding environment. The second law of thermodynamics is circumvented biologically, heat physically dissipating over time. This occurs in the cell, but as opposed to the outward environment in which the rate of dissipation can be precisely expressed as mathematical equivalencies, the cell regulates heat dissipation according to its self-referential requirements. Further then, all the information that a cell can use to sustain its own sense of homeostatic equipoise is ambiguous (Torday and Miller, 2017). As it has already been defended that all elemental processes in biology reiterate, it should not be surprising that the issue of ambiguity is omnipresent throughout biology, and will manifest in idiosyncratic forms at differing levels. This extends even to our human tendencies. Trivers (2011) insists that human behavior is actually centered within such ambiguities, which are used as both purposeful deception in our relationships with

others, but are so deeply ingrained that we unwittingly consistently deceive ourselves. Why then is there immorality among humans? The answer is direct. We, humans, as products of a Singularity that imposes conditional ambiguities on our living state, will each interpret our concept of morality in our own idiosyncratic manner. Some will disconnect with others and use deceptions to gain access to their own preferential status, as a permanent echo of our cellular selves.

9.6

Morality in the Anthropocene

We have now entered the Anthropocene (Waters et al., 2016); that is, a man-made environment. Given that we are responsible for forming our interrelationships with our environment, we define morality so that we know how to behave accordingly. Acknowledging the role of homeostatic control as the basis for a form of morality in the pre-Anthropocene would be one logical basis for formulating a human moral code moving forward. As an example, when the virtual reality program “Go to Meeting” was created, it seemed like a way to facilitate interrelationships in cyberspace. However, some participants were having their icons behave in ways that they would not otherwise have exhibited in real life. With the foregoing background, this aberrant behavior can be understood. There are always a fraction of an entire ecosystem who will deploy the ambiguity of information to achieve their own state of preference. That most of us cannot understand that motivation actually solidifies the case. No self-referential individual can intuit how another separate self-referential individual will either perceive or deploy ambiguous information. Within human society, this is sufficiently apparent that the majority needs to defend themselves from destructive outliers by their own form of niche construction: rules of behavior had to be formulated and codified. These are not merely arbitrary. All human behaviors are centered within elemental processes. As a condition of information and cell–cell communication, there is always a group of individuals in any living society, including our human ones, which are outliers in either their assessment of information or their communication abilities. Clearly then, a systematic codification of what a substantial majority believes is “moral” becomes an absolute essential for collaboration and cooperation towards meeting a rigorous environment in a productive, collective manner. Therefore, if we are to function, we must establish rules of behavior based on a coordinated set of principles. Since we are cellular beings, no matter our own sense of ourselves, it follows that anything that we do has origins in basic cellular principles, such as homeostasis, or any other elemental process that permits cellular survival. Those fundamental principles that guide cells can be logically examined as one foundational aspect of our common sense of morality. It follows that deviations from natural cellular principles have moral risks that extend beyond technological faults. Both clustered regularly interspaced short palindromic repeats (CRISPR) and artificial intelligence are stratagems that have the real potential risk of profoundly upsetting the balanced systems that have governed our planet. It can be urged as an imperative that these be scrutinized both for their conceivable advantages and their moral hazards. In such circumstances, a few individuals, some of whom may be absent from any common morality, might exert overwhelming influence on planetary existence. Clearly, there must be carefully considered constraints put in place.

9.7

Altruistic Behavior in Bacteria

Arthur Reber addresses what he refers to as altruism in bacteria in his book The First Minds (2018). The conventional criterion for altruism is that it benefits another while having a potential detrimental effect on the actor. In Gurol Suel's study of bacterial altruism, bacteria in one part of a colony adjust their metabolism and cell division rates in response to molecular signals from bacteria in another part of the colony. The cells at the periphery of the colony enjoy access to the nutrientrich environment, placing themselves at risk of predators, antibiotics and toxins. Meanwhile, the cells at the center of the colony enjoy the protection of their locale, but have less access to food. If the nutrient supplies in the core of the colony drop too low, those cells secrete a signaling molecule that asks the cells at the edge of the colony to slow down metabolically and stop reproducing in order to let some of the nutrient-rich material flow inward. When the cells on the periphery accommodate in this way they are, in effect, engaging in altruism, i.e. they behave in ways that increase the welfare of their colony-mates but have placed themselves at risk. The danger from predators and noxious molecules still lurks in the surrounding environment, and by lowering metabolism and decreasing cell division they are decreasing their chance of passing their genes on to the next generation. The same phenomenon also occurs between bacterial colonies, and both within and between different strains of bacteria. The reason for this phenomenon is that bacteria within a complex biofilm will consensually sub-specialize in order to better protect their individualized states of homeostatic equipoise. Some bacteria will voluntarily repress certain metabolic capabilities in order to better perform others. In effect, they are betting their lives on the principle of cooperative association and the active trading of colonial resources. Such behavior can be likened to kin selection in multicellular holobionts. In that framework, an evolutionary strategy favors the reproductive success of an organism's relatives with similar genetic material at the potential risk of an organism's own survival and reproductive success. This phenomenon has been well described, with its cause attributed to increased gene frequencies by Hamilton (1964). But describing a mechanism is not the same as knowing how and why it works (Nicholson, 2012). In the process of niche construction, which is fundamental to the living state and its evolution, cells must cooperate to successfully assimilate environmental stresses. Kin or not, cooperation to maintain homeostatic equipoise is essential. In such circumstances, small, mutualized “sacrifices” can be reinforced to achieve common goals. In this way, from primordial cells forward, there is a definable impulse to collaborate within limits, even at some disadvantage, to assure common ends.

9.8

Discussion

Darwinian evolution based on “survival of the fittest” assumes that the major driving force for organisms is competition for reproductive success. Tennyson's “Nature, red in tooth and claw” expresses this perception of how and why evolution occurs, but it is an extreme distortion of the situation. Certainly, it catches our attention, since it is monikered as “if it bleeds, it leads.” Yet, this narrative is fundamentally flawed. One reason that this perspective persists is that for both scientists and the public, combat footage on the Serengeti is far more interesting than the more consequential changes that occur in the microscopic cellular realm.

Further yet, a measurement of “survival of the fittest” as the raw number of offspring is much easier than trying to deconvolute the intricacies of complex cellular/molecular processes. Yet, it is this latter reality that actually underlies survival since it is at successive cellular levels that metabolic cooperation prevails. A clear message emanates from this reality that should guide our human evaluation of morality. Being good should come naturally if “being good” is construed as respectful cooperation with others. The problem of understanding the origin of cooperation within a Darwinian framework of “survival of the fittest” is well acknowledged. Some are satisfied with the concept of kin selection. Axelrod and Hamilton (1981) offered an elegant alternative explanation for the evolution of cooperation based on their analysis of the “Prisoner's Dilemma.” In their model, mutual cooperation can develop even if the participants can detect an advantage by not doing so, if there are grounds for the expectation of reciprocation. If reciprocation is presumed to operate, then cooperation is reinforced and cheating and defection is suppressed to support mutualistic responses to similar threats. If reciprocation breaks down, then cooperation is imperiled. In their modeling, reciprocation attains a high level of robustness, sufficient to account for its persistence over the course of evolution. In biological terms, as opposed to computer models, the principle of reciprocation is an embedded feature of life. It begins through those reciprocations from the natural order that reflect within the living circumstance. For example, the negentropic interior of the cell is a reciprocal response to universal expansion according to Newton's third law. Further reciprocations are present in each of the enumerated first principles of physiology (Torday and Rehan, 2017). Cellular reciprocations are then furthered by the central principle of the ambiguity of information, which requires its collective appraisal and the ubiquity of cellular communication. There is no means of sustaining multicellular life without the sharing of information by unimpeded cell–cell communication. All multicellular activity is based within requisite reciprocations. Hence, cooperation is a completely embedded aspect of living. Trying to better understand the origin of moral behavior takes on some further urgency in our modern era. In an age of artificial intelligence, it behooves us to understand how and why we behave, since we will inevitably be programming powerful machines to behave and perform in like kind. For example, a debate is now raging as to what metrics to use in a situation where an autonomous vehicle must “decide” whether to kill a senior citizen or a mother with a baby carriage in its path. For many, such decisions reduce to “cost” (Gerdes and Thornton, 2015). Yet, if morals derive from fundamental biology, then there should be a robust biological means that can account for such relationships, including their moral equivalencies.

9.9

Conclusion

Moral behavior is conventionally founded on religious precepts, made secular by humanistic principles and societal laws. In this article, it is stipulated that moral behavior can be reasonably founded on fundamental biologic principals that derive from universal natural laws. Based on that logic, it could be superficially assumed that we all would behave morally since it is directly inculcated in our own natures. However, our living world informs us differently. There will always be many who are not in compliance with any general universal moral principles. The crux of the issue is direct. Our origins are within ambiguity. It begins with the first reproductive

cell with its conditional negentropic interior state juxtaposed against an agitating higher entropic external environment. In order to maintain that living differential, all cells cope with definitional ambiguities that govern the information they receive and the communications that they might share. To attain a preferential state, one cell might deceive another to gain access to resources. In order to do that more efficiently, we often deceive ourselves to better deceive others (Torday and Miller, 2017). Perforce, our conditional human morality must arise from within these entirely basic cellular contexts. As these are elemental principles, they would be expected to perseverate over the course of evolution from the first individual primordial cells to ourselves. As opposed to all other creatures, only humans have codified moral laws, and only we seem to require some means of restraining ourselves to enforce orderly cooperation. To rise above this predicament, we must look to our most basic cellular-molecular pathways. Once it is realized that “being good” ought to be our natural state of being, based on perpetual principles of cellular cooperation in requisite adherence to fundamental physical laws, perhaps an enlightened ethical order and a scrupulous moral stance can become universal touchstones.

References Axelrod R. and Hamilton W. D., The Evolution of Cooperation, Science, 1981, 211, 1390–1396. Gerdes J. C. and Thornton S. M., (2015, ), Implementable Ethics for Autonomous Vehicles, Autonomes Fahren, Berlin: Springer Vieweg. Hamilton W. D., The genetical evolution of social behaviour, J. Theor. Biol., 1964, 7, 1–52. Hobson J. A., Hong C. C. and Friston K. J., Virtual reality and consciousness inference in dreaming, Front. Psychol., 2014, 5, 1133. Light A., (1998, ), Social Ecology After Bookchin, New York: Guilford Press. MacFarquhar L., (2011, ), How to be Good, New York: The New Yorker. Miller Jr W. B., (2013, ), The Microcosm Within: Evolution and Extinction in the Hologenome, Boca Raton: Universal Publishers. Miller Jr W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016, 4, 96. Miller Jr W. B., Torday J. S. and Baluška F., Biological evolution as the defense of ‘self’, Prog. Biophys. Mol. Biol., 2019, 142, 54–74. Nicholson D. J., The concept of mechanism in biology, Stud. Hist. Philos. Biol. Biomed. Sci., 2012, 43, 152–163. Nilsson E. E., Sadler-Riggleman I. and Skinner M. K., Environmentally induced epigenetic transgenerational inheritance of disease, Environ. Epigenet., 2018, 4, dvy016. Perrimon N., Pitsouli C. and Shilo B. Z., Signaling mechanisms controlling cell fate and embryonic patterning, Cold Spring Harbor Perspect. Biol., 2012, 4, a005975. Pinker S., (2011, ), The Better Angels of Our Nature, New York: Penguin Books. Reber A., (2018, ), The First Minds, Oxford: Oxford University Press. Schrodinger E., (1944, ), What is Life?, Cambridge: Cambridge University Press. Torday J. S., Life Is Simple—Biologic Complexity Is an Epiphenomenon, Biology, 2016, 5(2), 17.

Torday J. S., Quantum Mechanics predicts evolutionary biology, Prog. Biophys. Mol. Biol., 2018, 135, 11–15. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S. and Miller Jr W. B., The resolution of ambiguity as the basis for life: A cellular bridge between Western reductionism and Eastern holism, Prog. Biophys. Mol. Biol., 2017, 131, 288–297. Torday J. S. and Miller W. B., The Unicellular State as a Point Source in a Quantum Biological System, Biology, 2016, 5(2), 25. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, Hoboken: Wiley. Trivers R., (2011, ), The Folly of Fools, Basic Books, New York. Waters C. N., Zalasiewicz J., Summerhayes C., Barnosky A. D., Poirier C., Gałuszka A., Cearreta A., Edgeworth M., Ellis E. C., Ellis M., Jeandel C., Leinfelder R., McNeill J. R., Richter D. d., Steffen W., Syvitski J., Vidas D., Wagreich M., Williams M., Zhisheng A., Grinevald J., Odada E., Oreskes N. and Wolfe A. P., The Anthropocene is functionally and stratigraphically distinct from the Holocene, Science, 2016, 351, aad2622.

CHAPTER 10

Aging, Senescence and Death as a Systematic Breakdown in Cell–Cell Communication 10.1 Introduction Medawar's mutation accumulation theory (Medawar, 1952), Williams’ antagonistic pleiotropy theory (Williams, 1957), and Kirkwood's disposable soma theory of aging (Kirkwood, 1977) have formed the basis for genetic studies of aging. But none of these theories have advanced our understanding of senescence or aging. More recently, Kirkwood (2005) has attempted to reconcile the disposable soma and oxidative stress theories of aging with other mechanistic theories of aging, but have been similarly unsuccessful. It can be securely argued that any fundamental understanding of aging has failed due to a monolithic focus on genes as the be-all and end-all causal agents for evolution (Futuyama, 1998). Conversely, it has been proposed that cell–cell communication is the basic means by which biology and its evolution unfolds. Given that all biology and its evolution have their origins in cellular mechanisms, valuable insights into senescence and aging should be gained by examining these life-cycle changes through a cellular lens (Torday and Rehan, 2017).

10.2 Why We Age It is now acknowledged that life began within the context of ambiguity. The information that must be utilized by all cells for survival is imprecise, by definition (Miller, 2016; Miller, 2017). Cell–cell signaling and communication are subject to a variety of sources of degradation. Even the differential between the internal entropic state of any cell and its external environment is itself an ambiguity (Torday and Miller, 2017) as a state that circumvents the second law of thermodynamics. Physical systems progress from ordered to disordered states. Instead, and only in the living condition, relative order is sustained by chemiosmosis (Mitchell, 1961) and controlled by homeostasis within cellular boundaries over the course of the life of the organism. These, together, enact the first principles of physiology (Torday and Rehan, 2009a). Unicellular organisms dominated life on Earth for approximately 3.3 billion years prior to the advent of multicellular organisms approximately 500 million years ago (Morris, 1993). The formation of multicellular organisms may have begun in reaction to prokaryotic-centered adaptations, which expressed as biofilms, enabled by robust cell–cell communication as quorum sensing. In response, eukaryotes (organisms with true nuclei), competed and cooperated, through cell–cell communications, to coexist in challenging environments, driven by rising levels of atmospheric oxygen (Torday and Rehan,

2012). Oxygen in the atmosphere did not increase gradually from zero to 21%, instead fluctuating between 15 and 35% over the course of the last 500 million years (Berner et al., 2007). Much has been written about the increases in oxygen. One theory is that this was the factor that fueled gigantism among animal life (Payne et al., 2012); but little has been said about the accompanying decreases in oxygen, which would have caused hypoxia, the most physiologically potent agonist known. Previously, it has been advanced that hypoxia can be exploited to explain the evolution of warm-blooded organisms, namely, mammals and birds; and that this warm-bloodedness fostered bipedalism, which only birds and some mammals share (Torday, 2015). It follows that the liberation of the forelimbs from bipedalism allowed sets of serial adaptations that permitted flight in the case of birds, and toolmaking in the case of humans. It might even be postulated that this might hypothetically have given rise to oral communication in order to accommodate having one's “hands full.” Such specialized traits are significant morphogenetically, since both birds and mammals are deuterostomes, developing from the anus to the mouth. When that process is seen in light of terminal addition (Torday and Miller, 2018) as cell–cell interactions mediated intracellularly by “second messengers,” it casts a new light on the process of human evolution, and hypothetically on aging. That is to say, as we age we lose those phenotypic characteristics that were added last over the course of evolution, namely, the head structures – mind, sight, hearing and taste – all of which were added in adaptation to land, largely as a consequence of bipedalism (Torday, 2015) generating positive selection for these traits. As explained in Evolutionary Biology, Cell–Cell Communication and Complex Disease (Torday and Rehan, 2012), the life cycle is characteristically “binary” (see Figure 10.1).

Figure 10.1

The Life Cycle is “binary.” Embryonic growth and differentiation (far left) mediated by cell–cell signaling of growth factors and their receptors culminates in homeostasis. That mechanism reaches its peak in the fertile reproductive phase of life (top), endocrine hormones optimizing physiology to ensure reproductive success. Once the reproductive phase of the life cycle is complete, the optimal bioenergetic state of the organism begins to wane, in what we describe as the aging process (far right).

Embryonic growth and differentiation mediated by cell–cell signaling of growth factors and their receptors culminates in homeostasis in support of that bimodal lifecycle distribution. That mechanistic cycle reaches its peak in the fertile reproductive phase of life during which endocrine hormones optimize physiology to ensure reproductive success (Frisch, 1994). Once the reproductive phase of the life cycle is complete, this optimal bioenergetic state of the organism begins to wane, in what we describe as the aging process. In the aging process, there is a resulting “programmed” sequence for the loss of cellular signaling for homeostasis, beginning with the most recently acquired traits. This can be seen as consonant with the principle of terminal addition, in which cellular capacities add on to the tail end of the developmental process. This cellular-based aging requirement is reflected in the age-related loss of thyroid and pulmonary function and in cognitive abilities as the most common afflictions of aging (Aronson, 2019). Some step-by-step retrograde loss of physiologic traits is commonly accepted as “healthy aging.” In contrast to this, various diseases that undermine and/or accelerate the innate aging process are referred to as “disease-based” aging.

10.3 Dying and the Microbiome All organisms must ultimately succumb to the aging process and death. If we are buried in the soil, we decay, but our microbiome returns to the earth, to the aquafer, is assimilated by plants, which are eaten by animals, allowing us to ultimately “recycle” ourselves, as in some religious beliefs. The idea that our microbiome continues on after death has been demonstrated, and is referred to as the necrobiome (Burcham et al., 2019), or our bacterial “footprint.” In this context, it behooves us to do our best to maintain our corporeal health as the vehicle for our microbiome.

10.4 Phenotype as Agent It has been previously asserted that the adult form is not the major object of the life cycle, despite our human biases. Instead, it has been argued that the actual object of our evolutionary narrative is the obligatory recapitulation through the unicellular stage of the zygote (Torday and Miller, 2016a, 2016b, 2016c; Miller and Torday, 2018). Phenotype is the unicellular zygote's means of experiencing the outward environment and remaining in consistent complementarity with it (Torday and Miller, 2016c). Based on epigenetic inheritance, phenotype is an organism's way of actively interacting with the environment and collecting epigenetic “marks.” Such marks are absorbed by the body and assimilated by the DNA of the egg and sperm through chemical modifications such as methylation, and then carried through the process of meiosis, modifying the effective genetic readout. Such DNA adducts are sorted for adaptive or maladaptive traits, and the adaptive marks are subsequently integrated into the offspring as heritable changes during the zygotic phase and during the process of embryogenesis. Such epigenetically inherited traits inform the offspring of changes in the environment in order to adapt efficiently, providing a selection advantage for survival.

10.5 The Red Queen and the Singularity The reason why organisms return to their unicellular state during their life cycle has been an enduring mystery of biology. It remained intractable because evolutionary biologists have viewed life from its ends instead of its means. By alternatively superimposing the embryologic developmental “history” of the organism on longterm phylogenetic “history”, the mechanism of evolution has been deconvoluted (Torday and Rehan, 2012). Using that approach, complex physiologic traits can been traced back to the unicellular state (Torday and Rehan, 2017), based on evolution as serial pre-adaptations, or exaptations (Gould and Vrba, 1982). This evolutionary sequence offers insight into the mandatory recapitulation of all multicellular organisms through a unicellular zygotic state for reproduction. It can be argued that the unicellular state is the originating form of life and its perpetual object (Miller and Torday, 2018); that is, an ultimate living unity, itself derived of the Singularity and perhaps its own form of exaptation of universal unity. If so, then the cell is the point source of life, constantly referencing the Singularity, as the point source of the cosmos (Torday, 2019). Life is continuously running as fast as it can, through the continuous acquisition of epigenetic marks to adjust to the contemporaneous environment, just so that it can stand still; i.e. perpetually maintaining the three cellular domains (Miller and Torday, 2018).

Just as evolution can only be understood by a change in the frame of reference, aging can now be approached as the effort of life to resolve the ambiguous dualities generated by the Big Bang using the first principles of physiology, in service to circumventing the second law of thermodynamics. In the case of physics and chemistry, such dualities are resolved by recombinations of energy and mass to form stable matter, whereas in the case of biology, founded on negative entropy, the mission is to perpetuate itself based on self-referential self-organization. Knowledge of the environment is gleaned from the environment as epigenetic impacts, is assimilated, and then transferred as heritable adjustments to the next generation in order to remain “ahead of the curve” of ever-changing environments. In Kirkwood's disposable soma theory of aging, there is an evolutionary trade-off between growth and reproduction, which is concentrated toward the beginning of “natural aging” and an ongoing requirement for DNA repair and molecular proofreading. (Kirkwood and Rose, 1991). All are costly in energetic terms. In theory, organisms have only limited energy resources or “soma,” which can be purposed to any of those activities, and consequently, there is increasing cellular damage in older organisms as total “soma” is depleted. As a requirement to optimize reproduction, reinforced by selection, the bioenergetics of the life cycle shift towards the beginning of life when bioenergy is most plentiful (Frisch, 1994). As a result, there is a shortage of bioenergy towards the post-reproductive stage, or end of life, since bioenergy is finite (Hayflick, 2007). One advantage of the soma theory of aging is that it directly relates senescence to deteriorating cellular mechanisms. However, its concentration on DNA repair is a significant limitation compared with the even more consequential deterioration of cell functions that occurs from the collective loss of robust cell–cell signaling as the hallmark of aging. Yet, there is an advantage to soma theory. It lends credence to the significance of epigenetic inheritance. Life has evolved the ability to monitor its environment and detect changes in order to perpetuate itself using the mechanism of epigenetic inheritance (Haque et al., 2016). Epigenetic adjustments are gene-centered cell-wide modifications in support of continuous organismal–environmental complementarity. Such consonance is energy-sparing and would be protective of total “soma” reserves.

10.6 Epigenetic Inheritance and Aging There is emerging evidence that all organisms inherit epigenetic marks from their environments, whether it is in the unicellular (Nowacki and Landweber, 2009) or multicellular (Perez and Lehner, 2019) form. In this context, it should be borne in mind that only about 3–5% of human genetic diseases are Mendelian, making it highly likely that the majority are epigenetic in nature, since effective interactions with the environment optimize the likelihood of keeping abreast with environmental changes, given the robustness of the environment. As a result of bipedalism, birds and humans are able to occupy environments that are far more diverse than those of quadrupeds, in turn rendering them far more susceptible to epigenetic inheritance, which may, in turn, account for their unique ability to occupy so many environmental niches. It may be no coincidence that all organisms assimilate epigenetic impacts, and all organisms age.

10.7 Physiology as Niche Construction It is argued that the key to understanding the nature of the aging process is through the intimate relationship between life and its elemental conditional terms, and its consistent reciprocation with the outward environment, which is itself the product of cosmic forces. That interrelationship is best seen in the generation of ecosystems due to endogenization of factors in the environment. This is best known as the symbiotic endogenization of previously free living bacteria to affect the eukaryotic cell, known as endosymbiosis theory (Cazzolla Gatti, 2018). Yet endosymbiosis was not a new process when it achieved the Eukaryotic cell form. The endogenization of heavy metals, ions and gases – which are also existential threats – and their respective compartmentalization, also constitute types of endosymbiosis. Nor is this the only means that living entities have to endogenize the environment. Niche construction is the term used to indicate the process by which organisms modify their immediate environments, such as beavers building dams, or humans building homes or cities. In this manner, an organism, or groups of organisms accommodate the external environment by modifying it. It is possible to consider this to be an advanced, though indirect, form of endogenization. That conclusion is based on the fact that the results of niche construction and direct endogenization are one and the same, i.e. an individual organism or a group of organisms assimilate the outward environment in support of survival and the maintenance of reproductive faculties. It follows that these same processes continue across the Earth, at every scope and scale and becomes the source of Gaia. In 1979, James Lovelock translated the mythological Gaia into modern ecological terms (Lovelock, 1979). His proposition was that all living organisms and every particle of planetary inorganic material are part of a dynamical system that shapes the Earth's biosphere and maintains it as a habitable planet. As a result, the Earth itself should be regarded as an entire living organism. When this path is assumed to be a continuum, then a unified holistic system based within a fundament of cellular faculties and necessities unfolds. Cells join together to make multicellular physiology in compliance with physical principles, in synchrony with basic physical forces, so that the inorganic and the organic entwine to become the basis for life. It is therefore hypothesized that the physical begins with the Singularity and moves forward diachronically, across space–time, in a perpetual cycle that unites the inorganic and the organic. All must be in perfect synchrony with the environment, on this planet and across the universe, and all must share a uniting compliance with the proscriptions of quantum mechanics (Torday, 2018).

10.8 Insight to Aging in the Context of Cell–Cell Signaling By merging cell–cell signaling during development with phylogeny, a novel understanding of evolution, beginning with its origin in the Singularity, emerges (Torday and Rehan, 2012; Torday and Rehan, 2017; Torday, 2019). That perspective has given rise to the idea that aging is a consequence of the first principles of physiology (Torday and Rehan, 2009a,b) – that is, negentropy, chemiosmosis and homeostasis – combined with selective filtering to assure continued reproductive success. It has been previously noted that there may be only a finite amount of bioenergy available over a lifetime (Hayflick, 2007) and that, if so, it would justify an energy skew towards the beginning of the life cycle to optimize reproductive success (Frisch, 1994). After that reproductive expenditure,

the total available bioenergy would decline, causing failure to maintain cell–cell signaling for homeostasis, consonant with the aging process. Disease processes add their separate costs and more quickly diminish the amount of available bioenergy.

10.9 Empiric Evidence for Aging as Loss of Cell–Cell Signaling In connection with bioenergy, a hypothesis can be offered that aging, senescence and death are a consequence of the retrogressive failure of evolved cell–cell communications. Experimentally, this can be advanced through the example of the three hormone receptors known to have duplicated during the water–land transition: the parathyroid hormone-related protein receptor (PTHrPR), glucocorticoid receptor (GR), and β-adrenergic receptors (β-AR) (Torday and Rehan, 2017). PTHrPR levels decrease in the aging rat duodenum (Gentili et al., 2003), and lung (Kovacs et al., 2014). And there are several studies on aging that document declines in the response of bone to both endogenous PTHrP (Gardinier et al., 2018; Zhang et al., 2018), and a waning response of bone to exogenous PTHrP (Ricarte et al., 2018; Rachner et al., 2019). Furthermore, there is evidence of loss of bioactivity of PTHrP in regulating calcium activity in rat aortic smooth muscle (Ishikawa et al., 1995). Similarly, there is evidence for decline in GR levels with aging (Cristofalo et al., 1972; Roth and Hess, 1972; Kalimi, 1984). As for the β-adrenergic receptor, its levels also decline with age (Scarpace et al., 1991; Frerrara et al., 2014).

10.10 Gender Differences as Proof of Principle for Aging as Loss of Cell–Cell Signaling With that as a base, then senescence and aging would be mirror images of development, merely unfolding in reverse, and just one other example of the requirement of equal and opposite reactions in compliance with Newton's Third Law. As part of this cyclical phenomenon, there is a relatively extensive literature on the role of androgens and transforming growth factor beta (TGF-β) in inhibiting development, and data inferring the role of these agents in aging and senescence. The following can be proposed as having a predictive role in aging based on cycles of androgens and transforming growth factor beta. Women age and die later than men. In birds, the opposite occurs. Extensive study of this phenomenon culminated in the realization that it is actually the homogametic sex that lives longer (Torday and Nielsen, 1987). In mammals, the female is homogametic (XX), whereas in birds, the male is homogametic (ZZ). The consensus for the sex difference in longevity is that the Y or W chromosome, which determines the heterogametic sex lacks the balancing effect of genes on the X or Z chromosome, respectively, such that deleterious traits on the Y or W chromosome can cause premature senescence and demise. This imbalance impacts the cycle of androgens and transforming growth factor beta: the production of testosterone inhibits development and accelerates senescence mediated by TGF-β (Torday, 1992), which antagonizes growth factor receptor signaling.

10.11 Loss of Homeostatic Control Is Marked by Increased Wingless/Int Expression

This mechanistic view of aging as a continuum of epithelial–mesenchymal interactions is founded on Grobstein's observation of tissue–tissue interactions during embryogenesis (Grobstein, 1967). For example, during normal lung development, epithelial–mesenchymal interactions generate the 40 different celltypes that constitute the lung (Warburton et al., 2010), culminating in homeostatic regulation for gas exchange (Whitsett and Weaver, 2015). Such factors as prematurity (Urs et al., 2018), mechanical over-distension (Rehan et al., 2011), oxidative injury (Deuber and Terhaar, 2011) and infection (Jobe, 2016) can prevent or disrupt the full formation of the alveolus and homeostatic regulation. All of these conditions are characterized by failure of the mature regulatory pathway interconnecting the lipofibroblast and epithelial type II cell. As a consequence, the lipofibroblast defaults to a myofibroblast, dominated at the molecular level by Wnt/beta-catenin signaling (Rehan and Torday, 2003). Various agents have been used experimentally to prevent or treat lung immaturity and recover or retain normal homeostatic control, as measured by the normal production of lung surfactant, the bellwether for alveolar homeostasis (Cerny et al., 2008). For example, the peroxisome proliferator-activated receptor (PPAR) gamma (PPARγ) agonist, rosiglitazone, has been shown to prevent or treat alveolar dyshomeostasis, inhibiting Wnt/beta-catenin and up-regulating PTHrP receptor expression to re-establish homeostasis as proof of principle (Dasgupta et al., 2009). The kidneys, liver, bone and brain similarly form embryologically based epithelial–mesenchymal interactions. Injury to the cellular–molecular maturational signaling pathway predictably disrupts homeostatic control. Conversely, such agents as rosiglitazone, rapamycin, statins and anti-inflammatory agents that target the step-wise development of these organs have been shown to prevent the loss of homeostasis or, in some cases, to restore homeostatic control. Other consequential properties of physiologic homeostasis are also disrupted during the process of aging due to loss of mitochondrial bioenergetics (Wei et al., 2001). For example, there is a loss of homeostasis with a reversion to Wnt/betacatenin signaling by fibroblasts in chronic lung disease (Torday and Rehan, 2006). In the case of the pulmonary alveolus, various growth-factor signaling agonists have been shown to either prevent the loss of homeostatic control or promote it, which can also extend the life span of mice (Gómez-Linton et al., 2019).

10.12 Discussion The subject of aging has been debated for centuries. Nearly all of this speculation has been based on descriptive biology or has been driven by a bias toward a genetic view of biology (Khan et al., 2019). This latter viewpoint has centered on the generally shared conviction that Darwinian evolution is adequately understood as a process based on random mutations and natural selection. That perspective has now been effectively questioned (Steves et al., 2012; Miller, 2016; Miller, 2017; Miller and Torday, 2017; Miller and Torday, 2018; Miller et al., 2019). In comparison, utilizing contemporary embryology, Torday and Rehan (2012) have exploited cell– cell communication mechanisms of growth factor-receptor signaling to deconvolute vertebrate evolution. In a series of journal articles and books based on that approach, it has been hypothesized that aging is the natural consequence of the loss of bioenergy over the course of the life cycle beyond the peak reproductive stage (Torday and Rehan, 2012). To that end, it has been speculated that this is a result of a gradual loss of phenotype bioenergy consumption due to an age-related loss of

mitochondrial function (Kelbauskas et al., 2017). Consequently, the mechanisms of cell–cell communication fail, resulting in senescence and death. The power of this distinctly alternative approach is its transformative view of aging from an “absolute” to a “relative” process, which can be considered separate from age-related diseases (Hayflick, 2007). Aging may be inevitable, but in and of itself, it need be no end-point to be unnecessarily feared or stigmatized as a lesser stage of life. Instead, it should be accepted as just another part of an eternal narrative (Torday, 2019), written through our cells, as we remain in perpetual consort with the cosmos.

References Aronson L., (2019, ), Elderhood, New York : Bloomsbury Publishing. Berner R. A., Vandenbrooks J. M. and Ward P. D., Evolution. Oxygen and evolution, Science, 2007, 316, 557–558. Burcham Z. M., Pechal J. L., Schmidt C. J., Bose J. L., Rosch J. W., Benbow M. E. and Jordan H. R., Bacterial Community Succession, Transmigration, and Differential Gene Transcription in a Controlled Vertebrate Decomposition, Model. Front Microbiol., 2019, 10, 745. Cazzolla Gatti R., Endogenosymbiosis: from hypothesis to empirical evidence towards a Unified Symbiogenetic Theory, Theor. Biol Forum., 2018, 111, 13– 26. Cerny L., Torday J. S. and Rehan V. K., Prevention and treatment of bronchopulmonary dysplasia: contemporary status and future outlook, Lung, 2008, 186, 75–89. Cristofalo V., Roberts J. and Adelman R., ,(1972, ), Exploration in Aging, New York: Plenum. Dasgupta C., Sakurai R., Wang Y., Guo P., Ambalavanan N., Torday J. S. and Rehan V. K., Hyperoxia-induced neonatal rat lung injury involves activation of TGF-{beta} and Wnt signaling and is protected by rosiglitazone, Am. J. Physiol.: Lung Cell. Mol. Physiol., 2009, 296, L1031–L1041. Deuber C. and Terhaar M., Hyperoxia in very preterm infants: a systematic review of the literature, J. Perinat. Neonatal Nurse, 2011, 25, 268–274. Ferrara N., Komici K., Corbi G., Pagano G., Furgi G., Rengo C., Femminella G. D., Leosco D. and Bonaduce D., β-adrenergic receptor responsiveness in aging heart and clinical implications, Front. Physiol., 2014, 4, 396. Frisch R. E., The right weight: body fat, menarche and fertility, Proc. Nutr. Soc., 1994, 53, 113–129. Futuyama D., (1998, ), Evolutionary Biology, Sunderland: Sinauer Associates. Gardinier J. D., Rostami N., Juliano L. and Zhang C., Bone adaptation in response to treadmill exercise in young and adult mice, Bone Rep., 2018, 8, 29–37. Gentili C., Morelli S. and de Boland A. R., Characterization of PTH/PTHrP receptor in rat duodenum: effects of ageing, J. Cell. Biochem., 2003, 88, 1157– 1167. Gómez-Linton D. R., Alavez S., Alarcón-Aguilar A., López-Diazguerrero N. E., Konigsberg M. and Pérez-Flores L. J., Some naturally occurring compounds that incrdsease longevity and stress resistance in model organisms of aging, Biogerontology, 2019, 20, 583–603.

Gould S. J. and Vrba E. S., Exaptation—a missing term in the science of form, Paleobiology, 1982, 8, 4–15. Grobstein C., Mechanisms of organogenetic tissue interaction, Natl. Cancer Inst. Monogr., 1967, 26, 279–299. Haque M. M., Nilsson E. E., Holder L. B. and Skinner M. K., Genomic Clustering of differential DNA methylated regions (epimutations) associated with the epigenetic transgenerational inheritance of disease and phenotypic variation, BMC Genomics, 2016, 17, 418. Hayflick L., Biological aging is no longer an unsolved problem, Ann. N. Y. Acad. Sci., 2007, 1100, 1–13. Ishikawa M., Ouchi Y., Akishita M., Kozaki K., Toba K., Namiki A., Yamaguchi T., Ito H. and Orimo H., Age-related decrease in the effect of parathyroid hormone-related protein on cytosolic free calcium level and tension in rat aortic smooth muscle, Naunyn Schmiedeberg's Arch. Pharmacol., 1995, 351, 517–522. Jobe A. H., Mechanisms of Lung Injury and Bronchopulmonary Dysplasia, Am. J. Perinatol., 2016, 33, 1076–1078. Kalimi M., Glucocorticoid receptors: from development to aging. A review, Mech. Ageing Dev., 1984, 24, 129–138. Kelbauskas L., Glenn H., Anderson C., Messner J., Lee K. B., Song G., Houka J., Su F., Zhang L., Tian Y., Wang H., Bussey K., Johnson R. H. and Meldrum D. R., A platform for high-throughput bioenergy production phenotype characterization in single cells, Sci. Rep., 2017, 7, 45399. Khan A. H., Zou Z., Xiang Y., Chen S. and Tian X. L., Conserved signaling pathways genetically associated with longevity across the species, Biochim. Biophys. Acta, Mol. Basis Dis., 2019, 1865, 1745–1755. Kirkwood T., Evolution of ageing, Nature, 1977, 270, 301–304. Kirkwood T. B., Time of our lives. What controls the length of life?, EMBO Rep., 2005, 6, S4–S8. Kirkwood T. B. and Rose M. R., Evolution of senescence: late survival sacrificed for reproduction, Philos. Trans. R. Soc. London, Ser. B, 1991, 332, 15–24. Kovacs T., Csongei V., Feller D., Ernszt D., Smuk G., Sarosi V., Jakab L., Kvell K., Bartis D. and Pongracz J. E., Alteration in the Wnt microenvironment directly regulates molecular events leading to pulmonary senescence, Aging Cell, 2014, 13, 838–849. Lovelock J., (1979, ), Gaïa: a new look at life on Earth, Oxford : Oxford University Press. Medawar P. B., (1952, ), An Unsolved Problem of Biology, London: H.K. Lewis & Co. Miller W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016, 4, 96. Miller W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Miller W. B. and Torday J. S., A systematic approach to cancer: evolution beyond selection, Clin. Transl. Med., 2017, 3, 2. Miller W. B. and Torday J. S., Four Domains: The Fundamental Unicell and PostDarwinian Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2018, 140, 49–73. Miller W. B., Torday J. S. and Baluška F., Biological evolution as the defense of ‘self’, Prog. Biophys. Mol. Biol., 2019, 142, 54–74.

Mitchell P., Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism, Nature, 1961, 191, 144–148. Morris S. C., The fossil record and the early evolution of the Metazoa, Nature, 1993, 361, 219–225. Nowacki M. and Landweber L. F., Epigenetic inheritance in ciliates, Curr. Opin. Microbiol., 2009, 12, 638–643. Payne J. L., Groves J. R., Jost A. B., Nguyen T., Moffitt S. E., Hill T. M. and Skotheim J. M., Late paleozoic fusulinoidean gigantism driven by atmospheric hyperoxia, Evolution, 2012, 66, 2929–2939. Perez M. F. and Lehner B., Intergenerational and transgenerational epigenetic inheritance in animals, Nat. Cell Biol., 2019, 21, 143–151. Rachner T. D., Hofbauer L. C., Göbel A. and Tsourdi E., Novel therapies in osteoporosis: PTH-related peptide analogs and inhibitors of sclerostin, J. Mol. Endocrinol., 2019, 62, R145–R154. Rehan V. and Torday J., Hyperoxia augments pulmonary lipofibroblast-tomyofibroblast transdifferentiation, Cell Biochem. Biophys., 2003, 38, 239–250. Rehan V. K., Fong J., Lee R., Sakurai R., Wang Z. M., Dahl M. J., Lane R. H., Albertine K. H. and Torday J. S., Mechanism of reduced lung injury by highfrequency nasal ventilation in a preterm lamb model of neonatal chronic lung disease, Pediatr. Res., 2011, 70, 462–466. Ricarte F. R., Le Henaff C., Kolupaeva V. G., Gardella T. J. and Partridge N. C., Parathyroid hormone(1-34) and its analogs differentially modulate osteoblastic Rankl expression via PKA/SIK2/SIK3 and PP1/PP2A-CRTC3 signaling, J. Biol. Chem., 2018, 293, 20200–20213. Roth G. and Hess G., Changes in the mechanisms of hormone and neurotransmitter action during aging: current status of the role of receptor and post-receptor alterations, Mech. Ageing Dev., 1972, 20, 75–194. Scarpace P. J., Tumer N. and Mader S. L., Beta-adrenergic function in aging. Basic mechanisms and clinical implications, Drugs Aging, 1991, 1, 116–129. Steves C. J., Spector T. D. and Jackson S. H., Ageing, genes, environment and epigenetics: what twin studies tell us now, and in the future, Age Ageing, 2012, 41, 581–586. Torday J. S., Cellular timing of fetal lung development, Semin. Perinatol., 1992, 16(2), 130–139. Torday J. S., A central theory of biology, Med. Hypotheses, 2015, 85, 49–57. Torday J. S., Quantum Mechanics predicts evolutionary biology, Prog. Biophys. Mol. Biol., 2018, 135, 11–15. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S. and Miller W. B., Biologic relativity: Who is the observer and what is observed?, Prog. Biophys. Mol. Biol., 2016a, 121, 29–34. Torday J. S. and Miller W. B., Phenotype as Agent for Epigenetic Inheritance, Biology, 2016b, 5, 30. Torday J. S. and Miller W. B., The Unicellular State as a Point Source in a Quantum Biological System, Biology, 2016c, 5, 25. Torday J. S. and Miller W. B., The resolution of ambiguity as the basis for life: A cellular bridge between Western reductionism and Eastern holism, Prog. Biophys. Mol. Biol., 2017, 131, 288–297. Torday J. S. and Miller W. B., Terminal addition in a cellular world, Prog. Biophys. Mol. Biol., 2018, 135, 1–10.

Torday J. S. and Nielsen H. C., The sex difference in fetal lung surfactant production, Exp. Lung Res., 1987, 12, 1–19. Torday J. S. and Rehan V. K., Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/betacatenin gene regulatory network, Pediatr. Res., 2006, 60, 382–388. Torday J. S. and Rehan V. K., Lung evolution as a cipher for physiology, Physiol. Genomics, 2009a, 38, 1–6. Torday J. S. and Rehan V. K., The Evolution of Cell Communication: The Road not Taken, Cell Commun. Insights, 2009b, 2, 17–25. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology, Cell-Cell Communication and Complex Disease, Hoboken: Wiley. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, Hoboken: Wiley. Urs R., Kotecha S., Hall G. L. and Simpson S. J., Persistent and progressive longterm lung disease in survivors of preterm birth, Paediatr. Respir. Rev., 2018, 28, 87–94. Warburton D., El-Hashash A., Carraro G., Tiozzo C., Sala F., Rogers O., De Langhe S., Kemp P. J., Riccardi D., Torday J., Bellusci S., Shi W., Lubkin S. R. and Jesudason E., Lung organogenesis, Curr. Top. Dev. Biol., 2010, 90, 73– 158. Wei Y. H., Lu C. Y., Wei C. Y., Ma Y. S. and Lee H. C., Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system, Chin. J. Physiol., 2001, 44, 1–11. Whitsett J. A. and Weaver T. E., Alveolar development and disease, Am. J. Respir. Cell Mol. Biol., 2015, 53, 1–7. Williams G. C., Pleiotropy, natural selection, and the evolution of senescence, Evolution, 1957, 11, 398–411. Zhang W., Du G., Zhou J. and Chen J., Regulation of Sensing, Transportation, and Catabolism of Nitrogen Sources in Saccharomyces cerevisiae, Microbiol. Mol. Biol. Rev., 2018, 7, 82.

CHAPTER 11

A Holistic Perspective on Consciousness 11.1 Introduction In conventional terms, consciousness is described as the state of awareness of an individual organism's existence, sensations, thoughts and surroundings (Margulis and Sagan, 1995). There have been many theories of consciousness, yet none have captured what consciousness actually constitutes. Even Nagel's imaginative answer to the question, “What is it like to be a bat?” (Nagel, 1974) leaves the question of what consciousness “is” unresolved. The experiment by Libet et al. showed a measurable time-delay between our reaction to a stimulus and the brain's processing of it. If confirmed, this might suggest that there is an unknown mechanism that underlies the mind (1983) that further challenges the enigmatic nature of consciousness; Kelz and Majour's study of patients recovering from general anesthesia recapitulating the evolution of the brain (2019) underscores the corporal nature of consciousness. Hameroff and Penrose (1996) have hypothesized that the microtubules in neurons form networks in the brain that constitute consciousness (2014). Yet every cell of the body has microtubules. It defaults that if this cellular property is so widely distributed, that consciousness is the aggregate of cell–cell signaling throughout the body (Torday and Rehan, 2012; Miller, 2016, 2017; Torday and Rehan, 2017; Miller et al., 2019). How then might such cellular pathways become our own cellular form of consciousness? One productive direction is through the observation by Hobson et al. that the brain “cools” during rapid eye movement sleep. Since brain activity generates free energy as work, it can be inferred that its warming references the evolution of warm-bloodedness (Hobson et al., 2014). It can be supposed that the beginning of this stress pathway has its origins within the water-to-land transition some 500 million years ago. Accumulating carbon dioxide in the atmosphere caused a “greenhouse effect” (Romer, 1949), partially drying up the ocean to form land masses. That forced some boney fish out of water onto land. The force of gravity on the skeleton increased on land, in combination with the evolution of the lungs, kidneys and skin. Mechanistically, the combined stress on all of these organs caused the duplication of the parathyroid hormone-related protein (PTHrP) receptor (Torday, 2015a, 2015b, 2015c). The step-wise cell–cell interactions that mediated the evolution of the lung from the swim bladder periodically resulted in oxygen shortages that stimulated the hypothalamic–pituitary–adrenal (HPA) axis, hypoxia being the most potent stimulus for the HPA axis. That, in turn, increased adrenaline production by the adrenal gland, alleviating the inefficiency of the lung acutely by increasing the production of lung surfactant, allowing greater distension of the alveoli, generating a larger surface for gas exchange (Torday, 2015a, 2015b, 2015c). That conditional stress response also increased the release of free fatty acids from fat cells due to lypolysis, providing fuel for metabolism, increasing body

temperature; that adaptive response was replaced by the genetic expression of oxytocin as the constitutive regulator of body heat (Kasahara et al., 2013). Etienne Roux (2014) has pointed out the teleologic fallacy in using functions to define physiology. In contrast, the cell–cell signaling pathways as the basis for physiology are a radical departure. When this is considered from the proximate vantage point, and further that the singular purpose of evolution is the perpetuation of the three originating cellular forms beginning 3.8 billion years ago, and continuously in an unbroken arc to this present moment, it offers a diachronic across space–time transcendent perspective. The cosmos originated from the Singularity/Big Bang, and by default, consciousness is one of its organic manifestations. As Schopenhauer said, we understand matter because we are it (Schopenhauer, 2018).

11.2 Evolution, From Its Origin Unicellular organisms biologically dominated the Earth for the first 3.8 billion years (Woese, 1987). Polycyclic hydrocarbons (such as lipids) produced by cosmic forces were embedded in the snowball-like asteroids that pelted the Earth prior to the formation of the oxidative atmosphere to form the oceans (Deamer, 2017). Lipids in water naturally form primitive “cells,” or micelles (Moroi, 2013). When such micelles are delimited by their semi-permeable lipid membranes, they give rise to negative entropy, chemiosmosis (Mitchell, 1961) and controlled by homeostasis (Cannon, 1963), or the first principles of physiology (Torday and Rehan, 2009). Lynn Margulis Sagan had hypothesized that eukaryotic cells evolved through the process of endosymbiosis (Sagan, 1967), internalizing bacteria from the environment that would otherwise have destroyed them. Yet, that endogenization was not the first of its kind. It is an essential component of our living system. From the first protocell, there was a necessity to assimilate potential toxins such as heavy metals (iron, zinc), ions (sodium, potassium) and gases (oxygen, nitrogen). Our physiology (Margulis and Bermudes, 1985) is the aggregate of the endogenization, compartmentalization and utilization of environmental threats within the cell to become internalized assimilated components of an otherwise destabilizing external environment. Bacteria improvised, forming such pseudo-multicellular forms as biofilms (Ghannoum et al., 2015) and quorum sensing (Winans and Bassler, 2008), threatening the existence of unicellular eukaryotes. Eukaryotes countered by devising cell–cell communications, which ultimately gave rise to multicellular organisms, the communications evolving into the homeostatic regulatory mechanisms that characterize metazoans (Winans and Bassler, 2008). At the level of the organism, such homeostatic regulatory mechanisms are referred to as allostasis (McEwen, 1998). Allostasis, as whole-organism homeostasis, is interoception – that is, being conscious of our internal organs – which is what we ultimately think of as consciousness (Damasio, 2010). Thus, consciousness has been assimilated to form physiologic traits, having been derived directly from the environment. And since physical principles determine the environment, consciousness is the “organification” of those processes. An alternative way of conceptualizing consciousness is as a metaphoric data operating system; that is, matter emerged from energy due to the force of homeostasis acting as the “equal and opposite reaction” to the Big Bang. Environmental factors that posed an existential threat to life were internalized and

assimilated within the cell, yet they remained adherent to the laws of nature. Thus, like computer software and hardware, the internal and external environments ascribe to the same physical principles, with conscious organisms complying with the prevailing laws of nature.

11.3 Why Do We See “Red” in Association with Pain? In “Facing up to the problem of consciousness,” David Chalmers (1995) posed his “hard question” (Chalmers, 1995) as subjective experience, such as why we see “red” when we injure ourselves. The reason for this is obscure when the issue is only explored at the level of the human “mind” since we are attempting to explore the subjective realm through our own subjective senses. The limitations of that search are clearly apparent. However, when consciousness is considered within a cellular frame, and it is further granted that even cells are conscious at their scale (Miller, 2016; Miller et al., 2019; Reber, 2018) then firm answers emerge. Cellular consciousness refers back to the Singularity/Big Bang. It is therefore rooted in elemental physical processes that link to the cosmos, but are locally experienced. Those linkages are based on the cell–cell communication mechanisms that mediated evolution, acting as a web-like network of cells as nodes, under the auspices of homeostasis as the mechanism for both sustaining and also for re-establishing homeostasis (Torday, 2015c). Consequently, when homeostasis is disrupted, the cellular signaling partners auto-engineer themselves, modifying structure and function until they have re-established homeostasis. In so doing, they reconnect to earlier conserved processes, triggering signaling sets that would not ordinarily be operating. In effect, the resulting experience is the result of an unfamiliar connection that is only activated under stress and not part of ordinary cell–cell communication of conscious cells. It could be hypothesized that a similar mechanism might account for “out-of-body” experiences as cellular pathways recruited during stress that are typically unused.

11.4 Restoring Cellular Homeostasis The same cell–cell signaling mechanisms for embryogenesis that culminate in homeostasis also monitor on-going equipoise, directing the cellular partners to remodel in order to re-establish homeostasis either for injury/repair, epigenetic adaptation or evolutionary adaptation (Torday, 2015a, 2015b, 2015c) as a function of the time-frame. As a stop-gap, cells will re-establish homeostasis through scarring; on a longer-term basis, between generations, signaling cells remodel structure– function developmentally (Demayo et al., 2002); cells will re-engineer themselves phylogenetically because environmental stresses persist. In turn, physiologic stress on internal organs causes elevated blood pressure, the increased blood flow through the microcirculation generating radical oxygen species (ROS) due to shearing of the capillary walls. ROS cause gene mutations and duplications (Storr et al., 2013) that further promote re-engineering of the structure–function relationships to reestablish homeostasis, ultimately giving rise to new species (Torday and Rehan, 2017). The nervous system, over the course of such tissue and organ re-engineering, evolved in tandem to monitor homeostasis, self-referentially remodeling to monitor the homeostatic state of the organism (Madadi et al., 2018). That evolutionary transcendence of structure–function forms the basis for seeing red in association

with pain.

11.5 The Hard Problem, No Longer Cellular re-engineering must also ultimately lead to allostasis. Such processes derive from the neuroendocrine hormones that have evolved for this role. They integrate the structure and function of tissues at the organismal level. For example, endothermy evolved for the existential relief of hypoxia during the water–land transition. During the step-wise process of cell–cell interactions for lung evolution (Torday, 2015a, 2015b, 2015c), the diameter of the alveoli became smaller and smaller, increasing the surface-area-to-blood-volume ratio, resulting in increased oxygen transfer (Clements et al., 1970). The intermittent periods of low systemic oxygen stimulated the hypothalamic–pituitary–adrenal axis, increasing the production of adrenaline by the adrenal cortex (Wong, 2003). Stimulation of alveolar surfactant production by adrenaline acutely alleviated the low levels of circulating oxygen (Lawson et al., 1978). Longer-term, PTHrP production by the alveolar type II cells is increased by the distension of the alveoli (Sanchez-Esteban et al., 1998); PTHrP promotes alveolar formation (Rubin et al., 2004). Oxytocin production by the hypothalamus evolved to supersede the stress-based mechanism of warmbloodedness, acting to control body temperature constitutively (Kasahara et al., 2013). Oxytocin also integrates the physiologic cell–cell interactions between the cone photoreceptors for color vision and the retinal photoreceptor epithelium (Halbach et al., 2015). Perhaps that is why we mentally associate “red” with physical pain.

11.6 The Integration of Consciousness and the Ecosystem “Disembodied Consciousness” (Clark and Chalmers, 1998) constitutes another unanswered enigma that challenges consciousness. Clark says that taking notes is a way to “extend” consciousness beyond ourselves, into the environment. That idea is like niche construction as a way of “extending” our internal physiologic environment out into our surroundings. It is a way for us to gain greater control over our domain (Laland et al., 2011). Darwin was the first to document the phenomenon of niche construction in his book The Formation of Vegetable Mould Through the Action of Worms, with Observations on their Habits (1881). In it, he noted that earthworms are able to retain their aquatic kidneys on land by manipulating the soil around them. That is, like beavers building dams, or people building towns. As has been presented previously, the cell is properly considered a niche construction in its own right. As the cell is the foundational unit in biology, it follows that niche construction would be a reiterating pattern across evolutionary space–time. In this way, niche construction can be seen as unifying the processes of evolutionary biology and ecology as one continuum (Torday 2016a), engendering the unicell as cosmologic (Morch, 2017). This way of conceiving the relationship of biology to physics runs counter to the way we think of the human condition along a line of identity between the ambiguity of our origins and coping through deception. The only means we have for extricating ourselves from this condition is the scientific method. Along these lines of thinking, David Bohm tells us that this has resulted from our highly evolved senses filtering our perception of the Explicate Order in order to survive (Bohm,

1980). But there is an Implicate Order obtainable through experimentation just beyond our natural perceptive abilities. The cellular approach to evolution provides a way of understanding structure and function systematically, based on experimentation (Torday and Rehan, 2012). Flipping the process of development for form and function around by 180 degrees has made otherwise dogmatic concepts transparent, ranging from evolution itself (Torday and Rehan, 2012), to the cell (Torday, 2015b), heterochrony (Torday, 2016d), the life cycle (Torday, 2016b), phenotype (Torday and Miller, 2016b), terminal addition (Torday and Miller, 2018) and homeostasis (Torday, 2015c). All can be coherently understood as the result of cellular processes emanating from elemental physical laws, reiterating across an evolutionary landscape.

11.7 Human Consciousness as Cell–Cell Communication Human cognition is considered the paragon of consciousness. One potential pathway toward that form of idiosyncratic ability can be deconstructed by tracing the evolution of warm-bloodedness (Torday, 2015a). Hominins have evolved to naturally walk on our hind legs (Marino, 2008). That trait would have proven impossible in cold-blooded organisms because of the inefficiency of their metabolism, requiring multiple isoforms of the same metabolic enzyme in order to function optimally at different ambient temperatures. Mammals, on the other hand, only require one form of any given metabolic enzyme. That renders their metabolism far more efficient, facilitating bipedalism, because it requires more energy than does quadrapedalism (Rodman and McHenry, 1980). Walking on hind legs relieved the forelimbs for tool-making. That directed selective advantage to a more complex peripheral and central nervous system to accommodate this newly acquired function. The novel combination of enhanced mobility and a more capacious nervous system facilitated interfacing with the environment and the collection of epigenetic marks. Consequently, hominins have ranged far and wide over the face of the Earth, and beyond, into space. Suffice it to say that the interplay between endothermy, locomotion and epigenetics fosters evermore complex consciousness in hominins. One way to consider consciousness is that it might be deeply related to cosmic connection. Consciousness could then be thought of as our innate knowledge of the laws of nature, in effect acting as our data operating system, with our physiology as software. If so, then this rationalizes the persistent feeling that many humans have that there is something greater than ourselves. David Bohm explores this in Wholeness and the Implicate Order (Bohm, 1980), in which two orders operate simultaneously, the Implicate Order of superimposed possibilities and the Explicate Order of our physical reality. Bohm's concepts merge comfortably with cosmic linkages, exactly the opposite of Raymond Kurzweil's vision of the Singularity of technology (Kurzweil, 2005). Kurzweil thinks that gadgets can propel us forward in the Explicate Order and ultimately explain everything. This perspective perpetuates the synchronic view of existence, but in so doing, it is missing the Implicate Order. If we are ever to develop truly deep knowledge of ourselves, our software will need to transcend the Explicate and move closer and closer, asymptotically, to the Implicate Order. Yet, it must be accepted that that journey has no end-point. We can never fully attain the entire scope of the Implicate Order because we are living, and our living purpose is to perpetually dwell within both the ambiguity of our origin, and those of our own making in our confrontation with an ever-changing

environment.

11.8 Consciousness Revealed by Cartesian Coordinates We make the systematic error of thinking that life is complicated (Torday, 2016c) because we exist between ambiguity and deception (Torday and Miller, 2017). We cope with our paradoxical existence by making up Just So Stories (Kipling, 1978). However, it can be appreciated that life is actually “simple.” This counterintuitive insight derives from merging cell–cell communication with the process of evolution (Torday and Rehan, 2012) and the mechanism of epigenetic inheritance, leading to the realization that the zygote is the primary level of selection. That is like Lewis Carroll expressing the idea that the Red Queen in “Alice in Wonderland” is running as fast as she can to stay in place (Torday, 2018). We hominins are also “running in place.” We acknowledge this by iteratively returning to the unicellular state over the course of our life cycle, when in reality we never leave it, in service to the first principles of physiology, which ultimately reference the Singularity (Torday, 2019). Carlo Rovelli, in his book, Reality is Not What it Seems (2014), tells us that time is an anthropocentric fallacy. This was exemplified as Darwin's metaphoric “Tangled Bank,” which is his expression for the complexities of life (1859). In evolutionary terms, the time component that we use to measure evolutionary “progress” is just an epiphenomenon. The real anthropocentric fallacy is our presumption that the macro-organic form of life is the point of evolution. However, examination of the planetary record reveals something different. The three cellular forms (prokaryota, archaea, eukaryota) are perpetual. All other life forms are ephemeral. The existing form is merely an epiphenomenon of the phenotype as agent (Torday and Miller, 2016a). That is, forms acting as vehicles for optimizing the adult organism's capacity to collect data from the on-coming environment. However, by reverse-engineering specific phenotypic traits like the lungs, kidneys, skin and brain from their present forms back to the unicell, their evolutionary paths project backwards as a set of Cartesian coordinates, towards an intersection with the Singularity (see Figure 11.1).

Figure 11.1

Regression of phenotypic evolution. Cell–cell interactions mediate the evolution of metazoan organs, originating with the Singularity/Big Bang.

It can be proposed that consciousness, too, has its origin from within the Singularity, no matter when its actual instantiation occurred. It can be proposed that deeper investigation into the properties of the unicell might offer further insights into that consciousness, by interrogating it through quantum mechanics, string theory, or elemental particles such as the Higgs boson, moving progressively forward towards our consciousness of the Singularity (Torday, 2019).

11.9 Consequences of the Hypothesis and Discussion It is a mistake to only regard consciousness in anthropocentric terms (Rowlands, 2016). Until now, we have had no rational alternative. But a novel mechanistic approach to evolution based on cell–cell signaling has offered a way of understanding our evolutionary origins based on a causal mechanism for life as a continuum (Torday and Rehan, 2012; Torday and Rehan, 2017). From that perspective, even the logic for “why we control a scientific experiment” (Torday and Baluska, 2019) can be brought into question, revealing how we deceive ourselves (Trivers, 2011) by reasoning after the fact using our subjective senses (Bohm, 1980). This realization reopens the case for logical empiricism (Hempel, 2000), given that the cellular approach to evolution provides mechanistic explanations for dogmas ranging from the cell (Torday, 2015b), to phenotype (Torday and Miller, 2016b), heterochrony (Torday, 2016d) and the life cycle (Torday, 2016b). It also has the power to predict that the zygote is the primary level of selection (Torday, 2016a), leading to the conclusion that life is “simple,” not complex as we tend to think, based on after-the-fact reasoning (Kauffman, 1996). The approach taken here to understanding consciousness correlates with Plattner

and Verkhratsky's perspective on the homologies between calcium signaling in both paramecia and neurons (Plattner and Verkhratsky, 2018), framing it in a cohesive context of evolution as all of biology (Torday, 2015a; Torday and Rehan, 2017). As such, it is consistent with Trewavas and Baluska's view of plants as conscious (Trewavas and Baluska, 2011), effectively allowing consciousness to encompass all organisms, unicellular, multicellular, plant and animal alike, linking them to the cosmos through endosymbiosis theory (Sagan, 1967; Margulis and Bermudes, 1985). This vantage point offers the prediction that there is a demonstrable continuum from the unicell to Gaia (Torday, 2016a), and to the Singularity of Nature (Torday, 2019).

References Bohm D., (1980, ), Wholeness and the Implicate Order, New York: Routledge & Kegan Paul. Cannon W. B., (1963, ), The Wisdom of the Body, New York: WW Norton. Chalmers D., Facing up to the problem of consciousness, J. Conscious. Stud., 1995, 2, 2002–2019. Clark A. and Chalmers D. J., The extended mind, Analysis, 1998, 58, 7–19. Clements J. A., Nellenbogen J. and Trahan H. J., Pulmonary surfactant and evolution of the lungs, Science, 1970, 169, 603–604. Damasio A., (2010, ), Self Comes to Mind, New York : Vintage Books. Darwin C., (1859, ), On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life, London : John Murray. Deamer D., The Role of Lipid Membranes in Life's Origin, Life, 2017, 7(1), 5. Demayo F., Minoo P., Plopper C. G., Schuger L., Shannon J. and Torday J. S., Mesenchymal-epithelial interactions in lung development and repair: are modeling and remodeling the same process?, Am. J. Physiol.: Lung Cell. Mol. Physiol., 2002, 283, L510–L517. Ghannoum M. A., Parsek M., Whitley M. and Mukherjee P., (2015, ), Microbial Biofilms, Washington : ASM Press. Halbach P., Pillers D. A., York N., Asuma M. P., Chiu M. A., Luo W., Tokarz S., Bird I. M. and Pattnaik B. R., Oxytocin expression and function in the posterior retina: a novel signaling pathway, Invest. Ophthalmol. Visual Sci., 2015, 56, 751–760. Hameroff S. and Penrose R., Orchestrated reduction of quantum coherence in brain microtubules: A model for consciousness, Math. Comput. Simulat., 1996, 40, 453–480. Hempel C. G., (2000, ), Selected Philosophical Essays, Cambridge: Cambridge University Press. Hobson J. A., Hong C. C. and Friston K. J., Virtual reality and consciousness inference in dreaming, Front. Psychol., 2014, 5, 1133. Kasahara Y., Sato K., Takayanagi Y., Mizukami H., Ozawa K., Hidema S., So K. H., Kawada T., Inoue N., Ikeda I., Roh S. G., Itoi K. and Nishimori K., Oxytocin receptor in the hypothalamus is sufficient to rescue normal thermonregulatory function in male oxytocin receptor knockout mice, Endocrinology, 2013, 154, 4305–4315. Kauffman S. A., (1996, ), At Home in the Universe, Oxford: Oxford University

Press. Kelz M. B. and Mashour G. A., The Biology of General Anesthesia from Paramecium to Primate, Curr. Biol., 2019, 29, R1199–R1210. Kipling R., (1978, ), Just So Stories, Sturbridge: Weathervane. Kurzweil R., (2005, ), The Singularity is Near, New York: Viking. Laland K. N., Sterelny K., Odling-Smee J., Hoppitt W. and Uller T., Cause and effect in biology revisited: is Mayr's proximate-ultimate dichotomy still useful?, Science, 2011, 334, 1512–1516. Lawson E. E., Brown E. R., Torday J. S., Madansky D. L. and Taeusch Jr. H. W., The effect of epinephrine on tracheal fluid flow and surfactant efflux in fetal sheep, Am. Rev. Respir. Dis., 1978, 118, 1023–1026. Libet B., Wright E. and Gleason W., Readiness potentials preceding unrestricted spontaneous pre-planned voluntary acts”, Electroencephalogr. Clin. Neurophysiol., 1983, 54, 322–325. Madadi Asl M., Valizadeh A. and Tass P. A., Propagation delays determine neuronal activity and synaptic connectivity patterns emerging in plastic neuronal networks, Chaos, 2018, 28, 106308. Margulis L. and Bermudes D., Symbiosis as a mechanism of evolution: status of cell symbiosis theory, Symbiosis, 1985, 1, 101–124. Margulis L. and Sagan D., (1995, ), What is Life?, Oakland : University of California Press. Marino F. E., The evolutionary basis of thermoregulation and exercise performance, Med. Sport Sci., 2008, 53, 1–13. McEwen B. S., Stress, adaptation, and disease. Allostasis and allostatic load, Ann. N. Y. Acad. Sci., 1998, 840, 33–44. Miller Jr. W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016, 4, 96. Miller W. B., Torday J. S. and Baluška F., The N-Space Episenome Unifies Cellular Information Space-Time within Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2019, 150, 111–139. Miller W. L., Steroidogenesis: Unanswered Questions, Trends Endocrinol. Metab., 2017, 28, 771–793. Mitchell P., Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism, Nature, 1961, 191, 144–148. Morch H. H., Is Matter Conscious?, Nautilus, 2017, 6. Moroi Y., Micelles, New York : Springer, 2013. Nagel T., What is it like to be a bat?, Philos. Rev., 1974, 83, 435–450. Plattner H. and Verkhratsky A., The remembrance of the things past: Conserved signalling pathways link protozoa to mammalian nervous system, Cell Calcium, 2018, 73, 25–39. Reber A., (2018, ), The First Minds, Oxford: Oxford University Press. Rodman P. S. and McHenry H. M., Bioenergetics and the origin of hominid bipedalism, Am. J. Phys. Anthropol., 1980, 52, 103–106. Romer A. S., (1949, ), The Vertebrate Story, Chicago: University of Chicago Press. Roux E., The concept of function in modern physiology, J. Physiol., 2014, 592, 2245–2249. Rovelli C., (2014, ), Reality is Not What it Seems, New York: Riverhead Books. Rowlands P., (2016, ), The Foundations of Physical Law, Singapore: WSPC. Rubin L. P., Kovacs C. S., De Paepe M. E., Tsai S. W., Torday J. S. and

Kronenberg H. M., Arrested pulmonary alveolar cytodifferentiation and defective surfactant synthesis in mice missing the gene for parathyroid hormone-related protein, Dev. Dyn., 2004, 230, 278–289. Sagan L., On the origin of mitosing cells, J. Theor. Biol., 1967, 14, 225–274. Sanchez-Esteban J., Tsai S. W., Sang J., Qin J., Torday J. S. and Rubin L. P., Effects of mechanical forces on lung-specific gene expression, Am. J. Med. Sci., 1998, 316, 200–204. Schopenhauer A., (2018, ), The World as Will and Representation, Cambridge: Cambridge University Press. Storr S. J., Woolston C. M., Zhang Y. and Martin S. G., Redox environment, free radical, and oxidative DNA damage, Antioxid. Redox Signaling, 2013, 18, 2399–23408. Torday J. S., A central theory of biology, Med. Hypotheses, 2015a, 85, 49–57. Torday J. S., The cell as the mechanistic basis for evolution, Wiley Interdiscip. Rev.: Syst. Biol. Med., 2015b, 7, 275–284. Torday J. S., Homeostasis as the Mechanism of Evolution, Biology, 2015c, 4(3), 573–590. Torday J. S., Life Is Simple—Biologic Complexity Is an Epiphenomenon, Biology, 2016a, 5(2), 17. Torday J. S., The Cell as the First Niche Construction, Biology, 2016b, 5(2), 19. Torday J. S., The Emergence of Physiology and Form: Natural Selection Revisited, Biology, 2016c, 5(2), 15. Torday J. S., Heterochrony as Diachronically Modified Cell-Cell Interactions, Biology, 2016d, 5(1), 4. Torday J. S., Quantum Mechanics predicts evolutionary biology, Prog. Biophys. Mol. Biol.,2018, 135, 11–15. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S. and Baluska F., Why Control an Experiment?, EMBO Rep., 2019, 20, e49110. Torday J. S. and Miller W. B., Biologic relativity: Who is the observer and what is observed?, Prog. Biophys. Mol. Biol., 2016a, 121, 29–34. Torday J. S. and Miller Jr. W. B., On the Evolution of the Mammalian Brain, Front. Syst. Neurosci., 2016b, 10, 31. Torday J. S. and Miller Jr. W. B., The resolution of ambiguity as the basis for life: A cellular bridge between Western reductionism and Eastern holism, Prog. Biophys. Mol. Biol., 2017, 131, 288–297. Torday J. S. and Miller Jr. W. B., Terminal addition in a cellular world, Prog. Biophys. Mol. Biol., 2018, 135, 1–10. Torday J. S. and Rehan V. K., Lung evolution as a cipher for physiology, Physiol. Genomics, 2009, 38, 1–6. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology: Cell–Cell Communication, and Complex Disease, Hoboken: Wiley. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, Hoboken: Wiley. Trewavas A. J. and Baluška F., The ubiquity of consciousness, EMBO Rep., 2011, 12, 1221–1225. Trivers R., (2011, ), The Folly of Fools, New York: Basic Books. Winans S. C. and Bassler B. L., (2008, ), Chemical Communication Among Bacteria, Sterling: ASM Press.

Woese C. R., Bacterial Evolution, Microbiol. Rev., 1987, 51, 221–271. Wong D. L., Why is the adrenal adrenergic?, Endocr. Pathol., 2003, 14, 25–36.

CHAPTER 12

Cell Division Seen as the Symmetry Breaking of the Singularity/Big Bang 12.1 Introduction Profound shifts in our understanding of our physical world have been the product of unconventional radical approaches to the received wisdom of that time. Examples include Einstein's revolutionary theory of relativity, Archimedes discovering the principle of buoyancy, and Alfred Wegener's tectonic plate theory. In the case of evolution, a similar transition stems from centering it within a framework of cell biology instead of population genetics (Torday and Rehan, 2012; Miller, 2016a; Miller, 2017; Miller and Torday, 2018). Historically, cell biology was rejected by evolutionary biologists back in the nineteenth century (Smocovitis, 1996) in favor of the newly emerging science of genetics, leading to the central dogma of biology – DNA:RNA:Protein (Watson, 2001) – as the determinate operating mechanism, instead of understanding the cellular mechanisms of evolution.

12.2 Homeostasis Is the Common Ground Between Physics and Biology Homeostasis is one of the three ontologic principles of cell physiology (Torday and Rehan, 2012) codified as negentropy, chemiosmosis and homeostasis. Morowitz has asserted that biological mechanisms are all homologous with basic physical principles that begin with electrons and protons balancing out one another (Morowitz, 2002). It is noteworthy that the homeostatic process exhibits features that can be viewed as homologies between physics and biology; namely, the Pauli exclusion principle, the Heisenberg uncertainty principle, and the principles of coherence, non-locality and wave collapse. Conversely, physics can also be understood in biologic terms. For example, Lee Smolin has rechanneled Darwinian evolution to explain cosmology. Therefore, it should not be surprising that physics can be exploited to explain evolution. Specifically, aspects of quantum mechanics have been found to be essential in understanding cell biology (Miller, 2016a; Miller, 2017; Miller et al., 2020; Torday, 2019). Because of these interrelationships between physics and biology, the former should be expected to predict the characteristics of the latter. The premise of this chapter is that cell division is a manifestation of the Singularity/Big Bang. It is proposed that this novel viewpoint provides an explanation for cell division, furthering our understanding of it for the first time beyond its mere description. It has previously been argued that the animate living frame exhibits selfreferential and self-organizational properties that derive as an equal and opposite reaction to the Big Bang, based on Newton's third law of motion (Torday and

Miller, 2017). With that as a base, mitotic cell divisions themselves can be seen as recurrent echoes of the breakup of the absolute symmetry of the Singularity, and meiotic recombination as a reverberating re-establishment of that symmetry as a further type of rechanneling of Newton's third law. One requirement of this re-exploration of biology is to question the nature of both time and space as they relate to biological phenomena. Certainly, on a conventional level, both space and time seem like absolutes based within our own obvious physical reality. Within our corporeal selves, we consistently gauge space and time as distinct and separate. However, others have seen it differently. For instance, Einstein regarded space and time as a continuum. For him, space and time are inseparable and together they make the actual reality of “space-time,” for which his equations for the theory of relativity apply. Instead of absolutes, space and time are relative to one another within the fabric of “space-time.” Time does not flow in any conventional sense as a definitive sequence of events. It is a consistent set of concurrent moments, separate from an actual historical vector. All of time exists at once, just as the universe does, from the instant of the Big Bang inflation onward. We know that we occupy some spot in space, and we accept that there is an immense amount of additional space, even though we do not occupy it. Time is similar; that is, it is not just as a present now, but is an eternal time (Tozzi et al., 2018). The great physicists Richard Feynman and Steven Hawking shared similar views. For Feynman, time was just a direction in space, or “random walk,” rather than an absolute chronology. With that as background, it is possible to re-examine biology from the concept that what we casually regard as an evolutionary history of time may not be as fundamentally applicable as the fossil record encourages us to believe. An alternative can be proposed. Once self-referential self-organization began, evolution proceeded on a different course that can stand apart and alongside the particulars of the fossil record. From the point of view of cell biology, the centrality of evolution is the cellular forms that have existed for billions of years (Miller and Torday, 2018). In this framework, evolution is the continuous perpetuation of the three cellular domains (prokaryota, archaea, eukaryota). Evolution is therefore largely timeless since all the wondrous creatures that capture our attention are there to deploy their various phenotypes to explore the environment and gather epigenetic marks for maintaining and sustaining the unicellular state as their perpetual adaptive life form. In essence, because of the self-referential, self-organizing nature of biology, life has “authored itself” as timeless, to remain consonant with conditions imposed by the Singularity/Big Bang. Indeed, since everything originates with the Singularity, by definition, the pertinent question is exactly how biology complies with natural law and the further details of how its exquisite manifestations occurred. In support of that unorthodox perspective, the cytoskeleton inheres all three states of the cell – homeostasis, mitosis and meiosis – within itself. Mechanistically, these states of the cell are determined by the target of rapamycin gene, which also servocontrols many of the physiologic elements of the cell (ions, gases, nutrients, mechanotransduction) by acting through the cytoskeleton. As a result of such selfreferential and self-organizing actions, cell division can be considered as biology's self-reflexive expression of the symmetry breaking that was first realized by the Singularity/Big Bang. Since it is well accepted that biology is a series of fractal reiterations, it can be argued that the symmetry breaking of cell division is a direct reiteration of the Big Bang, whose universal expansion is considered as the first and most fundamental symmetry breaking event (Mainzer, 2005).

Is cell division “symmetry breaking?” Certainly, both cell division and homeostasis have been described by other researchers as gauge symmetry breaking (Tozzi et al., 2016). It is certainly an elemental part of the biological order. All known life is cellular, and cellular division is essential to the maintenance of the living state. However, if evolution is timeless in its task of the illimitable perpetuation of the cellular form, then cell division itself is part of that timeless system, since it is absolutely necessary for that perpetuity. That case is strengthened by noting that this timeless perpetuity is sustained by epigenetic processes. It is this epigenetic feedback that modulates organismal inheritance that maintains the fundamental unicellular forms by consistently permitting the endogenization of the outside environment. This is how biology ensures continuous organismalenvironmental complementarity. Yet that epigenetic process is explicitly centered within cell division. Two conclusions emerge from this. First, cell division is essential to life. And secondly, all of biology in some direct manner to fundamental physical forces emanating from the Singularity and cell division must, too. It directly follows that the process of cellular splitting and reorganization can be reasonably analogized to symmetry breaking and its reiterative restoration. From this, it can now be understood that Darwinian interpretation of how reproduction functions on an evolutionary basis is deeply flawed, and merely being characterized based on descriptive biology. Darwin necessarily concentrated on what he could see with the naked eye, and centered his arguments on the primacy of the adult reproductive stage. However, when cellular-molecular mechanisms are examined, the true epicenter of evolutionary action is at the level of the unicellular zygote, produced through meiosis. This is the stage that yields the critical adaptations to an ever-changing environment. It is during meiotic reduction division and combination within the zygote that epigenetic marks gleaned from the environment are somehow identified as to which will be retained and expressed, which will be up- or downregulated, and which will be expunged (Torday and Miller, 2016a, 2016b). At that point in the process, DNA is chemically bound to methyl groups or histones in order to modify the genetic readout in accord with those epigenetic marks to permit epigenetic modifications of living organisms to become heritable changes.

12.3 Are We in the Cosmos or of the Cosmos? The consensus regarding human beings’ place in the cosmos is expressed by the anthropic principle. In that perspective, we are simply fortunate to have ended up in this universe, which is “just right” for our physiology. However, it is possible to turn that inside out. Instead of glibly assuming that we have been simply lucky to be on this hospitable planet, it is possible to counter that life has succeeded despite an inhospitable planet. That hard-won success is the net result of the serial endogenizations of factors in the environment that would otherwise have destroyed us long ago, such as gases, heavy metals, ions and gravity. Life is here because it can compartmentalize a treacherous environment into living physiologic mechanisms. Life succeeds here because it is not merely a part of the universe and on this planet, but is “of” the planet and the greater universe. From the origin of life onward, endogenization has acted in service to the maintenance of homeostasis. That origin has been hypothesized to have been the result of lipids embedded in snowball-like asteroids bombarding the atmosphereless Earth, forming the oceans some 3.8 billion years ago. The Earth was dominated by unicellular organisms for 3.5 billion years. Multicellular eukaryotic organisms

have subsequently evolved over the course of the last 500 million years in intimate collaboration with bacteria and archaea. True, these latter domains have their own means of separate survival by practicing quorum sensing and forming biofilm. Yet, all macro-organic eukaryotes are holobionts as a combined form of multi-domain cellular life, sustained by cell–cell communications (Miller, 2013; Miller, 2016a; Miller, 2016b). In effect, a holobiont can be seen as just another form of endogenization of the planetary environment. For all the varieties of participants, cell–cell communications became the mechanism for metazoan development, homeostasis and repair, based on the self-referential, self-organizational basis of life. The subsequent evolution of life was caused by the ever-changing environment, challenging organisms to adapt or become extinct. This was particularly true for atmospheric oxygen, which is needed to fuel metabolic drive, beginning with the appearance of cholesterol, requiring 11 atoms of oxygen to synthesize one molecule of cholesterol. The appearance of cholesterol in the cell membrane made the membrane more compliant, enhancing locomotion, metabolism and oxygenation, the three fundamental principles of vertebrate evolution. The utility of cholesterol in vertebrate evolution raises the question as to why lipids were employed in the face of rising oxygen levels in the atmosphere? Since evolution is characterized by serial pre-adaptations, or exaptations, it raises the question as to what event occurred prior to the advent of cholesterol that facilitated life. It is distinctly possible that the lipids present on the asteroids that populated the primordial Earth to form the oceans also gave rise to micelles, which spontaneously form from lipids immersed in water. Micelles provided a protected space for the evolution of catalysis, fueled by chemiosmosis, fostering negative entropy, maintained by homeostatic control. That, in turn, raises the question as to what the precedent for the micelle was? As a “unity,” the prototypical micelle can be considered, at least metaphorically, as resembling the Singularity. In response, based on Newton's third law of motion, there would have been an equal and opposite reaction, promoting the resolution of the symmetries broken by that cataclysmic explosion into localized forms of “unity.” Life began as an ambiguity characterized by the two conditional living realities: internal negative entropy and external positive entropy and the inherent ambiguity of all the information upon which life depends. The cell has the capacity to recognize ambiguities, temporarily resolve them through endogenizing and compartmentalizing them and harnessing them as physiology. From within this framework, one way to regard consciousness is that it is the further endogenization of environmental properties that obey the laws of nature. This internalization forms the basis for what we think of as consciousness, or “consciousness as the mind's idea of physiology.” In that case, our consciousness is our internally subjective version of the aggregated external environment. And taking this frame further, consciousness can be seen as ultimately referencing the Singularity of the Big Bang, either as its origin or as a derivative instantiation that followed.

12.4 Epigenetic Inheritance It has been proposed that cell division is a biologic homolog of the Big Bang. Still, that does not explain why it occurs. One possible explanation is that this was the only cellular means of achieving sustainable epigenetic inputs. Based on epigenetic inheritance, the organism acts as an “agent” for the collection of epigenetic marks

that inform the offspring of changes in the environment. In order to communicate such “marks” to the next generation, the organism must reproduce. It might simply be that it is only through cellular reproduction that cells can accomplish this, i.e. the immortality of the three eternal cellular forms is specifically conditioned within reiterative reproduction. In other words, there can be no such thing as an immortal single cell based on physical laws, so the living form must be a perpetual refreshment of those first principles from which it is instantiated.

12.5 The Systematic Error in Seeing the Phenotype as Object, Not Agent The radical concept that the purpose of phenotype is to act as an agent of environmental exploration is based on our growing knowledge that the phenotype is an (inter)active mechanism for collecting epigenetic marks. It is not the end-point, as Darwinists construe. The phenotype is simply a biomaterial iteration of the living process of life as a verb rather than a noun. Some examples can be offered in support of this unconventional viewpoint.

12.5.1 Yeast/Lung/Bone/Gravity Gravitational effects are one prime example of phenotype as process. For example, when yeast are put into microgravity, their capacity to polarize (orient) and to bud (reproduce) is impaired. This reduction in the ability to polarize can be analogized as rendering the organism “comatose” because it cannot conduct calcium fluxes as a primary form of cellular communication. Since budding is yeast reproduction, its impairment obviates the possibility of epigenetic inheritance. Similarly, when lung or bone cells are exposed to microgravity they lose some of their evolved capacity for intercellular communication, limiting their ability to express all aspects of their mature evolved phenotypes.

12.5.2 Turritopsis dohrnii Turritopsis dohrnii is considered an “immortal” jellyfish, which regresses to its immature form under stress. It has a highly complex life cycle, achieving its relative “immortality” by being entirely clonal throughout that life cycle. This way, although individual cells die, the clonal lineage has no inherent limitation to its lifespan. Reverting to an immature polypoid stage requires “transdifferentiation” as a process of cell development in which cells transform into new cell types (Matsumoto et al., 2019). Research indicates that this process involves significant shifts in the clonal transcriptome, meaning that this transitive process, including its multi-stage life cycle, is the jellyfish's solution to acquiring and imprinting epigenetic alterations that permit consistent conformity with environmental necessities.

12.5.3 Slime Mold, or Dictyostelium discoideum Under conditions of nutrient stress, the amoeboid form of Dictyostelium will revert to its sessile colonial phenotype. Given that these two divergent phenotypes collect epigenentic marks, but exhibit radically different behaviors, this strategy may be in service to the phenotype-appropriate collection of epigenetic marks, wherein there

are potential dual mechanisms for experiencing the environment. Importantly though, Dictyostelium discoideum exist for long periods in a unicellular life form (Schaap, 2011), supporting the phenotype-as-process-agent concept.

12.5.4 Nutrient Restriction Model of Metabolic Syndrome The inter-generational consequences of human starvation were fist documented in studies of the “Dutch Hunger Winter.” Children born to women who experienced that event became obese and hypertensive, which is characteristic of metabolic syndrome. When laboratory animals are used to model this phenomenon, their offspring also develop metabolic syndrome in association with accelerated puberty, due to premature adrenarche, which accelerates sexual maturity. Apparently, metabolic syndrome has physiological links to premature sexual maturity. Both can be considered, in a medical sense, as manifestations of an accelerated life cycle. It may be that by using this strategy, an organism hastens its entry into a more desirable food-abundant environment, making up for the reproductive deficit that is routinely experienced during times of famine.

12.5.5 Piaget's Perspective on Human Development The developmental psychologist, Jean Piaget, hypothesized that infants experience protracted childhoods in order to allow our over-sized brains to develop fully by occupying each of the stages of development in succession – on the breast, crawling, toddling, adolescence, teenage-hood, adulthood – for protracted periods of time. The complication for this theory is that each of these developmental stages toward adulthood imposes some limits on exploration of the environment, which reciprocally affects which epigenetic marks can potentially be acquired. This speculation, contrary to Piaget, is reinforced by the epigenetic control of the endocrine system, inferring that the stages of the life cycle, which are under hormonal control, are being directed epigenetically. To frame this phenomenon of epigenetic control, the developmental biologist Lewis Wolpert has famously said it is “not birth, marriage or death, but gastrulation which is truly the most important time in your life.” That is because it is at that stage of embryological development that the mesoderm appears between the endoderm and ectoderm. The mesoderm confers plasticity of the other two germ layers during development, and it is under hormonal control.

12.6 Discussion 12.6.1 Cell Division as the Singularity/Big Bang: Reductio Ad Absurdum of Holistic Cosmology? The position being defended is that physics and biology are homologous at the quantum mechanical/unicellular level, and that cell division is the biologic equivalent of the symmetry breaking that was first expressed by the Singularity/Big Bang. This way of linking biology to fundamental physical processes is contrary to conventional perspectives, but has the advantage of explicating many biologic properties such as homeostasis, heterochrony, pleiotropy, the life cycle and terminal addition. All have been abundantly described, but their origins have never been

explained. However, if biology is given a new starting point, with the Singularity/Big Bang as the archetype for cell division and all other cellular processes with their own homologues, it opens up to new avenues of thought and permits biology to transcend being merely descriptive.

12.6.2 Space-time is an Artifact The role of the supporting structures of the cell is clarified. It can now be understood that the cytoskeleton and its control of homeostasis, meiosis and mitosis, and its active correspondence with target of rapamycin (TOR) signaling are all directed towards maintaining and perpetuating the equipoise of the perpetual unicellular form. This can be productively restated. All aspects of the cell, including genes, are tools of cellular homeostasis and reproduction as reiterations of fundamental physical processes that begin with the Singularity. As has been defined, in order to grasp the analogous homology between cell division and the Singularity/Big Bang, space and time must be re-cast. Consequently, the role of time in biology that forms the basis of Darwinian evolutionary theory can be viewed as a subjective artifice. Instead, in actual “spacetime,” evolution begins and ends with the fundamental unicellular forms. All that can be observed biologically is in service to their perpetuation, for they are timeless, and we, both individually and as a species, are not. Clearly, this is not a comforting thought, since instead of our being an evolutionary pinnacle, we would need to reappraise our role as just one of myriad evolutionary players whose adventurous acquisition of epigenetic experiences is purposed for their return to the primal unicell as part of the requisite of its survival. We participate in our own unique manner through our restless exploration of our planetary environment. In our own way, we acquire a great variety of epigenetic marks that permit a wide range of subtle phenotypic variations that promote a consistent endogenization of the planetary environment. Thus, we are useful participants in the perpetuation of our unicellular line, which is one branch of a universal eukaryotic cellular domain. Thus, our obligatory recapitulation through the unicellular zygotic form is explained. We are participants in a timeless biology as useful cellular iterations of elemental physical laws. It can be hoped, then, that through such a radical shift in our perspective, by finally grasping our planetary place in support of perpetual unicellular life, that this might lead to a re-calibration of our sense of self in the biosphere that drives us toward greater planetary responsibility.

References Mainzer K., (2005, ), Symmetry and Complexity: The Spirit and Beauty of Nonlinear Science, Hackensack: World Scientific Pub Co Inc. Matsumoto Y., Piraino S. and Miglietta M. P., Transcriptome characterization of reverse development in Turritopsis dohrnii (Hydrozoa, Cnidaria), G3: Genes, Genomes, Genet., 2019, 9, 4127–4138. Miller Jr. W. B., (2013, ), The Microcosm Within: Evolution and Extinction in the Hologenome, Boca Raton: Universal Publishers. Miller Jr. W. B, Cognition, information fields and hologenomic entanglement: evolution in light and shadow, Biology, 2016a, 5, 21. Miller Jr. W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016b, 4, 96.

Miller Jr. W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Miller Jr. W. B., Torday J. S. and Baluška F., The N-space Episenome unifies cellular information space-time within cognition-based evolution, Prog. Biophys. Mol. Biol., 2020, 150, 112–139. Miller W. B. and Torday J. S., Four Domains: The Fundamental Unicell and PostDarwinian Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2018, 140, 49–73. Morowitz H., (2002, ), The Emergence of Everything, Oxford: Oxford University Press. Schaap P., Evolutionary crossroads in developmental biology: Dictyostelium discoideum, Development, 2011, 138, 387–396. Smocovitis V. B., (1996, ), Unifying Biology, Princeton: Princeton University Press. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S. and Miller Jr. W. B., Biologic relativity: Who is the observer and what is observed?, Prog. Biophys. Mol. Biol., 2016a, 121, 29–34. Torday J. S. and Miller Jr. W. B., The Unicellular State as a Point Source in a Quantum Biological System, Biology, 2016b, 5(2), 25. Torday J. S. and Miller Jr. W. B., The resolution of ambiguity as the basis for life: A cellular bridge between Western reductionism and Eastern holism, Prog. Biophys. Mol. Biol., 2017, 131, 288–297. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology: Cell–Cell Communication, and Complex Disease, Hoboken: Wiley. Tozzi A., Peters J. F., Chafin C., Torday D. and De Falco J. S., A timeless biology, Prog. Biophys. Mol. Biol., 2018, 134, 38–43. Tozzi A., Peters J. F., and Marijuán P. C., (2016, ), In Search of Gauge Theories for Living Cells: A Topological Exploration on the Deep Structure of Biological Complexity, http://vixra.org/pdf/1610.0021v1.pdf. Watson J. D., (2001, ), The Double Helix, New York: Touchstone.

CHAPTER 13

Minding the Gap, or the Unicell Fills the Gap Between Proximate and Ultimate Causation Etienne Roux, a French physiologist, has stated that describing the function of physiologic properties is not the same as understanding the “how and why” of any given trait (Roux, 2014). He points out that there is a significant constraint on the mission to understand the ontology and epistemology of evolution if proceeding according to Ernst Mayr's attempted justification in his classic essay, “ProximateUltimate Causation.” The proximate determination of how things work and the ultimate process by which they actually work can be independent of one another. The two are not necessarily causally related, which discourages any attempt to connect micro- and macro-causal associations. In this same regard, Mayr's stance was also taken to task by Kevin Laland et al. in their article, “Cause and Effect in Biology Revisited: Is Mayr's Proximate-Ultimate Dichotomy Still Useful?” (LaLand et al., 2011). That article called for a “reciprocal” view of evolution in order to better synthesize the mechanisms of evolution. That synthesis, their extended evolutionary theory, maintained that the issue of causation can only be explored by recognizing that organisms have a means of directly reciprocating with their contemporaneous environment through epigenetic mechanisms. Even though this principle is squarely in keeping with the central theme of this book, unfortunately, their synthesis generally ignores cells in favor of concentrating on macro-organisms. Even though some academics express their conflicts with conventional Darwinism, there is no ready recognition of the primacy of cellular mechanisms or any specific understanding of how central cellular mechanisms cohere to any understanding of biological and evolutionary development. According to Vassiliki Betty Smocovitis's book, Unifying Biology (1996), this situation is due to an “accident” of history. Evolutionists of the mid-nineteenth century became enamored of a fledgling form of genetic inheritance in lieu of Schleiden and Schwann's cell theory in order to sustain the momentum of Haeckel's biogenetic law and Spemann's identification of the embryologic “organizer” in tadpole development. In subsequent decades, this trend has been consistently amplified by our increasing knowledge of DNA and RNA, which has led to a philosophical biology based on the primacy of genes rather than cells. As an alternative, Torday (2016) emphasized the central role of the cell in evolution by merging a cellular approach to evolution with niche construction theory by hypothesizing that the unicell was the first niche construction (Torday, 2016); and then, further, Torday connected the cell across evolutionary space-time as a Singularity of Nature (Torday, 2019). Such a perspective, acting to integrate all aspects of biology as a concerted process within evolution, akin to Dobzhansky's

dictum that “Evolution is all of biology” (Dobzhansky, 1973) was long overdue. None of the established dualisms in biology, whether they be issues of proximate versus ultimate, gene mutation/natural selection, ontogeny/phylogeny or health and disease can be explored with any rigor except through a cell-based approach to cellcentered non-random processes rather than random genetic mutations, and none can be coherently understood without placing self-referential self-organization at the center (Miller, 2016; Miller, 2017; Miller et al., 2019). As a pertinent example of the utility of the cellular-molecular approach, the elegant explanation for the evolution of the glucocorticoid receptor from the mineralocorticoid receptor provides a description of the change in the binding site of the latter due to the addition of three peptides (Bridgham et al., 2006), but fails to hypothesize the mechanism underpinning that series of events, the assumption being that such an adaptation was due to a Darwinian random mutation. However, it has been previously hypothesized that these mutations were the result of shear stress on the microvasculature, producing radical oxygen species known to generate gene mutations and duplications like those described for the evolutionary duplication of the glucocorticoid receptor. This event is proposed to have occurred during the vertebrate water-land transition, in which physostomus fish self-selected to adapt to land. A clue can be found in the configuration of their swim bladder that gives their species its name, “physostomous,” a pneumatic duct connecting the esophagus to the bladder as a structure that is homologous with the trachea of transitional amphibians and land vertebrates. In support of this hypothesis, the top 50 transcribed genes mediating the development of the swim bladder of physostomous zebra fish are identical to those found in the developing lung (Zheng et al., 2011). So the consideration of the context in which a specific gene mutation occurred as exaptations based on pre-adaptive structure provide hypothetical constraints on variables for the prevailing causal conditions that mediate any given evolutionary change in question. Using this approach, the evolution of the gasexchanger could be traced back to the unicellular state based on congruent developmental, phylogenetic and gene deletion experiments, providing an evidencebased explanation for the evolution of the lung alveolus. Other experiments have explored other like-kind pathways. Torday et al. (2009) showed that treatment of the Xenopus tadpole lung with leptin, a key signaling molecule in the development of the mammalian lung, stimulated its structural and functional development, causing thinning of the gas-exchange surface and increased lung surfactant protein. Similarly, the evolution of the vertebrate glomerulus from the glomus of the fish kidney (Smith, 1953) can be traced using the same approach. And since both of these evolved traits appear during the water-land transition, this approach can be expanded to other traits that evolved during this period of vertebrate evolution, particularly those determined by the duplication of the parathyroid hormone-related protein receptor (PTHrPR), glucocorticoid receptor (GR) and β–adrenergic receptor (β–AR). This perspective has proven invaluable for a more broad-based understanding of the “how and why” of vertebrate evolution (Torday and Rehan, 2012; Torday and Rehan, 2017). For example, the true nature of the heart has been questioned by Binney, not confining its definition to its description as a pump, but indicating that it perhaps originated from within a set of evolutionary principles that would provide greater insight to heart health and disease, echoing Roux's concern about defining physiologic traits based on their overt functions. Anecdotally, the stem cells for the formation of the developing heart in Ciona intestinalis arise from the “beating” tail,

potentially providing insight to the origin of the heartbeat. Further, it has been observed that inhibiting β–AR signaling in embryonic mice results in failure to form a four-chambered heart, resulting instead in a three-chambered frog-like heart, intimating the role of the β–AR in heart evolution. Not all such mutational events are necessarily an adaptive advantage, as Gould and Lewontin pointed out in their classic essay, “The Spandrels of San Marco” (Gould and Lewontin, 1979). When vertebrates moved from water to land some 500 million years ago, cellular problem-solving was directed toward increased barrier function in the lung, kidneys and skin in order to adapt to terrestrial conditions. This was apparently accomplished by molecular changes in type IV collagen (MacDonald et al., 2006), which acts to support the walls of the air sacs, glomeruli and skin infrastructure. Based on studies of Goodpasture syndrome, the three alpha isoforms of type IV collagen appeared sometime between fish and amphibians during vertebrate phylogeny, i.e. the water-land transition. It was the result of amino acid substitutions that rendered the barrier more hydrophobic and negatively charged, forming a molecular barrier for preventing the leaking of water and electrolytes from the microcirculation of the alveolar and glomerular spaces, in turn allowing for increased exchange of gases, fluids and electrolytes necessary for life on land. Goodpasture syndrome is an autoimmune disease that causes the failure of the kidney, lung and skin barriers that are interposed between the microvasculature and external space. The failure of these barriers is caused by an immune reaction to the α3 chain of type IV collagen (α3[IV]NC1) in the basement membranes of alveoli and glomeruli. This is referred to medically as the Goodpasture autoantigen. The basement membranes of worms, flies and fish do not have such antigens, whereas those of frogs, chickens, mice and humans do, indicating an evolutionary basis for this disease.

13.1 The Unicell as Resolution of the Mayr's Proximate and Ultimate Causation in Evolution Mayr's proximate and ultimate processes exist in two different time frames, the synchronic in the case of the proximate, and the diachronic in the case of the ultimate. This presents an inherent dichotomy, but it is resolved at the level of the unicell, which exists in both realms simultaneously across evolutionary space-time as a perpetual cellular form, which acts through its unification of the proximate and ultimate. Mayr's schema was an attempt to make sense of an evolutionary process that was presumed to be based on the adult form, best understood through its reproductive capacity. Now, a more fully informed perspective is available. Cellular mechanisms and requisites have primacy. The adult stage exists to gather epigenetic information from the outward environment through the expediency of phenotype, only to be returned to the unicellular form to assure its perpetuation. When both are acceded, the proximate and ultimate have no proper meaning in evolution: causation is ever and always epicentered at the unicellular level.

References Bridgham J. T., Carroll S. M. and Thornton J. W., Evolution of hormone-receptor complexity by molecular exploitation, Science, 2006, 312, 97–101.

Dobzhansky T., Nothing in biology makes sense except in the light of evolution, Am. Biol. Teach., 1973, 35, 125–129. Gould S. J. and Lewontin R. C., The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme, Proc. R. Soc. B, 1979, 205, 581–598. Laland K. N., Sterelny K., Odling-Smee J., Hoppitt W. and Uller T., Cause and effect in biology revisited: is Mayr's proximate-ultimate dichotomy still useful?, Science, 2011, 334, 1512–1516. MacDonald B. A., Sund M., Grant M. A., Pfaff K. L., Holthaus K., Zon L. I. and Kalluri R., Zebrafish to humans: evolution of the alpha3-chain of type IV collagen and emergence of the autoimmune epitopes associated with Goodpasture syndrome, Blood, 2006, 107, 1908–1915. Miller Jr. W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016, 4, 96. Miller Jr. W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Miller Jr. W. B., Torday J. S. and Baluška F., Biological evolution as the defense of ‘self’, Prog. Biophys. Mol. Biol., 2019, 142, 54–74. Roux E., The concept of function in modern physiology, J. Physiol., 2014, 592, 2245–2249. Smith H., (1953, ), From Fish to Philosopher, Boston: Little Brown. Smocovitis V., (1996, ), Unifying Biology, Princeton: Princeton University Press. Torday J. S., Life Is Simple—Biologic Complexity Is an Epiphenomenon, Biology, 2016, 5(2), 17. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S., Ihida-Stansbury K. and Rehan V. K., Leptin stimulates Xenopus lung development: evolution in a dish, Evol. Dev., 2009, 11, 219–224. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology: Cell–Cell Communication, and Complex Disease, Hoboken: Wiley. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, Hoboken: Wiley. Zheng W., Wang Z., Collins J. E., Andrews R. M., Stemple D. and Gong Z., Comparative transcriptome analyses indicate molecular homology of zebrafish swimbladder and mammalian lung, PLoS One, 2011, 6, e24019.

CHAPTER 14

The Big Bang: The Vectoral Origin of the Periodic Table and Evolution 14.1 Introduction Science (Whyte, 1929; Wilson, 1999) and the humanities (Snow, 1959) are analytic or intuitive ways, respectively, of expressing the true nature of the cosmos (De Chardin, 1979; Kahn, 1979; Whitehead, 1978), yet the fundamental basis for this remains elusive (Polanyi, 1968; Prigogene and Stengers, 1984). Indeed, there are scientific breakthroughs based on experimentation that encourage us to continue seeking the ultimate truth of the cosmos, such as heliocentrism, the gas laws, the periodic table, evolutionary biology, the Big Bang and relativity theory. Hypothetically, the common origin for these should be identifiable as self-similar patterns. The identification of such self-similar patterns in the periodic table and evolutionary biology are the basis for this chapter.

14.2 The Periodic Table of Elements and You Eric Scerri (2006) tells us that Mendeleev rearranged the elements based on their atomic number, and also used their chemical reactivity as a guide for constructing his version of the periodic table. Such use of empirical knowledge is like conceiving of evolutionary biology based on the cell–cell communication mechanisms of developmental biology (Torday and Rehan, 2012); the three primary germlines – endoderm, mesoderm and ectoderm – interact with one another, ultimately giving rise to offspring. Since embryologic mechanisms are the only way we know of generating form and function biologically, by merging the developmental mechanisms with phylogenetic changes in phenotype the underlying mechanisms of change from the swim bladder to the lung, or the fish kidney glomus to the glomerulus are revealed (Torday and Rehan, 2012). Development and phylogeny are conventionally thought of as time-based processes. But since the physicists tell us that time does not exist (Feynman, 2011; Rowlands, 2011; Canales, 2015), the time-related properties of biology default to space. In 1888, William Crookes speculated that the periodic table could be explained in terms of a spiral representation of progressive evolutionary genesis of the elements in his Presidential address to the Chemical Section of the British Association. That way of thinking leads to consideration of how the dual forces of decreasing entropy and the sinusoidal oscillations/electric force yielding a double helical generation of elements would coincide with biology. The oscillatory aspect is reminiscent of the oscillating levels of oxygen in the atmosphere over the last 500 million years (Berner et al., 2007). The increases in oxygen caused “gigantism” (Berner et al., 2000), whereas the physiologic hypoxic effects of the decreases are not addressed anywhere in the scientific literature, other

than what has been hypothesized regarding the evolution of endothermy/homeothermy (Torday, 2015). Hypoxia is the most potent known natural physiologic stressor. Therefore, it is not surprizing that the documented decreases in atmospheric oxygen during the Phanerozoic Era (Berner et al., 2000) correlate with specific physiologic changes that occurred in the hypothalamic-pituitary-adrenal axis during this same period of time – the appearance of the parathyroid hormone-related protein (PTHrP) gene in both the anterior pituitary (Kawashima et al., 2005) and adrenal cortex (Nakayama et al., 2011). The evolutionary relevance is evidenced by the capillary “arcades” in the adrenal medulla expanding sometime during this era as well (Wurtman, 2002), likely due to the blood vessel promoting activity of PTHrP. The physiologic significance lies in the hormonal secretions of the adrenal cortex passing through the medulla on their way out of the adrenal to the systemic circulation. PTHrP initiates the formation of capillaries (Park et al., 2013), the PTHrP produced in the adrenal cortex enhancing the vasculature of the medulla. Consequently, the corticoids produced in the adrenal cortex passing through the adrenal medulla stimulate the rate-limiting step in adrenalin synthesis (Kvetnansky et al., 2013), amplifying adrenalin secretion by the medulla. This would be further amplified by the increased surface area of the adrenal medullary vasculature. Subsequently, the circulating adrenalin increases the production of surfactant by the alveoli (Lawson et al., 1978), increasing their distensibility, and therefore their oxygen uptake. Overall, this physiologic interaction between the hypothalamic-pituitary-adrenal axis and the lung alleviated the stress caused by the episodic hypoxia, facilitating the step-wise cell–cell interactions that advanced the evolution of the nascent lung in adaptation to land in the short-run. But in the long-run, PTHrP is necessary for the formation of alveoli (Rubin et al., 2004), which constitutively increases oxygenation, thus emphasizing that this lung surfactant-based evolutionary physiologic cascade references the advent of cholesterol in the unicellular cell membrane, acting to thin the membrane and increase oxygenation. As for why that all may have occurred, our forebears were small shrew-like organisms (O'Leary et al., 2013) that had to be quick and agile to survive, giving rise to the adaptive amplification of the fight-or-flight mechanism.

14.3 The Environment Gave Rise to Endothermy The above has been incorporated into a theory for the evolution of warmbloodedness, or endothermy/homeothermy (Torday, 2015). Adrenalin relieved the constraint on oxygenation by the alveoli, and in tandem it increased the release of fatty acids from fat stores (Carey, 1998), the most efficient substrate for metabolic production of body heat. So the increased metabolic activity would have raised the body temperature, ultimately becoming constitutive through the thermoregulatory action of oxytocin (Young, 2013), which is a neuroendocrine hormone. In the interim, increased body temperature would have fostered the evolution of bipedalism due to more efficient metabolism, since multiple enzyme isoforms are necessary for any given metabolic step in cold-blooded organisms in order to optimize the enzymatic activity at different environmental temperatures, whereas warm-blooded organisms only require one form of any given metabolic enzyme. Standing on two legs requires more energy than crawling on all fours (Nakatsukasa et al., 2006). This led to the freeing of the forelimbs for specialized adaptations such as tool-making, leading to oral and written language. Of course, that placed

additional selection pressure on the brain to integrate and control such complex activities. So that is how our shrew-like ancestors morphed into humans (O'Leary et al., 2013). The decrease in environmental entropy after the Big Bang placed ever-greater selection pressure on the first principles of physiology, the lipid facilitation of oxygenation being initiated by cholesterol in the cell membrane (Bloch, 1992). Subsequently, peroxisomes evolved to protect against the rising calcium levels within the cell using lipids to buffer it (De Duve, 1969), which were also used pleiotropically as substrate for steroid hormones (Wollam and Antebi, 2011), the endocrine system (Melmed et al., 2015), and physiologic evolution (Torday and Rehan, 2012). The realization that lung surfactant evolved as serial pre-adaptations (Torday and Rehan, 2007) provided deep insights to the fundamental interrelationship between lipids and oxygen uptake, from lung surfactant lipids all the way back to the unicellular state based on the biosynthesis of cholesterol, the most primitive of lung surfactants (Orgeig et al., 2003). Konrad Bloch hypothesized that cholesterol was a “molecular fossil” since it took 11 atoms of oxygen to produce one molecule of cholesterol (Bloch, 1957), so there had to have been enough oxygen in the atmosphere to do so, linking oxygen and cholesterol together mechanistically in space-time, offering insight to the evolution of many other physiologic traits, particularly those determined by parathyroid hormone-related protein (PTHrP) (Torday and Rehan, 2012), which amplified during the water-land transition due to the documented duplication of the PTHrP receptor. Tiktaalik provided scientific evidence for the fossilized remains of the transition from fish to tetrapods (Shubin et al., 2004), but there are no fossil data for the internal organ adaptations that occurred during that process in adaptation to land. However, when this event is seen in the context of the environmental changes that prevailed, there are extensive data for the cellular-molecular development of the organs that were essential for land adaptation, which – when superimposed on the phylogenetic physiologic changes in specific organs such as the skeletal system, lung, kidney, skin and brain – reveal the underlying cellular-molecular changes that occurred over the course of evolution. These relationships are conventionally categorized as convergent evolution, but when seen as commonly held mechanisms, it becomes causal. Such hypotheses have been corroborated by gene deletions and over-expressions consistent with such evolutionary changes.

14.4 Diachronic Vectors of the Big Bang PTHrP signaling across space-time is homologous (of the same origin) with Mendeleev's implementation of atomic number and chemical reactivity to construct his periodic table of elements. Significantly, receptor signal amplification through “second messengers” such as cyclic adenosine monophosphate and inositol phosphates gave even deeper insights to other such cell–cell signaling mechanisms occurring in tandem in other tissues and organs (Torday and Rehan, 2012). Such signaling pathways constitute evolutionary vectors originating in the unicellular state, which has persisted on Earth for 3.5 billion years. That biologic “lens” compares with Mendeleev's use of chemical reactivity to assemble the periodic table of elements (Scerri, 2019). Importantly, both the chemical and biologic reactions transcend space-time diachronically, shifting the focus from the material to energy. The magnitude and direction of those chemical and biologic vectors refer

back as far as the Singularity, from which they emerged as echoes of the Big Bang. William Ockham declared that the simplest answer is the right answer. Tracing evolution as the energetic vector of the Big Bang rather than as phenotypic change phylogenetically presents the shortest distance between two points, beginning (and ending, cyclically) with the unicell as the biologic Singularity. Mathematically expressing such vectors would lead to a way of “calculating” the value of any given property of nature. Peter Rowlands is devising such a mathematical system, basing it on fundamental principles of physics underlying all that we experience (Rowlands, 2011). In his analysis, all of reality can be described as “zeros and ones,” the “ones” giving our reality material value, but it is actually zeroes that do that (Rowlands, 2011). That is because material things are merely epiphenomena of the energy that actually constitutes the cosmos, and zero refers to the energy state. Focusing on the cell as the basis for biologic evolution amounts to the same thing, because the negative entropy within the cell is “zero” relative to the positive entropy outside of the cell. Therefore, both the animate and inanimate can be reduced to the same set of fundamental principles. This way of thinking about cosmology is synonymous with Alfred North Whitehead's process theory (Whitehead, 1978). He thought that all existence was energy, and that occasionally matter would appear, but was transient. Whitehead thought that our focus on the material at the expense of the non-material was misguided because it did not focus on relationships. In his book, Science and the Modern World (Whitehead, 1997), he expressed the idea that matter is “senseless, valueless, purposeless” because it is merely a transient product of the underlying energetic forces of the cosmos; a by-product. He called this perspective “scientific materialism.” Whitehead found fault with the irreducible nature of matter because it masks the importance of change, that nothing ever stays the same. Whitehead placed the emphasis of reality on change, and that “all things flow” (Whitehead, 1978). This concept was first voiced by Heraclitus, who said that “No man ever steps in the same river twice, for it is not the same river and he is not the same man.” Moreover, Whitehead thought that interpersonal relationships were undermined by materialism. Since each object is an inert mass that is only superficially related to other things, viewing objects as separate and distinct from all other objects is a systematic error. The idea that the material is the primary state of being leads people to conclude that objects are all separated by time and space, and are not related to anything. On the other hand, Whitehead thought that relationships were the primary state of being. Whitehead describes any entity being nothing more or less than the aggregate of its relationship to other entities, as the synthesis of and reaction to the world around it (Whitehead, 1985). Relationships are not secondary to what a thing is, they are what the thing is. Whitehead and Mendeleev each saw the world as energy flow rather than as matter, Mendeleev seeing the elements as Whitehead's relationships, the elements reacting with one another instead of having superficial characteristics like those described by alchemists. In that sense, it was the alchemist who determined how to make gold out of dross, not the innate characteristics of the elements that enabled them to interrelate with one another. All biologic properties fundamentally interrelate with one another structurally and functionally, by definition. That can be seen mechanistically by seeing organisms through the lens of development literally recapitulating phylogeny at the cellular-molecular level, offering the retrograde retracing of the process of evolution back to the unicellular state as a series of pre-adaptations. Such

interactions between the organism and its environment over the course of evolution subordinates the material in favor of the process. Therefore, both the periodic table of elements and evolutionary biology are expressions of the process of change. Whitehead's perspective was therefore correct, yet he had no experimental evidence to support it.

14.5 Information Theory Meets Informatics Information theory typifies Whitehead's focus on process because it represents the mechanism for forming, storing and sharing information. But since it subordinates the transmission of the information to the materialism of the information, it is misguided. As a result, informatics tends to be conflated with knowledge, which is syllogistic reasoning that has undermined human thought and action. The mantra in informatics is that if you have not solved the problem you just need more data. That may be valid at NASA, where informatics is used to keep track of the parts for the assembly of the space shuttle, but not for biologic systems. In the case of the shuttle, the data are a closed set, whereas biology is an open set, the whole being greater than the sum of its parts.

14.6 Truth Be Told Because of the relationship between materialism and process, we have been able to advance as a species among species. However, we continue to exist within the Explicate Order (Bohm, 1980), made subjective by our evolved senses, whereas there is a true reality just out of reach, referred to as the Implicate Order. The pseudo-reality periodically causes us to rise up, and then fall down, ultimately succumbing to the laws of nature. Whether it is climate change or a false economy, we are vulnerable to our failure to comply fully with the prevailing forces of nature as we approach the Implicate Order. Though we naturally evolve by endogenizing the environment, our narcissistic human tendencies may supersede the former due to the artifices of materialism. Once we begin artificially engineering our heredity using CRISPR we will deviate from our naturally evolved path towards the Singularity, evolving more like “silicon-based life forms” instead.

14.7 There Is Only Space, There Is No Time Since physicists have concluded that time is an anthropocentric artifact (Rowlands, 2011), how do we reconcile the temporal aspects of development and phylogeny? It would have to be assumed that the latter are exclusively space-filling properties of biology. In this vein, we have learned that epigenetic inheritance affects evolution, and it has been proposed that it fosters “running in place” to maintain homeostasis in consilience with the first principles of physiology (Torday and Rehan, 2009), which would subsume a spatial, non-temporal way of thinking about biology. This question is reminiscent of the well-documented debate between Einstein and Bergson in 1922 (Canales, 2015); Einstein insisting that time is an artifact of biology, Bergson countering that time is critical for understanding any and all of biology and psychology. It has been suggested that the Singularity is the template for the cell as the basis of biology (Torday, 2018), and that evolution is the means for remaining faithful to it, striving to emulate the Singularity, time dropping out of the “equation,” space

remaining as a point source at its minimum, the cosmos at its maximum.

14.8 A Novel Prediction of Consciousness as the Singularity The idea that consciousness derives from the Singularity is because of their mutual relationships to physiology, the latter being the endogenization of the cosmologic environment. That is, when the Singularity was disrupted by the Big Bang (Hawking and Penrose, 2015), that information was fragmented, but it had to conform with the laws of nature nonetheless, endogenizing the environment and making it useful, compartmentalizing it as physiology, requiring compliance with the laws of nature (Sagan, 1967). And in the aggregate, our physiology ascribes to the Singularity as its origin, in the way physiology functions to maintain homeostasis based on the same set of principles. In other words, our interoceptive sense of self (Damasio, 2010) is founded on the Singularity as the origin of the cosmos, actualized by the physiologic principles that have evolved from the cosmos. The principle of homeostasis integrates all of these properties. When the Big Bang occurred some 13.8 billion years ago, there was an “equal and opposite reaction” based on Newton's third law of motion. It is the pre-adaptation referred to as homeostasis. It determines the equipoise of both inanimate balanced chemical reactions and life forms alike. Without homeostasis there would be no matter, there would only be energy. Alfred North Whitehead's “Process Philosophy” states that all is energy; matter is a transition between energy states (Whitehead, 1978).

14.9 The Vertical Integration of Gravity, Chemistry and Biology as Consciousness PTHrP signaling facilitated vertebrate physiologic adaptations to land. Such vertically integrated physiologic mechanisms offer deep insight to the interrelationships between physics, chemistry and biology. When lung or bone cells are exposed to microgravity, PTHrP messenger RNA declines (Torday, 2003). That interrupts the cell–cell communication mechanisms PTHrP mediates for breathing, salt/water balance, and bone calcification (Pinheiro et al., 2010). Even more fundamentally, yeast exposed to microgravity lose their ability to polarize or reproduce (Purevdorj-Gage et al., 2006), dissociating them from their biology. Mechanical forces like gravity affect the cell via the target of rapamycin (TOR) gene, which is controlled by the cytoskeleton (Boppart et al., 2006; Olsen et al., 2019). Consequently, supportive proteins in the extracellular space connect with intracellular signaling mechanisms, coordinating the many chemical reactions that govern cell physiology on a moment-to-moment basis. Thus, the gravitational force originating from the Big Bang (Hawking and Penrose, 2015) refers to the Singularity as the unity of the cell (Torday, 2019), endogenized over the course of evolution (Sagan, 1967); ultimately generating consciousness as the holism of being.

14.10 Biology and Chemistry as Vectors of the Big Bang Mendeleev's periodic table of elements was genius, not in his use of atomic weight as the organizing principle, but in further fine-tuning it based on the chemical reaction products that further characterized each element. In so doing, rather than

merely arranging the elements based on atomic weight synchronically, he calibrated the elements diachronically across space-time. The same approach holds true by exploiting the cell–cell interactions that generate form and function developmentally, merged with phylogeny to understand evolution, which is also diachronic. In contrast to that approach, forming cladograms, for example, merely describes the progression of evolution without any underlying understanding of how or why it occurred. Empirically determined chemical and biologic vectors approximate the primary vector formed by the Big Bang. As a corollary, the more proximate the chemical and evolutionary biologic vectors are to the vector formed by the Big Bang, the more fundamental they are. Yet, like Zeno's paradox, we can never attain congruence with the vector of the Big Bang because we are obligated to evolve in response to changes in the environment, or become extinct. This is why William of Ockam's razor is predicative of the right solution, the shortest distance between two points being the simplest path.

14.11 Conclusions It had been proposed (Torday, 2013) that the cellular-molecular path for lung evolution would pass through the origin of a set of Cartesian coordinates, which if carried back, would eventually intersect with the Singularity. In that circumstance, all that follows would become a series of pre-adaptations from the Singularity based on physical probabilities (Gabora et al., 2013) forming a vector congruent with the vector of the Big Bang. The nature of consciousness has remained an unresolved problem for thousands of years. Beginning with the Greek philosophers, right up to the present day, philosophers and physiologists alike have tried to solve the problem; such as Chalmers and Clark, who posed difficult questions about qualia (Kriegel, 2014). In the current context, it is proposed that consciousness lies at the intersection of cosmology and physiology, the product of which is what we think of as being conscious, or mind. It is hypothesized that the existing physical, chemical and biological properties in existence are all vectors of the Big Bang, which could be tested by mathematically by modeling key reactions for each.

References Berner R. A., Petsch S. T., Lake J. A., Beerling D. J., Popp B. N., Lane R. S., Laws E. A., Westley M. B., Cassar N., Woodward F. I. and Quick W. P., Isotope fractionation and atmospheric oxygen: implications for phanerozoic O(2) evolution, Science, 2000, 287(5458), 1630–1633. Berner R. A., Vandenbrooks J. M. and Ward P. D., Evolution. Oxygen and evolution, Science, 2007, 316, 557–558. Bloch K., The biological synthesis of cholesterol, Vitam. Horm., 1957, 15, 119– 150. Bloch K., Sterol molecule: structure, biosynthesis, and function, Steroids, 1992, 57, 378–383. Bohm D., (1980, ), Wholeness and the Implicate Order, London: Routledge. Boppart M. D., Burkin D. J. and Kaufman S. J., Alpha7beta1-integrin regulates mechanotransduction and prevents skeletal muscle injury, Am. J. Physiol.: Cell

Physiol., 2006, 290, C1660–C1665. Canales J., (2015, ), The Physicist and the Philosopher, Princeton University Press: Princeton. Carey G. B., Mechanisms regulating adipocyte lipolysis, Adv. Exp. Med. Biol., 1998, 441, 157–170. Damasio A., (2010, ), Self Comes to Mind, Vintage: New York. De Chardin P. T., (1979, ), The Heart of Matter, Harcourt Brace Jovanovich: New York. De Duve C., Evolution of the peroxisome, Ann. NY Acad. Sci., 1969, 168, 369– 381. Feynman R., (2011, ), The Feynman Lectures on Physics, Basic Books: New York. Gabora L., Scott E. O. and Kauffman S., A quantum model of exaptation: incorporating potentiality into evolutionary theory, Prog. Biophys. Mol. Biol., 2013, 113, 108–116. Hawking S. and Penrose R., (2015, ), The Nature of Space and Time, Princeton University Press: Princeton. Kahn C., (1979, ), The Art and Thought of Heraclitus: Fragments with Translation and Commentary, Cambridge University Press: Cambridge. Kawashima M., Takahashi T., Yanai H., Ogawa H. and Yasuoka T., Direct action of parathyroid hormone-related peptide to enhance corticosterone production stimulated by adrenocorticotropic hormone in adrenocortical cells of hens, Poult. Sci., 2005, 84, 1463–1469. Kvetnansky R., Lu X. and Ziegler M. G., Stress-triggered changes in peripheral catecholaminergic systems, Adv. Pharmacol., 2013, 68, 359–397. Kriegel U., (2014, ), Current Controversies in Philosophy of Mind, Taylor & Francis: New York. Lawson E. E., Brown E. R., Torday J. S., Madansky D. L. and Taeusch H. W., The effect of epinephrine on tracheal fluid flow and surfactant efflux in fetal sheep, Am. Rev. Respir. Dis., 1978, 118, 1023–1026. Melmed S., Polonsky K. S., LarsenPR and Kronenberg H. M., (2015, ), Williams Textbook of Endocrinology, Elsevier: Amsterdam. Nakatsukasa M., Hirasaki E. and Ogihara N., Energy expenditure of bipedal walking is higher than that of quadrupedal walking in Japanese macaques, Am. J. Phys. Anthropol., 2006, 131, 33–37. Nakayama H., Takahashi T., Oomatsu Y., Nakagawa-Mizuyachi K. and Kawashima M., Parathyroid hormone-related peptide directly increases adrenocorticotropic hormone secretion from the anterior pituitary in hens, Poult. Sci., 2011, 90, 175–180. O'Leary M. A., Bloch J. I., Flynn J. J., Gaudin T. J., Giallombardo A., Giannini N. P., Goldberg S. L., Kraatz B. P., Luo Z. X., Meng J., Ni X., Novacek M. J., Perini F. A., Randall Z. S., Rougier G. W., Sargis E. J., Silcox M. T., Simmons N. B., Spaulding M., Velazco P. M., Weksler M., Wible J. R. and Cirranello A. L., The placental mammal ancestor and the post-K-Pg radiation of placentals, Science, 2013, 339, 662–667. Olsen L. A., Nicoll J. X. and Fry A. C., The skeletal muscle fiber: a mechanically sensitive cell, Eur. J. Appl. Physiol., 2019, 119, 333–349. Orgeig S., Daniels C. B., Johnston S. D. and Sullivan L. C., The pattern of surfactant cholesterol during vertebrate evolution and development: does ontogeny recapitulate phylogeny?, Reprod., Fertil. Dev., 2003, 15, 55–73.

Park S. I., Lee C., Sadler W. D., Koh A. J., Jones J., Seo J. W., Soki F. N., Cho S. W., Daignault S. D. and McCauley L. K., Parathyroid hormone-related protein drives a CD11b+Gr1+ cell-mediated positive feedback loop to support prostate cancer growth, Cancer Res., 2013, 73, 6574–6583. Pinheiro P. L., Cardoso J. C., Gomes A. S., Fuentes J., Power D. M. and Canário A. V., Gene structure, transcripts and calciotropic effects of the PTH family of peptides in Xenopus and chicken, BMC Evol. Biol., 2010, 10, 373. Polanyi M., Life's irreducible structure. Live mechanisms and information in DNA are boundary conditions with a sequence of boundaries above them, Science, 1968, 160, 1308–1312. Prigogene I. and Stengers I., (1984, ), Order out of Chaos, Bantam: London. Purevdorj-Gage B., Sheehan K. B. and Hyman L. E., Effects of low-shear modeled microgravity on cell function, gene expression, and phenotype in Saccharomyces cerevisiae, Appl. Environ. Microbiol., 2006, 72, 4569–4575. Rowlands P., (2011, ), The Foundations of Physical Law, WSPC: Singapore. (wrong date – 2015). Rubin L. P., Kovacs C. S., De Paepe M. E., Tsai S. W., Torday J. S. and Kronenberg H. M., Arrested pulmonary alveolar cytodifferentiation and defective surfactant synthesis in mice missing the gene for parathyroid hormone-related protein, Dev. Dyn., 2004, 230, 278–289. Sagan L., On the origin of mitosing cells, J. Theor. Biol., 1967, 14, 225–274. Scerri E., (2006, ), The Periodic Table: Its Discovery and Significance, Oxford University Press: Oxford, 1st edn. Scerri E., (2019, ), The Periodic Table: Its Story and Its Significance, Oxford University Press: Oxford, 2nd edn. Shubin N. H., Daeschler E. B. and Coates M. I., The early evolution of the tetrapod humerus, Science, 2004, 304, 90–93. Snow C. P., Two Cultures, Science, 1959, 130, 419. Torday J. S., Parathyroid hormone-related protein is a gravisensor in lung and bone cell biology, Adv. Space Res., 2003, 32, 1569–1576. Torday J. S., Evolutionary biology redux, Perspect. Biol. Med., 2013, 56, 455– 484. Torday J. S., A central theory of biology, Med. Hypotheses, 2015, 85, 49–57. Torday J. S., Quantum Mechanics predicts evolutionary biology, Prog. Biophys. Mol. Biol., 2018, 135, 11–15. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S. and Rehan V. K., The evolutionary continuum from lung development to homeostasis and repair, Am. J. Physiol.: Lung Cell. Mol. Physiol., 2007, 292, L608–L611. Torday J. S. and Rehan V. K., Lung evolution as a cipher for physiology, Physiol. Genomics, 2009, 38, 1–6. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology, Cell-Cell Communication and Complex Disease, Wiley: Hoboken. Whitehead A. N., (1978, ), Process and Reality, The Free Press: New York. Whitehead A. N., (1985, ), Symbolism: Its Meaning and Effect, Fordham University Press: New York. Whitehead A. N., (1997, ), Science and the Modern World, Free Press: New York. Whyte L. L., On the characteristics of a unified physical theory. I. The presence

of a universal constant with the dimensions of a length, Z. Phys., 1929, 56, 809. Wollam J. and Antebi A., Sterol regulation of metabolism, homeostasis, and development, Annu. Rev. Biochem., 2011, 80, 885–916. Wurtman R. J., Stress and the adrenocortical control of epinephrine synthesis, Metabolism, 2002, 51, 11–14. Wilson E. O., (1999, ), Consilience, Vintage Books: New York. Young W. S., Shedding heat on oxytocin, Endocrinology, 2013, 154, 3961–3962.

CHAPTER 15

The Physiological and Evolutionary Significance of Deuterostomy Descriptively, deuterostomes develop from the anus to the mouth, whereas protostomes develop from the mouth to the anus. In terms of embryological development as it applies to evolution, this fundamental difference between these two superphyla has profound evolutionary implications, given that the direction and magnitude of cell–cell interactions during development determine the form and function of the organism. For example, consider the spatio-temporal changes that occur during deuterostome versus protostome development, and the cell–cell signaling mechanisms that mediate them. The defining characteristic of the deuterostome is the fact that the blastopore (the opening at the bottom of the forming gastrula) becomes the anus, whereas in protostomes the blastopore becomes the mouth. The deuterostome mouth develops at the opposite end of the embryo from the blastopore, and a digestive tract develops in the middle, connecting the two. In many animals, such early developmental stages later evolved in ways that no longer reflect their original patterns. For instance, humans have already formed a gut tube at the time of formation of the mouth and anus. The mouth forms during the fourth week of development, and the anus forms four weeks later, temporarily forming a cloaca, which is a common structure for both urination and defecation.

15.1 Early Embryologic Developmental Differences Between Protostomes and Deuterostomes In both deuterostomes and protostomes, the zygote develops into a hollow ball of cells, called a blastula, which subsequently gastrulates as a further stage of embryonic maturation. It is during gastrulation that the third germ layer, the mesoderm, is introduced between the endoderm and ectoderm. In deuterostomes, the mesoderm forms as evaginations of the developed gut that pinch off, forming the coelom, referred to as the enterocoel, having profound effects on the conformation of the viscera. As a consequence of the intimate interrelationship between the organism's surroundings and epigenetic inheritance, environmental influences on the development of the phenotype run very deep in the history of vertebrates. The early cell divisions in deuterostomes occur parallel or perpendicular to the polar axis, referred to as radial cleavage. Deuterostomes largely effect cleavage in which the cells in the developing embryo are not dictated by the identity of the parent cell. This is why epigenetic inheritance has such a profound effect on the offspring. Gill slits in the pharynx are another feature of both the Hemichordata and

Chordata. They are also found in some primitive fossil echinoderms. All chordates have a hollow nerve chord. Some hemichordates also have a tubular nerve cord, which looks like the hollow nerve cord of chordates during early embryogenesis. Because of the highly modified nervous system of echinoderms, their ancestry is hard to follow in this regard. But it is feasible that deuterostomes evolved from a common ancestor, given that they all have gill slits, circular and longitudinal muscles, a segmented body and a hollow nerve cord.

15.2 Evolution of Endothermy as Positive Selection for Bipedalism and Specialization of Forelimbs: Universal Consciousness as Past/Present/Future The onset of endothermy/homeothermy (Torday, 2015) marks a radical change in human evolution. Warm-bloodedness facilitated bipedalism, which requires more energy than walking on all fours; that, in turn, was mediated by the reduction in the number of isoenzymes necessary for metabolism since endothermy requires only one form of any given enzyme, whereas cold-blooded organisms require multiple isoenzymes in order to function optimally at various ambient temperatures. Bipedalism freed the forelimbs of birds and humans for specialized functions such as flight and tool-making, respectively. In turn, it is possible that because hands were preoccupied with tool-making, verbal communication was augmented. There would certainly be an advantage for aggregates of intelligent cells to develop means of enhancing their collective survival by potentiating collective responses to stress through the evolution of a central nervous system, which would then promote the advancement of brain structure and function, particularly the neocortex. From within this background of increasing cellular complexity and sub-specializations within multicellular organisms, central nervous system functions became speciesspecific manifestations of consciousness that permitted each to problem-solve adequately within its environmental niche to survive and reproduce. Our human abilities, which seem to be unlike any other species, therefore represent our own idiosyncratic form of conscious deliberateness and abstract reasoning capacity that arises from within a universal planetary spectrum.

15.3 Plasticity of the Foregut The deuterstome body plan fostered the evolution of the mouth-end of the organism through terminal addition. In support of this, several novel traits evolved from the foregut. The foregut is a plastic structure from which the thyroid, lung and pituitary arise through Nkx2.1/TTF-1 gene expression. Evolutionarily, this is consistent with the concept of terminal addition, given that the deuterostome gut is formed from the anus to the mouth, in sequence. Moreover, when Nkx2.1/TTF-1 is deleted in embryonic mice, the thyroid, lung and pituitary do not form during embryogenesis, providing experimental evidence for the genetic commonality of all three organs. Their phylogenetic relationship has been traced back to amphioxus, and to cyclostomes, since the larval endostyle, the structural homolog of the thyroid gland, expresses Nkx2.1/TTF-1.

15.4 The Phylogeny of the Thyroid The endostyle is retained in urochordates after metamorphosis, and in amphioxus

adults, but the lamprey has a follicular thyroid gland post-metamorphosis that is a transformed endostyle. The presence of an endostyle in larval lampreys does not indicate direct descent of lampreys from protochordates, but rather that the evolutionary history of lampreys is of ancient origin, and that they share the common feature of having filter-feeding mechanisms in their larval stage of development. It is, however, noteworthy that the other extant agnathan – the hagfish – possesses thyroid follicles before hatching. Since hagfish evolution is considered to be conservative, hagfish history can be traced back about 550 million years, suggesting that thyroid follicles could likewise be considered to have an ancient history. Variations in the ontogeny of the thyroid gland are another example of divergence of lampreys and hagfish early on in their evolutionary history. In this regard, it is of interest that the method of development of thyroid follicles from a broad pharyngeal epithelium in hagfish embryos is similar to that during lamprey metamorphosis, when follicles arise from clumps of cells emanating from the transforming endostyle epithelium. Hagfish embryology may reflect a step in the development of agnathan thyroid follicles that occurred later in lampreys, when metamorphosis appeared in their ontogeny. The phylogenetic history of the endostyle and non-follicular thyroid tissues of vertebrates and invertebrates has been reviewed by Eales (1997). He highlights the role of environmental compounds on metabolic mechanisms in regulating thyroid status, influencing the course of the phylogenetic development of the vertebrate thyroid gland. A hallmark of thyroid-like tissue is its ability to store iodine using iodine-binding capacity. Iodine compounds that are ingested or absorbed, such as iodothyronines from plants and microorganisms, can be metabolized and gut bacteria may assist. Absorption of iodine compounds has not been shown in the larval lamprey gut, but it is the primary site for the conversion of thyroxine to triiodothyronine, which also appears to be the case for ascidians. The endostyle is only found in marine invertebrates with notochords – or in freshwater lamprey larvae – which may have been promoted by filter feeding in this specialized region of the alimentary tract, which – like many invertebrate tissues that developed secondarily – already had iodine-binding capacity. Endostyle binding of iodine in larval lampreys and ascidians is well documented; the presence of the endostyle throughout the evolution of lampreys reflects its importance in the filter-feeding apparatus, suggesting its origin when lampreys were in their pelagic marine phase. The vertebrate follicular thyroid gland evolved in response to strong selection advantage for a gland that favored thyroid hormone and iodine storage during the period when ancient chordates moved from an iodine-rich marine environment to an iodine-poor freshwater habitat. The presence of an endostyle in larval lampreys reflects their ancient marine origins, and the adult follicular thyroid gland arose after the organism moved toward freshwater. Since the adult lamprey thyroid gland appears only after the transformation of the endostyle during metamorphosis, a selection advantage was created by the freshwater environment for metamorphosis during the ontogeny of lampreys. This perspective on the ontogeny of the lamprey thyroid gland, and the belief that the freshwater habitat of lampreys is a secondary niche, implies that metamorphosis might not have originated as a developmental strategy, but instead occurred when lampreys moved into freshwater during their evolutionary history. Alternatively, metamorphosis of the follicular thyroid gland in the marine environment was the primary reason why lampreys could inhabit freshwater. The presence of an

endostyle in early lampreys was not a requisite for living in a marine (brackish) environment, since present-day larvae with endostyles cannot tolerate even dilute seawater. Pre-metamorphic lampreys have lost the ability of the hypothetical ancestral larval form to inhabit a marine environment of any type. It is only after metamorphosis that juveniles of some species can tolerate full-strength seawater. Larval and reproductive intervals of the lamprey life cycle only occur in freshwater. The ability of juveniles of some species to osmoregulate in seawater could also be a character that was secondarily derived following the advent of metamorphosis in the ontogeny of lampreys. Extant parasitic lampreys of the most ancient lineage (e.g. Ichthyomyzon unicupis) are confined to freshwater. An explanation of how marine osmoregulation may have been secondarily derived following the primary derivation of metamorphosis may be found in modern views of the phenomenon called “developmental integration.”

15.5 An Evolutionary Vertical Integration of the Phylogeny and Ontogeny of the Thyroid The increased bacterial load due to filter feeding through the endostyle would have stimulated the cyclic adenosine monophosphate (cAMP) dependent protein kinase A (PKA) pathway, since bacteria produce endotoxin, a potent PKA agonist. This pathway may have evolved into regulation of the thyroid with thyroid stimulating hormone (TSH), since TSH acts on the thyroid via the cAMP-dependent PKA signaling pathway. This mechanism hypothetically generated novel structures such as the thyroid, lung and pituitary, all induced by the PKA-sensitive Nkx2.1/TTF-1 pathway. The brain–lung–thyroid syndrome, in which infants with an Nkx2.1/TTF1 mutation develop hypotonia, hypothyroidism and respiratory distress syndrome, or surfactant deficiency disease, is further evidence for the coevolution of the lung, thyroid and pituitary. In mice, the thyroid evaginates from the foregut one day before the lung and pituitary emerge, suggesting that the thyroid may have been a molecular prototype of the lung during evolution, providing a testable and refutable hypothesis. The thyroid made molecular iodine in the environment bioavailable by binding it to threonine to generate thyroid hormone, whereas the lung made molecular oxygen bioavailable, first by inducing lipofibroblasts as cytoprotectants, which then stimulated surfactant production by producing leptin, placing increased selection pressure on the blood–gas barrier by making the alveoli more compliant. That may have created an environment encouraging selective filtering for a metabolic system to utilize the rising oxygen level, reciprocating with the alveolar cells, giving rise to the stretch-regulated surfactant system mediated by parathyroid hormone-related protein and leptin. Further reciprocations and selective filtering of the cardiopulmonary system may have facilitated liver evolution, since the progressively increasing size of the heart may have induced precocious liver development, fostering increased glucose regulation. The brain serves as a glucose reservoir, and there is experimental evidence that increasing glucose during pregnancy increases the size of the developing brain. The further evolution of the brain, specifically the pituitary, would have served to promote the evolution of complex physiologic systems. The thyroid and the lung have played similar adaptive roles during vertebrate evolution. The thyroid has facilitated the utility of iodine ingested from the

environment, whereas the lung has accommodated the rising oxygen levels during the Phanerozoic era. In both cases, these structures have used otherwise toxic substances for biologic purposes that have allowed vertebrates to adapt to their environment. Importantly, the thyroid and the lung may have interacted cooperatively in facilitating vertebrate evolution. Thyroid hormone stimulates embryonic lung morphogenesis during development, while also accommodating the increased lipid metabolism needed for surfactant production by driving fatty acids into muscle to increase motility, as opposed to oxidization of circulating lipids to toxic lipoperoxides. The selection pressure for metabolism was clearly facilitated by the synergy between these foregut derivatives.

15.6 Plasticity of the Vagus The polyvagal theory (Porges 1995) integrates the development, phylogeny and structure-function of the autonomic nervous system via the vagal nerve. The nerve emerges from the posterior end of the organism as a non-myelinated neuron, acting to monitor local function. But over the course of phylogeny, the vagus advances from the posterior to the anterior of the organism, becoming myelinated, developing in tandem with the gut. As a result of this longitudinal migration of the vagus, it also acts to integrate the adrenal gland with other physiologic properties. Eventually, it terminates in the anterior end of the organism, acting to integrate heart rate and craniofacial actions, including vocalization and language formation. Had humans evolved from proteostomes, the endothermy/warm-bloodedness fostered by physiologic stress that gave rise to bipedalism, facilitated tool-making and enhanced language utilization as another form of tool-making, would not have transpired.

15.7 Acquisition of Epigenetic Marks Overlayed on the above Makes for a Highly Robust Form of Consciousness The inversion of the deuterostome “bauplan” from anus to mouth goes counter to the force of Earth's gravity, which has played a central role in the evolution of life forms. For example, if yeast are put into an environment with close to zero gravity, their ability to polarize is impaired, preventing them from generating the calcium waves that may be considered a form of consciousness. When this is seen in the context of phenotypic agency for obtaining epigenetic “marks” from the environment, it makes for a dynamic interplay between the organism and its surroundings, which leads to novel traits, such as the thyroid, lung, pituitary and the cephalad brain, or head structure. As described above, endothermy fostered bipedalism and the freeing of the forelimbs, which may have energized the role of language as perhaps the epitome of human evolution. This process is the opposite of what occurs in plants, in which their robust adaptations emerge from their roots, which are oriented in a downward direction, toward the source of gravity. This fundamental difference between animal and vegetable, predicated on geophysical “orientation,” speaks to the dynamic nature of phenotypic agency and its respective mechanisms for obtaining epigenetic marks.

15.8 “From Horizontal to Vertical”, or the Grand Synthesis As an object lesson in deuterostomy, the transition from fish to human exemplifies the effect of gravity on vertebrate physiology. There are strong homologies between the fish swim bladder and the mammalian lung, beginning with the fact that the bladder is inflated and deflated through the pneumatic duct, a trachea-like structure that emanates from the esophagus in physostomous fish, which are defined by that structure. Fossil evidence for such a transition was first provided by Neal Shubin's quadruped Tiktaalik (2006). The swim bladder evolved in adaptation to gravity by generating buoyancy, facilitating feeding for efficient metabolism. By homology, the lung evolved for efficient oxidative metabolism, facilitating bipedalism as an adaptation to gravity. In either case, these adaptations can be seen to extend back to the unicell, which is defined by its negentropic state in opposition to the external environment. In homologous reiteration, the functioning swim bladder and the lung exert their own negative counterbalances to physical pressures acting to reconcile the ambiguity of negative internal entropy. A developmental view of either structure gives insight to their common evolution, as follows. During development, fish fry hatch from eggs, and over the course of the next five days they develop their swim bladder, which they must actively inflate, much like the mammalian newborn, taking the first breath of air to inflate the lung alveoli. In both cases, the air space must be lined adequately with surfactant to effectively inflate both of these structures. In the case of the swim bladder, cholesterol is secreted by the epithelial cells lining the bladder to prevent the walls of the structure from sticking to one another. In the case of the mammalian lung, surfactant must be present to counter the effect of the high surface tension of the thin water layer that lines the alveoli. In either case, failure to form such a lipid lining causes the death of the offspring. This intimate relationship between the so-called gas exchanger and lipids refers all the way back to the putative origin of life, lipids having formed the membrane interface between the cell and its watery surroundings, since lipids immersed in water spontaneously form micelles, or lipid spheres, surrounded by a semipermeable membrane. Such primitive “cells” have certain characteristics, such as their “molecular memory” due to lipid hysteresis, and semi-permeability, allowing substances from the environment to enter and exit the cytoplasm of the cell. The former confers the memory needed for evolution, the latter allowing for endosymbiosis, the basis for evolution. The subsequent advent of cholesterol synthesis, and its insertion in the cell membrane facilitated metabolism, oxygenation and locomotion, the three “pillars” of vertebrate evolution. These features of the unicell evolved due to the effect of cholesterol thinning the cell membrane, increasing gas exchange, and therefore metabolism. Locomotion was facilitated, since the resulting increased fluidity of the cell membrane allowed for increased cytoplasmic streaming, the basis for locomotion in protozoans. Seen from a phylogenetic perspective, the interrelationship between the swim bladder and the lung recapitulates the relationships referenced above. Both the swim bladder and lung mediate gas exchange, the former in service to buoyancy in order to adapt to gravity in water, the latter acting to mediate the flow of oxygen from the environment to the peripheral cells of the organism, ultimately to cope with gravity indirectly through the generation of bioenergy to maintain proprioception, or balance.

15.9 Ontogeny Recapitulates Phylogeny – Ernst Haeckel Was Right The following sections have been stated in earlier chapters of this book, but bear repeating in the context of deuterostomy. Developmentally, both the swim bladder and lung express the parathyroid hormone-related protein (PTHrP) gene. Deletion of the PTHrP gene in embryonic mice prevents the formation of alveoli, causing the death of the offspring at the time of birth. The increased force of gravity on land (versus water) caused selection pressure for skeletal strengthening, which was mediated by PTHrP, which regulates calcium fixation in bone. The duplication of the PTHrP receptor enhanced PTHrP signaling, collaterally affecting the evolution of the skin, kidney and lung, as evinced by the effects of deleting PTHrP during embryonic mouse development, inhibiting the normal formation of the bone, skin, kidney and lung.

15.10 Gravity Is the “Stretching” of the Fabric of SpaceTime; So Too Is the Stretching of the Swim Bladder or Lung Einstein stated that the force of gravity was due to the “stretching” of the fabric of space-time. By homology, biologic systems such as the alveolus of the lung, the glomerulus of the kidney and bone osteocytes all function physiologically in response to distension, forming a link between physiology and gravity. In support of this, rats flown into outer space have lower levels of parathyroid hormone-related protein in their bones than their land-based litter-mates. As gravity is a product of the Singularity, there is an intimate connection between the cosmos and many of our daily physiologic functions. The cytoskeleton mediates the effects of gravity on the cell through the target of rapamycin or TOR gene, which is directly connected to it. The cytoskeleton determines all of the biologic “states” of the cell: homeostasis, mitosis and meiosis. In similar experiments using bone and lung cells, it has been shown that microgravity causes a significant decrease in the amount of PTHrP mRNA, representing a loss of PTHrP signaling. PTHrP is necessary for the phenotypic expression of numerous cell types, namely, the bone, lung, skin and brain. Thus, the cell–cell communication mechanisms that mediate the differentiation of these organs is reduced under microgravity conditions, attesting to the significance of the interrelationship between the organism and its environment in metazoans, not unlike the effects of microgravity described for yeast earlier in this chapter.

15.11 Gastrulation, Epigenetic Inheritance, Formation of the Coelomic Membrane Covering the Reptilian/Bird Lung There is a fundamental difference between the lungs of reptiles, birds and mammals, first made evident during the study of embryogenesis of these species. In mammals, the lungs are free-floating within the chest cavity, whereas the lungs of reptiles and birds are fixed to the dorsal chest wall, covered by a thin membrane that isolates them from the rest of the coelomic cavity. Furthermore, birds do not have diaphragms, as these are unnecessary since they breathe in a unidirectional

flow of air. This is unlike the reciprocal breathing of mammals, in response to the drop in the diaphragm generating negative pressure within the lung, causing inhalation. Elsewhere, it has been argued that the intimate relationship between the endocrine and pulmonary systems is due to the step-wise evolution of the vertebrate lung on land. Under hypoxic stress due to alveolar insufficiency, the hypothalamicpituitary-adrenal axis, or HPA was stimulated to produce catecholamines, which in turn stimulated surfactant secretion by the alveoli, increasing alveolar distention for gas exchange, acutely relieving hypoxia. Over the course of evolution, the overdistension of the alveoli stimulated the secretion of PTHrP, which increased the number of alveoli, constitutively increasing the surface area of the lung in adaptation to oxygenation. In contrast to that, the bird lung is a “stiff,” non-reciprocating organ. Moreover, birds are normally hyperglycemic, so they do not require free fatty acid release from fat cells as an on-demand source of substrate for “fight or flight” as in mammals. In association with these traits, the chromaffin tissue that produces catecholamines is interspersed within the adrenocortical tissue, so the stress reaction does not stimulate catecholamine production for “fight or flight.” In contrast, in mammals the adrenocortical tissue produces corticoids that pass through the adrenal medulla, where they stimulate the rate-limiting enzyme for catecholamine production, mediating the fight or flight mechanism.

15.12 On the Endocrine System and Vertebrate Evolution Phylogenetically, the chromaffin and cortical tissues of the adrenal are separate organs in fish, which merge together during the evolution to amphibians, reptiles, birds and mammals. It is in mammals that there is an intimate relationship between physiologic stress, increased corticoid production and catecholamine secretion by the adrenal medulla. The collateral effect of the catechols on lipolysis, giving rise to endothermy, is only relevant to mammals. The bird adrenal is composed of a cortex in which there are chromaffin “islands.” Birds, though warm-blooded, have evolved endothermy through a different mechanism. But both hominids and birds have evolved bipedalism, which is dependent on endothermy for additional energy, leading to specialization of the forelimbs, and brain cooling during rapid eye movement (REM) sleep.

15.13 The Commutative Principle as the Basis for the “Kaleidoscope” of Physiologic Adaptation The commutative property in mathematics states that the order of addition or multiplication does not affect the sum or product. Yet Darwinian evolution, which is based on conclusions only from observations stipulates that evolution is unidirectional. However, once the underlying cellular-molecular basis for evolution as the use and reuse of genes depending upon environmental stress is recognized, it can be realized that genetic organization is based on commutative properties. This same concept has previously been discussed in the context of heterochrony and pleiotropy, both of which are the results of this commutative property.

15.14 Discussion

The arcane interrelationships between various physiologic structures and functions are impossible to ascertain when seen only from their end results. It is only when they are understood at the cellular-molecular level – beginning with the unicellular state, moving forward in space and time – that integrated physiology can be correctly appreciated. And even then, it is necessary to factor in the geophysical and geochemical environmental conditions to which they have been subjected in evolutionary history to understand the how and why of evolution. Darwin seemed to have had an intuitive sense of this interrelationship, as expressed in The Origin of Species and conveyed as his impressions of the topography of Tierra del Fuego as he sailed on the Beagle. But again, it was only a retrospective impression, colored by his theory of evolution, not by the specifics. Some of these previously obscure relationships are revealed when the effects of microgravity on bone and lung are placed within the further context of deuterostomy, which helps to clarify unseen interrelationships between the swim bladder and the lung. However, any such associations have to be expanded through data gleaned from ontology, epistemology and pathology in order to understand the underlying processes and how they connect the dots for the formation of physiologic traits. The pieces of the puzzle are all there, but the correct algorithm must be consistent with life's actual organizing principles, namely the first principles of physiology. In this way, biological sleuthing proceeds by many unusual paths, not unlike how the puzzle of the Dead Sea Scrolls was solved. It took a clever insight to solve that riddle, since each scroll was in fragments and they were all mixed together. The key was that each scroll was written on the skin of an individual sheep. Since the individual animals bore unique DNA codes, the disparate shards could be matched and coordinated to permit their deciphering. It is just the same in biology. One thing links to another, but we often only see fragments of the whole. To make the match takes creative investigation that extends beyond the typical descriptive dogmas that have long been the mainstay of Darwinian evolution.

References Eales J. G., Iodine metabolism and thyroid-related functions in organisms lacking thyroid follicles: are thyroid hormones also vitamins?, Proc. Soc. Exp. Biol. Med., 1997, 214, 302–317. Porges S. W., Orienting in a defensive world: mammalian modifications of our evolutionary heritage. A Polyvagal Theory, Psychophysiology, 1995, 32, 301– 318. Shubin N. H., Daeschler E. B. and Jenkins Jr. F. A., The pectoral fin of Tiktaalik roseae and the origin of the tetrapod limb, Nature, 2006, 440, 764–771. Torday J. S., A central theory of biology, Med. Hypotheses, 2015, 85, 49–57.

CHAPTER 16

We Are All Denizens of Gaia 16.1 Gaia Is Us James Lovelock expressed the idea that the Earth is an organic whole in his groundbreaking book, Gaia Theory. He propounded that all living things interrelate within an entire reciprocating living planetary scaffold. Although generally accepted, the Gaia concept has never been robustly considered through a focus on cellular faculties and how they originated. The Gaia concept cannot be properly understood apart from these cell-based mechanisms, which are central to cell–cell communication and cellular niche construction, which are the backbone of life on the planet. It is therefore productive to explore the Gaia concept through a cellular lens that scientifically interconnects the environment with the actual mechanics of biological action and variation. Niche construction is the process by which organisms form their own personalized environments, a phenomenon which was first documented by Darwin (1881), who observed that earthworms retain their water-adapted kidneys, or nephridia, on land by actively modifying the soil around themselves both physically and chemically. Other organisms such as beavers build dams, various animals build burrows, and humans build homes, cities and nations. In Gaia theory, all such interactions are part of an eternal reciprocating planetary system. From this, all life springs. As Simon Conway Morris archly expressed it: “First there were bacteria, now there is New York.” Others, too, have incorporated the Gaia concept into their own fields of study. For example, Nicholas Christakis (2013) has attempted to quantify the spread of social ideas in groups as a planet-wide reciprocating social system. This is a form of human social niche construction based on a mathematical model known as social contagion theory. Although theoretically appealing, the underlying mechanism for such “contagion” communities remains unknown. What might be the impulse for this sort of niche construction activity? At least at a conjectural level, one potential explanation rests on the contention that all human behavior is derivative of essential unicellular traits. Since the cell can be considered as a first example of niche construction (Torday, 2016) and, further, that the endosymbiotic origin of Eukaryota was another form of niche construction, then social contagion is a reiteration of a very basic cellular drive. This reduces social contagion to a form of attempting to internalize the environment to solve informational ambiguities. When cells confront an existential threat in their environment, they cope with it through endogenization. Both niche construction and endosymbiosis are examples of internalization of the environment, which is an attempt to compartmentalize and assimilate an environmental stressor to make it part of evolving physiology. This is the essence of adaptation. It can be considered that this process is as old as life itself; perhaps older. It can be argued that this same process of internalization is how protocells achieved full cellular function. Any originating cellular homeostatic

milieu interieur had to have been an internalization of basic physical elements as a means of remaining compliant with fundamental physical forces. This originating endogenization of environmental toxins can be considered to be the first cellular niche construction. Since all living organisms are cellular, the same process reiterates. Thus, physical forces that begin with the Singularity begin an actual continuum that extends through the living state, which projects to the planet. In essence, as the Gaia concept asserts, the planet itself is another form of living organism. It is through a process of continuous reiterative niche construction that atomic processes and quantum mechanical forces have homologies with cellular function. Of course they must, since they both arose from the same point source of the Singularity.

16.2 Phenotypic Variation as Agency for Epigenetic Inheritance In “timeless” evolution, in which the perpetuation of the three basic cellular forms (Prokaryota, Archaea, Eukaryota) is the object of multicellular evolutionary variation (Miller and Torday, 2018), the scalable properties of evolution through niche construction clarifies. In the multicellular realm, reiterative niche construction is the product of phenotype as agent (Torday and Miller, 2016). Over the course of their life cycle, organisms collect epigenetic “marks” from their contemporaneous environment, and return them to the unicellular zygote through meiosis and sexual reproduction. In the zygotic stage and early embryogenesis, some of those epigenetic marks remain active and others are suppressed. The result is the biological development of a slightly altered adult organism that is in tune with the contemporary environment. Thus, the offspring become agents for repeating this process generation upon generation as an effective means of adaptation. It is this active “wandering” behavior of the phenotypes of organisms – which is applied to humans and described in great detail by Maura O'Conner in her book Wayfinding – that generates structurally and functionally integrated ecological niches. Niche construction promotes evolution by creating conditions for integrated epigenetic interactions. It is an attractive alternative to the “chance” Darwinian nature of evolution. By fostering phenotypic variation, epigenetics permits an organism to conform to its environment, and niche construction enables an organism to engineer aspects of the environment to be synchronous with its physiologic limits. By characterizing phenotypes as “agents” for the acquisition of epigenetic marks, the role of the adult organism is very different from how Darwin depicted it within standard evolutionary theory. Phenotypic agency is in service to the effective integration of the organism with its environment in order to continuously monitor for external changes in service to the perpetuation of the unicellular zygote; in the case of Darwinian selection, random mutations adaptively modify adults, and the traits are based on their reproductive success. By focusing on the adult stage of the life cycle, the evolutionary significance of the developmental phase, during which the unicellular zygote assimilates epigenetic “marks,” has been discounted. Yet, it is through this mechanism that Haeckel's “ontogeny recapitulates phylogeny” permits those terminal additions that allow for the evolution of complex life. This same internalization process reiterates to the planetary level. Gaia has

evolved via cybernetic feedback between the organic and inorganic realms, leading to stable homeostatic conditions for habitability at all planetary levels. Dynamic homeostatic interactions have established a global control system for the Earth's surface temperature, atmosphere and ocean salinity. This Earth-wide panhomeostasis is partially generated by living forms. This principle has been increasingly recognized in the fields of biogeochemistry and Earth system science. The Gaia hypothesis stands out because it is based on the precept that homeostatic equilibrium is an active mechanism for maintaining the optimal conditions for life and then, further, that life is necessary for planetary health as the ultimate niche construction. The importance of these reciprocations for planetary health is substantiated by recent findings that the Earth's modern nitrogen cycle is the end product of billions of years of linked microbial processes (Canfield et al., 2010).

16.3 On the Evolution of Metazoans Unicellular organisms dominated the Earth for 3.3 billion years before multicellular eukaryotic organisms evolved. These multicellular organisms are all holobionts as vast assemblages of coordinated cellular constituents from each of the three cellular domains and their viral symbionts (Miller, 2016a; Miller, 2016b; Ryan, 2019). As such, they represent their own form of niche constructions as conjoint forms of cellular problem-solving (Miller, 2017; Miller and Torday, 2018), and are now an embedded part of the entire planetary cycle.

16.4 Consciousness as the Product of Gaia – Why We Inherently Care About Mother Earth The fundamental interrelationship between the internal cytoplasm of the cell and external physical environment derives from their common origin in (the aftermath of) the Big Bang, both the inanimate and animate having to comply with fundamental thermodynamics and quantum mechanisms. The physical and chemical “equal and opposites” produced by the Big Bang resolve themselves through reactions controlled by homeostasis, hence the “equals” sign between the energy and mass of the reactants on the left, and the energy and mass of the products on the right (see Figure 16.1).

Figure 16.1

Balanced reaction. Energy (E) and mass (M) on either side of the equals sign is balanced by homeostasis.

Homeostasis governs living physical and chemical reactions by allowing for the equilibration of reactants and products in those proportions that permit the living state. This critical process proceeds from single cells to multicellular organisms through cell–cell signaling. Those signaling mechanisms are mediated by highenergy phosphate and inositide cascades, representing biologically based chemical reactions that yield coordinate cellular action. These physicochemical reactions, emanating from living organisms, must always be concordant with environmental

realities, since any violation of that inherent requirement becomes an extinction event. Thus, all thermodynamically driven inorganic or organic reactions, no matter their scale, must be in cohering reciprocation from atoms to planetary cycles as reflected by the Gaia hypothesis. It follows that consciousness must have a place within Gaia for that hypothesis to be valid. How might consciousness be reconciled with Gaia? One way is to assume, as many panpsychists do, that consciousness is an inherent property of the universe, and is invested in all aspects of the cosmos, whether animate or inanimate (Chalmers, 2015). An alternative approach to consciousness centered within Gaia is to approach the issue of consciousness as the organism's ability to problem-solve. This is not particularly problematic, since it has been contended that all of life is problem-solving (De Loof, 2015; Miller, 2016a; Miller and Torday, 2018; Miller et al., 2019, 2020). This derives from the principle that all life is based upon cognition (Shapiro, 2011). In that frame, all cells are equipped with basal self-referential consciousness (Baluska and Reber, 2019; Miller et al., 2019). Therefore, it directly follows that all cells are problem-solving agents. In the context of planetary life, cellular problem-solving is both the continuous internalizaton of the environment, and the linked ability of cooperating cells to modify their environmental space to better suit their living limits. In this way, cells are internalizing the planetary environment and altering it to permit their own life. The result, over the course of geological time, is our modern planet as Gaia. It is the problem-solving ability of cells that produces those reciprocating changes in the planetary cycle that effect a continuum in Gaia. Consciousness is one essential facet of that total planetary cycle. It may be that the panpsychists are correct, intuitively, but that concept lacks a mechanism that is scientifically testable and refutable. Perhaps consciousness is itself a direct product of the Singularity, rather than a further derivative. If so, there is room to consider consciousness as more than a planetary phenomenon. Instead, it may actually constitute a transcendent awareness across space-time, not merely being conscious of our mundane surroundings and self in the here and now, as our own manifestation of cosmic Gaia.

16.5 Morality as Gaia As has been emphasized, evolution proceeds through cellular cooperativity. Yet Darwinism focuses on competition as the driving force behind evolution. In a profile of Derek Parfit in The New Yorker magazine, entitled “How to be good” (Marquhar, 2011), the British philosopher and ethicist expresses his confusion regarding the paradox of reconciling Darwinian “Survival of the Fittest” with any requirement to be “good.” In Darwinian evolution, based on descriptive biology, evolution is presumed to be a consequence of the process of adult reproduction in which competition for mates is the dominating characteristic. In such a context, there is no natural drive to be “good,” since this is a narrative dominated by endless rounds of competitive advantage in which any ordinary concepts of morality would have no place. However, the paradox resolves when the actual dynamics of evolution are correctly ascribed. Life is problem-solving in accordance with inescapable thermodynamic principles (Torday, 2018, 2019) beginning with the first cell, which solved its living problem through its own niche construction, and has reiterated to Gaia as billions of years of coordinate cycling. This is a process of perpetual reciprocation, collaboration, cooperation and mutualized competition. In

such a circumstance, moral agency is invested as the continuous enactment of these perpetual living principles. In consequence, there are grounds for a real moral order in which “immorality” is one of those things that contradict that flow.

16.6 Climate Change, Gaia and Us Up until recently, the interrelationships between matter, energy and life on Earth have been a compatible interplay between living organisms and the planet. However, human ingenuity has disrupted that harmonious relationship, causing ever-greater upheavals in what is now being touted as the Anthropocene. Human engineering is capable of inducing a consequential state of disequilibrium for the orderly progression of planetary cycling. There is no precedent for this scale of dominating interaction with the biosphere by one species, and this disproportion can be rightly seen as violating the Singularity of Nature (Torday, 2019) and our evolutionary arc. Gaia theory envisions the Earth as a self-regulating complex system composed of the biosphere, the atmosphere, the hydrosphere and the pedosphere, tightly coupled together in a perpetually evolving system. As a holistic entity, Gaia seeks a physical and chemical planetary environment accordant with contemporary life. Upsetting the natural cycling of this planetary equilibrium must come at a price for the planet, and means divesting ourselves of our birthright. As the dominating engineering denizens of Gaia, it is our moral obligation, as just defined, to exert high levels of self-restraint to better maintain existential harmony with our living planet.

References Baluška F. and Reber A., Sentience and Consciousness in Single Cells: How the First Minds Emerged in Unicellular Species, BioEssays, 2019, 41, e1800229. Canfield D. E., Glazer A. N. and Falkowski P. G., The evolution and future of Earth's nitrogen cycle, Science, 2010, 330(6001), 192–196. Chalmers D., (2015, ), Panpsychism and panprotopsychism, Consciousness in the Physical World: Perspectives on Russellian Monism, Oxford: Oxford University Press. Christakis N. A. and Fowler J. H., Social contagion theory: examining dynamic social networks and human behavior, Stat. Med., 2013, 32, 556–577. Darwin C. R., (1881, ), The formation of vegetable mould, through the action of worms, with observations on their habits, London: John Murray. De Loof A., From Darwin's On the Origin of Species by Means of Natural Selection… to the evolution of life with communication activity as its very essence and driving force (=mega-evolution), Funct. Genomics, 2015, 3, 153– 187. Marquhar L., (2011, ), How to be Good, New York: The New Yorker. Miller Jr. W. B., Cognition, information fields and hologenomic entanglement: evolution in light and shadow, Biology, 2016a, 5, 21. Miller Jr. W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016b, 4, 96. Miller Jr. W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Miller Jr. W. B. and Torday J. S., Four Domains: The Fundamental Unicell and

Post-Darwinian Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2018, 140, 49–73. Miller W. B., Torday J. S. and Baluška F., The N-Space Episenome Unifies Cellular Information Space-Time within Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2019, 150, 111–139. Miller Jr. W. B., Baluška F. and Torday J. S., Cellular senomic measurements in Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2020, DOI: S00796107(20)30066-3. Ryan F., (2019, ), Visusphere: From Common Colds to Ebola Epidemics: Why We Need the Viruses that Plague Us, London: Harper Collins. Shapiro J. A., (2011, ), Evolution: A View from the 21st Century, Upper Saddle River: FT Press. Torday J. S., Life Is Simple—Biologic Complexity Is an Epiphenomenon, Biology, 2016, 5(2), 17. Torday J. S., Quantum Mechanics predicts evolutionary biology, Prog. Biophys. Mol. Biol., 2018, 135, 11–15. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S. and Miller Jr. W. B., The Unicellular State as a Point Source in a Quantum Biological System, Biology, 2016, 5(2), 25.

CHAPTER 17

Cell–Cell Signaling, the Energy Flow from the Big Bang to Civilization Like the red shift echoing the origin of the Big Bang, the intermediate cell–cell signaling steps in lung evolution echo the Singularity that predated the Big Bang. The continuum from the physical to the biological is revealed by tracing the cell– cell signaling mechanisms involved, beginning with the existential regulation of lung surfactant within the alveolus. Life has accommodated metabolism in order to cope with the rising and falling levels of oxygen in the atmosphere over the last 500 million years through the thinning of the wall of the gas exchanger, progressively ratcheting up the surface-area-to-blood-volume ratio from fish to amphibians, reptiles, mammals and birds. In all instances, this can be best understood as cells utilizing critical cell–cell communication to affect problem-solving and maintain intermediate states of cellular homeostasis (Miller, 2016; Miller, 2017; Miller and Torday, 2018; Miller et al., 2019). However, in order for that to work physiologically, the alveoli had to produce lung surfactant, a soapy material that lines the surfaces of the alveoli, reducing the surface tension that would otherwise have caused alveolar collapse, or atelectasis. By following the changes in the composition of lung surfactant backwards from the mammalian lung to the unicell, the evolution of the lung can be documented, beginning (and ending) with elemental lipids and calcium. The mammalian lung requires surfactant in order for the alveoli to function, regulated by parathyroid hormone-related protein (PTHrP) signaling, which coordinates the interactive “trafficking” of lipids from the microcirculation to the alveolar type II cell mediated by the lipofibroblast in order to maintain the integrity of the alveolus under the countering oncotic pressure of the fluids in the capillaries. That dynamic evolutionary interrelationship between oxygenation and metabolism refers as far back as the unicellular state if focus is maintained on the biochemical history of cholesterol in vertebrates. Cholesterol is the most primitive of the lung surfactants, being produced in the wall of the fish swim bladder to prevent the surfaces of the bladder from sticking together when the fish inflates or deflates it to adapt for buoyancy. And in the mammalian lung alveolus, cholesterol makes the complex mix of lipids and proteins more “fluid.” But, more to the point, this same process has reiterated from the unicellular state onward, beginning with the synthesis of cholesterol, when it is inserted into the cell membrane. As a result, the cell membrane thinned, increasing oxygenation, permitting efficient aerobic metabolism, which in the fullness of evolutionary time facilitated locomotion, all of which constitute the three pillars of vertebrate evolution. But how and why did the above traits evolve based on serial exaptations and, more pertinently, from where did the pre-adaptive traits emerge? That answer can be found by focusing on the signaling mechanisms that mediate all of the functions

of the cell, regulated by their elemental components. Lipids accompanied asteroids that pelted the Earth's surface early in its history. When lipids are submerged in water they naturally form primitive cell-like micelles, which would have tended to float on the surface of the primordial ocean. When the sun warmed those micelles, they would have liquified and deformed, facilitating the transfer of calcium ions through the micelle semi-permeable membrane. At night, the waters would cool and the micelles would reform due to hysteresis, progressively trapping more calcium. This effect was potentiated because the transit of ions across the membrane is temperature-dependent and, further, because the levels of calcium in the ocean rose over time due to the dissolving of atmospheric carbon dioxide in the atmosphere in the ocean, forming carbonic acid. The acidification of the ocean water leached calcium out of the bedrock. Calcium ions in high enough concentration disrupt micelles, so that those protocells that were able to devise ways of controlling the flow of ions across the membrane would have survived. It can be supported that this was the origin of the membranous channels that mediate the flow of calcium, and are the backbone of the semi-permeable membranes that enable cell activity in vertebrates. Such processes begin with the very first cell. Chemiosmosis, or the alignment of positive and negative ions along intracellular membranes, generated the energy necessary for negative entropy as one of the first principles of physiology that is basic to all cellular life. If we now fast-forward to more complex physiology, parathyroid hormonerelated protein (PTHrP) transduces mechanical force biologically. In that role, it plays an existential part in the development and homeostatic control of a wide variety of tissues and organs, ranging from the alveolus of the lung, to the glomerulus of the kidney, to the skin and brain. The best characterized of these PTHrP-dependent traits is the lung, which will not form alveoli if PTHrP is deleted from an embryonic mouse, as has been previously stated. It plays a pivotal role in cell–cell signaling between the epithelial and mesenchymal cells surrounding the developing alveolus, the epithelial cells producing PTHrP, which binds to the mesenchymal fibroblasts, stimulating cAMP and inositol trisphosphate (iP3), both of which stimulate the development of the fibroblast. The mature fibroblasts, referred to as lipofibroblasts, produce the hormone leptin, which stimulates the synthesis of lung surfactant by the alveolar epithelial type II cells, preparing the developing lung for air breathing at the time of birth. In a similar manner, the podocytes that line the glomeruli of the kidney produce PTHrP in response to fluid and electrolytes that accumulate within the glomerular space. The podocytes are stretch-sensitive, increasing PTHrP production in response to being filled with fluid. The PTHrP signals to the mesangial cells that regulate the flow of fluid and electrolytes from the glomerular space to the kidney tubules, thus regulating fluid and electrolytes in the systemic circulation. Developmentally, both the lung alveolus and kidney glomerulus contribute to the formation of amniotic fluid, which is necessary for the distension of both structures during embryonic development. This developmental interrelationship initiates the coordinate homeostatic interrelationship between the lung and kidney after birth. The mechanical control of the lung and kidney are somewhat obscure. However, when lung cells are put into microgravity conditions, their ability to produce PTHrP signals is inhibited, demonstrating the interconnection between the adaptation to gravity and the functional relevance of stretch-regulation of PTHrP. This adaptation became highly relevant during the water-land transition, when boney fish adapted to

land life. The first organ affected was the skeleton, because the force of gravity is greater on land than in water. PTHrP mediates the hardness of bone by regulating the deposition of calcium, referred to as Wolf's law. The PTHrP signaling pathway was amplified during the water-land transition, the PTHrP Receptor gene duplicating during this era, enhancing the strength of the skeleton of Tiktaalik, which represents critical fossilized evidence for the breaching of land by quadrupeds. Positive selection for PTHrP signaling was also existential for air breathing, increased fluid and electrolyte regulation and the formation of the skin barrier, all three of these physiologic traits having benefited from the amplification of the PTHrP signaling pathway due to the duplication of the PTHrP receptor. These primary adaptations for terrestrial life mediated by PTHrP signaling were greatly facilitated by the duplication of two other receptors, the glucocorticoid receptor (GR) and the beta-adrenergic receptor, the latter two being vital for terrestrial life. The GR evolved from the mineralocorticoid receptor (MR), the MR being remodeled by attaching three peptides to the active binding site, which Thornton et al. have referred to as “molecular exploitation.” This effective siphoning off of MRs to generate GRs was advantageous because mineralocorticoids increase blood pressure, which was already being exacerbated by the effect of gravity on land. The amplification of GR signaling was also advantageous because it facilitated the appearance of beta-adrenergic receptors in the lung circulation, leading to independent regulation of the pulmonary and systemic blood pressures. That adaptation was further complemented by the duplication of the beta-adrenergic receptor, benefiting the lung vascular control, and also facilitating the evolution of the four-chambered heart. The coordinate effects of the evolution of the lung, kidney and heart allowed for the successful transition of vertebrates from water to land. That complex cascade of physiologic events was paralleled by the evolution of the skin, necessitated by the need for greater regulation of fluid and electrolytes on land than in water. The skin forms a lipid barrier between the stratum corneum and the underlying epithelium. The cellular-molecular mechanism involved is homologous with both the synthesis of surfactant in the alveolus and the myelinization of neurons in the brain. In all three instances, neuregulin, an epidermal growth factor signaling intermediate, plays a pivotal role in neuronal development and homeostatic control. The proximate “cueing” mechanism for this series of cellular-molecular events precipitated by the transition from water to land were environmental pressures exerted by the partial drying up of the primordial ocean. The cellular response was the continuous endogenization of the environment to permit the continued maintenance of homeostatic control, which required robust systems of cell–cell communication to support multicellularity. In this way, environmental pressures cues cells to collaborate to yield a stronger skeleton in combination with air breathing, and changes in salt and water balance produced the lung, kidney and skin of terrestrial organisms from amphibians to reptiles, birds and mammals. The concerted effort made by boney fish to breach land is characterized by at least five independent attempts to do so. The capacity to make the transition in a step-wise manner is underpinned by the cell–cell interactions that mediated such saltatory progress. It is within that context that the evolution of the internal organs, particularly that of the lung, must be understood. As it evolved, there would have been stages when the amount of oxygen in circulation would have been inadequate for the metabolic demand of the organism. That would have precipitated periods of

hypoxia, the most potent stimulus for the hypothalamic-pituitary-adrenal axis, stimulating the hypothalamic-pituitary-adrenal axis (HPAA). Increased cortisol production by the adrenal cortex would have passed through the adrenal medulla on its way to the systemic circulation. Within the medulla cortisol would have stimulated phenylethanolamine-N-methyltransferase, the rate-limiting step in adrenalin production. Adrenalin would then have stimulated lung surfactant production by the alveoli, increasing oxygenation by allowing the alveoli to further distend, relieving the constraint on the alveoli of the lung. In tandem, adrenaline would also have stimulated the release of free fatty acid from fat cells in the peripheral circulation. Free fatty acids are high-energy fuel for metabolism, increasing body heat. Ultimately, this ad hoc increase in body heat was genetically modulated by the advent of oxytocin production by the posterior pituitary. The advent of endothermy was of critical importance in human evolution because it allowed us to stand naturally on two legs, since it takes much more energy than to stand on four legs. Bipedalism frees the forelimbs for specialized functions, primarily for tool-making. That, in turn, placed positive selection pressure on language formation, given the preoccupation of the hands with tool-making (Kolodny and Edelman, 2018). The structural common ground for tool-making and language formation is that both require complex integrations of cognitive function with language centered in the area of Broca, in the frontal lobe. Tool-making involves distributed regions of the brain, including primary cortical and subcortical motor and somatosensory regions (Stout et al., 2000). However, both require intense cognitive integration. So, tool-making might have energized language acquisition since both rely on our singular human ability to synthesize abstract concepts. No matter the exact pathway, one conclusion is paramount. The complementary effect of toolmaking and language led to the written word, which led to moveable type, which ultimately amplified as word processing and human-designed computers. All of these separate yet indisputably connected events facilitated the growth of culture as the crowning achievement of human civilization.

References Kolodny O. and Edelman S., The evolution of the capacity for language: the ecological context and adaptive value of a process of cognitive hijacking, Philos. Trans. R. Soc., B, 2018, 373(1743), 20170052. Miller W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016, 4, 96. Miller W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Miller W. B. and Torday J. S., Four Domains: The Fundamental Unicell and PostDarwinian Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2018, 140, 49–73. Miller W. B., Torday J. S. and Baluška F., Biological evolution as the defense of ‘self’, Prog. Biophys. Mol. Biol., 2019, 142, 54–74. Stout D., Toth N., Schick K., Stout J. and Hutchins G., Stone tool-making and brain activation: position emission tomography (PET) studies, J. Archaeol. Sci., 2000, 27, 1215–1223.

CHAPTER 18

The Physics of Biology Conforms to the Singularity Any assertion that the living circumstance originates from within the parameters set by the Singularity must be viewed as a straightforward identity. In geological terms, life was instantiated on this planet at a brief point after the Earth's formation, and became epitomized in the cellular form. This living instantiation within cellular boundaries requires continuous conformity with the first principles of physiology (negentropy, chemiosmosis, homeostasis) (Torday and Rehan, 2009). It further follows that life must observe thermodynamic proscriptions and obey cellular– molecular quantum fundamentals (Baverstock and Rönkkö, 2014; Torday and Miller, 2016). Therefore, it is pertinent to explore the nature of those quantum relationships, chemical necessities and biomolecular reactions, which are enabled through cellular boundary constraints that permit the emergence of biological phenotypes. It is proposed that, through such an undertaking, physics, chemistry and biology might be successfully reconciled from the Singularity forward. However, that expedient can only be realized if the terms of quantum engagement can be demonstrated to be consonant across each of these disciplines. One productive thrust towards that goal extends through the study of criticalities in physicochemical reactions, which might reflect the Singularity as its own form of universal initiating criticality (Pack et al., 1966). For example, it has been shown that some types of chemical reactivity involve singularities as abrupt catastrophic changes in the timing of bond-making and bond-breaking events (Menger and Karaman, 2010). The behavior of solid–liquid–gas systems near their three-phase interface has been modeled as a singularity based on surface criticalities (Sibley et al., 2013). Further, a class of solutions to problems in chemotaxis has been explored as criticalities that permit “chemotactic collapse” (Herrero and Velázquez, 1996). Given these known relationships, it should be useful to explore how criticalities feature more broadly across the basic sciences. In physics, concepts of criticalities are familiar territory. Quantum critical phenomena in quantum-mechanical systems at zero or low temperatures have been the subject of long-term study (Hertz, 1976). Research into dynamic critical phenomena and phase separations has been a salient aspect of modern physics during the latter half of the twentieth century (Hohenberg and Halperin, 1977). This work is no longer considered just theoretical. The ability to manipulate single atoms now permits the construction of useful quantum structures as fundamental building blocks. Using contemporary tools such as low-temperature scanning tunneling microscopy, arrays of magnetic atoms on a surface can be constructed to test the thermodynamic limits of sudden ground state changes (Toskovic et al., 2016). When such criticalities are reached as an atomic field approaches a critical value, behavior abruptly shifts according to size and structural complexity.

It has only been in the last few decades that criticality theory has had a substantial impact on the natural sciences, linking critical phenomena to chaos theory, fractals and theories of self-organization (Sornette, 2006). At the theoretical level, emergent behavior in both physical and biological systems has been modeled as forms of self-organizing criticalities (Jensen, 1998). Reflecting this initiative, Bak (2013) argues that, “complex behavior in nature reflects the tendency of large systems with many components to evolve into a poised, ‘critical’ state, way out of balance, where minor disturbances may lead to events called avalanches of all sizes. Most of the changes take place through catastrophic events rather than by following a smooth gradual path” (Bak, 2013). In consequence, there is an impulse to explain dimensional systems differently than in the past by concentrating on nonequilibrium models (Domb, 2000). Along with chemistry and physics, biological systems are now being evaluated as integrated quantum phenomena with their own kinds of criticalities. A variety of quantum biological phenomena have been documented as conforming to criticalities across a wide range of physicochemical processes. This includes photosynthesis and the complex operations of the olfactory apparatus as it copes with the noisy cellular environment of animals (Tarlacı and Pregnolato, 2016). The directional magnetic effects in migrating birds and mammals have been traced to a series of quantum phenomena (Ritz, 2011). An avian chemical compass that enables long-distance navigation has been linked to magnetic iron-containing particles in the upper beak, which acts as a magnetometer, determining geographical position dependent on the quantum spin dynamics of photoinduced radical pairs as a form of radical pair quantum entanglement (Pauls et al., 2013; Solov'yov et al., 2014). Naturally then, it would be expected that there should be corresponding quantum experiences in human biology. Experiments demonstrate that biological phenomena in humans are directly dependent on the quantum reception of information. Physicochemical research indicates that human hearing, though not acute compared with many animals, is sensitive to atomic-level fluctuations. Our sense of touch has nanoscale sensitivity, and our olfactory chemoreception is sensitive to one trillion distinct olfactory stimuli (Brookes, 2017). Our human vision has been experimentally shown to be sensitive to single photons (Tinsley et al., 2016). Each of these senses operates on the basis of critical phenomena based on the explicit reception of the correct environmental cues as circumscribed forms of singularities. Indeed, research on our biological sensation of taste has confirmed that the reactions of taste receptors conform to types of singularities (Erickson and Covey, 1980). As part of these criticalities, significant features of physiology relate to a variety of quantum phenomena, such as non-localization, quantum coherence and quantum entanglement (Torday and Miller, 2018). The geneticist, Ho (2008), noted that the adenosine triphosphate (ATP) transfer that permits coordinated muscle contraction, such as a human moving an arm, requires the coordination of an astronomical number of cells. The scale of the distances involved spans nine orders of magnitude, and requires the coordinate and simultaneous splitting of trillions of ATP molecules (Ho, 2008). Yet there is no set of chemical reactions or known physical processes that can account for these instantaneous reciprocations unless non-local quantum phenomena are invoked. One approach towards these types of critical transitions and quantum coherences has been through the investigation of physical biofields as matrices of energy, information and communication (Kafatos et al., 2015). Muehsam et al. (2015) had

defined the field concept as: “an organizing principle for the dynamic information flow that regulates biological function and homeostasis” (Muehsam et al., 2015). Increasingly, research is being directed towards biofield physiology by investigating electromagnetic, biophotonic and other types of coherent fields that permit multicellular organisms to respond in an integrated manner (Fels, 2018). Such fields are not theoretical. Physiologic function is currently assessed through electrocardiograms, magnetocardiograms and electroencephalograms (Hammerschlag et al., 2015). Such biophysical fields have even been implicated as their own kinds of criticalities, especially through origin of life studies. The origin of life has typically been considered a chemical transition. As another alternative, endogenous coherent oscillating electromagnetic fields and partially ordered water have been postulated as the origin of life as a physical, rather than chemical, criticality (Jerman, 2018). Any living organism is a thermodynamic unit that dissipates non-equilibrium energy. In effect, it is a temporary manifestation of a collapse of a superimposition of possibilities of a variety of entropic and enthalpic moments (Miller, 2016). Each of these represents rates of thermodynamic exchange that reflect a snapshot of its homeostatic status as a living state of cellular balance, expressed by temperature, volume, pressure, entropic status or free energy reserves. It is these exchanges, linking chemistry, physics and biological physicality, which represent natural bridges between thermodynamic exchanges and biologic entities (Miller, 2016; Miller, 2017; Miller et al., 2019). For instance, photosynthesis permits the direct conversion of energy from sunlight to the sugars that are required for metabolism and growth by phototrophs. Chemotrophs (organisms that obtain energy by the oxidation of electron donors in their environments) use the process of chemosynthesis to extract energy for the manufacture of sugars using electrons as their source of energy. Chemolithoautotrophs derive energy from the oxidation of inorganic substances. A metal-reducing bacterium, Shewanella loihica PV-4, can form an electrically conductive network, which can self-organize to transfer electrons over long distances using outer-membrane proteins and semi-conductive minerals (Nakamura et al., 2009). Importantly, though, each of these bioenergetic solutions can be regarded as representing fundamental principles of quantum physics, criticalities and symmetries that connect through cellular chemistry to channel biologic expression. The search for quantum coherences and criticalities that might have explanatory power in the biological sciences has been productively extended into evolutionary biology. The concept of discontinuities and criticalities in evolution has been the subject of research and conjecture for decades. Indeed, the basic framework of criticalities in natural phenomena was a feature of Darwin's Origin of Species in 1859. Darwin considered that the variations that led to evolutionary change might be of two types; one form would be a source of “continuous or blending” variation and another could account for bigger leaps in variation as criticalities, which he termed “sports” or “monstrosities” (Miller, 2013). This difference in the mechanisms of variation and evolution was the subject of long-standing debate in the early twentieth century. Some have argued for standard Darwinian gradualism, and others for “Saltationism,” or evolution through gaps and leaps (Larson, 2004). In the 1930s, the German paleontologist Otto Schindewolf proposed that evolutionary transformations occurred through critical discontinuities. This was monikered as the “Hopeful Monster” theory. Although championed by many, it never achieved general acceptance. In the latter part of the twentieth century, the

concept of major gaps in evolution as a series of unpredictable criticalities reemerged, based on the seminal work of Stephen J. Gould and Niles Eldredge (Eldredge and Gould, 1972). They tried to account for the disturbing gaps in the fossil record seen in the Cambrian explosion (∼541 million years ago) through a theory of punctuated equilibrium. During this period of the fossil record, there is the abrupt appearance of new body types with many novel features, suggesting that species can remain stable for extended periods and then undergo intermittent bursts of evolutionary activity. Although the issue of criticalities in evolution is still highly controversial, recent discoveries in genetics provide the specific genetic mechanisms that can account for them, including genetic inversions, transpositions, duplications and horizontal genetic transfers (Miller, 2016; Miller, 2017; Miller et al., 2019). As the microbiologist James Shapiro has observed about the fossil record, “We see the fossil record as episodic and characterized by geologically abrupt changes in the nature and distribution of organisms” (Shapiro, 2011). More recently, Miller (2013) has emphasized the concept of criticalities as essential to the evolutionary process. There is an increasing willingness to accede that the prior Darwinian model of gradual evolution through random genetic mutations during reproduction is untenable. Instead, the genome and the other genetic attributes of cells (mitochondrial DNA, cytoplasmic circular DNA, and the great number of varieties of RNA) can be intermittently altered by genetic incursions as infectious events or internal genetic transfers (Miller, 2016). In contrast to gradualism, a model of evolution based on these types of events can be considered as unique moments of criticality. Certainly, genomes can resist genetic impacts for prolonged periods of time (Miller and Torday, 2018). This is obvious when the stability of some species is recognized. For example, horseshoe crabs have remained unchanged for nearly 400 million years. That does not mean that they are genetically unaltered. Indeed, all genomes accumulate gradual changes from genetic incursions, random replication errors, and the transpositions of genetic segments over time. However, these remain latent until a triggering criticality exerts sufficient influence to initiate a cascade of events that leads to a demonstrable shift in genetic expression (TorresSosa et al., 2012). Although there is considerable resistance to accepting this new approach to evolution, criticalities in biology are actually freely observable. For example, in 1874, an unprecedented Rocky Mountain locust swarm swept across the mid-west of the USA. An estimated 12.5 trillion locusts blanketed a swath across America that was as large as California (1800 miles long and 100 miles wide). By 1902, all were gone and none have been observed since (Wagner, 2008). Even today, no one can adequately explain the occurrence of insect swarms such as this or others of lesser magnitude that frequently occur. Since criticalities are recognized as essential to an understanding of physics, chemistry and, more recently, biology, there has been a natural impulse to attempt to discern a common architecture that would unite them across the basic sciences. Longo and Montévil (2014) have attempted to provide a bridge between physics and biology by approaching criticalities as breaks in symmetry. They argue that the dynamics of biological organisms relate to critical transitions as symmetry changes. It is the breaks in those symmetries, as forms of structural stabilities, that provide diversity and ultimately lead to biological adaptations. Many concepts of biological symmetry comport quite well with inorganic chemistry. Symmetry breaking is recognized as a consequential feature of transition-metal chemistry and nano-chemistry. This same issue also pertains to the

dynamics of chirality, which is essential to both chemistry and biology. For example, it is known that two populations of chiral crystals of differing handedness cannot co-exist in solution. One population disappears in an irreversible autocatalytic process in deference to the other as inevitable chiral symmetry breaking (Viedma, 2007). In attempting to unify the basic sciences across a single quantum framework, Bohm and Hiley (1975) asserted that phenomena of all types depend on a quantum theory of non-locality grounded in the superimposition of possibilities. This abstruse framework implied that a system cannot be analyzed through a simple reduction. Instead, a universal descriptor must apply, in which all systems are considered in their entirety as supersystem-system-subsystem. Bohm argues that this construct leads to a coherent framework of “unbroken wholeness to the entire universe.” In this way, criticalities such as the discrete jumps in quantum processes, or wave-particle duality, or non-locality might be accounted for as the superimposition of possibilities, conceived as overlapping “implicates,” which upon reaching some critical stage, result in “explicates,” either as an inanimate material form or as a biological expression. The possibility that living activities might proceed within a quantum superimposition of possibilities has also been championed by the theoretical physicist and philosopher Amit Goswami (Goswami, 1990). A single organism might settle one set of superimposed possibilities and then, through its internal resources, settle those uncertainties into explicate biological action. Yet, any such resolution of contingent ambiguities into a discrete “explicate” as biological action simply yields another instantaneous set of “implicates” as further equivocal choices. Who might deny that this narrative defines our own living experience? Any of our choices yield other alternatives and a renewed set of fresh doubts. Organisms are forced to cope with these uncertainties through physicochemical pathways whose impact on any one organ system consistently reverberates with another. There is no specific area in which the concept of the superimposition of possibilities and its attendant criticalities has been more vigorously applied than in the study of consciousness. The eminent philosopher and mathematician Alfred North Whitehead, and the theoretical physicist David Bohm, both believed that an experiential component is embedded throughout the universe and even extends to the inanimate (Whitehead, 1967; Bohm and Hiley, 1975; Whitehead, 1985). Panpsychism insists that consciousness was instantiated with the Singularity as the ultimate criticality (Chalmers, 2015). In these terms, the universe is defined through a relational universal “sense-awareness” (Whitehead, 1920). A variant, known as cosmo-psychism, asserts that our ordinary experiences are grounded in an “allpervading cosmic consciousness” as an emergent aspect of quantum field theory (Shani and Keppler, 2018). If the foregoing is granted as a valid argument, all universal properties, including cosmic consciousness, must have their progenitors from within the Singularity. In this frame, the living circumstance and all of its evolution must extend across quantum space–time as an experiential and relational continuum, extending directly forward from the inanimate in a seamless arc from the Singularity (Torday and Miller, 2018). In that circumstance, physics and biology become a continuity rooted within fundamental and universal quantum properties that emanate forward from the Singularity. Thus, if consciousness originates with universal inflation, then all consciousness, even our own, must be seen as a timeless transfer of fundamental universal sense-awareness. Within this framework, it follows that all objects are

always connected to all other universal objects (Torday and Miller, 2018). Further then, if such connections are the actual basis of the universe, then self-referential organization is implicit to an originating Singularity and there is an identifiable and universal “oneness,” which would itself be the unifying link between physics and biology (Torday, 2019). Obviously, not all agree. Others vigorously defend that consciousness is the result of a series of critical emergences, contingent on criticalities, which becomes its own manifestation of a superimposition of possibilities constituted by as yet unknown phenomena (Goff, 2009). A number of further alternative modern theories for the origin of consciousness invoke a variety of known quantum mechanisms as a singular type of emergence. Hammeroff and Penrose (1996) have proposed that consciousness originates in a biomolecular “quantum underground” that originates within quantum coherences in brain cells originating from oscillations of microtubules. These effects are transmitted to peripheral neurons and then, ultimately, link to all of our other cells. Some potential biochemical pathways have been identified that support this putative mechanism. For example, it is believed that serotonin impacts intracellular brain microtubules through quantum effects that might eventually yield consciousness (Heron et al., 1980). The issue of the emergence of consciousness is highly debated. Some hold that consciousness might have been instantiated as a type of phase transition as a state function through which life instantaneously separated from the inanimate (Giuditta, 2010; Trewavas and Baluška, 2011; Miller, 2016). In effect, consciousness was instantiated within boundary conditions as a simultaneous criticality/singularity. Others, too, have considered the mystery of conscious self-reference through a framework of criticalities. In the well-known orchestrated objective reduction (Orch OR) model proposed by Penrose and Hammeroff, consciousness is due to a “wave function collapse” that localizes in the cytoplasmic reticulum (Hankey, 2019). In contrast, Hankey (2014) asserts that “mind” cannot be explained through classical physics or be defined within specific anatomic structures. Instead, mind derives from quantum phenomena as the result of “critical instabilities” that create “selforganizing criticalities” that loop back upon themselves (Hankey, 2014). These criticalities form a type of information feedback loop, which permits selfobservation through “perfect images of system states,” which loop back upon themselves. Therefore, it is not resonances that create self-reference. Instead, it arises as unstable anharmonic fluctuations as forms of coherent negentropy (Hankey, 2014). In consciousness studies, a primary issue is the exact means by which our objective reality, as local “classical” realism, can connect to subjective states as experientiality. Some suggest that these links must form along a metastable continuum guided by universal laws of the physical world, such as criticalities, selforganization and emergences (Fingelkurts et al., 2013). Indeed, there is evidence that instability is the actual norm insofar as there is evidence that the resting brain is in a state of criticality from which subjective experiences flow as levels of phase transitions (Werner, 2013). Subconscious experience may then emerge from “veiled non-localities” (Kak et al., 2014). This concept argues that there is much more information that an organism senses than it overtly recognizes; hence, many environmental cues are “veiled” and remain as a menu of superimposed implicates that become our sub-conscious thought. Deacon (2011) considers implicates as a thermodynamic phase-space that can be warped along a plane of trajectories. In the resulting regions of maximum curvature,

there is a condensation of “adjacent” options. In terms of dynamical system theory, these areas are deemed to be thermodynamic “attractors.” This framework has received support through a measuring mathematical construct applied by Tozzi and Peters (2017). Biological activity, including that of the brain, is theorized to take place in phase-spaces modeled as concavities or funnel-like locations where particle movements take place. As curvatures in phase-space, trajectories converge as time progresses, with particles taking the shortest path. In phase-space, the trajectory that will be taken follows the steepest descent direction within the phase-space concavity in seeking the nearest free-energy minimum. On the practical level of neural circuits, this would correspond to neuronal impulses tending to go by the shortest possible neural path. Such phase-space modeling merges with another proposition; that consciousness and other biologic processes are dependent on symmetries. Longo and Montévil (2014) propose that, although symmetries are common to both physics and biology, they play radically different roles in each. They argue that biological organization is not just “processes,” but permanent critical transitions, which are transient in and of themselves, but yield a “continually renewed structure,” which necessarily represents symmetry changes. It derives from this that, when it comes to symmetries, biology and physics are each in the opposite situation. The mathematical expression of symmetries requires a characterization of the dynamics of structural stability and variability. It depends on similarities and repeated congruities. The problem in biology is that it has very few invariances. Thus, the major path towards comprehending the physics of biological dynamics can only be gained by a better understanding of how criticalities relate to biological variability as changes in symmetries. Still, others assert that experiences arise from changes in gauge fields. In the mathematical construct of a gauge field, particle flow in space–time is in the direction of gauge symmetries that have a direct relationship to gauge potentials. Brain activity is driven by gauge fields through the maintenance or breakdown of these gauge symmetries (Tozzi et al., 2017). Kafatos (2014) connects “symmetry breaking” from particle physics to consciousness through three fundamental principles: complementarity, recursion and sentience. In quantum systems, complementarity unifies “apparent” opposites. Recursion assumes “as here, so elsewhere,” which permits the consciousness of one being to be like that of another. Sentience is the critical correspondence between internal and external states that maintains homeostasis. Each of these links through non-local correlations, thereby enabling subconscious experiences that might lead to intuition and creativity. These lead to “veiled” non-localities as superimposition of possibilities, symmetries and critical instabilities, which become a form of information entanglement and lead to the creative “bursts” that are part of our lexicon of human attributes (Miller et al., 2019). The concept of phase-space offers a means of uniting the inanimate with the living circumstance over evolutionary space-time. Kauffman and Gare (2015) propose that the phase-space of evolution must be reconceptualized as coexistent adjacent possible states that continuously constitute new boundary conditions that both impose and release evolutionary constraints. It is this continuous reciprocation that permits the continuation of the living state, which must always match a continuously shifting environment. In consequence, “nature is simultaneously observing and observed and in the process of becoming. But to get to this view we must surpass classical physics in which the world of actuals happen whether or not

observed.” It can be offered that if, such a construct is to be accepted, then matching states as a reciprocal of the environment must be proceeding through the collapse of a superimposition of states as a fundamental quantum mechanism. Given the increasing attention that quantum physicochemical mechanisms are receiving in biology, it might be a useful inversion to consider how biology might be able to inform physics and chemistry. Walker et al. (2016) have asserted that biology is a means of constraining unknown physics. Biology subsumes other properties beyond acknowledged mechanisms of physics that somehow permit biological self-organization. Walker et al. (2016) offer this perspective: “Biology is distinguished as a physical system not by its causal structure, which is set by the laws of physics, but in how the flow of information directs the execution of function” (Walker et al., 2016). One way of approaching that stream of information is by supposing that it flows through cells as a series of nodal state interactions as a Bayesian network. This type of interaction can be modeled along the lines of a Markov blanket as a network of nodes consisting of parents, its children and any other parents of its children. The integrity of each participant cell is maintained, since the probability distribution of each node within the network is conditionally independent of the other nodes in the network (Margaritis and Thrun, 2000). It has been proposed that all living systems are nested systems of such Markov blankets, and develop intrinsic self-organizing properties based on the resolution of uncertainties (Kirchhoff et al., 2018). In this way, the flow of information can be directed towards maintaining the homeostatic equipoise of each cell in the network, ramifying level by level. It is important to note, however, that homeostasis is not equilibrium. As the Hungarian biologist, Evin Bauer put it: “The living and only the living systems are never in equilibrium; they permanently invest work on the debit of their free energy budget against that equilibration which should occur for the given initial conditions of the system on the basis of the physical and chemical laws” (Grandpierre et al., 2014). It has been argued that the living state differs from the inanimate in having obligatory indeterminacies, which is why it is not an equilibrium system. Clearly, uncertainties are part of physical systems, and they are being better understood due to the quantum revolution (Grandpierre et al., 2014). Yet, there are still pertinent differences between the living and the inanimate. In the latter, physical states are expected to obey the principle of least action. Some biologists also insist that organisms obey the principles of thermodynamic least action (Baverstock and Rönkkö, 2014). What biology teaches us is that, although least action might rule in thermodynamic systems, this does not precisely define the living circumstance. In the living state, cells measure information so that their choices are guided by “least uncertainties,” i.e. higher predictive value (Miller et al., 2019b, 2020). If those choices are correct, that is, are consonant with environmental proscripts, then “least action” is also satisfied through the conservation of energy. Since cellular action proceeds through self-referential measurement, solving the mystery of self-referential consciousness may likely reveal a new physics and an upended chemistry. From the foregoing, it is not surprising that straightforward Newtonian rules are not a feature of biology as they are in the physical world. The cell and its subsystems cannot be explained by conventional physical principles. Witzany and Baluška (2015) note that “because cell-to-cell communication depends on shared rules to use signs according to contextual needs, physical principles are not an appropriate tool for a better understanding of biological processes and sub-cellular

organization” (Witzany and Baluška, 2015). The physicist Walter Elsasser maintained that “all attempts to seek ‘laws’ akin to those used in physics to explain biological phenomena are patently illogical” (Ulanowicz, 2007). However, that should not be interpreted as meaning that there are no foundational reiterative living principles. The origin of consciousness may not be known, but it is certain that conscious entities use that faculty to confront uncertainties and solve problems. This is biology's constant; perpetual flexible process, as opposed to inanimate invariance. Cells express these recapitulating processes through their measuring tools to maintain individual states of homeostatic equipoise. From this, a basic principle clarifies. Self-referential problem-solving is the reiterative fundament of biology (Miller et al., 2019). The express manner in which those tools are energized and deployed points the way to new essentials in physics and chemistry. How might we search for this answer? Schrödinger had conceived of life as a violation of the second law of thermodynamics. It has been previously defended that this negentropic state can be further understood as an expression of an equal and opposite reaction to the Singularity in conformity with Newton's third law of motion (Torday and Miller, 2018; Torday, 2019). In like kind, it can be further advanced that the Singularity, as its own initiating criticality, set in motion perpetuating reverberations, which yielded like-kind minor sub-wavelets from that instantiation as a set of initiating criticalities. Each by each, they become universal characteristics, as homeostasis in all its chemical and physical forms. Such a physical system is capable of absorbing environmental impacts only to some specific degree, beyond which its chemical integrity cannot shift without triggering an abrupt discontinuity. Thus, the loss of homeostasis or cell division can be appreciated as its own form of symmetry breaking through the build-up of superimposed non-equilibrium criticalities imposed by the living circumstance (Chapter 13). Schrödinger proposed that the consumption of negative entropy was dependent on an organism's ability to extract latent information from environmental complexity. It follows that information is itself a thermodynamic entity, since energy and information are inter-convertible (Miller, 2017). Therefore, in living systems, information has direct links to self-reference, which defines the living state. It follows that cellular organisms are transient intermediary manifestations of energy flux within the symmetry of information as entrained energy. It has previously been argued that energy that becomes information to a cell can be regarded as having undergone a phase transition in physical order, much the same as when water instantaneously transitions to steam (Miller, 2017). Such transitions in complex biological systems are not merely theoretical. Experiments in neural coding have validated that the measured probability that a fluctuating neuronal membrane voltage will exceed certain activation thresholds proceeds through abrupt phase transitions without any intermediary stages (Taillefumier and Magnasco, 2013). A concept of phase transitions has been previously applied to the origin of life. It has been proposed that an abrupt physical transition is required for life. In order to affect the living circumstance from the abiotic realm, a phase transition of energy to information is necessary in order to achieve context-dependent causal efficacy over the matter from which it was instantiated (Walker and Davies, 2013). Being “alive” means that energy is recognizable as information to that living entity. This necessitates observer/participant status. Without the “knowing” observer, energy is energy and not information. However, within the living state, there is one further

requirement. That the observer must “know” that all biological information has some level of indeterminacy. All information is ambiguous in the living circumstance. Since information is an uncertain quantity, it follows that living things measure. Perfect information does not require measurement. Since energy as information can be regarded as its own form of phase transition, it follows that the measuring capacity of each cell, as a “knowing” observer/participant, exists within a context that it is tasked to measure those phase transitions in the physical order that constitute its background experience (Miller, 2017). Since cells are agents of thermodynamic flux, they both measure (observe) and participate in phase transitions and criticalities. It follows that it must be by this means that cells maintain themselves as firmly centered within the injunctional negentropic requisite, which is imposed through the first principles of physiology (negentropy, chemiosmosis, homeostasis). It is only in this manner that cells can maintain homeostatic symmetry. Matsuno (2017) points out that any general or metabolic reaction cycle is a product of a measurement apparatus of natural origin. In the inanimate sphere, measurement is the transfer of material resources of some kind between arbitrary bodies in quantum terms. Thus, even within the inanimate, there is a definable difference between the measuring entity and the measured. This is a highly discrete form of molecular recognition, which can be understood as an exact transfer of material resources between any two objects. Measurement has also been considered the epitome of the living circumstance (Miller et al., 2019; Miller et al., 2019b, 2020). Its measuring difference from the inanimate is that living entities respond as a living cohesive unit between that which does the measuring and the measured. A crucial limiting condition exists among the living. The living state must cope with informational imprecision (Miller, 2016, 2017; Torday and Miller, 2017; Miller et al., 2019). Matsuno (2017) adroitly bridges this differential by arguing that measurement can be represented as a form of quantum “pull” in both the inanimate and animate realms. In either instance, whatever does the measuring institutes a “retro-causative propagation” that reverberates within the measured, whose reaction is an attempt to nullify the causation of that action (Matsuno, 2017). Both the inanimate and animate integrate that “pull,” but do so along different paths. Yet still, both are instances of quantum measurement as “an instance of demonstrating the act of measurement or identification for distinguishing between the subject of pulling in and the object being pulled in, exclusively on the material ground” (Matsuno, 2017). A quantum system is a superimposition of possibilities prior to an observation. It is the act of observation that triggers the wave function collapse of the superimposition of possibilities. As Theise and Kafatos (2016) have stated, “quantum phenomena are contextual, one cannot speak of ‘independent’ outcomes without the measurement context used to examine such phenomena.” It is proposed that it is this precise point that establishes the relationship between biology and the Singularity, by enabling the type of “retro-causative propagation” that enables negentropic biology. As a fundamental law, the entropic expansion of the Singularity/Big Bang must propagate an oppositional force (Torday and Miller, 2018). The result is cellular negentropy as an ordered state within cellular boundaries juxtaposed against its external environment. It is only in this manner that life can be maintained through the first principles of physiology (negentropy, chemiosmosis, homeostasis) (Torday and Rehan, 2009). Homeostasis is the state of self-referential “knowing” of an negentropic ordered state within boundary

conditions, and chemiosmosis reflects all the physicochemical processes that maintain the cell through ions and bioactive molecules and biofields. Those processes are supported by communications between cells, which are also information/energy transfers. Binder and Danchin (2011) argue that these energetic transfers should be viewed as a set of state correlations of “measured and measuring systems.”. It directly follows that any transfer of energy within a quantum system is an obliged subject of retro-causal regulation between “measured and measuring systems” yielding a correspondent action-reaction sequence. It is this reciprocation that is essential to the living state. According to Matsuno (2017), that living crux is only reached when reactions that are synchronous with the “present” moment are the ones that are exciting the retro-causal reactions. However, and crucially, only the self-referential state has the property that can enable retro-causal reactions as a cohesive unit between the measured and measuring (Miller et al., 2019). Thus, the fundamental retro-causal action-reaction sequence that originates from the Singularity and represents the essential aspect of the living frame is the selfreferential state. There is a further critical aspect of action-reaction among living entities that corroborates this viewpoint. Any cohesive biological action-reaction that is the result of fundamental retro-causative propagation must be considered a form of prediction. In living systems, the measuring assessment of imprecise information and its communication that become bioactive expression are default predictions (Miller et al., 2019). Since any biological expression is the collapse of the superimposition of possibilities in which a set of informational implicates is collapsed into explicate biological expression, the link between the Implicate and Explicate realms that Bohm championed is clarified. This same issue of action-reaction has been placed within a framework of criticalities. Hankey (2018) explored this possibility, in which “new” information becomes a form of critical instability. This framework completely inverts standard biology. Regulation of living systems does not come from well-ordered states, but emanates from critical instabilities that optimize regulatory responses. If the resolution of a specific instability leads to an improved biological result, it can go on to universal adoption as a self-generating set of internally generated feedback loops. Since cells are measuring instruments, it follows that they are sensitive to these criticalities. However, since criticalities, by definition, are a critical overlap of conflicting information for a cell, it follows that they must incur from cellular informational ambiguities. From this, it follows that any resolution of those ambiguities must proceed through cellular measurement to enable biological expression as prediction. Matsuno (2017) reached the same conclusion, stating that biology is conditioned within “inevitable incompatibilities between the detection and reaction at the present moment” (Matsuno, 2017). As the epitome of the living state, cells are dependent on imprecise information, some of which will be assessed as incompatibilities. Thus, in the self-referential living state, “inevitable incompatibilities” are a reflection of uncertain information as inescapable superimpositions of possibilities that exist prior to the collapse of any informational wave function to yield biological expression. In the circumstance in which information is always imprecise among biological participants, the context of information must be contingent on anticipation and prediction. This can be further considered as a deviation from sets of random variables within a probabilistic quantum system (Miller et al., 2019). If acceded to, uncertainty can be alternatively framed as incomplete information about an

operative system (Khrennikov, 2007). From this, it reduces that the degree of informational ambiguity directly relates to the capacity for measurement by a selfaware entity. That measurement can be considered as forms of quantum-like inferences as anticipations that can be directed towards problem-solving. Clearly then, living processes relate to pertinent quantum inferences as an organism encounters environmental stresses (Gunji et al., 2016). In effect, cellular decisionmaking involves an expectational status. This equates to cellular prediction based on experienced environmental stimuli. Biological expression extends through this cellular appraisal. Ultimately, whatever the explicit mechanisms self-reference, cells are always in the business of prediction. From this, a summation can be offered. Cells receive imprecise information and then, through a series of direct quantum inferences, measure to enable prediction (Miller et al., 2019b, 2020). Over the last decade, Christopher Fuchs (2011) has alternately framed the concept of the imprecision of biological information. Fuchs asserts that a quantum wave function can fully describe the physical systems of the universe according to an objective reality that is intrinsic to nature itself. Fuchs and his colleagues have posited that wave functions exist as Bayesian probabilities, which are defined as a quantum Bayesian system or “QBism.” This is an observer frame, in which every wave function is subject to “degrees of belief about the system” (Gefter, 2015). In this framework, reality is observer-dependent, since all physical phenomena are only describing the observer. When wave functions collapse, they are not reflecting an actual concrete reality. Instead, every such collapse of a wave function is the act of a specific observer updating its own “beliefs” after making a measurement (Fuchs, 2011). In QBism, the universe does not comprise physical objects as we typically appraise them. Instead and at all times, there are “at the moment” encounters with subjective reality that are being consistently updated by successive measuring observations. It follows in this frame that quantum wave functions cannot be any objective ultimate reality since they are only a representation of an observer's immediate “subjective” knowledge. If this line of reasoning is accepted, then a useful reduction can be offered. All such particulars are dependent on “selfreference.” It further follows that biology and physics are differentiated only by their means of measuring “self-referential” environmental phenomena, which can only be appraised within the conditional definitions and properties of what it means to be “subjective.” It has been maintained that the superimposition of possibilities and their attendant criticalities are forms of informational ambiguity (Miller, 2017; Torday and Miller, 2017). For a cell, its boundaries place implicates into an ordered set by which the cell confronts uncertainties. Criticalities then become zones that have extended beyond prior normative expectational boundaries. It defaults that such instabilities extend beyond predictable space–time information sets. It follows that cells, or any living organism for that matter would deal with informational ambiguity by utilizing a perception pattern that minimizes measurement discrepancies. There is evidence that supports this supposition. The transmission of signals via the cytoskeleton conforms to this kind of pattern of perception (Igamberdiev and Shklovskiy-Kordi, 2017). This phenomenon follows what has been termed the “principle of optimality,” which asserts that the spatiotemporal patterns that organisms use are established to achieve maximal predictability in space–time (Igamberdiev and Shklovskiy-Kordi, 2017). What then is the specific differential crux between chemistry and physics or

biology? Among the inanimate, abiotic chemical reactions are understood through classical and quantum measurements, which conform to mathematical patterns. Their reactions are mediated by the transfer of quantum resources, which can be reliably and conclusively replicated. Life as “living measurement” is contrary. Living measurement is a consistently variable superimposition of possibilities, ambiguous criticalities and inevitable incompatibilities among active observer/participants. Therefore, life can be presented as shifting sets of probabilities that exist along a “living” quantum wave function that is neither random nor deterministic (Miller, 2016; Torday, 2019). Matsuno (2017) has stated that “measurement is anti-symmetric in time since it cannot tell what can be measured prior to the actual event of measurement.” This can be assumed in the inanimate realm, but does not necessarily represent the living frame. From this, the differences between measurement in chemistry and physics, and measurement in biological terms crystalizes. Compared with all inanimate things, the living state is a prediction of an anticipated environment. Cells anticipate and predict in order to successfully maintain homeostatic integrity (Ben-Jacob, 2009; Ford, 2009; Ford, 2017). Biology is a prediction system consistently assessing information among a range of implicates and their attendant criticalities to become organic expression in a context of contingent distinctions. Thus, biological measurement stands apart and distinct from the exact and reproducible measurements of the inanimate realm. Since everything exists within physicochemical parameters, studies of criticalities and symmetries across the basic sciences open a pathway towards rapprochement between physics, chemistry and biology. Over the centuries, discoveries in physics and chemistry have been grounded in testables based within reproducible measurements sufficient to enable observer-based predictions. In this manner, the physical characteristics of Mendeleev's “missing elements” in the periodic table were predicted long before they were identified (Scerri, 2019). Eddington was able to devise an experiment that would confirm Einstein's theory of relativity. The characteristics of a number of sub-atomic particles had been predicted, and then eventually confirmed (Dzierba et al., 2000). Only biology remained apart as a field based on descriptive observation, rather than discrete predictive measurements. Now, through our greater understanding of the complex chemistry of the cell and advances in molecular biology, new forms of biological measurement with predictive value should be possible. Among the many unknowns that remain in the task of a grand reconciliation among chemistry, physics and biology, one essential commonality is identifiable. At the microscopic level, fundamental principles of uncertainty undergird both the animate and inanimate (Grandpierre et al., 2014). Within this elemental constraint, the self-referential cell can now be understood as a measuring apparatus whose success is dependent on the consistent confrontation of that uncertainty. The path towards the reconciliation of all the basic sciences can productively progress within these foundational proscripts. All that can be observed emanates from the Singularity. Yet, the range of phenomena that are its yield have such particular manifestations that they each strike our human sensibilities as unique and exceptional. Consequently, every branch of science has independently interrogated them as exclusive phenomena. Chemistry is thereby separated from physics, and both have been regarded as distinct from biology. In contradistinction, it can now be asserted there is a direct and ineluctable kinship among them. All cohere as differing modes of measurement of critical phenomena that began in the Singularity, and continue unabated as perpetual reverberations. Therefore, a pathway towards reconciliation between

chemistry, physics and biology can be discerned. Their ultimate unification presides within the identification and the concordant measurement of each of the foundational criticalities and symmetries that extend back to the Singularity.

References Bak P., (2013, ), How Nature Works: The Science of Self-organized Criticality, New York: Springer Science & Business Media. Baverstock K. and Rönkkö M., The evolutionary origin of form and function, J. Physiol., 2014, 592, 2261–2265. Ben-Jacob E., Learning from bacteria about natural information processing, Ann. N. Y. Acad. Sci., 2009, 1178, 78–90. Binder P. M. and Danchin A., Life's demons: information and order in biology: What subcellular machines gather and process the information necessary to sustain life?, EMBO Rep., 2011, 12, 495–499. Bohm D. J. and Hiley B. J., On the Intuitive Understanding of Nonlocality as Implied by Quantum Theory, Found. Phys., 1975, 5, 93–109. Brookes J. C., Quantum effects in biology: golden rule in enzymes, olfaction, photosynthesis and magnetodetection, Proc. R. Soc. A, 2017, 473, 20160822. Chalmers D., (2015, ), Panpsychism and panprotopsychism. Consciousness in the physical world: Perspectives on Russellian monism, Oxford: Oxford University Press. Deacon T. W., (2011, ), Incomplete Nature: How Mind Emerged from Matter, New York: WW Norton & Company. Domb C., (2000, ), Phase Transitions and Critical Phenomena, Amsterdam : Elsevier. Dzierba A. R., Meyer C. A. and Swanson E. S., The Search for QCD Exotics: Particles predicted by the theory of quantum chromodynamics help explain why the fundamental building blocks of matter are impossible to isolate, Am. Sci., 2000, 88, 406–415. Eldredge N. and Gould S. J., (1972, ), Punctuated equilibria: an alternative to phyletic gradualism, Models in Paleobiology, San Francisco: Freeman Cooper. Erickson R. P. and Covey E., On the singularity of taste sensations: What is a taste primary?, Physiol. Behav., 1980, 25, 527–533. Fels D., The Double-Aspect of Life, Biology, 2018, 7(2), 28. Fingelkurts A. A., Fingelkurts A. A. and Neves C. F., Consciousness as a phenomenon in the operational architectonics of brain organization: criticality and self-organization considerations, Chaos, Solitons & Fractals, 2013, 55, 13–31. Ford B. J., On intelligence in cells: The case for whole cell biology, Interdiscip. Sci. Rev., 2009, 34, 350–365. Ford B. J., Cellular intelligence: microphenomenology and the realities of being, Prog. Biophys. Mol. Biol., 2017, 131, 273–287. Fuchs C., (2011, ), Coming of Age with Quantum Information, Cambridge: Cambridge University Press. Gefter A., (2015, ), A private view of quantum reality, June 4, https://www.quantamagazine.org/quantum-bayesianism-explained-by-itsfounder-20150604/. Giuditta A., The origin and philogenetic role of mind, Hum. Evol., 2010, 25, 221–

227. Goff P., Why panpsychism doesn't help us explain consciousness, Dialectica, 2009, 63, 289–311. Goswami A., Consciousness in quantum physics and the mind-body problem, J. Mind Behav., 1990, 11, 75–96. Grandpierre A., Chopra D. and Kafatos M. C., The universal principle of biology: determinism, quantum physics and spontaneity, NeuroQuantology, 2014, 12, 364–373. Gunji Y. P., Sonoda K. and Basios V., Quantum cognition based on an ambiguous representation derived from a rough set approximation, BioSystems, 2016, 141, 55–66. Hameroff S. and Penrose R., Orchestrated reduction of quantum coherence in brain microtubules: A model for consciousness, Mathematics and computers in simulation, Quantum Conscious., 1996, 40, 453–480. Hammerschlag R., Levin M., McCraty R., Bat N., Ives J. A., Lutgendorf S. K. and Oschman J. L., Biofield physiology: a framework for an emerging discipline, Global Adv. Health Med., 2015, 4, gahmj. Hankey A., Complexity biology-based information structures can explain subjectivity, objective reduction of wave packets, and non-computability. Cosmos and History, J. Nat. Soc. Philos., 2014, 10, 237–250. Hankey A., (2018, ), Mathematical Model of Free Will Based on Experience Information in a Quantum Universe, Unified Field Mechanics II: Formulations and Empirical Tests, Hackensack: Worldwide Scientific. Hankey A., Instability physics: Consciousness and collapse of the wave function, J. Phys.: Conf. Ser., 2019, 1251, 012019. Heron D. S., Shinitzky M., Hershkowitz M. and Samuel D., Lipid fluidity markedly modulates the binding of serotonin to mouse brain membranes, Proc. Natl. Acad. Sci. U. S. A., 1980, 77, 7463–7467. Herrero M. A. and Velázquez J. J., Singularity patterns in a chemotaxis model, Math. Annal., 1996, 306, 583–623. Hertz J. A., Quantum critical phenomena, Phys. Rev. B, 1976, 14, 1165. Hohenberg P. C. and Halperin B. I., Theory of dynamic critical phenomena, Rev. Mod. Phys., 1977, 49, 435. Ho M-W-W., (2008, ), The Rainbow and the Worm: The Physics of Organisms, Singapore: World Scientific. Igamberdiev A. U. and Shklovskiy-Kordi N. E., The quantum basis of spatiotemporality in perception and consciousness, Prog. Biophys. Mol. Biol., 2017, 130, 15–25. Jensen H. J., (1998, ), Self-Organized Criticality: Emergent Complex Behavior in Physical and Biological Systems, vol. 10, Cambridge: Cambridge university press. Jerman I., (2018, ), Emergence of Organisms from Ordered Mesoscopic States of Water (Liquids)—Physical Instead of Chemical Origin of Life, Biological, Physical and Technical Basics of Cell Engineering, Singapore : Springer. Kafatos M. C., Physics and consciousness: quantum measurement, observation and experience. In White paper in the workshop, Front. Conscious Res., 2014, 4, 1–14. Kafatos M. C., Chevalier G., Chopra D., Hubacher J., Kak S. and Theise N. D., Biofield science: current physics perspectives, Global Adv. Health Med., 2015, 4, 25–34.

Kak S., Chopra D. and Kafatos D., Perceived reality, quantum mechanics, and consciousness, Cosmology, 2014, 18, 231–245. Kauffman S. and Gare A., Beyond Descartes and Newton: Recovering life and humanity, Prog. Biophys. Mol. Biol., 2015, 119, 219–244. Khrennikov A., Can quantum information be processed by macroscopic systems?, Qantum Inf. Process., 2007, 6, 401–429. Kirchhoff M., Parr T., Palacios E., Friston K. and Kiverstein J., The Markov blankets of life: autonomy, active inference and the free energy principle, J. R. Soc., Interface, 2018, 15, 20170792. Larson E. J., (2004, ), Evolution: The Remarkable History of a Scientific Theory, New York-Toronto: Modern Library. Longo G. and Montévil M., (2014, ), From physics to biology by extending criticality and symmetry breaking, Perspectives on Organisms, Berlin: Springer. Margaritis D. and Thrun S., Bayesian network induction via local neighborhoods, Adv. Neural Inf. Process. Syst., 2000, 12, 505–511. Matsuno K., From quantum measurement to biology via retrocausality, Prog. Biophys. Mol. Biol., 2017, 131, 131–140. Menger F. M. and Karaman R., A singularity model for chemical reactivity, Chem.– Eur. J., 2010, 16, 1420–1427. Miller W. B., (2013, ), The Microcosm Within: Evolution and Extinction in the Hologenome, Boca Raton: Universal Publishers. Miller W. B., The Eukaryotic Microbiome: Origins and Implications for Fetal and Neonatal Life, Front. Pediatr., 2016, 4, 96. Miller W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Miller W. B. Jr., Baluška F. and Torday J. S., Cellular senomic measurements in Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2020, DOI: S00796107(20)30066-3. Miller W. B. and Torday J. S., Four Domains: The Fundamental Unicell and PostDarwinian Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2018, 140, 49–73. Miller W. B., Torday J. S. and Baluška F., Biological evolution as the defense of ‘self’, Prog. Biophys. Mol. Biol., 2019, 142, 54–74. Miller W. B. Jr., Torday J. S. and Baluška F., The N-space Episenome unifies cellular unifies cellular information space-time within cognition-based evolution, Prog. Biophys. Mol. Biol., 2019b, 150, 112–139. Muehsam D., Chevalier G., Barsotti T. and Gurfein B. T., An overview of biofield devices, Glob. Adv. Health Med., 2015, 4, 42. Nakamura R., Kai F., Okamoto A., Newton G. J. and Hashimoto K., SelfConstructed Electrically Conductive Bacterial Networks, Angew. Chem., Int. Ed., 2009, 48, 508–511. Pack R. T. and Brown W. B., Cusp conditions for molecular wavefunctions, J. Chem. Phys., 1966, 45(2), 556–559. Pauls J. A., Zhang Y., Berman G. P. and Kais S., Quantum coherence and entanglement in the avian compass, Phys. Rev. E, 2013, 87(6), 062704. Ritz T., Quantum effects in biology: Bird navigation, Procedia Chem., 2011, 3(1), 262–275. Scerri E., (2019, ), The Periodic Table: Its Story and Its Significance, 2nd edn, Oxford: Oxford University Press.

Shani I. and Keppler J., Beyond combination: how cosmic consciousness grounds ordinary experience, J. Am. Philos. Assoc., 2018, 4, 390–410. Shapiro J. A., (2011, ), Evolution: A View from the 21st Century, Upper Saddle River: FT Press. Sibley D. N., Nold A., Savva N. and Kalliadasis S., On the moving contact line singularity: Asymptotics of a diffuse-interface model, Eur. Phys. J. E, 2013, 36, 26. Solov'yov I. A., Ritz T., Schulten K. J. and Hore P. J., (2014, ), A chemical compass for bird navigation. Quantum Effects in Biology, Cambridge: Cambridge University Press. Sornette D., (2006, ), Critical Phenomena in Natural Sciences: Chaos, Fractals, Self Organization and Disorder: Concepts and Tools, Berlin/Heidelberg: Springer Science & Business Media. Taillefumier T. and Magnasco M. O., A phase transition in the first passage of a brownian process through a fluctuating boundary with implications for neural coding, Proc. Natl. Acad. Sci., 2013, 110, E1438–E1443. Tarlacı S. and Pregnolato M., Quantum neurophysics: From non-living matter to quantum neurobiology and psychopathology, Int. J. Psychophysiol., 2016, 103, 161–173. Theise N. D. and Kafatos M. C., Fundamental awareness: A framework for integrating science, philosophy and metaphysics, Commun. Integr. Biol., 2016, 9, e1155010. Tinsley J. N., Molodtsov M. I., Prevedel R., Wartmann D., Espigulé-Pons J., Lauwers M. and Vaziri A., Direct detection of a single photon by humans, Nat. Commun., 2016, 7, 1–9. Torday J. S., The Singularity of nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31. Torday J. S. and Miller W. B., Biologic relativity: Who is the observer and what is observed?, Prog. Biophys. Mol. Biol., 2016, 121, 29–34. Torday J. S. and Miller W. B., The resolution of ambiguity as the basis for life: A cellular bridge between Western reductionism and Eastern holism, Prog. Biophys. Mol. Biol., 2017, 131, 288–297. Torday J. S. and Miller W. B., The Cosmologic Continuum From Physics to Consciousness, Prog. Biophys. Mol. Biol., 2018, 140, 41–48. Torday J. S. and Rehan V. K., Lung evolution as a cipher for physiology, Physiol. Genomics, 2009, 38, 1–6. Torres-Sosa C., Huang S. and Aldana M., Criticality is an emergent property of genetic networks that exhibit evolvability, PLoS Comput. Biol., 2012, 8(9), e1002669. Toskovic R., van den Berg R., Spinelli A., Eliens I. S., van den Toorn B., Bryant B., Caux J. S. and Otte A. F., Atomic spin-chain realization of a model for quantum criticality, Nat. Phys., 2016, 12, 656–660. Tozzi A. and Peters J. F., From abstract topology to real thermodynamic brain activity, Cognit. Neurodyn., 2017, 3, 283–292. Tozzi A., Sengupta B., Peters J. F. and Friston K. J., (2017, ), Gauge fields in the central nervous system, The Physics of the Mind and Brain Disorders, New York : Springer. Trewavas A. J. and Baluška F., The ubiquity of consciousness, EMBO Rep., 2011, 12, 1221–1225. Ulanowicz R. E., Emergence, naturally!, Zygon, 2007, 42, 945–960.

Viedma C., Chiral symmetry breaking and complete chiral purity by thermodynamic-kinetic feedback near equilibrium: implications for the origin of biochirality, Astrobiology, 2007, 7(2), 312–319. Wagner A. M., Grasshoppered: America's response to the 1874 Rocky Mountain Locust Invasion, Nebraska Hist., 2008, 89, 154–167. Walker S. I. and Davies P. C., The algorithmic origins of life, J. R. Soc., Interface, 2013, 10, 20120869. Walker S. I., Kim H. and Davies P. C., The informational architecture of the cell, Philos. Trans R Soc. A, 2016, 374, 1–10. Werner G., Consciousness viewed in the framework of brain phase space dynamics, criticality, and the renormalization group, Chaos, Solitons Fractals, 2013, 55, 3–12. Whitehead A. N., (1920, ), The Concept of Nature: The Tarner Lectures Delivered in Trinity College, November 1919, Fairford: Echo Library. Whitehead A. N., (1967, ), Adventures of Ideas, New York: Free Press. Whitehead A. N., (1985, ), Symbolism: Its Meaning and Effect, New York: Fordham University Press. Witzany G. and Baluška F., Can subcellular organization be explained only by physical principles?, Commun. Integr. Biol., 2015, 8, e1009796.

CHAPTER 19

Foundational Physicochemical Principles Drive Human Economics 19.1 Basic Principles of Cellular Cooperation If the Singularity is acknowledged as a cosmic point source from which all further physical manifestations project, then even those phenomena that might be regarded as expressly human would be expected to have progenitor imprints in earlier universal processes. It can therefore be argued that our human economic structure must have some relationship to fundamental and universal forces and further, that examining our human economic actions from within that perspective might be productive. Certainly, there is precedent for such assertions. Many economists have attempted to frame human economic behavior within Darwinian terms that presumes that natural selection is a universal living force (Stoelhorst, 2008; Burnham, 2013). Typically, this leads to casting human economic behavior within the easily comprehended and familiar reduction of “survival of the fittest.” In this type of theoretical framework, competition is the primary motive in economic endeavors, allowing for a convenient contrast between communism, socialism and capitalism. In the last few years, there has been a growing trend to rethink standard Darwinian tenets (Pigliucci, 2007; Koonin, 2009). In particular, Cognition-based evolution has emerged as an alternative framework in which biological development and its evolution center on the impact of foundational self-referential cognition, shaped from within a set of first principles of physiology (negentropy, chemiosmosis, homeostasis) (Miller, 2016; Miller, 2017; Miller and Torday, 2018; Miller et al., 2019). The advantage of this differing perspective is that it permits a productive re-examination of economics as extrapolating from within those perpetual cellular faculties that enable us to be successful multicellular organisms. It is now accepted that the physical rules of the universe were established at the Singularity. Therefore, those processes that establish the relationships of energy to matter, and of atom to atom would be expected to be sustained by all universal forms, whatever their appearance. It follows then that all the basic principles that enable physical processes such as chemical bonds must also somehow pertain to all other universal physical manifestations, thereby even extending to human behavior. What basic features of chemistry and physics could possibly be identified that might permit a set of universal transitions of this kind? How could chemical bonds and other basic chemical processes be reasonably related to the idiosyncratic human economic activity that seems to separate us from all other living creatures? That answer rests upon those distinguishable fundamental forces that are shared between the inanimate and the animate, and are merely expressed in alternative ways at every living scale. These are the universal forces of resonances, reciprocations and reiterations, from which cellular collaboration, co-dependence and mutualized

competition derive. When these are each examined in context, a foundation for our human economic behavior can be discerned that is based on physical forces that originate in the Singularity, supporting an underlying premise that primordial cellular faculties can be correctly generalized to explain human economic behavior. This conceptual frame is by no means a new one, especially when it comes to the issue of reiteration. Plato invoked repetitive themes by applying the aesthetic of symmetry to molecular beauty as “the reiteration of forms in the macroscopic world from the unseeable universe of molecules” (Spector, 2014). The supposition was that, through repetitive processes, molecules become “graphic” representations with an innate “tension” that refers simultaneously to the chemical and biological realms (Spector, 2014). In this way, form emerges as various reiterations from a basal state. The further concept of fractal reiteration is now well established, and generally regarded as a basal characteristic of nature. Mendelbrot's fractals have been used to define physical substances such as crystals (Vacher et al., 1989; Colceag, 2003), biological molecules (Meléndez et al., 1999) and biological structures (Losa, 2012). Describing chemical bonding as a form of resonance has a long history, having been initially proposed in 1899 in Johannes Thiele's “Partial Valence Hypothesis” (Lewis, 1923). In valence bond theory, certain ions or molecules combine as resonance structures, and form a resonance hybrid in which some molecules or ions combine and obey certain rules (Lewis structure) (Purser, 1999). The concept of resonances in chemistry and physics was introduced by Werner Heisenberg in 1926, and has become a mainstay of quantum mechanics. It has been previously maintained that the negentropic state that enables the living state within boundary conditions can be ascribed to an equal and opposite reaction to Newton's third law of motion (Torday and Miller, 2018; Torday, 2019). Clearly though, the nature of this reaction to instantiate the living state is not a simple equal and opposite set of forces that can be denoted by a mathematical equation, as would be done among inanimate objects. Although it is certainly a true reaction in opposition to a defined force, it is also a transition, which cannot be defined as an exact mathematical equality. Thus, negentropy can be reasonably considered a reciprocating reaction to the universal expansion from the Singularity as the foundation of those further reciprocations that reiterate throughout biology. It can be further argued that reciprocative actions and their further expression in biology as cooperation and competition can be productively considered as arising from within the basic aspects of the atomic hypothesis. The essence of this relationship was articulated by Richard Feynman (2011) in volume one of Lectures on Physics: “If, in some cataclysm, all of scientific knowledge were to be destroyed, and only one sentence passed on to the next generation of creatures, what statement would contain the most information in the fewest words? I believe it is the atomic hypothesis that all things are made of atoms – little particles that move around in perpetual motion, attracting each other when they are a little distance apart, but repelling upon being squeezed into one another. In that one sentence, you will see, there is an enormous amount of information about the world, if just a little imagination and thinking are applied.” These same forces exert as reiterative ripples throughout nature, forming the very basics of cooperation and competition. The fractal reiterations of crystals can be considered to be forms of chemical cooperation through the maintenance of symmetries. In apposition, competition is explicitly demonstrated in chiral mixtures. Two populations of chiral crystals of opposite handedness do not co-exist in a solution. One population must disappear as

an irreversible autocatalytic process as a result of chiral symmetry-breaking (Viedma, 2007). If it is accepted that the universal forces of reiteration, reciprocation, resonances, and their derivatives as cooperation and competition apply to both the inanimate and animate realms, exactly how do these intersect with human economics? In explaining that pathway, it is necessary to correctly identify the two essentials that define the living circumstance. The first is self-referential awareness. Although the origin of life is unknown, it can be directly asserted that it was also the instantiation of the self-referential state (Miller, 2016). To be clear, this level of cognition is not in any way comparable to what we, as humans, display. However, at the scale of the cell, self-referential cognitive awareness is sufficient to permit cells to receive, assess and communicate biological information in contingent reaction to environmental stresses and further, to cooperate in reaction to those cues (Ford, 2009; Lyon, 2015; Miller, 2016; Baluška and Levin, 2016; Ford, 2017; Reber, 2018; Miller et al., 2019; Baluška and Reber, 2019). The second condition is that all information in the living circumstance is ambiguous (Miller, 2016; Torday and Miller, 2017). This is due to two overlapping factors. First, in the self-referential frame, information cannot be regarded as a discrete measurable point. Instead, it can be more accurately considered akin to a volume in which only portions are available for assessment from the vantage point of any single specific observer/participant (Miller, 2017). Therefore, each separate self-referential observer derives different measurements in the assessment of any phenomenon (Miller, 2016; Miller et al., 2019, 2020). Secondly, since all cells exist within boundaries, all information and all intercellular communication must cross membranes or intervening media with inevitable degradations in information quality during that transit. The ambiguity of information yields one imperative derivative that directly relates to all living things, and especially pertains to human economic activity. Since information is imprecise, in order for a cell to properly assess it, that information must be measured. Indeed, it can be conclusively asserted that cells are measuring instruments, and their measuring is directed to the maintenance of their homeostatic integrity (Miller, 2017; Miller et al., 2019, 2020). From this, the origin of multicellularity is clarified. It is the result of cells working together to protect their individual self-integrity through the cooperative measurement and sharing of information. This proceeds through abundant cell–cell communication that elaborates through an extensive number of pathways, including bioactive molecules and biofields (bioelectric, biophotonic, electromagnetic, mechanotransductive) that are products of local and non-local resonances. In effect, it is the proverbial wisdom of crowds: collective assessment of information improves the validity of environmental cues. In order to do this optimally, they reciprocally collaborate and mutually compete by sharing information and trading resources to maintain their individual self-integrity (Miller et al., 2019). The results are the reiterative forms that comprise our biological system, either as biofilms as collaborative aggregates that cooperatively solve microbial environmental problems in the unicellular realm, or as holobionts that are complex eukaryotic cellular structures that are in intimate partnership with a vast assemblage of obligatory microbial life. These same impulses reiterate to become the patterns of behavior that underlie human economic interchanges. To any casual consideration, human economics would seem to be widely separated from our constituent cells. Yet, the progression from cells to the trading

of metals for grain or money can be traced. Cells consistently aggregate as multicellular organisms, either as biofilms or holobionts, in order to seek and attain greater levels of informational security, which is used to both survive and achieve individual self-identified states of preference (Miller et al., 2019). This is the motivation for cooperation at the cellular level, which then expresses in its physical form as natural cellular engineering and niche construction (Miller et al., 2019). Natural cellular engineering is the collaborative measurement and sharing of information that underpins the trading of resources within a framework of cooperation and mutualized competition. Through niche construction, cells modify their own circumstances and the niches of others by selectively altering the environment to fit the homeostatic imperatives of the participants. Cells measure information to assess its validity, and share those measurements as communication through sub-specializations to optimize the uses of shared resources (Miller, 2017). This is the same manner in which humans construct cities (Paula et al., 2020). It can be maintained, then, that these same processes can be successfully applied to complex human economic activity. More than two centuries ago, Adam Smith (2010) asserted that there are basic principles that guide human economic activity, stating that “How selfish so ever man may be supposed, there are evidently some principles in his nature which interest him in the fortune of others.” For centuries, it had been presumed that this type of activity was of a “higher” sort, and exclusive to humans. However, based on burgeoning research in cellular cognition and cell–cell communication, it is now recognized that the “fortune of others” actually derives from a cellular imperative to maintain individualized self-identity through the collaborative assessment of environmental stresses. At the cellular level, this impulse enables physical forms as phenotypes. It is also used by humans to achieve our own types of forms, either through the engineering of tools, cities, resorts, mines, farms or any other niche that promotes the self-interest of the individual and collective participants. It is important to note that these sorts of linked processes that permit a conjoint form of association and engineering among cells is by no means a recent evolutionary phenomenon. It can be correctly asserted that it is as old as life on this planet. It is believed that the cellular form may have been in existence for approximately 3.8 billion years (Moorbath, 2005). However, it is important to emphasize that the evidence for this does not come from single fossilized cells. Instead, all such evidence is based on fossilized microbial mats, or stromatolites. These microbial mats are the ancient remnants of aggregated microbial life into organized associations. Thus, the imperative for collaborative living is as old as life itself, established through those quantum mechanisms that are exhibited throughout inorganic and organic chemistry, reiterated into biological forms and, eventually, becomes our own economic systems (Miller, 2017). The path is direct. The basic principles of physics and chemistry extend through cellular necessities to enable human economics.

19.2 Cellular Principles Drive Human Economics Of all those principles that extend forward from the primordial cellular realm to this present moment, none has a higher place within the hierarchy of human expression than that of the primacy of self-identity. The economist, Milton Friedman (1955) addressed this in a celebrated essay: “Liberalism takes freedom of the individual – really, of the family – as its ultimate value. It conceives of man as a responsible

individual who is egocentric, in the sense not of being selfish or self-centered, but rather of placing greater reliance on his own values than those of his neighbors. It takes as the major problem of modern society the achievement of liberty and individual responsibility in a world that requires co-ordination of many millions of people in production to make full use of modern knowledge and technology. The challenge is to reconcile individual freedom with widespread interdependence.” This quote clearly articulates the major challenge in all human economic activity. Yet, it also highlights how cells have managed to aggregate with success over eons. Through their limited cognitive palette, they meet Friedman's challenge of balancing individual self-integrity with the requirements of interdependent associative living. Indeed, their relatively simple cognitive endowment that directs towards their unmediated maintenance of their own homeostatic self-integrity serves this purpose. Cells are not burdened by human egos, and their motivations are straightforward. All that cells seek to do is to sustain preferential states of homeostatic equipoise. They can do this best by partnering with varieties of differentiated eukaryotic cells and a multitude of microbial partners through natural cellular engineering and mutualized niche construction. Such activities are dependent on the salient faculty of self-reference. Cells are aware, anticipate and can predict (Saigusa, et al., 2008; Nakagaki et al., 2000; Schumann and Adamatzky, 2011; Bonifaci et al., 2012; Miller et al., 2019). The self-referential state can only be sustained through measurement, and any deployment of bioactive molecules as a consequence of any measurement is a prediction, by default (Miller et al., 2019, 2020). All collective forms of life, even biofilms, require anticipation and prediction. It is required to support the trading of resources and specializations that permit natural cellular engineering (Hellingwerf, 2005; Ben-Jacob and Levine, 2006; Ben-Jacob, 2009; Ford, 2009, 2017; Xavier et al., 2011; Miller and Torday, 2018; Miller et al., 2019). Yet, crucially, cellular predictions and the trading of resources that follows is always directed toward sustaining individual preferred cellular homeostatic states (Miller, 2013; Miller, 2016; Miller, 2017; Miller and Torday, 2018). It follows that cells accept collaborative life based on a prediction that is worth the risk. And further, any such prediction must be based on a cell's measured assessment that it is attaining information of sufficient value to willingly continue in the cooperative form. Thus, the self-organizing agency of multicellularity is the drive towards higher information quality, which directly translates into energy efficiency in the deployment of precious cellular resources to survive. It is now understood that all organisms that we can see with our unaided eyes are complex combinations of microbes and personal eukaryotic cells as multicellular collaboratives (Miller, 2013; Miller, 2016; Gilbert, 2014; Miller and Torday, 2018). Thus, we and all other macroscopic creatures are a “super assemblage” of cells of many types admixed with many microbial species (Miller, 2013; Gilbert et al., 2015; Miller, 2016; Bosch and Miller, 2016; Theis et al., 2016; Miller, 2017; Prasad, 2017). Nor is the microbial fraction of our totality any mere appendage. Indeed, it is estimated that we, as such a combined organism, have an approximate ratio of 10 microbial cells for each of our eukaryotic cells (Miller, 2016). Nor is this type of combination happenstance. It is an obligatory relationship, since we are dependent on our microbial companions for crucial aspects of our metabolism (Cani and Knauf, 2016; Francino, 2017). Importantly, this living form in a requisite partnership is essentially universal. It

is even true in single-celled organisms. Modern genetic sequencing has identified that at least nineteen different bacterial endosymbionts that include five different lineages have been identified in amoebas (Horn and Wagner, 2004; Goñi et al., 2014). The number of bacteria in any single amoeba has been estimated to range between five and one hundred. Therefore, amoebas, too, represent their own type of holobionic life. Thus, the holobionic structure consistently reiterates across the living scale. Such types of reiterative patterning have been termed “mosaic formulations” (Agnati et al., 2009). It is no surprise then that our human patterns of trading and societal organizations are also consistently repetitive. If the holobionic form is how multicellular organisms organize on the planet, how do these cells form differing species, all of which have different subspecializations that interact successfully? One means is through the consistent deployment of stigmergic signals. These cues provide a framework for selforganizing activities, which directly link to higher-quality information that is inherently self-organizing (Miller, 2016; Miller, 2017). Stigmergy is a type of feedback loop in which any action leaves some kind of trace in a medium (Heylighen, 2015). The presence of that bioactive trace in the environment then incites a follow-on action by either the individual who has left that trace, or another that follows. Heylighen (2015) defined it as “an indirect, mediated mechanism of coordination between actions, in which the trace of an action left on a medium stimulates the performance of a subsequent action.” The way in which termite mounds are constructed is the best studied case of stigmergic self-organization. Importantly, in stigmergic systems, there is no necessity for direct coordination among the participants. They sense and act on their own preferences. Further, there is no need for specific intentionality among individual players. The motivations of the individual participants need not have any direct bearing on the specific outcome. It is an emergent development from the loosely coordinated actions of individuals that are merely attempting to sustain themselves and follow cues from other organisms on how to best achieve their limited aims. Further yet, since each of the individual participants within a stigmergic system can have independent goals, there is a natural division of labor. Since any resulting organizational structure arises spontaneously, there is no need for any central planning agency, hence, there is no organized resistance to any path of action. Any “error” by one individual participant is countervailed by the actions of another that directs somewhat differently. In this manner, there is a general drift towards consensual outcomes. Thus, there is a natural basis for a generalized structure that can support the trading of resources to further the self-directed goals of the individual participants. Its yield is collaborative outcomes based on the maintenance of individual self-integrity, based on expectations of reciprocity. This is the manner in which tissue ecologies form and thrive. It is no accident that this resembles human trading markets. Thus, our human trading patterns are the end-product of a definable path that extends from the basic cognitive endowment of cells, and leads to the complex problem-solving that we deploy at our scale. The same principles explain why specialized cells, or auxotrophs, that are unable to produce essential metabolites are prevalent among symbiotic and free-living bacteria (D'souza et al., 2014; Miller, 2016). The impulse toward cooperation and reciprocation is great enough that some cells will stake their survival on this elemental pattern, and freely adapt to this streamlined form of living. This, too, is distinctly mirrored within our human economic framework (Tasoff et al., 2015; Miller, 2017).

The concept that there might be biological commonalities between cellularmicrobial life and our human patterns of behavior have not previously gone unnoticed. Human economic equilibrium theory has been applied to the cellular biotic realm to explain bacterial metabolic exchange, and then reciprocally reversed to create a general equilibrium model that is useful for understanding human economic behavior (Miller, 2017). Further, there is a trend in both management studies and in economics to develop models of human organization that are based on cellular organizational structure (Daft and Lengel, 1986). One model emphasizes the primacy of multiple mutualist effects, explaining it as selective advantage and as a series of reciprocations based on a consumer-resource approach (Afkhami et al., 2014). Other efforts at understanding human economics have concentrated on the perceived strengths of cellular systems. Cells are adept at developing nodal architectures that retain degrees of semi-autonomous functions by which information is freely exchanged to achieve collective problem-solving. Effective communication of this type has been modeled through concepts of conveyance and convergence that define the manner in which senders and receivers of information are thought to reciprocate at the cellular level (Dennis and Valacich, 1999; Miller, 2017). These models indicate that the robustness of information concentrates closest to the level of individual participants, as opposed to ever higher ecological levels. Pertinently, this cellular modeling contradicts typical management systems and the recurrent zeal for centralized governments and ever-larger companies. Instead, the cellular realm instructs that the highest levels of efficiency are achieved through the maintenance of high levels of local control, as exemplified in cellular biological systems (Miller, 2017).

19.3 Cellular Principles, Trading and Behavioral Economics With this as background, it should not be surprising that there are other cellular traits that are derivative of processes that originate in the Singularity that impact human economic behavior. At the most fundamental level, the unicellular zygote, which initiates the cycle of embryogenesis, is instructive in this regard. All multicellular eukaryotes as holobionts are required to pass through an obligatory recapitulation through the unicellular zygote stage during the reproductive cycle. When evolution was considered to be a product of Darwinian selection, this had remained unexplained. However, when evolution is placed in the proper selfreferential frame, the role of the unicellular recapitulation can be productively recast. During the adult elaboration, every living organism acquires environmental experience and undergoes a series of epigenetic adjustments (Torday and Miller, 2016a). This is the actual purpose of the phenotype as the various forms of anatomic appearance, metabolic/physiologic processes and behaviors (Torday and Miller, 2016a). As adult organisms, we extend out into the environment, and our phenotypes experience it. Epigenetics is the process by which the expression of the existing genetic code can be modified by the resulting environmental stresses. This process of adjustment to current environmental stresses is a crucial mechanism in support of life. It has now been established that some of these epigenetic modifications can be heritable, whereas others are expunged (Torday and Miller, 2016a). Research has demonstrated that the major focus of adjudication of these epigenetic marks is during the unicellular zygotic stage, with some further modifications during embryogenesis. Based on that zygotic modulation, the next

adult organism elaborates with a slightly differing set of phenotypic traits to again confront the environment. When the focal point of this decision matrix is instilled within the unicellular zygote, it defaults that the zygotic cell must be highly attuned to environmental cycles within its scope. How then does this fundamental unicellular form make its decisions about which epigenetic marks to keep and which to eliminate or suppress? Certainly, as a master cell, the unicellular zygote is as aware of the noisy ambiguity of biological information as any other cell. Therefore, there is no reason to assume that its measuring assessment is based on any simple linear extrapolation. It has been argued that this basic cell is capable of simple forms of manipulation of information that are similar to that used in the study of economic forces. One such example of this type of data manipulation is the anamorphic stretch transform (Jalali and Asghari, 2014). This mathematical transformation is used to capture and digitize signals that occur at a faster rate than the speed of the sensing apparatus. Most importantly, it is a common method of minimizing the volume of generated data. In the process, the signal is reshaped. Sharp features are accentuated, essentially stretched in the Fourier domain, compared with less distinctive constellations of data. In most circumstances, those highlighted sharp spectral features will have a greater impact on any resultant waveform. Conversely, those that do not reach such a threshold can be conveniently considered to be noise. Such time-stretch mechanisms for data manipulation are basic to physics, and it has been previously argued that this same process of data manipulation is within the capacities of cells, and most particularly exemplified within the unicellular zygotic form (Miller, 2017). The reason is that this type of data manipulation is necessary for the maintenance of cellular homeostatic mechanisms. In that defense, it follows that there has to be a means for distinguishing sharp features that have significance from coarse features that are noise. Cells are not automata. They do not react like simple thermostats, as they are obviously much more complicated (Torday and Rehan, 2012). Cells in holobionts are specialized. Many cells, such as T-cells, are pluripotent. They can significantly differentiate under a variety of stresses and circumstances (Thomas-Vaslin et al., 2008; Miller, 2017). As the same physiological principles of homeostasis that apply to any basic cell must be equally applicable to any cells that have a wide range of pluripotential adaptations to stress, a robust means of assessing information is vital. Simple thermostatic mechanisms could not possibly accommodate this flexible and continuously adaptive response palette. In order to satisfy this capacity, acute means of measurement are essential, especially ways in which noise in the system can be accurately separated from lifealtering environmental impacts (Miller et al., 2019, 2020). As it has been confirmed that the unicellular zygote has a substantial role in determining which epigenetic imprints become heritable, it follows that this cellular form must be capable of handling large volumes of information. The stretch domain is one mechanism of handling these large volumes of information. The constraining regulatory apparatus of the zygotic unicell meets the challenges of environmental adaptation by leveling off the sharp peaks of shorter-term environmental adaptation in the interests of a longer-term moving average. That “moving average” is the middle zone of lower risk through which an organism can vary based on contemporaneous environmental cues, yet still remain adherent to long-term environmental necessities. In the absence of such a regulatory mechanism, organisms would inevitably fatally skew. The need for such a system is obvious

when it is understood that all multicellular eukaryotes are holobionts in which the numbers of cellular participants are enormous, and further, of a wide variety of species and sub-specializations comprising a variety of eukaryotic cells and a multitude of microbial species. Obviously, in such a context, the problems of data evaluation and communication increase exponentially with the numbers of participants. The math is direct: the number of total possible connections for any network where N equals the number of participants is N2. Obviously then, numbers quickly become astronomical in cellular terms (Miller, 2017). Clearly then, any organism must have faculties that are advantaged for coping with long-term environmental changes, yet are still capable of accommodating with sufficient pliability to respond to contemporary environmental stresses. An assertion can be justified that human trading techniques mirror these same types of challenges. The concept of backtest overfitting fits this contention. In technical trading, back-test overfitting is one of the means by which potentially profitable strategies are commonly tested. In back-test overfitting, historical data are used to create an optimized model as a future trading strategy. Typically, traders fit a pattern of results that seem the most robust within the test period. Yet, even though seemingly sensible, there is a critical “trader's fallacy.” This downfall can be mathematically modeled based on a concept of backtest overfitting. In any sample period, if there is an attempt to find optimal performance, then the better the median performance Me[R] within the sampling period, the higher the probability of being overfit to the sample data, with a deteriorating performance in out-of-sample price movements. This can be directly explained. In trading, random probability theory is routinely overlooked by inexperienced traders. In their zeal to find a profitable system, traders attempt to find the strategy with the highest overall win rate and probability of overall profitability based on a measurements of draw-downs, extent of cumulative loss, the necessary commitment of resources to each trade and win rate. What is typically overlooked is the non-uniform distribution of random price data, and its impact on future price fluctuations. In simple terms, a system that shows a 50% probability of a profitable trade might be expected by an individual with little experience to have 50% winning trades going forward. This is a sure path to trading failure. Chaotic inputs do not repeat in the same progression. Studies and personal experience have proved that back-fitted data routinely yield strategies that pose a systemic risk that is greater than mere noise in any system. The crux of the problem is direct. The failure of this attempt at modeling is that it is driven by already established price action rather than through a nuanced understanding of general risk structure (Bailey et al., 2015). As well-experienced traders learn to their pain, any trading scheme that is fitted to perform extremely well within a specific backtest period has a significant risk of failure as future price action unfolds (Lopez de Prado, 2013). Although the problem of overfitting may be complex, it can be shown to conform to an equation set relating to sample size. This has been defined as the non-null probability of backtest overfitting (Lopez de Prado, 2013). This equation addresses a non-obvious statistical reality. In a stochastic system with memory, if inputs are variably trending, the closer the fit for any sample data within any arbitrary time duration, the more inaccurate its choices become for out-of-sample time frames. Any trader knows that if one sample size is too closely aligned with one data set, the underlying system is sub-optimal when used on another set of out-of-sample data. Any attempt to optimize responses of a confined data set, no matter the time

frame, leads to subsequent systematic losses, which extend beyond the level of noise within the system. What is being overlooked in backtest overfitting is the nonuniform distribution of random price data and its impact on future price fluctuations, even though this is simple probability theory. In trading, random probability is systematically overlooked by inexperienced traders. Of course, this type of error is not confined to those who consider themselves traders. Investors for the long-term also commit this cardinal error in their own terms. In their quest to find a profitable system, each attempts to find the strategy with the highest overall win rate, roughly estimating the probability of loss versus an imputed probability of trading success. Each overlooks the non-uniform distribution of random price data and its impact on future price fluctuations. The cardinal error lies within a common systematic error in judgment. A system that shows a 50% probability of a profitable trade might be expected by an individual with inexperience to have 50% of trades that are profitable, and 50% that are a loss. Crucially though, in a stochastic system, the success of such a system is a direct function of sample size. For example, it could be possible to have eight consecutive losses out of the first eight trades and still be compatible with the system, if the sampling period is long enough. The failure arises from the inappropriate background assumption that the same trading strategy in differing time periods will yield similar results. Experience proves that real-world results in out-of-sample periods can deviate widely from trading simulations based on historical data. How do experienced traders cope with this necessary reality? They learn to limit the size of their bets. Too large and out of scale bets in trading are the surest path to disaster, no matter the robustness of the underlying system. The experienced trader takes the largest bets off the table. Smaller-scale bets permit a string of losses without unrecoverable draw-downs. This is classic bet-hedging, and this is how the unicellular zygote behaves. When it judges the impact of epigenetic impacts as potential heritable adaptations, it excludes the widest adaptations even if they are the best “fit” to the immediate environmental cycle as experienced by the reproductive adult. Instead, it chooses those that are better fit for a longer-term moving average of environmental conditions. The reason is plain. Those organisms that demonstrate the swiftest adaptations with the greatest amplitude of change may be ill equipped for a backward environmental shift. If that happens, they are out of phase with the environment, and are at a higher risk of being culled. Anyone with trading experience understands the necessity of this approach. There is a pertinent further derivative from this unicellular dynamic. As is commonly acknowledged in trading circles, trading success is not a direct function of intellectual firepower. It depends on a combination of traits, including an overarching discipline. There is ample proof of this assertion. Long Term Capital Management collapsed in the 1990s in tumultuous markets. It had two Nobel Prize winners in economics on its board of directors and based its trading scheme on their acclaimed economic theories (Lowenstein, 2000). The crux of their downfall was overconfidence, which led to a pattern of excessive commitment to trades that were overly matched to short-term trends. Despite a series of initial successes, they failed spectacularly. This same dynamic explains why hedge funds often “blow up” and mutual funds rarely do. The nimble hedge fund can shine in short bursts through quick adaptation, and by attempting to exploit every emerging financial trend. Over short periods, this can appear to be adroit, and might even yield an enviable initial string of successful trades. However, if systemic speculation is excessive, there is always the risk of a catastrophic draw-down. Markets are subject to unanticipated

bouts of chaotic movement such as black swan events with the potential for complete failure (Aven, 2013). In contrast, many mutual funds have demonstrated enduring success over many financial cycles. They succeed by taking smaller risks and making choices that are framed within a more expansive time frame. This is the method by which the unicellular framework succeeds. It adheres to an internal understanding of “long-term” environmental cycles through its consistent adherence to foundational first principles of physiology, making steady and deliberative adjustments that are still sufficient to accommodate contemporary environmental stresses and sustain immediate homeostatic balance. Is there proof for this assertion? The basic cellular domains (Prokaryota, Archaea, Eukaryota) are the only perpetual living forms on the planet: they have existed uninterruptedly for billions of years (Miller and Torday, 2018). Research on bacteria confirms the disadvantage of overly rapid adaptations to stress. A series of experiments have been conducted that have measured the migration of bacteria within defined boundary conditions. The resulting pattern of migration has been termed a “Tortoise-Hare” adaptive fitness pattern (Nahum et al., 2015). For these experiments, bacterial migration was simulated over a “fitness landscape” as a series of environmental stressors through which a population of bacteria needs to move to reach a nutrient source. The results of this experiment were surprising. The slow movers, the “tortoises” ended up crossing the fitness matrix in a shorter time than the “hares,” which are bacteria that actually moved the fastest at the beginning of the migration matrix. The latter became trapped within specific high-amplitude fitness “hills.” Their swift motion was linked to overly rapid and specific adaptations in response to encountered stressors. On average, their adaptations were significantly less than optimal. The slow migrators had time to explore more potential adaptations, and eventually settled on better overall choices. In this way, the “tortoises” acted more methodically, adapted more slowly, and were consistently more successful in an entire migration pattern. Since environmental inputs can be chaotic, the enduring success of any life form is not exclusively dependent on its successes. Equally, it is a function of appropriate constraints. From this pattern, two cellular lessons pertain to our own economic framework. First, greater freedom of action is not necessarily associated with better outcomes. And secondly, bet-hedging with an ample willingness to risk small exploratory failures is a sustainable form of reciprocation with the external environment for cells, and is a useful framework for human economic choices. From these cautions, it becomes apparent that in approaching markets or in financial trading, successful systems are as much dependent upon the proper assessment and control of inevitable failures as on successful business choices or rewarding financial trades. In trading, success is based on the deliberate measuring of a flow of chaotic inputs. This requires patience while awaiting the relatively infrequent appropriate trade with substantial risk-reward characteristics to emerge from within background noise. This is basic trading risk-management. Consequently, many attempts have been made to attempt to mathematically quantify systemic risk under multiple scenarios to better govern our human biases and emotions under stress (Al Janabi, 2009). However, the unicellular realm, which remains connected to the inherencies of the Singularity, does not need equations. Indeed, the unicellular form has a distinct advantage. It is a limited organism that lacks human ego. Indeed, it is this limitation that acts as a perpetual keel amid extreme events, leaning against environmental turbulence. Generations of evolutionary biologists have pondered the mystery of the obligatory passage of all

multicellular eukaryotic organisms, like us, through a unicellular stage. From the foregoing, an answer becomes clarified. It is within this frame that necessary biological constraints modulate against unwarranted freedom of action (Torday and Miller, 2016b; Miller and Torday, 2018). It is a surprising feature of human behavior that lack of constraint can be the result of high levels of self-discipline. This phenomenon is now termed the “illusion of self-control” (Konnikova, 2013). Studies indicate that those people with a high degree of self-control are at elevated risk for failure in trading. It seems that individuals who regard themselves as highly controlled are prone to illusions of control. They imagine that they can control outcomes when an objective analysis of the data discloses high levels of random price action. Consequently, and almost perversely, individual traders with self-assessed high levels of self-control tend to underperform compared with those with low self-esteem (Konnikova, 2013). It is an issue of overconfidence, which also links to a prejudice that higher intelligence directly connects to better decisions. Indeed, some studies have quantified that assessment of work-place intelligence and job performance by supervisors becomes more positive as cognitive intelligence decreases (Cote and Miners, 2006). Tests of “rationality” have found that unbiased decision-making is largely independent of IQ (Stanovich et al., 2013). This is rather easily understood within the context of human egos. Highly intelligent individuals are more likely to see past their own flaws, which can be roughly translated to a “bias blind spot” (Xue et al., 2012). High-intellect individuals are less able to see their own flaws and, at the same time, are more highly motivated to criticize the foibles of others. Consequently, they have a greater tendency to fall for the “gambler's fallacy,” the idea that if a tossed coin lands on heads ten times, it will be more likely to land on tails on the eleventh toss, even though they fully understand the issue. This fallacy has led to the ruin of many gamblers. Since the basic cellular forms lack ego and do not evaluate environmental data within idiosyncratic human terms, they are well equipped for long-term survival (Miller, 2017; Miller and Torday, 2018). Still, no matter our flaws, we are successful organisms as holobionts as a combined form of living partnership among trillions of communicating and cooperating eukaryotic and microbial cells (Miller, 2016). In our collective form, our cellular microbes are unlike our eukaryotic cells, which are “personal” cells comprising many thousands of differentiated cells performing specialized functions. What mechanisms exist to assure the smooth collaborative functioning of these cells? Only two realistic possibilities exist. One would be that our cells co-exist through the dominating effect of an overriding central command center with tight down-stream regulation and minimal local individual autonomy. Yet, clearly, this is not how cells collaborate. Instead, they co-exist and thrive through consistent negotiation (Walsh, 2014; Miller et al., 2020). It is in this manner that subspecialized cells engage in the voluntary trading of resources. And further, it is crucial to this dynamic that individual self-identity is not sacrificed to cooperation (Miller, 2013; Miller, 2016; Miller, 2017; Miller et al., 2019). All cellular action is ever and always directed toward individual states of homeostatic equipoise. Given the obvious complexity of this kind of dynamic process, it follows that there must be some trading structure that permits the smooth functioning of cellular ecologies and the negotiated trading of resources. In that regard, we can look to ourselves and modern economic activity to answer how cells contend with this problem. Cellular networks organize along the lines of bitcoin exchange (Miller et al., 2020). Bitcoin is a form of a digital ledger that is distributed as a blockchain across a

widely dispersed network of computers. The blockchain is a massive real-time spreadsheet in which information is stored in blocks that are linked across a peer-topeer network by performing a consistent method of mathematical calculation (Verde et al., 2019). The resulting “bitcoin” represents a method of exchange, which has a consistently negotiated value through simultaneous assessment across the network. Any individual can log a financial transaction, which can be simultaneously viewed across the network. Transactions are strings of complex data, which can contain any kind of information. The network is trusted as an exchange mechanism since no single source controls the flow of bitcoin. Thus, bitcoin, which is digital information, is also regarded as money, precisely because it is agreed by all participants that it is. This exchange mechanism can be advanced as the model of communication across cellular ecological communities that permits the fluid exchange of resources (Miller et al., 2019, 2020). In blockchain, the currency is digital information that has measurable value. This measured assessment of value has a high level of robustness since, at all times, it represents the collective assessment of all of the participants within the blockchain network. The crucial requisite of the living state is valid information. In multicellular life, valid information is the operative currency, which can be used to protect individual self-identity and homeostatic equipoise. Since individual cells are not programmed or controlled by a central agency, multicellular life depends upon a decentralized mechanism for the sharing of information for the collective measured assessment of environmental stress. For all cells, validation of information is crucial and has distinct value and propels the cellular trading of resources that permits multicellular differentiation for complex life. In economic terms, value is determined by two overlapping factors: utility and scarcity. Bitcoin is valuable since the maximum number of bitcoins that can be created is set at a disclosed cap, and creating new bitcoin is demanding and difficult. It is designed to be a scarce measure of value. Since it is widely acknowledged as having value, it has utility as a means of economic exchange. Cells operate within the same parameter. For cells, valid information is scarce, and can be exchanged among collaborators to improve opportunities to maintain preferential homeostasis. A pertinent example is the transfer of antibiotic resistance among microbial participants in a biofilm (Penesyan et al., 2015). In any biofilm, some microbes might have the correct genetic sequencing that confers antibiotic resistance, while other cells will not. In the collaborative biofilm structure, those participants that are antibiotic resistant can offer genetic material that confers antibiotic resistance in trade via a plasmid (a small extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently) to those participants that are not resistant in exchange for food. The exchange between the donor microbe and the recipient is conducted via a nanotube termed a conjugative pilus that enables the two-way transfer. This is the way in which Enterococus faecalis operates under antibiotic stress in biofilms. Antibiotic resistance is conferred to susceptible recipient cells from plasmidcarrying donor cells through conjugative plasmid pCF10 transfer (Goldenfeld and Woese, 2011). This type of exchange is dependent on the self-assessment by each participant of its individual status as part of a collective and collaborative appraisal of the level of environmental stress that the biofilm is experiencing through quorum sensing and fluid cell–cell communication (Popat et al., 2015). This is a classic example of the trading. Cellular resources are determined to be available for

exchange, based on shared information and the measured value for that shared information as a scarce resource. From this, a “negotiated” price for the two-way exchange is established among cells. This type of complex interaction obviously mirrors human economic behaviors, and is self-organizing in much the same manner between the two disparate realms. Among cells, one pattern of behavior that has self-organizing properties is the use of stigmergic cues in the environment that trigger follow-on activities as previously described. Another is based on a fundamental disposition outlined by Agnati et al. (2009), which is termed the “Principle of Biological Attraction.” This principle states that “the assembly of basic biological units into a more complex system is navigated by an inherent drive for spontaneous attraction and merging of lower order complementary biological units/systems to generate higher organization level units/systems.” (Agnati et al., 2009). Research has confirmed that this attractional impulse is demonstrated at every living scope and scale as a feature in biofilms and across macroscopic life (Miller, 2017). One manifestation is the self-reinforcing flocking behavior that can be observed in all types of organisms from bacteria to birds, insects, fish and humans (Dyer et al., 2008). In each instance, coordinated actions seem to arise spontaneously without apparent leadership. It is not clear yet exactly why the principle of biological action operates. Most likely, it is a function of similar types of individuals receiving and assessing shared information and responding in congruent reactive patterns. However, no matter the exact cause, it is obvious that this type of coordinated behavior is a common feature of human consumer and trading patterns, as a form of herd instinct. Herd instinct is a primary feature of social animals. Individuals in social groups tend to imitate the attitudes or actions of those in their surroundings. Although the phenomenon is freely observable, its evolutionary origins are still debated. Moreover, beyond “herd” animals, it is commonly used to describe economic and trading trends (Lux, 1995). There is research to support that herd instinct is a quantifiable factor in trading and investing where individuals gravitate to similar behavioral patterns in groups. Patni et al. (2014) did a detailed analysis of this phenomenon using 13 sectoral indices from the Bombay Stock Exchange from 2006–2013. Their linear regression model identified significant evidence of herd instinct that linked to structural inefficiencies across market sectors. This same herd behavior interconnects to stock market and real estate bubbles (Young et al., 2004). The basic tendency towards group-think as reiteration of a basic cellular principle of attraction has also been tied to market crashes by behavioral psychologists and economists. Typically, that analysis focuses on the development of self-reinforcing positive and negative feedback loops (Corsi and Sornette, 2014). Others have modeled this trend through complex systems theory that attempts to correlate the development of large-scale collective behaviors from “repeated non-linear interactions among constitutents” (Sornette, 2017). One derived conclusion from these studies is that herd instinct might be an “intrinsic property resulting from the repeated non-linear interactions between investors” (Sornette, 2017). If this is accepted, then the “intrinsic property” can be well categorized as the principle of biological attraction, which is itself a product of the simultaneous collective measurement of environmental information by self-similar individuals. It should not be surprising then that, among humans with egos, the amplitude of such selfreinforcing behaviors will proceed in periodic waves of sentiment to a critical excess. In such a critical state, a small trigger from an otherwise inconsequential exogenous shock can have disastrous ramifications (Youssefmir et al., 1998).

Although it is always assumed that market crashes are symptomatic of “irrational exuberance,” it can be adduced from the cellular realm that this is not the actual case. Cells collaborate to collectively measure information. The collective measurement of information is considered to have higher measuring value, which has been formally defined in biological circumstances as an increase in “Effective Information” (Miller, 2017). Cells deploy their resources based on this shared information, sustained by levels of cell–cell communication that are so abundant that it has been likened to “chatter” even among microbes (Visick and Fuqua, 2005). When considered from within this context, the rising amplitude of sentimentbased price movements is actually rational behavior. The greater the collective agreement, the higher the value and validity that is assigned to it among cells. It is “rational” insofar as it is a natural outcome of our cellular nature. Among cells, each remains an individual. We struggle then to assess what the total collective assessment picture might be for only one individual within the mix. This inherent quandary has been reinforced by a mathematical proof offered by Kenneth Arrow that indicates there is no method for reliably constructing aggregate social preferences from a subset of arbitrary individual preferences (Sornettte, 2017). It is always an emergent property of the collective participants. From this, it is possible to consider that stock market, real estate or commodity crashes, or the capricious collapse of consumer demand are analogous with those criticalities in chemistry and physics, which are part of magnetism, or melting, or a phase transition from liquid to gas (Sornette, 2002). In economics, criticality theory presumes that small independent shocks to different economic sectors do not cancel one another in the aggregate since they are significantly non-linear local interactions. Separate parts of the economy remain insulated for variable periods of time. Ultimately, though, that set of interactions brings patterns of reinforcement that become a “self-organizing criticality” (Scheinkman and Woodford, 1994). When the true nature of the crucial connections between biology, chemistry and physics are properly framed, then it is no surprise that we, humans, will manifest criticalities in our own idiosyncratic fashion. Indeed, criticalities and triggers can be traced from the Singularity forward, and are basic to our biological systems (see Chapter 18). The issue of fundamental criticalities has direct application through the wellknown “House of Cards” model. This model relates to the stacking of playing cards that pyramid atop one another until a collapse suddenly occurs. It is an example of structural instability that is used to conceptualize critical instabilities in economics (Emerson, 2008) and biology (Hodgins-Davis et al., 2015). It can therefore be considered that it is a useful framework to conceptualize biological phenomena. Indeed, it has been used as a conceptual model to explain gaps in phenotypic forms that are central to biological novelty (Miller, 2013). Since the publication of On the Origin of Species in 1859, Darwinism has been upheld by two steady pillars. Evolution proceeds by a process of natural selection through the gradual modification of inherited features. An important aspect of the argument has been that these modifications must be nearly infinitesimal since the variations that natural selection can influence are thought to arise from random genetic errors during reproduction. Any large genetic mutations would imperil survival through genetic destabilization. In 1972, Gould and Eldredge advanced a provocative contrary thesis based on their study of the Cambrian explosion, which occurred approximately 541 million years ago. The fossil record from this era demonstrates a sudden and dramatic appearance of fossils of new types without

clear ancestral forms. Even Darwin was aware of this problem and had no ready explanation. Gould and Eldredge (1972) proposed that evolution does not proceed in only tiny steps but is instead interrupted by intermittent leaps, termed “punctuated equilibrium.” Species are stable for long periods of time, and then there are bursts of evolutionary activity, followed again by long periods of evolutionary stasis. Complexity theory offers some insight through the study of the non-equilibrium dynamics of heterogeneous systems such as gases or rocks, exploring how they relate to other systems with mutually interacting parts, and how these features pertain to emergent properties (Sornette, 2017). Such studies reveal that there are hidden underlying forces below any surface, which seems to be in “perfect” balance that can lead to catastrophic events. Thus, criticalities are an inherent property of all complex systems. Of course, this should not be particularly surprising. A state of “perfect” balance was upended by the Singularity. The planet itself is shaped in infinitesimal steps, only to be consequentially reshaped by multi-millennium precipitous changes in climate, or by an asteroid strike or monumental volcanic activity. In the same way, human economic activity is well characterized by long periods of orderly trading that is unpredictably shaken by intermittent rare events, including stock market crashes that subsequently re-stabilize. Experienced traders know that there can be long periods of time where prices stay within a tight bandwidth, termed “range-bound” trading. In these periods, even when abrupt price gaps occur, there is almost always a reversion back towards prior mean price levels. The exceptions are quite unusual and termed “runaway” gaps. They are uncommon, but when they occur, they announce a new price trend. A reasonable analogy can be made between evolutionary trends and the microcosm of trading markets. Both are subject to house of cards dynamics: long relatively static stretches abruptly interrupted by criticalities that trigger chaotic action that then restabilizes. In both trading and in evolution, the sudden emergence of consequential gaps is often the result of high-amplitude environmental stresses. Each denotes the breakdown of a previously established level, which, after a time, settles into a next one with separable characteristics from the prior.

19.4 Conclusion All human behavior is necessarily rooted within cellular predilections. The primordial impulses that guide natural cellular engineering emanate from the Singularity, express themselves through basic chemical pathways, are disciplined within thermodynamic and quantum rules, and then ultimately display as our idiosyncratic human behaviors. Therefore, it is no accident that those fundamental principles that sustain cells mirror themselves in human economic activity. Cognitive cells, which derive from the Singularity maintain their self-identity by adhering to requisite first principles of physiology to maintain individual states of homeostatic composure. Cells aggregate into the collective form as their preferred mode of living since this represents an advantaged means of appraising complex environmental cues. The collective assessment and judgment of environmental stresses increases the validity of available information to each of the participant cells. In order to best cope with their uncertain environment, cells share information, communicate abundantly and willingly share collective resources. This impulse towards cooperation expresses at the cellular level and in our human frame alike. Collective action rests on the self-referential appraisal of individual advantage

within a collaborative structure. From within the multitude of constituents that comprise cellular networks, resonances emerge that amplify cellular decisionmaking. This, too, reiterates in our human frame as waves of enthusiasm, which yield to cyclical criticalities, triggers, and collapses. Among all these congruities, a few predominate. Just as in humans, cells act consistently to preserve self-integrity (Miller et al., 2019). Humans engage in the trading of resources for individual advantage. Cellular ecological dynamics center within a framework of active negotiation for the trading of resources supported by copious cellular communication (Walsh, 2014). Bargaining and dialogue are the lifeblood of human economics. All cellular actions are implicit predictions (Miller et al., 2019, 2020). So, too, is human economic activity. All human trading is a forecast, and so are those phenotypes as products of cellular engineering that enable our survival. From these immutable connections, an unambiguous message can be gleaned. Despite our intellect and panache, human economic actions are conditioned as echoing reverberations of those patterns of information appraisal and communication that have assured cellular life over countless eons.

References Afkhami M. E., Rudgers J. A. and Stachowicz J. J., Multiple mutualist effects: conflict and synergy in multispecies mutualisms, Ecology, 2014, 95(4), 833– 844. Agnati L. F., Baluška F., Barlow P. W. and Guidolin D., Mosaic, self-similarity logic and biological attraction principles: Three explanatory instruments in biology, Commun. Integr. Biol., 2009, 2, 552–563. Al Janabi M. A., Commodity price risk management: Valuation of large trading portfolios under adverse and illiquid market settings, J. Deriv. Hedge Funds, 2009, 15(1), 15–50. Aven T., On the meaning of a black swan in a risk context, Saf. Sci., 2013, 57, 44–51. Bailey D. H., Borwein J. M., Lopez de Prado M. and Zhu Q. J., The probability of back test overfitting, J. Comput. Finance, 2015, DOI: 10.2139/ssrn.2326253. Baluška F. and Levin M., On having no head: cognition throughout biological systems, Front. Psychol., 2016, 7, 902. Baluška F. and Reber A., Sentience and Consciousness in Single Cells: How the First Minds Emerged in Unicellular Species, BioEssays, 2019, 41(3), DOI: 10.1002/bies.201800229. Ben-Jacob E., Learning from bacteria about natural information processing, Ann. N. Y. Acad. Sci., 2009, 1178(1), 78–90. Ben-Jacob E. and Levine H., Self-engineering capabilities of bacteria, J. R. Soc., Interface, 2006, 3(6), 197–214. Bonifaci V., Mehlhorn K. and Varma G., Physarum can compute shortest paths, J. Theor. Biol., 2012, 309, 121–133. Bosch T. C. and Miller D. J., (2016, ), The holobiont imperative, Vienna: Springer. Burnham T. C., Toward a neo-Darwinian synthesis of neoclassical and behavioral economics, J. Econ. Behav. Organ., 2013, 90, S113–S127. Cani P. D. and Knauf C., How gut microbes talk to organs: the role of endocrine and nervous routes, Mol. Metab., 2016, 5, 743–752.

Colceag F., (2003, ), Informational fields, structural fractals. [online], Austega.com, [Viewed 3 March, 2020], Available from: http://austega.com/florin/INFORMATIONAL%20FIELDS.htm. Corsi F. and Sornette D., Follow the money: the monetary roots of bubbles and crashes, Int. Rev. Financial Anal., 2014, 32, 47–59. Cote S. and Miners C. T. H., Emotional intelligence, cognitive intelligence, and job performance, Adm. Sci. Q., 2006, 51, 1–28. D'souza G., Waschina S., Pande S., Bohl K., Kaleta C. and Kost C., Less is more: Selective advantages can explain the prevalent loss of biosynthetic genes in bacteria, Evolution, 2014, 68(9), 2559–2570. Daft R. L. and Lengel R. H., Organizational information requirements, media richness and structural design, Manage. Sci., 1986, 32(5), 513–644. Dennis A. R. and Valacich J. S., (1999, ), Rethinking media richness: Towards a theory of media synchronicity, Proceedings of the 32nd Annual Hawaii International Conference on Systems Sciences, DOI: 10.1109/HICSS.1999.772701. Dyer J. R., Ioannou C. C., Morrell L. J., Croft D. P., Couzin I. D., Waters D. A. and Krause J., Consensus decision making in human crowds, Anim. Behav., 2008, 75, 461–470. Emerson C. D., A Troubled House of Cards: Examining How the Housing and Economic Recovery Act of 2008 Fails to Resolve the Foreclosure Crisis, Okla. L. Rev., 2008, 61, 561. Feynman R., (2011, ), The Feynman Lectures on Physics, New York: Basic Books. Ford B. J., On intelligence in cells: The case for whole cell biology, Interdiscip. Sci. Rev., 2009, 34, 350–365. Ford B. J., Cellular intelligence: microphenomenology and the realities of being, Prog. Biophys. Mol. Biol., 2017, 131, 273–287. Francino M. P., The Gut Microbiome and Metabolic Health, Curr. Nutr. Rep., 2017, 6, 16–23. Friedman M., (1955, ), Liberalism, Old Style, in 1955 Collier's Year Book, New York: P. F. Collier & Son, pp. 360–363. Gilbert S. F., Symbiosis as the way of eukaryotic life: the dependent coorigination of the body, J. Biosci., 2014, 39, 201–209. Gilbert S. F., Bosch T. C. and Ledón-Rettig C., Eco-Evo-Devo: developmental symbiosis and developmental plasticity as evolutionary agents, Nat. Rev. Genet., 2015, 16, 611–622. Goldenfeld N. and Woese C., Life is physics: evolution as a collective phenomenon far from equilibrium, Annu. Rev. Condens. Matter Phys., 2011, 2, 375–399. Goñi P., Fernández M. T. and Rubio E., Identifying endosymbiont bacteria associated with free-living amoebae, Environ. Microbiol., 2014, 16, 339–349. Gould S. J. and Eldredge N., (1972, ), Punctuated equilibria: an alternative to phyletic gradualism, in Schopf T. J. M., (ed.), Models in Paleobiology, San Franscisco: Freeman, Cooper & Co. Hellingwerf K. J., Bacterial observations: a rudimentary form of intelligence?, Trends Microbiol., 2005, 13, 152–158. Heylighen F., (2015, ), Stigmergy as a Universal Coordination Mechanism: Components, varieties and Applications, in Lewis T. and Marsh L., (ed.), Human Stigmergy: Theoretical Developments and New Applications, New

York: Springer. Hodgins-Davis A., Ric D. P. and Townsend J. P., Gene expression evolves under a house-of-cards model of stabilizing selection, Mol. Bio. Evol., 2015, 32, 2130–2140. Horn M. and Wagner M., Bacterial Endosymbionts of Free-living Amoebae, J. Eukaryotic Microbiol., 2004, 51, 509–514. Jalali B. and Asghari M. H., The anamorphic stretch transform: Putting the squeeze on “big data”, Opt. Photonics News, 2014, 25, 24–31. Konnikova M., (2013, ), The limits of self-control: Self-control, illusory control, and risky financial decision making, Ph.D. Thesis, Columbia University [online]DOI: 10.7916/D8QR54B5. Koonin E. V., Darwinian evolution in the light of genomics, Nucleic Acids Res., 2009, 37, 1011–1034. Lewis G. N., (1923, ), Valence and the Structure of Atoms and Molecules, New York: Chemical Catalog Company. Lopez de Prado M., (2013, ), What to Look for in a Backtest, SSRN, [online]DOI: 10.2139/ssrn.2308682. Losa G. A., Fractals and their contribution to biology and medicine, Medicographia, 2012, 34, 364–374. Lowenstein R., (2000, ), When genius failed: the rise and fall of Long-Term Capital Management, New York: Random House. Lux T., Herd behaviour, bubbles and crashes, Econ. J., 1995, 105, 881–896. Lyon P., The cognitive cell: bacterial behavior reconsidered, Front. Microbiol., 2015, 6, 264. Meléndez R., Meléndez-Hevia E. and Canela E. I., The fractal structure of glycogen: a clever solution to optimize cell metabolism, Biophys. J., 1999, 77, 1327–1332. Miller W. B., (2013, ), The Microcosm Within: Evolution and Extinction in the Hologenome, Boca Raton: Universal Publishers. Miller W. B., Cognition, information fields and hologenomic entanglement: evolution in light and shadow, Biology, 2016, 5, 21. Miller Jr. W. B., Biological information systems: Evolution as cognition-based information management, Prog. Biophys. Mol. Biol., 2017, 134, 1–26. Miller Jr. W. B. and Torday J. S., Four Domains: The Fundamental Unicell and Post-Darwinian Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2018, 140, 49–73. Miller Jr. W. B., Torday J. S. and Baluška F., Biological evolution as the defense of 'self', Prog. Biophys. Mol. Biol., 2019, 142, 54–74. Miller W. B., Baluška F. and Torday J. S., Cellular Senomic Measurements in Cognition-Based Evolution, Prog. Biophys. Mol. Biol., 2020, 156, 20–33. Moorbath S., Dating earliest life, Nature, 2005, 434, 155. Nahum J. R., Godfrey-Smith P., Harding B. N., Marcus J. H., Carlson-Stevermer J. and Kerr B., A tortoise–hare pattern seen in adapting structured and unstructured populations suggests a rugged fitness landscape in bacteria, Proc. Natl. Acad. Sci. U. S. A., 2015, 112, 7530–7535. Nakagaki T., Yamada H. and Tóth Á., Intelligence: Maze-solving by an amoeboid organism, Nature, 2000, 407, 470. Patni I., Jain V. and Gupta D., Testing the existence of herd instinct: an empirical study on BSE sectoral indices, Int. J. Res. Manage. Soc. Sci., 2014, 2(3), 61– 67.

Paula A. J., Hwang G. and Koo H., Dynamics of bacterial population growth in biofilms resemble spatial and structural aspects of urbanization, Nat. Commun., 2020, 11, 1354. Penesyan A., Gillings M. and Paulsen I., Antibiotic discovery: combatting bacterial resistance in cells and in biofilm communities, Molecules, 2015, 20, 5286–5298. Pigliucci M., Do we need an extended evolutionary synthesis?, Evolution, 2007, 61, 2743–2749. Popat R., Cornforth D. M., McNally L. and Brown S. P., Collective sensing and collective responses in quorum-sensing bacteria, J. R. Soc., Interface, 2015, 12, 20140882. Prasad G. V., (2017, ), The Emergence of a New Human Superorganism After Organ Transplantation, Ph.D. Thesis, University of Waterloo [online], Available at: https://uwspace.uwaterloo.ca/bitstream/handle/10012/12281/Prasad_G%20V%20Ramesh.pd sequence=3. Purser G. H., Lewis structures are models for predicting molecular structure, not electronic structure, J. Chem. Educ., 1999, 76, 1013. Reber A., (2018, ), The First Minds: Caterpillars, Karyotes, and Consciousness, Oxford: Oxford University Press. Saigusa T., Tero A., Nakagaki T. and Kuramoto Y., Amoebae anticipate periodic events, Phys. Rev. Lett., 2008, 100, 018101. Scheinkman J. A. and Woodford M., Self-organized criticality and economic fluctuations, Am. Econ. Rev., 1994, 84, 417–421. Schumann A. and Adamatzky A., Physarum spatial logic, New Math. Nat. Comput., 2011, 7, 483–498. Smith A., (2010, ), The Theory of Moral Sentiments, London: Penguin Books. Sornette D., Predictability of catastrophic events: material rupture, earthquakes, turbulence, financial crashes and human birth, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 2522–2529. Sornette D., (2017, ), Why stock markets crash: critical events in complex financial systems, Princeton: Princeton University Press. Spector T., (2014, ), Of atoms and aesthetics, Chemistry World, [online], Available at: https://www.chemistryworld.com/opinion/of-atoms-andaesthetics/7522.article. Stanovich K. E., West R. F. and Topla M. E., Myside bias, rational thinking, and intelligence, Curr. Dir. Psychol. Sci., 2013, 22, 259–264. Stoelhorst J. W., Darwinian foundations for evolutionary economics, J. Econ. Issues, 2008, 42, 415–423. Tasoff J., Mee M. T. and Wang H. H., An economic framework of microbial trade, PLoS One, 2015, 10, e0132907. Theis K. R., Dheilly N. M., Klassen J. L., Brucker R. M., Baines J. F., Bosch T. C., Cryan J. F., Gilbert S. F., Goodnight C. J., Lloyd E. A. and Sapp J., Getting the hologenome concept right: an eco-evolutionary framework for hosts and their microbiomes, Msystems, 2016, 1, e00028–16. Thomas-Vaslin V., Altes H. K., de Boer R. J. and Klatzmann D., Comprehensive assessment and mathematical modeling of T cell population dynamics and homeostasis, J. Immunol., 2008, 180, 2240–2250. Torday J. S., The Singularity of Nature, Prog. Biophys. Mol. Biol., 2019, 142, 23– 31.

Torday J. S. and Miller Jr. W. B., Phenotype as Agent for Epigenetic Inheritance, Biology, 2016a, 5(3), 30. Torday J. S. and Miller Jr. W. B., The Unicellular State as a Point Source in a Quantum Biological System, Biology, 2016b, 5(2), 25. Torday J. S. and Miller Jr. W. B., The resolution of ambiguity as the basis for life: A cellular bridge between Western reductionism and Eastern holism, Prog. Biophys. Mol. Biol., 2017, 131, 288–297. Torday J. S. and Miller Jr. W. B., The Cosmologic Continuum From Physics to Consciousness, Prog. Biophys. Mol. Biol., 2018, 140, 41–48. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology: Cell–Cell Communication and Complex Disease, Hoboken: Wiley-Blackwell. Vacher R., Woignier T., Phalippou J., Pelous J. and Courtens E., On the fractal structure of silica aerogels, J. Phys. Colloq., 1989, 50, 127–131. Verde F., Stanzione A., Romeo V., Cuocolo R., Maurea S. and Brunetti A., Could Blockchain Technology Empower Patients, Improve Education, and Boost Research in Radiology Departments? An Open Question for Future Applications, J. Digit. Imaging, 2019, 32, 1112–1115. Viedma C., Chiral symmetry breaking and complete chiral purity by thermodynamic-kinetic feedback near equilibrium: implications for the origin of biochirality, Astrobiology, 2007, 7, 312–319. Visick K. and Fuqua C., Decoding Microbial Chatter: Cell-cell communication in bacteria, J. Bacteriol., 2005, 187, 5507. Walsh D. M., The negotiated organism: inheritance, development, and the method of difference, Biol. J. Linn. Soc., 2014, 112, 295–305. Xavier R. S., Omar N. and de Castro L. N., (2011, ), Bacterial colony: Information processing and computational behavior, Third World Congress on Nature and Biologically Inspired Computing, pp. 439–443, https://doi.org/10.1109/NaBIC.2011.6089627. Xue G., He Q., Lei X., Chen C., Liu Y., Chen C., Lu Z. L., Dong Q. and Bechara A., The gambler's fallacy is associated with weak affective decision making but strong cognitive ability, PLoS One, 2012, 7(10), e47019. Young S., Li S. J. and Huang Y. Y., (2004, ), Analyze word-of-mouth effect in terms of macro-behavior: The herd behavior in Chinese market, System Dynamics Society, [online], Available at: https://proceedings.systemdynamics.org/2007/proceed/papers/LI491.pdf. Youssefmir M., Huberman B. A. and Hogg T., Bubbles and market crashes, Comput. Econ., 1998, 12, 97–114.

CHAPTER 20

Singularity, Life and Mind: New Wave Organicism 20.1 Introduction In The Rise of Scientific Philosophy, the Logical Empiricist/Positivist and former card-carrying member of the Vienna Circle, Hans Reichenbach, sketched an influential and widely accepted history of the progress of modern philosophy that culminated with Analytic philosophy and merged it ineluctably with the progress of logic and the exact sciences (Reichenbach, 1951). Reichenbach's basic idea, then, was that philosophy is legitimate only and precisely to the extent that (i) it is analysis, and (ii) it works on all and only foundational problems and conceptual puzzles arising from logic and the exact sciences. This is an exceptionally important metaphilosophical thesis, not only because it resuscitates John Locke's seventeenth-century conception of philosophy as merely an “underlaborer” for the leading sciences of the Scientific Revolution, but also, and indeed primarily because, its unabashed scientism is the engine that has driven post-classical Analytic philosophy from the second half of the twentieth century through to the second decade of the twenty-first. Correspondingly, it is plausibly arguable, and has indeed been compellingly argued by, e.g. Hilary Putnam and John McDowell (Putnam, 1990, 1994, 1999; McDowell, 1994), that the basic problem of post-classical Analytic philosophy and so-called “Continental” philosophy after 1950 alike – and perhaps also the fundamental problem of modern philosophy – is how it is possible to reconcile two sharply different, seemingly incommensurable, and apparently even mutually exclusive metaphysical conceptions, or “pictures,” of rational human animals and their world. On the one hand, there's the objective, nonphenomenal, perspectiveless, mechanistic, value-neutral, impersonal and amoral metaphysical picture of the world and ourselves that is delivered by pure mathematics and the fundamental natural sciences. And on the other hand, there is the subjective, phenomenal, perspectival, teleological, value-laden, person-oriented, and moral metaphysical picture of the world and ourselves that is yielded by the conscious experience of rational human beings. Wilfrid Sellars evocatively and famously dubbed these two sharply opposed world-conceptions “the scientific image” and “the manifest image” (Sellars, 1963a). So we shall call the profound difficulty raised by their mutual incommensurability and inconsistency The Two Images Problem. In turn, the philosophical doctrine known as scientific naturalism offers a possible complete solution to The Two Images Problem, by holding, according to Sellars's famous formulation, that [i]n the dimension of describing and explaining the world, science is the measure of all things, of what is that it is, and of what is not that it

is not. (Sellars, 1963b: 173) Here, Sellars's term-of-art “science” clearly refers to the exact sciences, including mathematics, physics, biology and chemistry, whereas, strictly speaking, logic is one of the formal sciences. In any case, according to the standard construal of scientific theory-reduction, both biology and chemistry have a fully mathematically describable and microphysical basis in fundamental physical entities, properties, facts, and processes; and therefore they are both fully grounded in a fundamental, naturally mechanistic physics. Scientific naturalism includes four basic theses: (i) anti-mentalism and antisupernaturalism, which says that we should reject any sort of explanatory appeal to non-physical or non-spatiotemporal entities or causal powers; (ii) scientism, which says that the exact sciences are the paradigms of reasoning and rationality, as regards their content and their methodology alike; (iii) materialist or physicalist metaphysics, which says that all facts in the world, including all mental facts and social facts, are either reducible to (whether identical to or “logically supervenient” on) or else strictly dependent on, according to natural laws (aka “naturally supervenient” or “nomologically supervenient” on) fundamental physical facts, which in turn are naturally mechanistic, microphysical facts; and (iv) radical empiricist epistemology, which says that all knowledge and truths are a posteriori. So, to put it in a nutshell, scientific naturalism holds first, that the nature of knowledge and reality are ultimately disclosed by pure mathematics, fundamental physics and whatever other reducible natural sciences there actually are or may turn out to be; second, that this is the only way of disclosing the ultimate nature of knowledge and reality; and third, that even if everything in the world, including ourselves and all things human (including language, mind and action), cannot be strictly eliminated in favor of or reduced to fundamental physical facts, nevertheless everything in the world, including ourselves and all things human, is metaphysically grounded on and causally determined by fundamental physical facts. But it is critically essential, and indeed also both morally and mortally essential, to recognize that if scientific naturalism were true, then not only would (i) philosophy as a form of inquiry, as a practice, and as a social institution, be superseded by the exact sciences, which directly entails the death-by-redundancy of philosophy itself (Mabaquiao, 2011); but also, (ii) because our consciousness, intentionality, free agency, normative principles, truth, ideals-and-values, etc. are all either (iia) mere eliminable myths; (iib) fully reducible to fundamentally physical facts; or, at the very least, (iic) strictly dependent on fundamentally physical facts and thus epiphenomenal, with no causal powers of their own, then it follows that (iii) we are nothing but biological machines with a built-in strong tendency to deceive ourselves by falsely believing in the irreducible and causally efficacious nature of our own consciousness, intentionality, free agency, normative principles, truth, ideals-and-values, etc.; hence (iv) by the same token, then we would be just as likely to be self-deceived about the truth of scientific naturalism itself as not, so it follows that we are not rationally justified in believing it, all of which directly entails (v) the death-by-self-stultification of the doctrine of scientific naturalism itself. Clearly, then, something has gone deeply and even tragically wrong between philosophy and science since 1950 (and we will briefly speculate about precisely what has gone so very wrong later in this chapter), and therefore it is high time for a new and revolutionary Kuhnian paradigm-shift (Kuhn, 1962). Our contention in this

essay is that, in order to bring about this paradigm-shift, we need to re-think what A. N. Whitehead so aptly called our concept of nature itself (Whitehead, 1920), from the Big Bang Singularity forward to organismic life, and then on to conscious mind, including both the mind-body relation and free agency. The new and revolutionary paradigm that emerges from re-thinking our concept of nature in this way, is what we call new wave organicism. But that is not all. New wave organicism is also a grand synthesis of philosophy, the formal and natural sciences (or what Whitehead calls “the special sciences”), and the applied and fine arts, that fully satisfies what we will call Thoreau's Dictum: When one man has reduced a fact of the imagination to be a fact to his understanding, I foresee that all men will at length establish their lives on that basis. (Thoreau, 1960: 7)

20.2 Singularity and Nature A century ago, Einstein's formulation of the equivalency of energy and mass (E=mc2) changed our concept of nature by radically equating energy and matter. Through this simple equation, the entire gamut of existence was circumscribed, the more surprising since this awe-inspiring breakthrough occurred to Einstein in a dream when he was sixteen years old (Isaacson, 2007). Just as physics was unsettled by this illuminating brilliance, that equation also challenges us to determine how biology conforms to this entailing perspective. Biology is unlike physics. As a history of continuous dynamic changes, biology has been long presumed to exist without an underpinning of eternal laws. Nonetheless, one belief has become central to biology. As Dobzhansky (1973) memorably pronounced: “Nothing in biology makes sense except in the light of evolution.” Any attempt at reconciling chemistry and physics must therefore explain how basic chemical and physical laws can seamlessly yield the biological forms that populate our planet.

20.3 On the Causal-processual Mechanisms of Biological Evolution Daniel J. Nicholson (2012) defines biological mechanisms in three ways: “It may refer to a philosophical thesis about the nature of life and biology (‘mechanicism’), to the internal workings of a machine-like structure (‘machine mechanism’), or to the causal explanation of a particular phenomenon (‘causal mechanism’).” The third, or causal, sense of mechanism corresponds to the third meaning that the Oxford English Dictionary assigns to the term “mechanism”: “the mode of operation of a process.” Therefore, it is accurate to call this the causal-processual sense of mechanism. In a series of publications by Torday, Rehan, Miller and others, biologically operative mechanisms in the third or causal-processual sense of biological mechanisms have been addressed by examining evolution, starting from its unicellular origins (Torday and Rehan, 2012; Torday and Miller, 2016a; Torday and Rehan, 2017). They have defended the view that this yields a novel predictive form of evolutionary biology. Starting from the origin of life, which is based on cellular-molecular principles of ontogeny applied to phylogeny, the biological causal-processual mechanisms for successfully coping with environmental stresses can be elucidated (Torday, 2015b). It can be correctly asserted that the first principles of physiology – negentropy, chemiosmosis and homeostasis – provide the

initial conditions for evolution and homeostasis (Torday and Rehan, 2012), providing insight to how and why organisms have evolved.

20.4 Biology as a Continuum Recognizing biology as a continuum is long overdue. It must become a predictive science, comparable with chemistry and physics (Birks, 1962) in order to effectively utilize all of the “omics” now available to biology and medicine. The constraint toward this goal has largely been historic, due to the usurping of cell biology by genetics (Smocovitis, 1996). Even with the recognition of the relevance of developmental biology to evolution, or “evo-devo” (Hall, 2003), a further appreciation of a central requirement to recognize cell biology as the fundament of embryology (Slack, 2014), biological development and evolution has been lacking. With the realization of the central role of cell–cell communication in evolution (Torday and Rehan, 2007; Torday and Rehan, 2012; Torday and Rehan, 2017), many biological dogmas have been redefined mechanistically (Torday, 2015a, 2015b, 2015c, 2016). This offers a new-found transparency for biology that had remained opaque in the descriptive mode, which has consistently dominated biology. As a result, the linguistic and conceptual framework of biology changes, resulting in a Kuhnian paradigm shift (Kuhn, 1962). This enlightened view of biology has led to the novel recognition of the first principles of physiology (Torday and Rehan, 2012), and to a central theory of biology (Torday, 2015b), predicting the advent of endothermy based on developmental and phylogenetic physiologic principles instead of ex post facto rationalization (Bennett and Ruben, 1979). Such insights are on par with heliocentrism, the Copernican recognition that the sun is the center of the solar system. Like that, the displacement of humans from the center of the biosphere would offer a new vista for understanding our place in the biological universe. That realization is critically important to consideration of climate change, artificial intelligence and genetic engineering (CRISPR). There is great danger in misjudging the significance in the case of the former, and a risk of misapplication in the case of the latter phenomenon at this critical juncture in human history, now being referred to as the “Anthropocene” (Steffen et al., 2011; Edwards, 2015). Moreover, by understanding the principles of biology, we can formulate ways of affecting the arc of our evolution based on congruent ethical principles, rather than blindly invoking technological change, and then having to correct it after the fact.

20.5 Conscious Mind and Its Emergence in the Continuum from Inanimate to Animate As per the preceding sections, a case can be made for the interrelationship between the physical and biological realms based on the “logic” of each. Conscious mind can be considered to be the interface between the two (Torday and Miller, 2016b), forming a conduit for the flow of information between the inanimate and animate. This provides the beginnings of a solution to what is referred to in the consciousness literature as “the hard problem” (Chalmers, 1996), which attempts to separate the mystery of subjective experience, or consciousness, from those processes that seem to have a direct biochemical and anatomic basis. By providing a level playing-field between the atom and the cell (Torday and Miller, 2016a), in

combination with such quantum concepts as non-locality, the bigger venue of conscious mind becomes understandable as dynamically emerging from reiterative cell–cell communication. It follows that solutions at one cellular level can be carried and adjusted within the context of the next, just as physiological properties are serial pre-adaptations. Seeing “red” when you whack your thumb with a hammer might easily reduce to an atavistic “remembrance of things past” (Proust, 1982), which is, in this instance, a recollection of a prior pattern of cellular responses at a different level from that of our consciousness. This in turn brings us up to the “hard problem” again, or more generally, up to what philosophers call “the mind-body problem.”

20.6 Mind is a Form of Life 1: Solving the Mind–Body Problem The metaphysics of the mind–body relation that directly answers to the above conception of the continuity between the Big Bang Singularity, organismic life, and conscious mind, is that the mental–physical relation is a two-way necessary complementarity, that is, a mental-to-physical and physical-to-mental necessary equivalence that captures the manifest essence of minded animals like us. In short, as Hanna and Maiese put it in Embodied Minds in Action (Hanna and Maiese, 2009), minded animals like us are essentially embodied minds, hence they call this “the essential embodiment theory,” or EET. EET is a specially restricted version of “dual-aspectism.” For other dual-aspect theories, one can compare and contrast Spinoza's theological monism (in The Ethics), Russell's neutral monism (in The Analysis of Mind and The Analysis of Matter), or Whitehead's universal panpsychist organicism (in Process and Reality). Unlike Whitehead's universal panpsychist organicism, however, EET does not say that everything, everywhere in the world is somehow minded, as an intrinsic nonrelational property of that thing, from the fundamental level up. For that would mean, for example, that even Dale's Pale Ale and the cans that contain it are somehow minded, as an intrinsic nonrelational properties of those things, which is clearly an excessively strong metaphysical thesis. Nevertheless EET does, in a specially restricted way, share some of the metaphysical benefits of panpsychism – namely, that in all and only suitably complex kinds of organismic living creatures and their life-processes, causally efficacious mental and physical properties are related by two-way necessary complementarity. Or in other words: all and only everything in the world that is the right kind of organismic living creature and its life-process, is minded. So EET is a specially restricted version of psychoorganicism. More specifically, however, EET says: (i) that minds like ours are necessarily and completely embodied; (ii) that minds like ours are complex global dynamic structures of our living organismic bodies, i.e. forms of life; (iii) that minds like ours are therefore inherently alive; (iv) that minds like ours are therefore inherently causally efficacious, just like all forms of organismic life; and (v) that minds like ours emerge over time and in space in all and only certain kinds of living organisms, i.e. minded animals. Now minds like ours are inherently capable of: (i) consciousness, that is, subjective (= egocentrically centered in orientable space and unidirectional time) experience (= mental acts, states, or processes of any sort); and (ii) intentionality,

that is, directedness to all kinds of things as their cognitive, desiderative, emotional, etc. targets. And the two fundamental problems in the philosophy of mind are these: The mind-body problem: what accounts for the existence and specific character of conscious, intentional minds like ours in a physical world? The problem of mental causation: what accounts for the causal efficacy and causal relevance of conscious, intentional minds like ours in a physical world? Correspondingly, following are eight reasons why EET, when foregrounded against the backdrop of the Big Bang Singularity – organismic life – conscious, intentional mind continuity we have sketched above, is also truly revolutionary in the Kuhnian paradigm-shifting sense. First, EET fully avoids reducing the mental to the physical, aka reductive physicalism. Reductive physicalism, presenting itself via the sheep's clothing of the mind-body identity theory or the logical supervenience of the mental on the physical, de facto simply eliminates the mental. But what could be more epistemically primitive than our subjective experience of ourselves as conscious, intentional minds, and correspondingly, what then could be more metaphysically and ontologically primitive than the fact of the mental-qua-mental? Second, EET fully avoids making the mental naturally or nomologically supervenient on the physical, aka non-reductive physicalism. Reductive physicalism entails epiphenomenalism, hence it robs the mental of all its efficacious causal power. It is no solution to say that, from a non-reductive physicalist point of view, the mental can still have “causal relevance”: on the contrary, the mental has got to have efficacious causal powers, not merely an important informational bearing on causal processes. Third, EET fully avoids reducing the physical to the mental, aka subjective idealism. Subjective idealism makes nature's existence radically dependent on the existence of individual minds. It is highly implausible to hold that physical nature came into existence only after there were any minded animals. For, since animals are parts of physical nature, it would follow that animals came into existence only after there were minded animals. And it is equally highly implausible to hold that if all individual minds were to perish, physical nature would go out of existence too. For in that case, since all animals die, and in most cases after animals die, their corpses continue to exist for a while, it would follow that necessarily, the last minded animal would have no corpse. Fourth, EET fully avoids making the mental and the physical either essentially or even logically independent of one another, as per either Cartesian “interactionist substance dualism” or Cartesian “property dualism.” Any form of Cartesian dualism makes it impossible to explain how the mental and the physical causally interact without appealing to some sort of metaphysical mystery: for example, Descartes's God, Leibniz's divine pre-established harmony, an ectoplasmic medium, etc. And any form of Cartesian dualism also entails the metaphysical impossibility that subjective experiences could exist without embodiment. Fifth, EET fully avoids over-restricting mentality to the brain, i.e. it fully avoids the error of “the brain-bounded mind” (Hanna, 2011). Sixth, EET fully avoids over-extending the mental beyond the living animal body, i.e. it avoids the error of “the extended mind” (Clark and Chalmers, 1998). Seventh, EET provides adequate metaphysical foundations for a robust

metaphysics of free agency (Hanna, 2018), as we will briefly spell that out. Eighth, and perhaps most importantly, building on the sixth and seventh points, EET is an approach to the mind-body problem, including the problem of mental causation, that is perfectly scaled to the nature, scope, and limits of our “human, all too human” existence in a thoroughly nonideal natural and social world. Brainboundedness falls short of the human condition: it makes us much less than we manifestly are. The extended mind exceeds the human condition: it makes us more than we manifestly are. Only the essential embodiment of the mind adequately captures and reflects the human condition: it tells us exactly what we manifestly are. For I just am my minded animal body and its “human, all too human” life, for better or worse. In short, EET answers perfectly to Socrates's Delphic-Oracleinspired thesis that an ultimate aim of philosophy is to “know thyself.”

20.7 Dynamic Systems Theory and the Dynamic World Picture The essential embodiment theory of the mind-body relation, or EET, in turn, presupposes a comprehensive metaphysics of nature whose general outlines we will sketch in this section, and then supplement in the next section when we add a theory of free agency to EET. According to this comprehensive metaphysics of nature, which we call the Dynamic World Picture, the world is the totality of dynamic systems, not static things. But what, more precisely, are dynamic systems? Here is a very brief primer of contemporary “dynamic systems theory” or DST (Nicolis and Prigogine, 1977; Varela, 1979; Jantsch, 1980; Kauffman, 1993; Kauffman, 1995; Haken, 1996; Weber and Varela, 2002). DST is the mathematical theory of sets of physical elements – where each such set is perceived by us as a single entity – whose states change over time in ways that depend on their current states according to rules. The Dynamic World Picture entails the concept that dynamic systems are not merely perceived unities, but are also real unities in nature. So as we interpret DST, dynamic systems are real, unified physical processes whose collective behaviors, effects, and outputs occur in some ordered pattern that can be mathematically described in relation to their present conditions. This is not to say, however, that every dynamic system operates like two billiard balls colliding on a flat surface, like mechanical clockwork, or like a digital computer. Many dynamic systems – including the roiling movements of boiling water, traffic patterns, the weather, ecosystems, planets, solar systems, stars, star systems and the movements of living organisms – are complex. Complexity includes two essential features: (i) being nonequilibrium or far-from-equilibrium, and (ii) being non-linear. Being nonequilibrium or far-from-equilibrium means that a dynamic system is such that its energy sources, energy expenditures, information level, and material constituents are not constant in value – this phenomenon is also known as “fluctuation” – due to direct exchanges of energy, information and matter with the environment. For example, frozen water at temperatures approaching absolute zero is in thermodynamic equilibrium, and boiling water is far-from-equilibrium. On the other hand, being nonlinear means that a dynamic system is such that its outputs, effects, or collective behaviors: (a) are not a mere recursive or digitally computable function of their input;, (b) are not a posteriori predictable from our knowledge of the system's initial conditions, which include its individual elements and facts about

their past dynamic history, the currently existing relations between those elements, the currently existing relations between those elements and other things, and the current laws of nature; and (c) are not a priori derivable from all the facts about the system's initial conditions. Non-linear dynamic systems are describable by nonlinear functions, while linear dynamic systems are describable by linear functions. For example, the movements of colliding billiard balls on a flat surface are describable by linear functions, while the movements of billiard balls on a curved surface are describable by non-linear functions. The most interesting dynamic systems have what is called “dissipative structure” and are self-organizing. The notion of being “dissipative” here means that the energy-loss or entropy of a system is absorbed and dispersed (hence “dissipated”) by the systematic re-introduction of energy and matter causal balance between the inner states of the system and its surrounding natural environment: With the help of this energy and matter exchange with the environment, the system maintains its inner non-equilibrium, and the non-equilibrium in turn maintains the exchange process …. A dissipative structure continuously renews itself and maintains a particular dynamic regime, a globally stable space-time structure. (Jantsch, 1980, as quoted in Weber, 2018) Self-organization is how a non-equilibrium, non-linear dynamic system with dissipative structure internally generates forms or patterns of order that determine its own causal powers, and in turn place constraints (“demands” or “needs”) on the later collective behaviors, effects, and outputs of the whole system, in order to maintain itself. Or in other words, self-organization is natural purposiveness or natural teleology. The prime example of self-organizing systems is of course living organisms, although nonliving complex systems such as the roiling movements of boiling water, traffic patterns, the weather, ecosystems, the Earth, solar systems, stars and star systems are all also self-organizing in the comprehensive sense of DST. The fact that DST is a mathematical theory is important. Its descriptive formalism specifically includes the following seven elements: (1) a state space, which is the set of points whose coordinates completely specify the range of possible collective behaviors of the system; (2) a phase space, which is the state space insofar as its points can be considered as functions of time; (3) a trajectory, which is a particular path taken by the system through the state space over time, i.e. a particular temporal sequence of collective behaviors of the system; (4) a control parameter, which is a constant that can be manipulated externally to the system and given different values to produce systems with varying behaviors; (5) an order parameter, which is a collective variable that determines the behavior of the individual elements of the system; (6) attractors, which are subsets or regions of the state space, specifying a certain repertoire of collective behaviors, towards which the whole system moves and in which the system temporarily or permanently lives, as time passes; and finally (7) the capacity for chaos, which is a form of non-linear, non-stochastic instability, in which small changes in initial conditions can lead to large changes in the behavior of the system in computationally intractable and unpredictable ways. Unlike other mathematical formalisms, DST essentially includes the actual or brute fact of the passage of time in its equations, functions and graphs. So the value of DST as a mathematical tool is that its formalism

captures patterned material change, process, and evolution over elapsed time in a fine-grained, systematic and intuitive way that cannot be captured by other formalisms. Considered purely as a mathematical theory, DST is metaphysically neutral. But even if the mathematics of DST is metaphysically neutral, DST itself is not exhausted by its mathematical tools and is not a metaphysically neutral theory. This is because it commits itself crucially to the notion of circular or reciprocal causality, which is how the “local” properties of the individual material proper parts or elements of the system on the one hand, and the “global” or system-wide properties of the system considered as an overall unity on the other hand, synchronously mutually determine the causal powers and the causal efficacy of the whole system. Below, we will analyze this circular or reciprocal causality in terms of dynamic emergence. Another crucial metaphysical commitment of DST is its orientation towards the life sciences, especially organismic biology. The concept of the living organism is absolutely central to DST in particular and to The Dynamic World Picture more generally. In this picture, the facts about conscious, intentional minds are strongly continuous with the facts about organismic life. As Peter Godfrey-Smith puts it, according to the strong continuity view, [l]ife and mind have a common abstract pattern or set of basic organizational properties. The … properties characteristic of mind are an enriched version of the … properties that are fundamental to life in general. Mind is literally life-like. (Godfrey-Smith, 1996: 320) In other words, biological life has everything that is metaphysically and naturally required for conscious, intentional minds, but is not always organized in a suitably complex way. Conscious, intentional minds are immanent structural properties of living organisms that dynamically emerge when and only when those biological systems reach a certain suitable level of complexity. Thus, the strong continuity of mind and life does not mean that every organism has a conscious, intentional mind, but it does mean that every creature with a conscious, intentional mind is necessarily also a living organism. Moreover, it is not true on the strong continuity view that biological life is somehow a form of “unconscious mind.” The metaphysical connection, instead, goes precisely the other way. Conscious, intentional mind is a specific structural kind of organismic life. So, too, is organismic life a specific structural kind of molecular, atomic and quantum fact. In the world described by DST, conscious, intentional mind are strongly continuous with organismic life, and in turn, organismic life is strongly continuous with molecular, atomic and quantum thermodynamics (Schrödinger, 1944). All the basic facts in the natural world are strongly continuous with each other. Imagistically speaking, the natural world is an ontological spiral, not an ontological bifurcated plane, and also not an ontological hierarchy of levels. In the world described by DST, conscious, intentional mind dynamically emerges from organismic life; in turn, organismic life dynamically emerges from molecular, atomic and quantum thermodynamics; and all three domains of facts dynamically continuously intertwine with each other. Now according to classical Cartesian interactionist substance dualism, the world consists of two essentially distinct kinds of substance (mind and matter) and correspondingly of two essentially different kinds of property (mental and

physical), each of which constitutes a domain of logically and metaphysically distinct substantial particulars (minds and bodies) under that kind and instantiating those properties. Then those two kinds of substances, properties, and substantial particulars are by some entirely unexplained means – perhaps as a result of God's incomprehensible and all-powerful will – supposed to interact causally, despite their splendid mutual logical and metaphysical isolation. This is of course the classical early-modern metaphysical picture of The Bifurcated World (Figure 20.1).

Figure 20.1

The Bifurcated World.

Historically speaking, The Bifurcated World Picture did not survive the rise of modern natural science. As Jaegwon Kim correctly observes, since the seventeenth century the Cartesian model of a bifurcated world has been replaced by that of a layered world, a hierarchically stratified structure of “levels” or “orders” of entities and their characteristic properties. It is generally thought that there is a bottom level, one consisting of whatever microphysics is going to tell us are the most basic physical entities out of which all matter is composed (electrons, neutrons, quarks, or whatever). And these objects, whatever they are, are characterized by certain fundamental physical properties and relations (mass, spin, charm, or whatever). As we ascend to higher levels, we find structures that are made up of entities belonging to the lower levels, and, moreover, the entities at any given level are thought to be characterized by a set of properties distinctive of that level. (Kim, 1993: 190) The Layered World Picture began to emerge in Boyle's seventeenth-century “corpuscularian” theory of matter, and took its final shape in the early twentiethcentury Rutherford–Bohr atomic theory of matter. More generally, The Layered World Picture is intimately bound up with the parallel developments of particle

physics and microscopy (Wilson, 1995; Galison, 1997). The Layered World is a world of increasingly small microphysical compositions, apparently all the way down, such that each lower level or stratum of reality is populated by a different sort of smaller material particle, out of which all the entities at higher levels are constructed. Just as The Bifurcated World Picture belongs to Cartesian substance dualism, so too the Layered World Picture belongs to materialism or physicalism. This is because in The Layered World the relation between the layers is one of asymmetric, non-reciprocal or one-way “upwards” necessary dependence based on the partwhole relation: the higher levels are all ultimately either identical with or (logically or nomologically) strongly mereologically supervenient on the lower levels, in the sense that higher levels are entirely built out of smaller and smaller items occurring at the lower levels (Figure 20.2.)

Figure 20.2

The Layered World.

The fatal metaphysical flaw in The Bifurcated World Picture was the incomprehensibility of the causal relationship between the two essentially distinct domains of mental and physical facts. But there are two fatal metaphysical flaws in The Layered World Picture. The first flaw is the great difficulty of reconciling inert particles with active forces, which leads to the several equally difficult subproblems of understanding action-at-a-distance, the ether, relativity, gravity, electromagnetic fields, waves, “wavicles,” quantum phenomena and so on. Neither relativity theory nor quantum mechanics conforms especially well to The Layered World Picture. The second flaw in The Layered World Picture is the great difficulty of understanding the nature of the conceptual, ontological, and causal gaps or transitions between levels, which is the same as the problem of reconciling the continuity of downward decomposition with the discontinuity of upward evolution, especially at the levels of biological and mental facts. The possibility of a downward decomposition of all entities and facts at any given level into

mereological sums occurring at lower levels in the hierarchy strongly suggests that all the higher levels should explanatorily, ontologically or at least causally collapse down onto the bottom level. But upward evolution of the levels over physical time strongly suggests, contrariwise, that each new higher level has its own conceptual, ontic or causal integrity and thereby resists any such downward collapse. This downward vs. upward tension in The Layered World Picture provided by materialism or physicalism, in the end, is every bit as theoretically vitiating as the bilateral dichotomy in The Bifurcated World Picture provided by Cartesian interactionist substance dualism. By sharp contrast, according to The Dynamic World Picture that lies behind EET, there are no such things as explanatorily or ontologically distinct physical and mental worlds, nor are there any such things as distinct explanatory or ontological levels of microphysical composition. The essential features of The Dynamic World are action and mutual interaction, energy, and force. Molecules, atoms, and quantum phenomena are just different ways in which different kinds of inherently active and interactive, energetic, and force-driven phenomena operate according to different sets of laws of varying scope. So there is one and only one natural world, which is essentially a law-governed spatiotemporal totality of processes in various kinds of patterned change, motion, and evolution (with limiting cases of dispersal, entropy, permanent equilibrium, heat-death, and stasis), some of which are the intentional body movements of motile, situated, forward flowing suitably neurobiologically complex living organisms with essentially embodied conscious, intentional minds. Therefore, in sharp opposition to the static binary oppositional world picture provided by Cartesian interactionist substance Dualism, and also in equally sharp opposition to the static hierarchical upwards-dependency picture provided by materialism or physicalism, The Dynamic World Picture seems best captured by the simple image of a hyperbolic spiral superimposed on a rectilinear grid (Figure 20.3).

Figure 20.3

The Dynamic World.

Now think of the rectilinear grid, like Wittgenstein's notion of “logical space” in his 1921 Tractatus Logico-Philosophicus (Wittgenstein, 1981: props. 1.13, 2.013– 2.0131, 2.11, 2.202, 3.4), as the totality of all possible natural facts. Then think of the hyperbolic spiral as the trajectory or unfolding of all the actual natural events in actual space and time. Some of these natural events are chemical facts but not biological facts, although all of the biological facts are also chemical facts. Some of these natural events are chemical and biological facts but not mental facts, although all of the mental facts are also biological facts and chemical facts. So some of these natural events are mental, biological and chemical facts, and all of these natural events are also molecular, atomic and quantum facts. The natural mental events and facts occur on the outermost edge of the infinitely unfolding spiral, and thereby necessarily link together all of the other kinds of events and facts. In this way, the mental facts, biological facts, chemical facts, molecular facts, atomic facts and quantum facts are all unevenly but still systematically distributed throughout the natural world-spiral. In The Dynamic World Picture, individual physical substances really exist, but they are themselves really nothing but differently inherently or intrinsically structured sets of inherently active and interactive, energetic, and force-driven physical events operating under causal laws – dynamic systems. Everything in nature is either a dynamic system itself or else a necessary proper part of some dynamic system. For example, the weather on a certain day is a dynamic system, and a certain cloud formation is a necessary proper part of it. Likewise, that cloud formation is itself a dynamic system, and a certain water droplet is a necessary proper part of it. It is also possible for the same thing to be a necessary proper part

of many different dynamic systems: the water droplet is a necessary proper part of both the cloud formation and the weather system alike. Necessary proper parthood in a dynamic system means playing a certain efficacious causal role within that system, and contributing in some definite way to the system's efficacious causal powers. So the natural world is nothing but causally empowered dynamic systems and their necessary proper parts, all the way around and all the way through. This is not, however, to say that each dynamic system is the same system. On the contrary, each dynamic system has its own immanent structural causal-nomological profile such that it is irreducibly the individual system that it is, and not some other one. And there are irreducibly different natural kinds of dynamic systems, not to mention irreducibly different classes of dynamic systems under various shared properties. In this way the ontology of dynamic systems is monistic, but non-reductive. The natural world is composed of a single kind of thing, dynamic systems, out of whose dynamics emerge an infinite variety of different properties. All of the dynamic systems exemplify fundamental molecular, atomic, and quantum physical properties that are instantianted spatiotemporally. And so, according to The Dynamic World Picture, there are no fundamentally mental, or essentially non-physical entities in the natural world. So too, according to The Dynamic World Picture, there are no fundamentally physical, or essentially non-mental entities in the natural world. No dynamic system is fundamentally physical in that it cannot instantiate an inherent or intrinsic mental property. At the same time, however, many dynamic systems are predominantly physical in that they do not instantiate intrinsic mental properties (for example, rivers, mountains, and weather systems). Similarly, many dynamic systems are predominantly mechanical since they do not instantiate intrinsic biological properties (for example, automobiles, soft drink machines and laptop computers). But not all dynamic systems are predominantly physical, just as not all dynamic systems are predominantly mechanical and unliving. Some dynamic systems not only can, but in fact also actually do instantiate intrinsic biological properties but not intrinsic mental properties (for example, plants), and some dynamic systems not only can but in fact also actually do instantiate intrinsic mental properties as well as intrinsic biological properties (for example, animals of a suitable degree of neurobiological complexity). And there may be real borderline cases between non-living and living dynamic systems (for example, viruses), and also between non-conscious and conscious dynamic systems (for example, insects). The crucial metaphysical point is that an infinite multiplicity of real non-living or mechanical, living or biological and conscious, intentional dynamic systems compatibly co-exist in the dynamic natural world. In other words, and coming back to the three contrasting philosophical pictures, the hyperbolic spiral image of The Dynamic World picture obviously contrasts very sharply with both the binary plane image of The Bifurcated World picture and also the stratified plane image of The Layered World picture. In The Dynamic World Picture there is at once an indissoluble holistic blending and an inevitable pluralistic scattering of quantum facts, atomic facts, molecular facts, chemical facts, facts about living organisms, facts about essentially embodied conscious, intentional minds and facts about rational minded animals or persons, over the infinitely many dynamic systems. To put a twist on Josiah Royce's pithy definition of idealism – “the world and the heavens, and the stars are all real, but not so damned real” (Royce, 1970: 217) – according to The Dynamic World Picture, the natural world of dynamic systems is everywhere and everywhen physical, but not always so damned

physical. Thus The Dynamic World Picture presents a dynamic neutral monism. The single kind of thing that composes the natural world is neither fundamentally mental nor fundamentally physical, but instead is inherently active and interactive, energetic and force-driven; like the spinning Saul Bass spiral graphic in the opening title sequence of Hitchcock's Vertigo.

20.8 Mind is a Form of Life 2: Solving the Free Will Problem The task [of understanding free agency] requires some reflection on the organizational principles of living creatures, for it is only through such reflection that we can start to understand where the difference really lies between, on the one hand those things that are true agents, and, on the other, mere machines, entities that nothing will ever be up to, however impressive they may be…. I am exceedingly hopeful that the next few years will see the beginnings of a revolution in our conception of the human person, as philosophical and everyday conceptions of the scientific picture of the world are freed from outdated Newtonian ideas and begin to take more note, both of the complexities of science as it really is and of the undeniable fact of our animal nature. (Steward, 2012: 198–199). Is human free agency really possible in the natural world as correctly described by contemporary physics, chemistry, biology and cognitive neuroscience – and if so, how is that really possible? Or, more briefly put, given the truth of the contemporary natural sciences, are you really a free agent – and if so, how? Yes; and given what we have argued so far in this essay, here is how. By free agency, we mean the conjunction of free will and practical agency, which in turn means: (i) that you can choose and do what you want to, or refrain from so choosing or doing, without being in any way compelled or prevented by irresistible inner or outer forces (i.e. free will); and (ii) that you can self-consciously choose and do what you want to, for reasons, and with deep moral or non-moral responsibility (i.e. practical agency). And by deep moral or non-moral responsibility for X, we mean: (i) that X is something you chose or did yourself, whose objective moral value flows from and directly attaches to your freely willed choice or action; and (ii) that deep moral responsibility requires free will – if you were not able to choose or do X, without being in any way compelled or prevented by irresistible inner or outer forces, then you could not be deeply morally or nonmorally responsible for X. An example of choice and action with deep moral responsibility would be your deciding, right now, either to join, or to quit, The Democratic Socialists of America. And an example of choice and action with deep non-moral responsibility would be creating a work of art. The thesis of natural determinism says that everything that happens now and in the future is strictly fixed by the laws of nature together with all the actual facts about the past. And the thesis of natural indeterminism says that at least some things, and perhaps all things that happen, are not strictly fixed by the laws of nature together with all the actual facts about the past, but also happen more or less randomly, according to mathematical laws of probability. Most contemporary philosophers and scientists, and many non-philosophers too, hold that you are not

really free, because they also believe that the truth of modern science entails a thesis we call natural mechanism. Natural mechanism says (i) that everything that happens is either deterministic, indeterministic or some mixture of both (say, macroscopically deterministic but microscopically indeterministic at the quantum level), and (ii) that all the causal and quantitative characteristics of those happenings are not only (ii.a) strictly fixed by the general causal laws of nature and/or the mathematical laws of probability, especially those laws governing the conservation of quantities of matter or energy, together with all the settled facts about the past, especially including the Big Bang Singularity, but also (ii.b) calculable from those laws and facts on an ideal digital computer. If natural mechanism is true, then you are not really free, because, instead, no matter what you may believe about your own freedom, you are really a deterministic or indeterministic natural automaton, ultimately caused by the Big Bang Singularity. We will now briefly present a new theory of free agency, which Robert Hanna calls natural libertarianism (Hanna, 2018),† that is neither contrary to contemporary natural science nor committed to the thesis of natural mechanism – indeed, it is not only smoothly consistent with but also presupposes The Dynamic World Picture – and, correspondingly, we will also briefly provide a new proof for the real possibility of human free agency, by explaining and proving its actual existence. Natural libertarianism flows from two simple but earth-shattering ideas proposed by Kant in the eighteenth century, and also from one slightly less simple but still earth-shattering idea proposed by Nobel laureate Ilya Prigogine in The End of Certainty (Prigogine, 1997), an idea that is fully in accordance with the Big Bang Singularity – organismic life – conscious, intentional mind continuity, as well as the essential embodiment theory of the mind-body relation, or EET, and also The Dynamic World Picture, that we have argued for in the preceding sections of this essay. First, action that is perfectly in conformity with a law, is not necessarily entailed or otherwise necessitated by that law (Kant's earth-shattering idea #1). Second, real freedom presupposes, in rational human animals, the natural processes specifically characteristic of living organisms; but living organisms are not natural automata, whether deterministic or indeterministic, because they are self-organizing and purposive; hence real freedom is grounded in biological anti-mechanism (Kant's earth-shattering idea #2). And third, the correct physics is a nondeterministic interpretation of non-equilibrium thermodynamics (Prigogine's earthshattering idea). For simplicity's sake, we will refer to Prigogine's earth-shattering idea by using the acronym “NDI-NET.” And let us suppose, for the purposes of argument, that NDI-NET, as worked out, for example, by Prigogine in The End of Certainty – actually, it should have been called The End of Mechanism – is true, and that all the general causal laws of nature and/or mathematical laws of probability, as formulated by modern science, are also true, under the NDI-NET interpretation. From these suppositions, taken together with Kant's two ideas, not only does it not follow that natural mechanism is true and that we are really natural automata, it also follows that natural mechanism is not true and that we are really not natural automata. To see this, suppose that everything we choose and do is at least consistent with those general causal natural laws and/or mathematical laws of probability, and that, therefore, we never violate any of them. And in particular, suppose that we never

bring any new matter or energy into the natural world, hence we never violate any of the general causal natural laws and/or mathematical laws of probability governing the conservation of quantities of matter or energy. Nevertheless, it does not follow that whatever we choose and do is entailed or otherwise necessitated by those laws. This is because, as Kant pointed out, mere conformity of action with laws is not the same as entailment or necessitation by laws. Indeed, for any general causal law of nature and/or mathematical law of probability whatsoever, no matter how specific it is, together with all the settled natural facts about the past, nevertheless, there is always some physical open texture that is not entailed or necessitated by that law, although it remains perfectly in conformity with the laws. More precisely, in the wake of the Big Bang Singularity, there is always and everywhere some physical open texture that, at various stages of far-fromequilibrium, temporally-unidirectional, complex, self-organizing thermodynamic activity, as studied in NDI-NET, creates targets for ultra-specific, context-sensitive natural activity, for example: (i) the roiling surface-structures of boiling water, (ii) the Belousov-Zhabotinsky chemical reaction, plus light excitation, (iii) the unfolding of weather systems, (iv) the development of viruses, (v) organismic activity including the purposive lives of simple organisms, plants, and animals, (vi) the feelings, desires, perceptions, and thoughts of conscious animals, and above all, (vii) really free choice and action by conscious animals, including rational human animals. Let us call these thermodynamic targets live options, and this physical open texture natural open space. Given some live options in natural open space, then, even though you never violate any general causal laws of nature and/or mathematical laws of probability and never bring any new matter or energy into the natural world, it remains really possible for you, in context, to choose and do some things you want to, in purposive, creative, and morally empowered ways, by spontaneously locally re-organizing and re-structuring the total quantity of matter or energy that is always already available then and there. For example, imagine Thoreau writing Walden. Needless to say, that amazing book had never been produced before in the actual history of the natural universe. Let us call this sort of activity, natural self-determination. Now, inspired by Thoreau's example, one of the authors of this book is going to do a little spontaneous dance by flapping his arms and legs, bobbing his head, and hopping up and down a bit (but also being very careful not to spill his coffee, or knock over his laptop computer); let us call this The Freedom Dance. The Freedom Dance, as an act of natural self-determination, is just like a creative artist who makes an original work of art by spontaneously locally re-organizing and restructuring whatever already-existing materials are given to her: in that sense, it is just like Thoreau creating Walden. As naturally self-determining animals, we are all creative natural artists, little bangs, little Singularities, who purposively bring new energy-structures into the world, and thereby actualize potential energy. As we have seen, the Big Bang Singularity has done many things. But it did not, on its own, write Walden, nor did it do The Freedom Dance. On the contrary, Thoreau wrote Walden, and one of us did The Freedom Dance, with actual free agency in both cases. Therefore, neither Thoreau, nor us, nor anyone else, is a natural automaton; instead we are all naturally self-determining animals fully capable of free agency.‡ So, self-evidently, natural libertarianism is true, given our original assumptions. It should be noted, before moving on, that epigenetic inheritance is fully consistent with natural libertarianism. The phenotype as agent (Torday and Miller,

2016b) collects “marks” or “data” from the environment and assimilates them in the egg and sperm, where they are processed to determine whether they are relevant to the “history” (read: ontogeny and phylogeny) of the individual. That interactive process for monitoring the ever-changing environment is the basis for evolution. Suffice it to say that the first principles of physiology are both deterministic (negentropy and chemiosmosis) and probabilistic (homeostasis), offering choice to the organism based on both sets of principles and the “molecular memory” of the organism. Homologously, the atom is also both deterministic and probabilistic, as in the case of the Pauli exclusion principle, in which the spin of an electron is determined by three deterministic quantum numbers, and one probabilistic quantum number. So the biology is homologous with the physics, allowing it to make “protodecisions” based on both ambiguity and certainty.

20.9 Thoreau and the Transcendence of the Cell–Cell Communication Approach to Evolution Thoreau was a key member of the Transcendentalist movement that flourished during the 1820s and 1830s in New England. Indeed, he and Ralph Waldo Emerson were the leading proponents of Transcendentalism, which in turn was importantly influenced by English and German Romanticism, Kant and German Idealism, and the spiritualism and philosophy of Hinduism, particularly the ancient Sanskrit texts of the Upanishads. Correspondingly, the scientific evidence for evolution based on the causalprocessual mechanisms of cell–cell communication that we described above, is also transcendent, in view of the unicellular first principles of physiology. Leaving aside Hinduism and the Upanishads, in the Western and European tradition prior to the Romantics, Kant and the German idealists, and the New England Transcendentalists – and, as we will see below, including both the first wave of organicist philosophers of the early twentieth century and also the emerging new wave organicist movement of the twenty-first century to which we belong – only the pre-Socratic philosophers, especially Heraclitus and Anaximander, hint at transcendence. Moreover, after the rise of classical Fregean, Moorean, Russellian and early Wittgensteinian Analytic philosophy from the late nineteenth century to the early 1920s, followed by Vienna Circle-style Logical Empiricism/Positivism from the mid-1920s through the 1930s and 1940s, and especially after the rise of the scientific naturalist approaches that have dominated Anglo-American philosophy since the end of World War II, no one else has addressed transcendence in evolution, either philosophically or scientifically, until now. By “transcendence,” in general, we mean that which logical truth, logical validity, logical soundness, logical laws, mathematical truth, the power-set operation over denumerably infinite collections, non-denumerable infinity or transfinite magnitude, strict moral obligation, absolute goodness, the moral law, aesthetic perfection or the absolutely beautiful, maximality in general, necessity in general, a priori knowledge of necessary truth, acting with a good will, and a priori knowledge of moral principles, all have in common. First, they all specify the highest ends, goals, ideals, standards, and values of various different kinds of rational human activity. And second, they all specify items or notions which, if they exist, are unconditional and strictly universal. (Hanna, 2015). Furthermore, the appropriate cognitive attitude to take towards transcendence is what the early

twentieth-century British organicist philosopher, Samuel Alexander – following the British Romantic poet, William Wordsworth – calls natural piety (Alexander, 1939: 299, 310–311, and 306). How does transcendence play out in evolutionary biology? By merging ontogeny with phylogeny, the artifacts of descriptive biology can be factored out of the analysis, leaving the underlying causal-processual mechanism of cell–cell communication as the basis for life, revealing the fact of homologies with quantum mechanics, and the further fact that evolution is a vector of the Big Bang Singularity. More specifically, if we think of ontogeny as the “X axis” of a Cartesian graph, and phylogeny as the “Y axis,” then regressing ontogeny against phylogeny yields the pure essence of evolution as the flow of energy, passing through the origin of the Big Bang Singularity. In so doing, the energy generated is the formation of the cosmos, whereby life imitates non-life by complying with the “equal and opposite reaction” to the Big Bang Singularity as homeostasis, without which there would be no matter in the cosmos, only free energy. Prototypically, the causal-processual mechanism of embryogenesis, mediated by cell–cell communication, generates high-energy phosphate compounds that act as what are called “second messengers,” which dictate whether a cell will grow or differentiate. In cosmological terms, that energy path leads all the way back to the Big Bang Singularity, leading to the conclusion that the overall process enables life to remain in existence in an unstable environment, or else become extinct. Therefore, the balanced equations of physics, chemistry, and biology alike are expressions of E=mc2, the equals sign representing homeostasis, precisely because, post-Big Bang, all of existence has been in service to resolving the dualities produced by that cataclysmic explosion. Importantly, life must comply with the first principles of physiology or suffer the consequences, i.e. extinction. That is the sine qua non of life, and why we must return to the unicellular state over the course of the life cycle. Otherwise and more imagistically put, biological transcendence is our “reality check,” not unlike the Red Queen in Alice in Wonderland, running as fast as she can in order to stay in place. Here we can add in Xeno's Paradox, now reinterpreted as the fact that we must continually experiment in order to survive, and also that we will never attain David Bohm's “implicate order” (Bohm, 1980), because it is an asymptote. That is to say, we began as an ambiguity of entropies, within and outside of the cell, and we must remain in that condition in perpetuity, precisely because ambiguity is the ultimate state of biological being. We are always in flux in order to remain ahead of the curve with regard to the environment. Indeed, that is precisely how epigenetic inheritance works, giving the egg and sperm of the parent organism a “heads-up” about coming changes in the environment that have to be met by epigenetic modifications expressed in the offspring. We shall explore this “transcendental-biological” line of thinking further in the final two sections.

20.10 The First Waves of Organicist Philosophy, Organicist Science, and Organicist Modernism; and What Went Wrong Between Philosophy and Science after 1950 Fully in accordance with The Dynamic World Picture, organicist philosophy is a

liberally naturalistic and robustly pro-scientific, but also anti-mechanistic and antiscientistic conception of the world, including ourselves. Organicist philosophy is committed to the metaphysical doctrine of liberal naturalism. Liberal naturalism says that the irreducible but also non-dualistic mental properties of rational minded animals are as basic in nature as biological properties, and metaphysically continuous with them. More precisely, according to liberal naturalism, rational human free agency is an immanent structure of essentially embodied conscious, intentional, human animal mindedness; essentially embodied conscious, intentional, human animal mindness is an immanent structure of organismic life; and organismic life is an immanent structure of spatiotemporally asymmetric, nonequilibrium matter and/or energy flows. Each more complex structure is metaphysically continuous with, and embeds, all of the less complex structures. Again: human freedom is dynamically inherent in and dynamically emerges from essentially embodied conscious, intentional, human animal mindedness. And essentially embodied conscious, intentional, human animal mindedness is dynamically inherent in and dynamically emerges from organismic life. Thus human freedom is dynamically inherent in and dynamically emerges from organismic life. Moreover, organismic life is dynamically inherent in and dynamically emerges from spatiotemporally asymmetric, non-equilibrium matter and/or energy flows. Therefore, human freedom, essentially embodied conscious, intentional human animal mindness, and life are all dynamically inherent in and dynamically emerge from spatiotemporally asymmetric, non-equilibrium matter and/or energy flows. But the “inherent in” here is not a reductive “inherent in,” and the “emerges from” is not a supervenient or dualistic “emerges from.” Freedom, mind, and life are all “dynamically inherent in” and “dynamically emerge from” asymmetric matter and/or energy flows only in the same basic metaphysical sense that transfinite numbers, complex numbers, and real numbers are all non-dynamically “inherent in” and non-dynamically “emerge from” the self-same dense mathematical structural continuum that also fully embeds the progressively simpler sub-structures consisting of the rational numbers or fractions, the integers, and the natural numbers. Inside this structural continuum, the transfinite, complex, and real numbers are not Turing-computable functions of the natural numbers, integers, or rational numbers. And yet, given the existence of the natural numbers, integers, and rational numbers, necessarily the real, complex, and transfinite numbers are all potentially there, most of them existing between the rationals, integers, and naturals, holding them all together within progressively more complex forms of unity, waiting to emerge by mathematical discovery. In short, the dynamic inherence of freedom, mind, and life is nothing more and nothing less than causally efficacious immanent structural inherence; and the dynamic emergence of freedom, mind, and life is nothing more and nothing less than causally efficacious immanent structural emergence. So, just as it would be mathematically absurd to try to reduce transfinite, complex or real numbers to recursive functions of the rationals, integers or naturals, so too it would be metaphysically absurd to try to reduce freedom, mind, and life to conservationlaws-governed causal functions of inert, mechanical matter or material processes. Yet that is precisely what defenders of reductive physicalism try to do. And just as it would be mathematically absurd to think of the transfinite, complex, or real numbers as existing “over and above” the rationals, integers, or naturals; on the contrary, the number designated by “2,” for example, is a distinct position or role

inside the system of natural numbers, inside the system of positive integers, inside the system of rational numbers, inside the system of real numbers, inside the system of complex numbers, and inside the system of transfinite cardinals—so too it would be metaphysically absurd to think of freedom, conscious mind, and life as existing “over and above” asymmetric matter/energy flows. Yet this is precisely what nonreductive physicalists and ontological dualists about freedom, conscious mind and life try to do. Against that explanatory backdrop, here is a simplified diagram of the basic metaphysical continuities and structural embeddings (‘X→Y’ means “X is embedded in Y”), according to the liberal naturalist conception:freedom→mind→life→asymmetric, non-equilibrium matter/energy flows In view of liberal naturalism, to borrow an apt phrase from the later Wittgenstein's Philosophical Investigations, our rational human free agency is just our own “form of life” (Wittgenstein, 1953: 226e), and free agency, as such, grows naturally in certain minded animal species or life-forms. Correspondingly, freedom grows naturally in certain species of minded animals, including the human species, precisely because essentially embodied conscious, intentional minds like ours grow naturally in certain species of animals, including the human species. So mind is in life (Thompson, 2007). Liberal naturalism says that essentially embodied conscious, intentional rational human mindedness grows naturally in the manifestly real physical world, in organisms whose lives have an appropriately high level of non-mechanical thermodynamic complexity and self-organization. The manifestly real natural physical world necessarily includes our real possibility and is immanently structured for the dynamic emergence of lives like ours and minds like ours. Or in Thomas Nagel's apt, crisp formulation: “rational intelligibility is at the root of the natural order” (Nagel, 2012: 17). Organicist philosophy's liberal naturalism is directly opposed to the doctrine of natural mechanism. The doctrine of natural mechanism says that all the causal powers of everything whatsoever in the natural world are ultimately fixed by what can be digitally computed on a universal deterministic or indeterministic real-world Turing machine, provided that the following three plausible “causal orderliness” and “decompositionality” assumptions are all satisfied: (i) its causal powers are necessarily determined by the general deterministic or indeterministic causal natural laws, especially including the conservation laws, together with all the settled quantity-of-matter-and/or-energy facts about the past, especially including the Big Bang Singularity, (ii) the causal powers of the real-world Turing machine are held fixed under our general causal laws of nature, and (iii) the “digits” over which the real-world Turing machine computes constitute a complete denumerable set of spatiotemporally discrete physical objects. In direct opposition to natural mechanism, however, organicist philosophy's liberal naturalism says that the causal powers of biological life (and in particular, the causal powers of living organisms, including all minded animals, especially including rational human animals) are neither fixed by, identical with, nor otherwise reducible to the conservation-lawdetermined, Big-Bang-caused, real-world-Turing-computable causal powers of thermodynamic systems, whether these causal powers are governed by general deterministic laws or general probabilistic/statistical laws. So if organicist philosophy's liberal naturalism is true, then anti-mechanism is true and natural mechanism is false.

As we noted earlier in the chapter, organicist philosophy is also committed to the doctrine of what Samuel Alexander – following Wordsworth – called natural piety. According to Alexander: I do not mean by natural piety exactly what Wordsworth meant by it– the reverent joy in nature, by which he wished that his days might be bound to each other–though there is enough connection with his interpretation to justify me in using his phrase. The natural piety I am going to speak of is that of the scientific investigator, by which he accepts with loyalty the mysteries which he cannot explain in nature and has no right to try to explain. I may describe it as the habit of knowing when to stop in asking questions of nature. [T]hat organization which is alive is not merely physico-chemical, though completely resoluble into such terms, but has the new quality of life. No appeal is needed, so far as I can see, to a vital force or even an élan vital. It is enough to note the emergence of the quality, and try to describe what is involved in its conditions…. The living body is also physical and chemical. It surrenders no claim to be considered a part of the physical world. But the new quality of life is neither chemical nor mechanical, but something new. We may and must observe with care out of what previous conditions these new creations arise. We cannot tell why they should assume these qualities. We can but accept them as we find them, and this acceptance is natural piety (Alexander, 1939: 299, 310–311, and 306) According to natural piety, neither are you alienated from nature (a Cartesian ghost-in-a-machine), nor are you a “lord and master” of nature (a Baconian/Cartesian technocrat). To believe both of these at once was Victor Frankenstein's tragic mistake, repeated endlessly and magnified infinitely in the deeply misguided epistemic and metaphysical doctrines, and scientistic-technocratic ideology, of natural mechanism: Learn from me, if not by my precepts, at least by my example, how dangerous is the acquirement of [naturally mechanistic] knowledge, and how much happier that man is who believes his native town to be the world, than he who aspires to become greater than his nature will allow. (Shelley, 1818: vol. 1, ch. 3) As we have noted above, against the metaphysical backdrop of The Dynamic World Picture, organicist philosophy and its liberal naturalism fully conform to contemporary biology-oriented physics, and in particular to non-equilibrium thermodynamics, under the non-deterministic interpretation of it offered by Prigogine, who also wrote this sharp criticism of natural mechanism: The attempt to understand nature remains one of the basic objectives of Western thought. It should not, however, be identified with the idea of control. The master who believes he understands his slaves because they obey his orders would be blind. When we turn to physics, our expectations are obviously different, but here as well, Vladimir Nabokov's conviction rings true: “What can be controlled is

never completely real; what is real can never be completely controlled.” The [natural mechanist] classical ideal of science, a world without time, memory, and history, recalls the totalitarian nightmares described by Aldous Huxley, Milan Kundera, and George Orwell. (Prigogine, 1997: 153–154) Correspondingly, against the metaphysical backdrop of The Dynamic World Picture, organicist philosophy and its liberal naturalism fully conform to the Big Bang Singularity – organismic life – conscious, intentional mind continuity we have described above, and also to other contemporary processual approaches to biology (Nicholson and Dupré, 2018), chemistry, and the cognitive neurosciences, insofar as these are all construed in terms of the non-deterministic interpretation of nonequilibrium thermodynamics and liberal naturalism. In other words, organicist philosophy and its liberal naturalism take formal and natural science fully seriously too. More specifically, it is not scientifically unserious to be a organicist philosopher and a liberal naturalist and hold that non-equilibrium thermodynamics, comprehending not only biology-oriented physics but also and above all the Big Bang Singularity – organismic life – conscious, intentional mind continuity, as well as other processual approaches to biology, chemistry and finally, cognitive neuroscience, are all anti-mechanistic. Why must all the basic sciences be interpreted in accordance with natural mechanism? After all, Church and Turing show us that logical truth in every system at least as rich as classical first-order polyadic quantified predicate logic with identity, aka “elementary logic,” cannot be determined by Turing-computable algorithms, and therefore cannot be naturally mechanized; and Gödel's incompleteness theorems show us that truth in every mathematical system at least as rich as Peano arithmetic cannot be determined by formal proof or Turingcomputable algorithms and therefore also cannot be naturally mechanized (Boolos and Jeffrey, 1989). Yet no one regards elementary logic and Peano arithmetic as less than seriously scientific. If formal piety about logic and mathematics is intelligible and defensible, as it surely is, then by the same token, so too is natural piety about physics, biology, chemistry and cognitive neuroscience. So if one can be fully serious about logic and mathematics without holding natural mechanism about them, then one can be fully serious about physics, biology, chemistry and cognitive neuroscience without holding that natural mechanism is true about them, since all of the natural sciences presuppose logic and mathematics. In particular, if The Dynamic World Picture, together with the non-deterministic interpretation of non-equilibrium thermodynamics, together with our conception of the Big Bang Singularity – organismic life – conscious, intentional mind continuity, together with Church's and Turing's discoveries about logic, together with Gödel's incompleteness theorems, are all true, then natural mechanism is false even about physics and yet we can still be fully serious about logic, mathematics and biology-oriented physics. Organicist philosophy and its liberal naturalism, together with the doctrines of formal piety and natural piety, clearly collectively meet this theoretical high standard of formal and natural scientific full seriousness. At the turn of the twentieth century, in the work of Charles Sanders Peirce and Henri Bergson, and then in the 1920s and early 1930s, in direct reaction to the cataclysmic devastation of World War I, there was in fact a short-lived first wave of organicist philosophy. We can find this directly expressed, for example, in Henri Bergson's Creative Evolution in 1907, in Samuel Alexander's Space, Time, and

Deity in 1920, in John Dewey's Experience and Nature in 1925, and in A. N. Whitehead's “philosophy of organism” in Process and Reality, originally published in 1929 (Whitehead, 1978). At roughly the same time, organicist philosophy was also integrated with and paralleled by what we will call organicist modernism in the applied and fine arts, especially including the architecture of Frank Lloyd Wright and the other members of the Prairie School, the “golden period of Scandinavian design” in Norway, Sweden, Denmark, Finland and Iceland, and the poetry of Robert Frost and Wallace Stevens. Organicist modernism, in turn, flowed naturally from the Arts and Crafts Movement: The Arts and Crafts movement was an international trend in the decorative and fine arts that began in Britain and flourished in Europe and North America between about 1880 and 1920, emerging in Japan in the 1920s as the Mingei movement. It stood for traditional craftsmanship using simple forms, and often used medieval, romantic, or folk styles of decoration. It advocated economic and social reform and was essentially anti-industrial. It had a strong influence on the arts in Europe until it was displaced by [High] Modernism in the 1930s, and its influence continued among craft makers, designers, and town planners long afterwards. The term was first used by T. J. Cobden-Sanderson at a meeting of the Arts and Crafts Exhibition Society in 1887, although the principles and style on which it was based had been developing in England for at least 20 years. It was inspired by the ideas of architect Augustus Pugin, writer John Ruskin, and designer William Morris. The movement developed earliest and most fully in the British Isles and spread across the British Empire and to the rest of Europe and America. It was largely a reaction against the perceived impoverishment of the decorative arts at the time and the conditions in which they were produced. (Wikipedia, 2020a) As a paradigmatic example of the Arts and Crafts movement, consider Figure 20.4.

Figure 20.4

William Morris's 1862 “Design for Trellis Wallpaper.”

Also, at roughly the same time, there were also several closely related and intellectually integrated important dynamicist-organicist conceptual developments in biology/ethology, the formal sciences, and physics, including C. Lloyd Morgan's Emergent Evolution in 1923, and, in 1944, Erwin Schrödinger's pioneering work on quantum mechanics and the nature of biological life, What is Life? The Physical Aspect of the Living Cell. Schrödinger's book initiated non-equilibrium thermodynamics and complex systems dynamics, as developed by Prigogine and J.D. Bernal in the second half of the twentieth century, and alongside this in the 1970s and 1980s, the autopoietic approach to organismic biology worked out by Francisco Varela and Humberto Maturana. But except for some suggestive remarks in Wittgenstein's (1953)Philosophical Investigations about “forms of life,” Hans Jonas's Phenomenon of Life in the mid1960s (Jonas, 1966), and the short-lived Process Philosophy movement in the USA in the late 1960s and early 1970s, the first wave of organicist philosophy simply crashed onto the barren, rocky shores of twentieth-century classical and postclassical Analytic philosophy (Hanna, 2020),§ and was destroyed.

What accounts for the fifteen-year gap between Whitehead's Process and Reality in 1929 and Schrödinger's What is Life in 1944? More generally, what ultimately destroyed the first wave of organicist philosophy and its elective affinity and holy alliance with organicist modernism, and with organicist formal and natural science? And most generally of all, what deeply and even tragically wrong thing happened between philosophy and science after 1950? The answer, we think, is three-part. First, there was the coming-to-power of the devilishly malevolent, totalitarian, imperialist Nazis in Germany in the 1930s, along with the rise of other forms of totalitarian, imperialist fascism in Japan and Italy, integrated with and paralleled by organic nationalism, aka organic romanticism in the applied and fine arts (Wikipedia, 2020b), e.g. Nazi visual art and architecture (Figure 20.5):

Figure 20.5

Haus der Deutschen Kunst (Munich), designed by Paul Ludwig (1933–1937). Reproduced from https://commons.wikimedia.org/wiki/File:Haus_der_deutschen_Kunst_1939.jpg, under the terms of the CC BY-SA 4.0 license, https://creativecommons.org/licenses/by-sa/4.0.

It is exceptionally easy to see how diametrically opposed in form, content and

spirit organicist modernism on the one hand, and organic nationalism/romanticism on the other, were and are, just by comparing and contrasting Ludwig's Haus der Deutschen Kunst and Frank Lloyd Wright's “Fallingwater” (Figure 20.6):

Figure 20.6

“Fallingwater,” designed by Frank Lloyd Wright in 1935 (Hoffman, 1993). Reproduced from https://commons.wikimedia.org/wiki/File:Fallingwater3.jpg under the terms of the CC0 1.0 Universal license, https://creativecommons.org/publicdomain/zero/1.0/deed.en.

Second, there was the second global cataclysm of World War II, then post-war Stalinist Russian communist totalitarian imperialism in Eastern Europe, and the Cold War. And third and finally, during the era of the Anthropocene since the end of World War II, especially including the early Cold War period during the 1950s, but also accelerating since the fall of the Berlin Wall in the 1980s, and now at the end of the second decade of the twenty-first century, there have been two highly unfortunate sociocultural and political developments, acting and interacting together like an apocalyptic one-two punch. On the one hand, there is what the political anthropologist James C. Scott, in his brilliant and highly influential 1998 book, Seeing Like a State, has called “the logic behind the failures of some of the great utopian social engineering schemes of the twentieth century”: I aim [in Seeing Like a State] to provide a convincing account of the logic behind the failure of some of the great utopian social engineering schemes of the twentieth century. I shall argue that the most tragic episodes of state-initiated social engineering originate in a pernicious combination of four elements. All four are necessary for a full-fledged disaster. The first element is the administrative ordering of nature and society—the transformative

state simplifications described above [which Scott calls “state maps of legibility,” according to which state “officials took exceptionally complex, illegible, and local social practices, such as land tenure customs or naming customs, and created a standard grid whereby it could be centrally recorded and monitored.”] …. By themselves, they are the unremarkable tools of modern statecraft; they are as vital to the maintenance of our welfare and freedom as they are to the designs of a would-be modern despot…. The second element is what I call a high-modernist ideology. It is best conceived as a strong, one might even say muscle-bound, version of the self-confidence about scientific and technical progress, the expansion of production, the growing satisfaction of human needs, the mastery of nature (including human nature), and, above all, the rational design of social order commensurate with the scientific understanding of natural laws. Only when these two elements are joined to a third does the combination become potentially lethal. The third element is an authoritarian state that is willing to use the fully weight of its coercive power to bring these high-modernist ideas into being. A fourth element is closely linked to the third: a prostrate civil society that lacks the capacity to resist these plans. In sum, the legibility of a society provides the capacity for large-scale social engineering, high modernist ideology provides the desire, the authoritarian state provides the determination to act on that desire, and an incapacitated civil society provides the leveled social terrain on which to build. (Scott, 1998: 2–5) And on the other hand, there has been what Arran Gare accurately calls an advancing “crisis” of “ecological civilization” (Gare, 2017), especially including actually and potentially disastrous global climate change.

20.11 The Second Waves of Organicist Philosophy, Organicist Science, and Organicist Modernism If we are correct, however, then in a direct reaction to the devastations of “the most tragic episodes of state-initiated social engineering” and the crisis of ecological civilization, we are now in the earliest stages of the second wave of organicist philosophy, which will finally bring to completion what the most brilliant and radical philosophy, formal and natural sciences, and applied and fine arts of the early twentieth century started, before fascism, World War II, the Cold War, stateinitiated social engineering, and the crisis of ecological civilization all so violently intervened. As we noted earlier in the chapter, contemporary British philosopher Helen Steward has remarked that [t]he task [of understanding free will and agency] requires some reflection on the organizational principles of living creatures, for it is only through such reflection … that we can start to understand where the difference really lies between, on the one hand those things that are true agents, and, on the other, mere machines, entities that nothing will ever be up to, however impressive they may be…. I am

exceedingly hopeful that the next few years will see the beginnings of a evolution in our conception of the human person, as philosophical and everyday conceptions of the scientific picture of the world are freed from outdated Newtonian ideas and begin to take more note, both of the complexities of science as it really is and of the undeniable fact of our animal nature. (Steward, 2012: 198–199, underlining added) Indeed, along with Steward, we believe that we are at the beginning of an organicist revolution in contemporary philosophy, formal and natural science, and the applied and fine arts, that is fully comparable to Kant's eighteenth-century heliocentric “Copernican Revolution” in philosophy. Kant's Copernican Revolution says that in order to explain rational human cognition and authentic a priori knowledge, we must hold that necessarily, the manifestly real world structurally conforms to our minds, rather than the converse. The organicist revolution, in turn, says that the real possibility of human consciousness, cognition, caring, rationality, and free agency, and therefore also the “Copernican” necessary structural conformity of world-to-mind, provided that we actually do exist, is built essentially into The Dynamic World Picture and the non-equilibrium thermodynamics of organismic life, and necessarily underdetermined by any and all naturallymechanical processes and facts. Hence the organicist revolution in philosophy, science, and the arts that is implied by liberal naturalism and natural piety not only includes Kant's Copernican Revolution, but also goes one full revolutionary cycle beyond it. Since the seventeenth century, philosophical revolutions have happened roughly every one hundred years, and each revolution takes roughly twenty years to unfold: (i) the late-seventeenth- and early eighteenth-century anti-Scholastic Rationalist revolution – Descartes, Spinoza and Leibniz, but also including Newtonian scientific mechanism, followed by an Empiricist reaction; (ii) the late-eighteenthand early nineteenth-century anti-Rationalist, anti-Empiricist Kantian Copernican Revolution and absolute idealism – Kant, Fichte, Schelling, and Hegel, followed by an anti-Hegelian reaction, including Kierkegaard and neo-Kantianism, then by Brentano, Husserl, Heidegger, Sartre, Merleau-Ponty and phenomenology (especially existential phenomenology) more generally, (iii) the late-nineteenth- and early twentieth-century anti-idealist Analytic philosophy revolution – Frege, Russell, Moore, and early Wittgenstein, followed by Vienna Circle Logical Empiricism/Positivism, then by Quinean and Sellarsian scientific naturalism, alongside the later Wittgenstein's work and ordinary language philosophy, then by Strawsonian conceptual analysis, direct reference theory and scientific essentialism, and currently, Analytic metaphysics (Hanna, 2020). Now it has been almost exactly 100 years since the neo-Kantian tradition went down into the ash-heap of history and was superseded by classical Analytic philosophy, in the late 1920s and 1930s. So if the historical pattern persists, then we are actually at the beginning of another philosophical revolution, over the next twenty years, and fully into the heart of the twentieth century, although it may be difficult to see its precise shape simply because we do not have the benefit of historical hindsight or an adequate emotional and reflective distance from actual historical processes, and because we are naturally distracted by our own everyday affairs, domestic politics, and global crises such as the COVID-19 pandemic. Moreover, if we are also correct, then, fully integrated with and paralleling The

Dynamic World Picture, organicist philosophy, and organicist formal and natural science, we are also in the earliest stages of the second wave of organicist modernism in the applied and fine arts.

20.12 Conclusion The works of Plato, Whyte (1949), Morowitz (2004) and Capra (2016), redirected our thinking about nature by attempting to account for all that we see, from rocks to life, from flora to fauna, into a single consistent system. Indeed, all throughout human history, many have encouraged that we think in this manner, for example, by equating mass and energy, or by merging all knowledge as Consilience (Wilson, 1998). Yet the great polymath Polanyi (1968), and the physicist Prigogine (1984) both concluded that the relationship between physics and biology is too complicated to be easily encompassed. The truth lies elsewhere. In the past, when scientists have been confronted with the complexities of science, some have defaulted to mysticism and metaphysics. But the key to the scientific approach is arrestingly different. For example, Mendeleev configured his version of the periodic table by identifying atomic number as the “lowest common denominator.” Others had attempted this feat, but failed to imagine the organizing principle behind the elements. By analogy, in a review article on the cellular-molecular perspective on evolution (Torday and Miller, 2016a), it was proposed that there are homologies between the atom and the cell that provide a unifying common denominator. In this way, the unicell communicates with its surroundings, both inanimate and animate, (Torday and Miller, 2016c), fulfilling the vision of the “One” seen by the Greek Atomists such as Heraclitus and Anaximander. The power of this concept lies in its empirical foundations (Torday and Rehan, 2012; Torday and Rehan, 2017), offering a new formal and natural scientific means of exploiting the information explosion occurring all around us. We began this chapter with Wilfrid Sellars's profoundly difficult Two Images Problem: “how is it possible to reconcile, on the one hand, the objective, nonphenomenal, perspectiveless, mechanistic, value-neutral, impersonal, and amoral metaphysical picture of the world and ourselves that delivered by pure mathematics and the fundamental natural sciences (the scientific image), and, on the other, the subjective, phenomenal, perspectival, teleological, value-laden, person-oriented, and moral metaphysical picture of the world and ourselves that is yielded by the conscious experience of rational human beings (the manifest image)?” and with the self-stultifying contradictions of scientific naturalism. In order to avoid these contradictions, we engaged in a systematic re-thinking of our concept of nature, from the Big Bang Singularity forward, to organismic life, and then to conscious mind, including both the mind-body relation and free agency, all of which are fully embedded inside The Dynamic World Picture. In so doing, we have provided what we believe is a new Kuhnian paradigm, new wave organicism, that is also a grand synthesis of philosophy, the formal and natural sciences, and the applied and fine arts, thereby fully satisfying Thoreau's Dictum, which we will now, with transformative zeal, reiterate by way of conclusion: When one man has reduced a fact of the imagination to be a fact to his understanding, I foresee that all men will at length establish their lives on that basis.

Acknowledgements Robert Hanna, Director of The Contemporary Kantian Philosophy Project, coauthored this Chapter.

References

Akehurst T., The Nazi Tradition: The Analytic Critique of Continental Philosophy in Mid-Century Britain, History Eur. Ideas,2008, 34, 548–557. Alexander S., (1939, ), Natural Piety, in Alexander S., Philosophical and Literary Pieces, London: Macmillan. Bennett A. F. and Ruben J. A., Endothermy and activity in vertebrates, Science, 1979, 206, 649–654. Birk J. B., (1962, ), Rutherford at Manchester, London: Heywood. Bohm D., (1980, ), Wholeness and the Implicate Order, London: Routledge & Kegan Paul. Boolos G. and Jeffrey R., (1989, ), Computability and Logic, Cambridge: Cambridge University Press. Capra F., (2016, ), The Systems View of Life: A Unifying Vision, Cambridge: Cambridge Univiversity Press. Chalmers D., (1996, ), The Conscious Mind, Oxford: Oxford University Press. Clark A. and Chalmers D., The Extended Mind, Analysis, 1998, 58, 7–19. Dobzhansky T., Nothing in Biology Makes Sense except in the Light of Evolution, Am. Biol. Teach., 1973, 35, 125–129. Edwards L. E., What is the Anthropocene?, Eos, 2015, 96. Galison P., (1997, ), Image and Logic: A Material Culture of Microphysics, Chicago: University of Chicago Press. Gare A., (2017, ), Philosophical Foundations of Ecological Civilization: A Manifesto for the Future, London: Routledge. Godfrey-Smith P., (1996, ), Complexity and the Function of Mind in Nature, Cambridge: Cambridge University Press. Haken H., (1996, ), Principles of Brain Functioning: A Synergetic Approach to Brain Activity, Behavior, Berlin: Springer. Hall B. K., Evo-Devo: evolutionary developmental mechanisms, Int. J. Dev. Biol., 2003, 47, 491–495. Hanna R., Minding the Body, Philos. Top., 2011, 39(2011), 15–40. Hanna R., (2018, ), Deep Freedom and Real Persons: A Study in Metaphysics, New York: Nova Science. Hanna R., (2020), The Fate of Analysis: Analytic Philosophy from Frege to the Ash-Heap of History, Available online at URL https://www.academia.edu/41899807/The_Fate_of_Analysis_Analytic_Philosophy_From_F Heap_of_History_2020_version_. Hanna R. and Maiese M., (2009, ), Embodied Minds in Action, Oxford: Oxford University Press. Hoffmann D., (1993, ), Frank Lloyd Wright's Fallingwater: The House and Its History, New York: Dover Publications. Isaacson W., (2007, ), Einstein: His Life and Universe, New York: Simon and Schuster. Jantsch E., (1980, ), The Self-Organizing Universe: Scientific and Human

Implications of the Emerging Paradigm of Evolution, New York: Pergamon. Jonas H., (1966, ), The Phenomenon of Life: Toward a Philosophical Biology, Chicago: University of Chicago Press. Kauffman S., (1993, ), The Origins of Order: Self-Organization and Selection in Evolution, Oxford: Oxford University Press. Kauffman S., (1995, ), At Home in the Universe: The Search for the Laws of SelfOrganization and Complexity, Oxford: Oxford University Press. Kim J., (1993, ), The Non-Reductivist's Troubles with Mental Causation, in J. Kim, Supervenience and Mind, Cambridge: Cambridge University Press. Kuhn T., (1962, ), The Structure of Scientific Revolutions, Chicago: University of Chicago Press. Mabaquiao N., (2011, ), The Death of Philosophy Through the Naturalization of the Mind. Available online at URL https://www.academia.edu/21801066/The_Death_of_Philosophy_Through_the_Naturalizatio McDowell J., (1994, ), Mind and World, Cambridge: Harvard University Press. Morowitz H., (2004, ), The Emergence of Everything, Oxford: Oxford University Press. Nagel T., (2012, ), Mind and Cosmos, Oxford: Oxford University Press. Nicholson D. J., The Concept of Mechanism in Biology, Stud. Hist. Philos. Biol. Biomed. Sci., 2012, 43, 1521–1563. Nicholson D. J. and Dupré J., (2018, ), Everything Flows: Towards a Processual Philosophy of Biology, Oxford: Oxford University Press. Nicolis G. and Prigogine I., (1977, ), Self-Organization in Nonequilibrium Systems, New York: Wiley. Polanyi M., Life's irreducible structure. Live mechanisms and information in DNA are boundary conditions with a sequence of boundaries above them, Science, 1968, 60, 1308–1312. Prigogine I., (1997, ), The End of Certainty, New York: The Free Press. Proust M., (1982, ), Remembrance of Things Past, New York: Vintage. Putnam H., (1990, ), Realism with a Human Face, Cambridge : Harvard University Press. Putnam H., (1994, ), Words and Life, Harvard University Press, Cambridge. Putnam H., (1999, ), The Threefold Cord: Mind, Body, and World., New York.: Columbia University Press. Reichenbach H., (1951, ), The Rise of Scientific Philosophy, University of California Press, Berkeley. Royce J., (1970, ), The Letters of Josiah Royce, Chicago: University of Chicago Press. Schrödinger E., (1944, ), What is Life?, Cambridge : Cambridge University Press. Scott J. C., (1998, ), Seeing Like a State: How Certain Schemes to Improve the Human Condition Have Failed, New Haven: Yale University Press. Sellars W., (1963a, ), Philosophy and the Scientific Image of Man, in W. Sellars, Science, Perception, and Reality, London: Routledge & Kegan Paul. Sellars W., (1963b, ), Empiricism and the Philosophy of Mind, in W. Sellars, Science, Perception, and Reality, London: Routledge & Kegan Paul. Shelley M., (1818, ), Frankenstein; Or, the Modern Prometheus, 1818 edn, Available online at URL http://www.rc.umd.edu/editions/frankenstein. Slack J., Establishment of spatial pattern, Wiley Interdiscip. Rev. Dev. Biol., 2014, 3(6), 379–388. Smocovitis V. B., (1996, ), Unifying Biology, Princeton: Princeton University

Press. Steffen W., Grinevald J., Crutzen P. and McNeill J., The Anthropocene: Conceptual and Historical Perspectives, Philos. Trans. R. Soc., A., 2011, 369, 843. Steward H., (2012, ), A Metaphysics for Freedom, Oxford: Oxford University Press. Thompson E., (2007, ), Mind in Life, Cambridge: Harvard University Press. Thoreau H. D., (1960, ), Walden, in Thoreau H. D., Walden and Civil Disobedience Houghton-Mifflin, Boston. Torday J. S., A central theory of biology, Med. Hypotheses, 2015a, 85, 49–57. Torday J. S., Pleiotropy as the Mechanism for Evolving Novelty: Same Signal, Different Result, Biology, 2015b, 4, 443–459. Torday J. S., The cell as the mechanistic basis for evolution, Wiley Interdiscip. Rev.: Syst. Biol. Med., 2015c, 7, 275–284. Torday J. S., Life Is Simple—Biologic Complexity Is an Epiphenomenon, Biology, 2016, 5(2), 17. Torday J. S. and Miller W. B., The Unicellular State as a Point Source in a Quantum Biological System, Biology, 2016a, 5(2), 25. Torday J. S. and Miller W. B., Phenotype as Agent for Epigenetic Inheritance, Biology, 2016b, 5(3), 30. Torday J. S. and Miller W. B., On the Evolution of the Mammalian Brain, Front. Syst. Neurosci., 2016c, 10, 31. Torday J. S. and Rehan V. K., Developmental cell/molecular biologic approach to the etiology and treatment of bronchopulmonary dysplasia, Pediatr. Res., 2007, 62, 2–7. Torday J. S. and Rehan V. K., (2012, ), Evolutionary Biology: Cell–Cell Communication, and Complex Disease, Hoboken: Wiley. Torday J. S. and Rehan V. K., (2017, ), Evolution, the Logic of Biology, London: Wiley. Varela F. G., (1979, ), Principles of Biological Autonomy, New York: Elsevier/North Holland. Vrahimis A., (2019, ), Russell Reads Bergson, In M. Sinclair and Y. Wolf, (eds.), The Bergsonian Mind, Oxon: Routledge (forthcoming). Weber A. and Varela F. G., Life After Kant: Natural Purposes and the Autopoietic Foundations of Biological Individuality, Phenomenol. Cognit. Sci., 2002, 1, 97–125. Weber B., (2018, ), Life. The Stanford Encyclopedia of Philosophy, (Summer 2018 edn). Available online at URL https://plato.stanford.edu/archives/sum2018/entries/life/. Whitehead A. N., (1920, ), The Concept of Nature, Cambridge: Cambridge University Press. Whitehead A. N., (1978, ), Process and Reality: An Essay in Cosmology, New York: The Free Press. Whyte L. L., (1949, ), The Unitary Principle in Physics and Biology, London: Cresset Press. Wikipedia, (2020a, ), Arts and Crafts Movement, Available online at URL https://en.wikipedia.org/wiki/Arts_and_Crafts_movement. Wikipedia, (2020b, ), Romantic Nationalism, Available online at URL https://en.wikipedia.org/wiki/Romantic_nationalism. Wilson E. O., (1998, ), Consilience: the Unity of Knowledge, New York: Vintage.

Wilson M., (1995, ), The Invisible World: Early Modern Philosophy and the Invention of the Microscope, Princeton: Princeton University Press. Wittgenstein L., (1953, ), Philosophical Investigations, trans. G. E. M. Anscombe, New York: Macmillan. Wittgenstein L., (1981, ), Tractatus Logico-Philosophicus, trans. C. K. Ogden, London: Routledge & Kegan Paul.

† It should be especially noted that natural libertarianism does not have anything to do with

political Libertarianism, which is a combination of psychological egoism, ethical egoism, and neoliberalism. Natural Libertarianism is a metaphysical doctrine, not a political doctrine. ‡ Notice that we are not saying that it is impossible to design and build a natural machine that,

when it is turned on, makes various motions that might fool someone, or even many people, into believing that it was me or you doing The Freedom Dance. It is logically, really, naturally, and perhaps even technologically possible that there is such a machine. On the contrary, what we are saying is that, necessarily, the deceptive naturally mechanical motions of such a natural mechanism could not be The Freedom Dance, since that and only that was actually freely performed by one of the authors of this essay, or for that matter by you, the reader, and not by any natural machine that was designed and built to resemble us in various ways. § Bertrand Russell's highly influential, but also highly polemical critique of Bergson, is a

paradigm case of this (Akehurst, 2008; Vrahimis, 2019).

CHAPTER 21

Conclusion: The Singularity Unites the Cosmos This volume has offered a substantial number of novel concepts that summate into an unorthodox and paradigmatic alternative world-view. In contending against previously entrenched beliefs, considerable detail was necessary. Nevertheless, all of these in-depth arguments can be reduced to a few salient and direct particulars that can reasonably circumscribe the entire breadth of our analysis. The ground state premise is that all the physical rules of the universe were established at the Singularity. This is not controversial. Based on convincing scientific measurement, modern cosmology instructs that everything began with the Singularity/Big Bang. From that inaugural moment on, all relationships between energy and matter must be sustained by cohering universal forces. It follows that all the basic principles that enable cosmic physical processes, from atomic bonds to all aspects of complex biology, must remain similarly adherent to those same rules. Necessarily too, everything that can be observed or analyzed, including our consciousness and subjective states, are inescapably derivative of that same beginning. It follows then that the remaining cardinal issues that require explanation are a specification of those pathways that have permitted us, as sentient humans with our own proclivities, to arise and experience the universe as we do. The answers that we have offered, if not obvious, are all the result of a series of defensible assertions about the exact nature of those connections that link the realm of the inanimate to our own living circumstances. There are only a few cardinal tenets that guide all life on this planet. The foremost requirement of the living state is the ability to sustain an orderly internal condition compared with an outward environmental context. This is the negentropic state, which circumvents the second law of thermodynamics and permits life. That privileged status is maintained by the flow of ions and nutrients as chemiosmosis across a vital semi-permeable membrane. The maintenance of negentropy through chemiosmotic action is the dynamic of homeostasis. Together, these foundational relationships form the first principles of physiology (negentropy, chemiosmosis, homeostasis). This vital triad underpins all living things and sustains the elemental cognition that is epitomized within the cellular form. Since everything in the universe began with the Singularity and all thermodynamic and quantum mechanical principles must necessarily issue forward from it, then each of these living principles must conform to these foundational physical forces. A further essential of the living state is that it is conditioned within ambiguity. All the information that any cell or organism can access is equivocal. This is true across the living scale, and explains the pre-eminence of multicellularity on the planet. Multicellularity is an enactment of the “wisdom of crowds” in the pursuit of the most valid information upon which cells can depend to meet environmental

stresses. Crucially, this can only express through cell–cell communication. It follows that all biology and evolution exist within the context of the varied potentials and limits of cell–cell communication. In our living circumstance, however, that cell–cell communication must also proceed within rules and constitutive patterns. Once the basic cell was fully established as the first niche construction, universal patterns of resonances, reiterations, and reciprocations spilled forward over evolutionary space-time. These specific living motifs, founded within basic thermodynamic and quantum principles, materialize further through cell–cell communication as the fundamental cellular qualities of cooperation, collaboration, co-dependence and competition. It is these further sub-patterns that permit multicellular biological materialism to enable concordant multicellular life, either as biofilms or holobionts. Through this limited palette of prime principles and recurring patterns, developmental physiology springs from isolated unicells to become interdependent multicellular life in successive fractal reiterations. It is precisely within these elemental linkages that the pathway from the initiating conditions of the Singularity extends across the life cycles of all organisms. Within this simple architectural base, the remaining integral guideposts of biology can now be identified. First among these is that life can be defined by selfreferential cognition. Beginning with the unicellular form, biological action was directed to the protection of self-identity, expressed as homeostatic equipoise versus an agitating environment. Importantly though, homeostasis is not a static state. It is a dynamical process that separates life from non-life that can only be successful by the active internalization of environmental stresses through continuous endogenization and endosymbiosis to cope with imprecise environmental cues. This is cognitive action, and its continuous enactment through cell–cell communication forms the basic thrust of evolution. To attain any consistent state of environmental complementarity over generations, cells must manipulate epigenetic acquisitions. From this living requirement, the purpose of phenotype clarifies. The phenotypes of organisms serve as the agency by which organisms accumulate epigenetic experiences to be returned to the primary unicellular zygote, to be sorted for continued living relevance. It follows from this that genes are tools of cells, serving as a codification of those primary patterns of cell–cell communication and protein deployment that enable biological and evolutionary development. Through mediating epigenetic experiences, only some of which will become further transmitted through vertical inheritance, cells accommodate the requisite assimilation of environmental factors that might otherwise pose an existential threat. Iteration after iteration, this becomes our own complex physiology. From within these principles, the evolutionary pathways of more complex life can be properly deconstructed from modern physiology. For instance, the waterland transition stimulated key genetic duplications molding the integral elements of the hypothalamic-pituitary-adrenal axis by increasing catecholamine production.This was directly related to the appearance of parathyroid hormonerelated protein (PTHrP) signaling in the anterior pituitary, which amplified adrenocorticotropic hormone (ACTH), synergizing with PTHrP signaling in the adrenal cortex. The resultant amplification of cortisol production reciprocally accelerated catecholamine production by the adrenal medulla. Since everything connects in the living state, the buttressing of the hypothalamic-pituitary-adrenal axis relieved the physiologic constraint for oxygenation by the lung alveoli. The result was an increase in lung surfactant production, which is critical to alveolar

distention. That alveolar expansion increased oxygenation, which crucially linked to a catecholamine-induced reduction in the thickness of cell membranes in support of cell–cell communication. It is through these types of deeply inter-linked pathways that our own layered physiology builds. Since everything emanates from the Singularity, our living narrative on this planet must proceed along subjoining quantum pathways that originated at that moment. Through this necessary conjuncture, biology reconciles with chemistry and physics. Many quantum phenomena have homologies with biological properties. These include the Pauli exclusion principle, the Heisenberg uncertainty principle, quantum entanglement, coherence, criticalities and symmetries. All are central to quantum mechanics and directly impact all of thermodynamics. Thus, it is no longer surprising that these same phenomena have their own distinct biological counterparts. Even the contention that there really is no arrow of time in physics, which seems to definitively divide the physical cosmological world from the living realm, can be reconciled. When the unicellular stage is considered the veritable “point” of evolution and, further, that this unicellular state is perpetual over billions of years, then time, as generally assessed, cancels. The arrow of time in biology as judged by the fossil record, genetic phylogeny or molecular clocks all become a categorical list of epiphenomena that merely reference the eternal unicellular form that has perpetuated over billions of years. As a result, biology can be seen to conform with the revolutionary concepts of the great twentieth-century physicists such as Feynman and Einstein. From this, our physiology and metabolism can now be better understood as the aggregated and concordant actions of individual cells. Viewing biology within this frame answers some of our most enduring biological questions. Physiological variabilities are the consistent interplay among cells based within reciprocations, resonances, and coherences that permit seamless cooperation, collaboration and mutualized competition. Disease directs to failures in cell–cell communication, leading to deteriorating coordinate action and skewed interpretations of vital homeostatic information at various interconnected levels. Some drift can be tolerated and amended, but only up to a limit. When a threshold is reached, the collective slide in cellular communication and homeostasis triggers a critical cascade. As an important principle, at all levels in biology, consciousness is the animate nexus. Although the centrality of cognition to life is now widely acknowledged, the origin of that consciousness remains a mystery. There are good reasons to conjecture that consciousness in its most prototypical form was instantiated within the Singularity along with matter, energy and space. Yet, even if not originating within the Singularity, its manifestations at every scope and scale must still appertain to its influences. Thus, it can be properly defended that those basic physical principles, which are entrained within the basic cellular architecture and form the dynamical basis of cell–cell communication must heavily bear on our idiosyncratic form of consciousness. Consequently, our human brand of cognitive self-awareness is the summation of all of our aggregated cells, and a function of our corporate physiology. Thus, it is no longer puzzling why humans suffer profoundly in isolation. Human behavior is necessarily rooted within cellular predilections. All of what we experience and do has its roots within the foundational principles of cellular life as inter-linked cooperation, collaboration, co-dependence and competition. When any of these essentials is expunged through circumstances, its loss is intensely felt. It naturally follows that other human behaviors also originate

from within basic thermodynamic and quantum proscriptions and collectively express through cellular pathways. Even free will and morality, which are generally regarded as exclusively human, can only be understood from within a cellular purview. Free will and morality can both be seen as exaptations of basic physical and cellular biological principles, all of which can be traced to the Singularity. It follows that our codified moral laws, whether or not they arise though theological belief, represent our fully human attempt to constrain our actions within cellular perquisites in consonant adherence to fundamental physical laws established from a grounding instantiation. By the same token, all of these same impulses are brought into our human engineering, which grant us such planetary privilege, and shape our economic actions. In economics, politics, cultural architectures or social advocacy, we act to preserve our self-integrity through mutualized associations. We trade resources, negotiate, cooperate and compete, sacrifice and dissemble. All of these are cellular attributes that we engage at our level, and direct towards our own purposes. At all times, we and all other living creatures conduct these activities, enfolded in living uncertainty and perpetual ambivalences. For all living things, phenomena of all types are local and non-local environmental cues that present as superimpositions of possibilities. Paradoxically, it is through these uncertainties, enacted from sub-system to system to super-system, from which an “unbroken wholeness to the entire universe” emerges. Level to level, superimposed possibilities as universal ambiguities link as overlapping “implicates.” Upon reaching some critical stage, these resolve as “explicates,” either as inanimate material form, or as biological expression. This process of resolution between the implicate and explicate realms may be considered to represent a universal consciousness, instantiated within the Singularity, and existing as relational universal “sense-awareness.” And in this way, all life extends across quantum space-time as an experiential and relational continuum, extending directly forward from the inanimate in a seamless arc from the Singularity. If so, this would represent the ultimate reconciliation of physics and chemistry with biology. Rooted within fundamental and universal quantum properties, all emanates forward as a timeless transfer of fundamental universal sense-awareness from the Singularity In the living state, sense-awareness serves a single perpetual planetary end. No matter the scale, the living principle is the continuous internalization of the outward environment to protect individualized states of cellular homeostasis. And herein lies the crux of the differences between the fields of chemistry and physics, as opposed to biology. Chemistry and physics utilize “equals” signs across transfer reactions with the expectation of predictable results. In biology, there is no such equivalence. Life's ambiguous circumstances, as superimpositions of possibilities, extend across sub-systems-systems-supersystems to become biological deployment. That transfer process, which necessarily passes from uncertainty to uncertainty, interdicts any exact end-identities. In biology, the same set of stimuli never produces results that are actually identical. Yet, they do match sufficiently to carry life forward, and they do so through a shared universal relationship to the Singularity, through which all objects are always connected to all other universal objects. Everything springs from the Singularity. Our cells are an embodiment of all the natural forces that began with that instantiation. Even as uniquely human beings, everything that we do derives from within this cellular mandate. Consequently, our paramount connections arise from perpetual reciprocities. It is these same correspondences that should govern our own attitudes toward our place on our

planet, and our relationship with the cosmos. We are never just “in” the environment, but are ever and always “of” an ageless planet. We are never merely “in” the cosmos, but are directly and immanently “of” it.

Subject Index action-reaction, retro-causal 176–7 adenosine monophosphate, cyclic (cAMP) 32, 85, 134, 146 adenosine triphosphate (ATP) 167 Adipocyte Differentiation Related Protein (ADRP) 47 adrenal corticoid synthesis 67–8 adrenalin lung evolution 66, 67–8, 106, 132, 133, 163 birds 150

ADRP (Adipocyte Differentiation Related Protein) 47 after-the-fact reasoning 112 Age of Reason 35–6 aging 92–101 bioenergy/mitochondrial function loss 100 cell–cell signaling loss 98 death/dying 94–5 epigenetic inheritance 96–7 gender differences 99 human aging reasons 92–4 phenotype as agent 95 physiology as niche construction 97–8 The Red Queen and the Singularity 95 Wingless/Int expression/homeostasis loss 99–100

Agnati's “mosaic formulations” (2009) 191 Agnati's “Principle of Biological Attraction” (2009) 200–1 Alexander's natural piety concept (1939) 230, 233–4 Alexander's Space, Time, and Deity (1920) 235 Alice in Wonderland (Carroll, L.) 78, 95–6, 111, 230 allostasis 61, 69–70, 75–6 altruism bacterial 88 see also moral behavior

ambiguity the Arts 25–7 biological driving force 7, 92–3, 248 biological information 177–8, 187–8 Henry Moore's sculptures 25 human morality/laws 84, 87, 90, 250–1 musical improvisation 25 observer/participant status 175 omnipresence 86 philosophical recognition 7 reciprocation behavior 89 self-referential choices 87 superimposition of possibilities 170 transcendence 230–1

“anamorphic stretch transform” (Jalali/Asghari, 2014) 193–4 “antagonistic pleiotropy” theory (Williams, 1957) 92 the anthropic principle 41–2, 120 Anthropocene Period 87–8, 157–8

“anthropocentric fallacy” (Rovelli, 2014) 111 anthropocentric view of consciousness 111–12 antibiotic resistance 200 anti-inflammatory drugs 100 Aristotle's “four causes” 22 artificial intelligence 87–8, 89–90 the Arts Arts and Crafts Movement 236 empiricism as common ground with Science 42–3 Explicate to the Implicate Order 25–6 Modern Art movement 26, 43 organicist modernism 235–6 science–arts schism 41

Arts and Crafts Movement 236 asteroid origins of lipids 6, 42, 46–7, 82, 120–1, 161 asthma 5, 48 atomic hypothesis 187 atomic mass 42 atomic number see Mendeleev's Periodic Table atomic theory (Rutherford/Bohr) 221 atopic dermatitis/asthma connection 48 ATP (adenosine triphosphate) 167 authoritarian states 237, 239 auxotroph symbiosis 192 Axelrod/Hamilton's “Prisoner's Dilemma” 89 back-test overfitting 194–5 Bacon's “empiric data” 22–7, 42–3 bacteria 88, 97, 197 balanced equations of science 230, 244 Bauer's equilibrium/free energy budget 173 Baverstock/Rönkkö's “least action” principle (2014) 174 Bayesian networks for biological information flows 173 Bayesian probabilities as wave functions (Fuchs, 2011) 178 behavior, human see economics; moral behavior Bergson's Creative Evolution (1907) 235 Bernard's milieu interieur (1854) 60–1, 154 β-adrenergic receptor 8, 163 aging as loss of cell–cell signaling 98 duplications during water–land transition 65–6, 67, 75, 128, 162, 163

The Better Angels of Our Nature (Pinker, 2011) 83 betting/gambling 195–7, 198 see also trading

The Bifurcated World 220–2, 225 Big Bang/Singularity aging 96 balanced equations 230 biology/physics interrelationships 118, 119 cell division as symmetry breaking 117–24 consciousness origins 170–1 cosmology/physiology intersection 131–9 external environment stresses 13 Gaia concept/life origins 76, 156

homeostasis origins 58 human economic behavior 185, 186 origin of life studies 167 Pauli exclusion principle 11 quantum phenomena are contextual 176 self-reference/self-organizaion 72–3 single cells formation 54 unites cosomos 247–51 universe point source 2

binary information (Whyte/Wilson, 1949/1998) 1, 3 bioenergetics 96, 98, 100 biofilm antibiotic resistance exchange 200 “biogenetic law” (Haeckel, 1866) 62, 149, 155, 230 biologic mechanisms action-reaction 176–7 evolution, reciprocating means 37 evolution of biological forms 4–5 lack of research into 36 physics interrelationships 117–20, 241–2 physics/chemistry reconciliation 165–80 see also Darwinian theory; evolution of biological forms; first principles of physiology (FPP); individual mechanisms

biological attraction (Agnati, 2009) 200–1 biomedical research: flaws in current practice 36 biophysical field-integrated responses by organisms 167 bipedalism 143–4, 147, 163–4 birds 9, 150, 166 bitcoin exchange, cellular/human 199–200 blockchains, bitcoin exchange 199–200 Bohm/Hiley's non-local quantum phenomena 169–70 Bohm's “empiric data” 22–7, 42 Bohm's “Implicate Order” (1980) 110, 177, 230 Bombay Stock Exchange study (Pati, 2014) 201 bone gravity/PTHrP 55, 74–5, 122, 149 middle ear bones 13, 24 water-land transition 10, 13, 49, 162, 163

Bookchin's “social ecology” (1960s) 85 Boyle's “corpuscularian theory of matter” (17th century) 221 brain brain cooling (Hobson & Friston) 77, 85 Holland's skin–brain hypothesis 47, 53 mind localization 49–50 N-acetylcholine receptors 48 vertebrate from invertebrate 47

brain–lung–thyroid syndrome 146 calcium dyshomeostasis 65 fluxes and consciousness 74 primitive oceanic micelles 161 signaling in paramecia/neurons 112 unicellular vertebrate evolution 10

cAMP (cyclic adenosine monophosphate) 32, 85, 134, 146

cardiac see hearts Carroll's “Red Queen” (Alice in Wonderland) 78, 95–6, 111, 230 Cartesian coordinates reveal consciousness 111 Cartesian “interactionist substance dualism” 216–17 “The Bifurcated World” 220–1, 223

catecholamines 66–8, 106, 132, 133, 150, 163 causal mechanisms definition 4 downward causation 63–4, 69 mental causal power in EET 211–12, 215–17 natural mechanism thesis 226 Nicholson's biological mechanisms (2011) 213 orderliness assumption 233 Prigogine's NDI-NET 227 proximate/ultimate causation 9

cell division epigenetic inheritance 121 holistic cosmology Singularity 123–4 humans’ place in cosmos 120–1 meiosis 4–5, 11, 32, 58–9, 95 phenotype as object, not agent: fallacy 122–4 space/time is an artifact 124 symmetry breaking theory 117–24

cell membranes see cholesterol; micelles cellular consciousness 107–8 cellular-microbial life/human trading parallels 190–1, 192 cellular–molecular approach 7, 9, 34–5 cell–cell communications/signaling aging process 98–9 ambiguous information sharing 188 basic principles 185–9 Big Bang to civilization 160–4 calcium in paramecia/neurons 112 centrality in evolution 213–14, 248 cytoskeleton 78, 178 drives human economics 189–92 embryogenesis 2, 4, 5–6, 64 human economics/behavior 192–203 key addition to evolutionary theory 30 loss in aging 98 moral behavior 82–90 paramecia/neurons calcium signaling 112 physiologic evolution 2–3, 9–10 protein kinase A pathway 146 receptors 8, 9, 32, 59 see also individual receptors

reciprocation behavior 89 skin/brain hypothesis 54 surfactant compensation in lungs 47, 161 terminal addition 8–9 Thoreau's transcendence approach to evolution 229–31 water–land transition 65–8

Central Theory of Biology (Torday, 2015) 3 Chalmers’ hard problem (1995) 52, 55, 74, 107, 108–9, 215 chaos theory 165–6

chemical reactivity 22–3, 42 chemiosmosis 4, 161 see also first principles of physiology (FPP)

chemistry/biology reconciliation 165–80 chirality and symmetry breaking theory 169 cholesterol horizontal to vertical bodies 148 lung surfactant 47, 161 molecular fossil 10 multicellular organisms 2 semi-permeable membranes evolution 14 swim bladder/lung homology 23–4, 46–9, 64, 65, 127–8, 148, 162 vertebrate evolution 121

Christakis’ “contagion theory” (2013) 78, 153–4 chromaffin, birds 150 cigarette smoking 5, 48 Ciona intestinalis tail/heart connection 13, 47, 128 Clark/Chalmers’ “extended mind” hypothesis 84 Classical Art vs Modern Art challenge 43 climate change 15, 136, 157–8, 214, 239 cloud formation/weather 224 clustered regularly interspaced short palindromic repeats (CRISPR) 15, 87, 136, 214 cognition-based evolution 185 the Cold War 237, 240 collaboration see cooperative behavior collagen type IV isotypes 9, 18, 128, 129 collective wisdom 188, 192 see also information

colonies of bacteria, altruism 88 color 1, 48, 54, 109 the commutative principle 151 competition, Darwinian theory 185 complex numbers 231–2 complexity theory 203 consciousness anthropocentric view 111–12 Big Bang origins 73–4 Cartesian coordinates reveal 111 cosmological diachronic theory 73–4 definition 76 dynamic systems theory 219–20 ecosystem integration 109–10 endogenization of environmental properties 121 evolution of biological forms 106–7, 143–4, 248 free will problem/solution 225–8, 250 Gaia concept/care for Mother Earth 156–7 Goff's concept 171 Hameroff & Penrose's theory 73 hard problem (Chalmers, 1995) 52, 55, 74, 107, 215 no longer 108–9

holistic perspective 105–12, 250, 251 inanimate/animate interface 14–15

life's initiating factor 79 mind as a fractal of cosmos 55–6 origins 105, 170, 171–3, 214–15 restoring cellular homeostasis 108 “seeing red” in association with pain 107–8, 214–15 superimposition of possibilities 170 transcending space/time to understand 52–6 Whitehead's universal sense-awareness 170–1 see also mind

conserved process access under stress 107–8 “consilience” (E. O. Wilson, 1998) 1, 3, 16, 136, 241 contagion theory (Christakis, 2013) 78, 153–4 continuity view (Schrödinger, 1944) 220 control illusions, human 198, 234 controls, experimental 24, 42–3 cooperative behavior Anthropocene period 87 bacteria 88 cells 185–9, 190, 199 cells/organisms/human economics 190 Darwinism problem 89 Smith's basic economic principles (2010) 189 termite stigmergic self-organization 191 see also reciprocation

Copernican Revolution (Kant, 18th century) 240–241 corpuscularian theory of matter (Boyle, 17th century) 221 the cosmos 76, 131–9 see also Big Bang/Singularity

Creative Evolution (Bergson, 1907) 235 creativity, natural self-determination 228 CRISPR (clustered regularly interspaced short palindromic repeats) 15, 87, 136, 214 criticality theory chemistry/physics/biology 165–6 complexity theory 203 consciousness 171 Darwin's Origin of Species 168 evolution 167–9 market crashes 202

Crookes’ spiral representation of the Periodic Table 132 currency of bitcoin 199–200 cyclic adenosine monophosphate (cAMP) 32, 85, 134, 146 cytoskeleton cell–cell signaling 78, 178 homeostasis control 124 TOR role 75, 119, 138, 149

Darwinian theory belief in its completeness 29–30 competition 185 downward causation concept 63–4, 69 flawed narrative 89, 100, 119–20, 168–9 life cycles function 4 problem 62

mechanism of evolution 7, 12, 59, 202, 203 morality problem 157 The Origin of Species (Darwin) 151 “phenotype as object” error 122–4 see also niche construction

Darwin's Origin of Species (1859) 151, 168, 202 Deacon's “thermodynamic phase-space” consciousness theory 172 Dead Sea Scrolls riddle 151–2 death/dying cell–cell communication 92–100 Goodpasture syndrome 9, 128–9 microbiome return to the earth 94–5 premature birth 69 PTHrP gene deletion 149 surfactant non-formation by fetus 148 see also aging

deceptions immorality 86–7 life is full of (Trivers, 2011) 8, 21, 83, 86 reasoning after the fact 112 role in biology 8

decompositionality assumption 233 decorative arts 236 defensins 48, 53–4 Descartes’ mind-body dichotomy 49, 52, 78 descriptive biology 3 consequences 30–1 fallacies 31 inadequacy 26–7, 29–30, 36 “stamp-collecting” (Rutherford) 26, 30, 43 versus cellular–molecular biology 34–5

“Design for Trellis Wallpaper” (Morris, 1862) 236 determinism/free will boundaries 7, 226, 227, 233 deuterostomes commutative principle for physiologic adaptations 151 endocrine system/vertebrate evolution 150–1 endothermy for bipedalism/forelimb specialization 143–4 epigenetic marks acquisition 147 foregut plasticity 144 gravity stretches space/time and swim bladders/lungs 149 horizontal to vertical bodies 147–9 lungs in reptiles/birds 150 morphogenesis 93 ontogeny recapitulates phylogeny 62, 149, 155, 230 physiological/evolutionary significance 142–52 protostomes/deuterostomes developmental differences 142–3 thyroid evolutionary vertical integration 146 phylogeny in lamprey/hagfish 144–5

vagus plasticity 147

developmental physiology cell biology 15 cell–cell communications 4, 5–6, 64, 230 energy/information transfers 2, 3 evolution of biological forms 4–5

gastrulation 86, 123, 143, 150 Grobstein's tissue–tissue interactions 99–100 homeostasis as a consequence 65–7, 68 integration 145–6 life cycle role 33–4 protostomes/deuterostomes 142–3 second messengers 230 space/time 31 Turritopsis dohrnii reverse development 33 Wolpert's importance of gastrulation 86, 123 see also life cycles

Dewey's Experience and Nature (1925) 235 “diachronic perspective” (Waddington) 12, 62–3, 78 diachronic signaling, homeostasis 64, 68 Dictyostelium discoideum (slime mold) 75, 122 digital ledgers, bitcoin 199–200 disease, homeostasis failure 250 disposable soma theory of aging (Kirkwood, 1977) 92, 96 dissipative structures 218–19 DNA (deoxyribonucleic acid) 5, 6, 48 downward causation concept 63–4, 69 Drosophila melanogaster (fruitfly) 45, 75 DST see dynamic systems theory (DST) dual-aspectism, essential embodiment theory 215–17 dualism 216–17, 220–1 dynamic inherence, human freedom/mind/life 231–3 dynamic systems theory (DST) 217–25 definition 217–18 dissipative structures 218–19 events/facts spiral for the Dynamic World 223–4 fluctuation 218 nature of mind 220 seven elements 219

Dynamic World Picture 225 Alexander's natural piety concept (1939) 233–4 definition 217, 222–4, 225, 231 dynamic systems definition 217–18 theory 219–20

events/facts spiral 223–4 human consciousness 240

dyshomeostasis 62 Earth, first life 165 ecological civilization crisis (Gare, 2017) 239, 240 economics 185–204 behavioral 192–203 cells to humans progression of information handling 188 cellular antibiotic resistance exchange 200 market crashes 201–2

ecosystem, the/consciousness integration 109–10 EET (essential embodiment theory) 215–25, 227, 231 “Effective Information” (Miller, 2017) 201 ego, human, risk-taking relationship 198 Einstein, Albert

biology/physics interrelationships 118 cell size/number vs. organ size 62–3 energy/mass equation 1–2, 212–13 relativity theory 7, 26–7, 43 space/time stretches under gravity effects 149

electrochemical fields 11, 76 electrons, Pauli exclusion principle 11 elementary logic cannot be naturally mechanized 235 Embodied Minds in Action (Hanna/Maiese, 2009) 215 embryology/development see developmental physiology The Emergence of Everything (Morowitz, 2004) 11 Emerson's “House of Cards” economic model (2008) 202, 203 empiricism, Bohm/Bacon 22–7, 42–3 End of Uncertainty (Prigogine, 1997) 227 endocrine system catecholamines 66–8, 106, 132, 133, 150, 163 heart 46 pituitary–adrenal axis 66, 132–3, 163 vertebrate evolution 150–1

endogenization activity 97, 120, 154 endostyle in thyroid phylogeny 144–5 endosymbiosis 2, 42, 97, 190–1 endothermy bipedalism 147 enzymes 143 evolution 77, 110, 133–4, 143–4, 163 mammalian endocrine system 150–1

energy bioenergetics 96, 98, 100 Dynamic World Picture 222–4 homeostasis 156 information transfers in embryologic development 2 mass equivalence 1–2, 212–13 origin of life 175 see also dynamic systems theory (DST)

entelechy 1, 3 entropy, negative intracellular see negentropy (Schrödinger) enzymes 110, 143, 150 epigenetic marks/inheritance 10–11 aging 95, 96–7 cell division as Big Bang homolog 121 cigarette smoking 5, 48 deuterostomes’ acquisition 147 DNA transcription 5 external environment stresses 8 Gaia concept 154–5 gene duplications during water–land transition 66 moral behavior 86 natural libertarianism 228–9 nicotine 63 phenotype as agent 58–9, 249 sorting/selection during meiosis 4–5, 11, 32, 58–9, 95 zygote significance 120, 193–4

epithelial–mesenchymal interactions (Grobstein, 1967) 99–100

equilibrium balanced equations of science 230, 244 dynamic systems 218 human economic equilibrium theory 192 living systems 173

essential embodiment theory (EET) 215–25, 227, 231 ethics see moral behavior events/facts spiral for the Dynamic World 223–4 evolution of biological forms 2, 3 bipedalism 163–4 cognition-based 185 consciousness, nature of 106–7 embryology/phylogeny distortion 95 endocrine system 150–1 genes vs cell as having central role 126–7 heart 13, 47, 128, 163 homeostasis significance 58–70 mechanisms 4–5, 23–4, 29–30, 160–4, 167–9, 213, 248–9 paradigm shifts 35–6 phenotypic regression 111, 112 pleiotropy 12 primacy of the unicellular state 31–2 scalarity 7 skin 163 summary 120–2 Thoreau's transcendence of cell–cell communication approach 229–31 timelessness 118–19 transcendence in 230 vertebrates 9–10 warm-bloodedness 110, 133–4 zygote significance 193–4, 197 see also terminal addition

Evolutionary Biology, Cell–Cell Communication and Complex Disease (Torday & Rehan, 2012) 93 Evolutionary Biology, the Logic of Biology (Torday & Rehan, 2012) 23, 42 The Evolutionary Continuum from Lung Development to Homeostasis and Repair (Torday & Rehan, 2012) 26, 43 Evolutionary Theory – The Unfinished Synthesis (Robert G. B. Reid, 1985)  60 exaptations concept, homeostasis 65 Experience and Nature (Dewey, 1925) 235 Explicate to the Implicate Order (Bohm, 1980) 22, 24, 230 action-reaction in living entities 177 the Arts 25–6, 42–3 consciousness evolution 110 Einstein's relativity theory 7, 26–7, 43 empiricism as path to 42–3 scientific method 27, 42–4

extended mind hypothesis (Clark/Chalmers) 52, 84 external environment stresses bacterial “Tortoise-Hare” adaptive fitness 197 Big Bang origins 13 conserved processes/homeostasis 107–8 diachronic regulation of homeostasis 68

endothermy causation 133–4, 163–4 epigenetic marks 8 gas exchange/oxygenation efficiency 48–9 life cycle role 33–4 receptor-mediated pathways evolution 59 Turritopsis dohrnii reverse development 33 zygote information handling 194

external environmental entropy, negentropy differential 7 facts/events spiral for the Dynamic World 223–4 “Fallingwater” house (Lloyd Wright, 1935) 237, 238 fascism, rise of 237, 240 feedback 61, 191 Feynman's Lectures on Physics (2011) 187 filter feeding, thyroid phylogeny 144, 145, 146 financial markets, sustainable betting 195, 196, 197 first principles of physiology (FPP) 6 aging 92–3, 98 basic cellular domains’ persistence 197, 247–8 causal-processual mechanisms of biological evolution 213 deuterostomal relationships/Dead Sea scrolls parallel 151 Earth formation 165 fractal view of life 12, 13 Gaia/cosmos formation 76 identification 75 non-localization 11–12

fish gills 46 hearts 45 swim bladder/lung homology 23–4, 46–9, 64, 65, 127–8, 148, 162 see also water–land transition

fluctuating dynamic systems 218 force (Dynamic World Picture) 222–4 foregut 144, 146 forelimb specialization, evolution 143–4 fossil evidence cholesterol as molecular fossil 10 disturbing gaps 168 Tiktaalik skeleton 134, 148, 162

FPP see first principles of physiology (FPP) fractal perspectives 12–14, 55–6, 166, 186 Frankenstein's mistake 234 Frankl's “logotherapy” theory (2006) 77 free will/agency definition 225–6 determinism/free will boundaries 7, 227, 233 dynamically inherent 231–3 essential embodiment theory 217 individual vs interdependence 190 mind is a form of life 225–9 moral behavior 82–90, 226, 250–1 natural self-determination 228 problem/new wave organicist solution 225–9 trading success 197, 198 Wittgenstein's Philosophical Investigations (1953) 232

The Freedom Dance 228 freshwater lampreys 145 Friedman's “individual freedom vs interdependency” (1955) 189–90 fruitfly (Drosophila melanogaster) 45, 75 Fuchs’ wave functions as Bayesian probabilities 178 Gaia concept climate change/humanity's part in 157–8 consciousness/care for Mother Earth 156–7 definition 153, 158 homology with consciousness 76 Lovelock's translation 97–8 metazoan evolution 155 moral behavior 157 phenotypic variation as agency for epigenetic inheritance 154–5

Gaia Theory (Lovelock, 1960s) 153 “gambler's fallacy” 198 gambling/betting 195–8 see also trading

Gare's ecological civilization crisis (2017) 239, 240 gas exchange swim bladder/lung homology 23–4, 46–9, 64, 65, 127–8, 148, 162 glucocorticoid receptor 8, 65, 66, 67, 75, 127, 128, 162 gravity 148 homeostasis 64, 65 leptin 128, 162 physiologic evolution basis 23–4 PTHrP signaling 162 symmorphosis (Weibel, 2015) 48–9

gastrulation 86, 123, 143, 150 Gatti's endosymbiosis theory 97 Gauche's disease 47 gauge field changes, consciousness theories 172–3 genes central role in evolution was proposed 126–7 criticalities in genetic events/transfers 168–9 DNA 5, 6, 48 genetic diseases and aging 96–7 genetic engineering threat 87–8 human genome size 6 Nkx2.1/TTF-1 gene expression 144, 146 reconfigurement under environmental stress 59

Gershwin's Rhapsody in Blue (1924) 26 gestation, small-for 69 gill slits 143 glucocorticoid receptor aging as loss of cell–cell signaling 98 duplications during water–land transition 8, 65, 66, 67, 75, 128, 162 random mutations 127

Go To Meeting virtual reality program 87 Gödel's “incompleteness” theorems 235 Godfrey-Smith's “Mind is life-like” 219–20 Goff's consciousness concept (2009) 171 Goodpasture syndrome 9, 128–9 Goswami's “quantum superimposition of possibilities” (1990) 170 Gould/Eldredge's “punctuated equilibrium” (1972) 203

Gould/Lewontin's The Spandrels of San Marco essay (1979) 128 gravity cell–cell signaling 74 deuterostome body plan vs plants’ body plan 147 lung/kidney PTHrP production 162 phenotype as process: yeast/lung/bone 122 PTHrP expression 55, 162 stretches space/time and swim bladders/lungs 149 swim bladder/lung homology 148, 162

Greek philosophers 1, 3, 15, 16 Aristotle's four causes 22 consciousness 52 continue to be instructive 41 Descartes’ mind-body dichotomy 49, 52, 78 “One” vision 242 Plato's repetitive themes 186

greenhouse effect 106 Grobstein's tissue–tissue interactions in embryogenesis (1967) 64, 99–100 Haeckel's biogenetic law ontogeny recapitulates phylogeny (1866) 62, 149, 155, 230 hagfish evolution 144 Hameroff & Penrose's consciousness theory (2014) 73 Hanna/Maiese's Embodied Minds in Action (2009) 215 Hanna's “natural libertarianism” (2018) 226–7, 228 hard problem (Chalmers, 1995) 52, 55, 74, 107, 108–9, 215 Haus der Deutschen Kunst (Ludwig, 1933–7) 237, 238 hearing in vertebrates 13, 167 hearts cardiac failure 46 Ciona intestinalis 13, 47, 128 different forms 45 evolution 13, 163 pump function 13, 46, 47, 128

hedge fund limited success 196–7 Heisenberg's “resonances” 186 Heisenburg's Uncertainty Principle 25, 76, 84, 118, 249 helices, Crookes’ periodic table/DNA 132 heliocentrism 15, 35–6 hemoglobin isotypes 9 herd instinct 201 heterochrony Big Bang/Singularity 123 cell–cell signaling 34, 112 commutative principle 151 phenotype 32 Turitopsis 33

Heylighen's “stigmergic self-organization” (2015) 191 Hobson & Friston's “brain cooling” concept 77, 85, 105–6 holistic thought cell division as biological symmetry breaking 123–4 consciousness 73–4, 105–12, 250, 251 Dynamic World Picture 222–4, 225 Lovelock's translation of Gaia 97–8, 153

see also Gaia concept; new wave organicism

Holland's skin–brain hypothesis 47, 53 holobionic microbial/multicellular forms 190–1 homeostasis allostasis as integrated 69–70 Bernard's milieu interieur (1854) 60–1, 154 consequence of developmental mechanisms 65–7 diachronic signaling 64, 68 downward causation 63–4, 69 dyshomeostasis 62 evolutionary significance 58–70 fractal view of life 13 homeostatic equipoise/cooperative behavior 88, 108 is dynamic 60 loss in aging/disease 100, 250 origins 54 physics/biology common ground 117–20 physiological principle 4, 6–7 retro-causation 176 vertebrate water-land transition 64 Waddington's diachronic perspective 62–3 Wingless/Int expression and loss of homeostatic control 99–100 see also first principles of physiology (FPP)

“Hopeful Monster” theory (Schindewolf, 1930s) 168 “House of Cards” economic model (Emerson, 2008) 202, 203 How to be Good article (Parfit, 2011) 83, 157 human beings the anthropic principle 41–2, 120 economics 185–204 ego/intelligence/risk-taking 196, 198, 201 evolution/consciousness 110 freedom vs interdependence 190 genome 6, 35 moral behavior 82–90 place in nature/cosmos 3, 77–8, 79, 120–1, 214 Steward's conception (2012) 240 stigmergic self-organized trading 192 see also anthro…; the Arts; free will/agency; philosophy

hydrophobicity of type IV collagen isotypes 9, 18, 128, 129 hypothalamic-pituitary-adrenal axis (HPAA) 106, 150, 163, 249 pituitary–adrenal axis (PAA) 66, 132–3, 150, 163

hypothesis proliferation 34 hypoxia adrenalin/PNMT production 66 endothermy development 93, 108 HPAA stimulation 106, 150, 163, 249 Phanerozoic Era 132 PTHrP expression 67

Igamberdiev/Shklovsky-Kordi's “principal of optimality” (2017) 178 “illusion of self-control” (Konnikova, 2013) 198 immortality of Turritopsis dohrnii 33, 122, 125 imperialist fascism 237, 238, 240 Implicate Order see Explicate to the Implicate Order (Bohm, 1980) incompleteness theorems (Gödel) 235

information ambiguities 177–8, 187–8 Bayesian networks 173 energy/information interconvertability 175 extraction from environment 174, 175 inevitable incompatibilities 177 sharing/handling bitcoin 199–200 cells/humans 203–4 collective wisdom 188, 192 Miller's “Effective Information” (2017) 201 multicellular life 199–200, 248 zygotes 194

inheritance, epigenetic see epigenetic marks/inheritance intelligence risk-taking relationship 196, 198 see also consciousness; mind

intentionality of human minds 191, 212, 216 “interactionist substance dualism” (Cartesian) 216–17, 220–1, 223 intracellular negative entropy see negentropy (Schrödinger) iodine-binding in thyroid-like tissue 145 Jacob's “tinkering” concept 59 Jalai/Asghari's “anamorphic stretch transform” (2014) 193–4 Jantsch's “dissipative structures” 218–19 jazz improvisation 25 jellyfish Turritopsis dohrnii 33, 122, 125 Joyce's Ulysses (1922) 25 Kant's causal laws observations 227 Kant's Copernican Revolution (18th century) 240–1 kidney evolution 13, 47, 106, 127–8, 162–3 Goodpasture syndrome 9, 128–9 podocytes 162 PTHrP-dependent characteristics 10, 55, 149, 162

Kim's “levels of entities” (1993) 220–1 kin selection 88, 89 Kirkwood's “disposable soma” theory of aging (1977) 92, 96 Konnikova's “illusion of self-control” (2013) 198 Kuhnian paradigm shifts 212, 214 Kurzweil's “Singularity of technology” (2005) 110 Lamarckian inheritance theory (1860s) 10 lamprey thyroid phylogeny 144–5 land adaptations see water–land transition Larson's “saltationism” 168 laws of biology 2, 3, 227 see also first principle of physiology (FPP)

Layered World Picture 221–2, 225 “least action” principle (Baverstock/Rönkkö, 2014) 174 Lectures on Physics (Feynman, 2011) 187 “levels of entities” (Kim, 1993) 220–1 liberal naturalism 231, 232–3, 234 life cycles binary nature 93–4, 95 bioenergetics variations 96, 98, 100

epigenetic marks 154, 155 lamprey 145 multicellular organisms 4–5 reappraisal as phenotype/environment interaction 33–4 “Red Queen” analogy 111 Turritopsis dohrnii 122, 123 unicellular state, return to 230, 248 Waddington's diachronic perspective 62

Linnaean binomial nomenclature 30, 43 lipids asteroid delivery 6, 42, 46–7, 82, 120–1, 161 micelles 82, 106, 121, 148, 161 skin/lung 48 see also cholesterol

living/inanimate distinction 173–4, 175 Lloyd Wright's “Fallingwater” house (1935) 237, 238 Locke's philosophy concept (17th century) 210 locust swarms as criticality example 169 logic cannot be naturally mechanized 235 “logical space” (Wittgenstein, 1981) 223 “logotherapy” theory (Frankl, 2006) 77 Long Term Capital Management downfall 196 Lovelock's translation of Gaia (1960s–1979) 97–8, 153 Ludwig's Haus der Deutschen Kunst (1933–7) 237, 238 lung asthma 5, 48 cell–cell communication 5–6 embryogenesis/aging 64, 99–100 evolution 13, 47, 48–9, 65, 128, 160 adrenalin 66, 67, 106, 132, 133, 163 gill connection 46 phenotype as process 122 thyroid/pituitary co-evolution 146 water–land transition 13, 47, 106, 128, 162–3

N-acetylcholine receptors 48 Phanerozoic Era 132–3 pleiotropic defensins 48 PTHrP-dependent characteristics 132–3, 161–2 skin/brain hypothesis 53 see also swim bladder/lung homology

“machine mechanism” definition 4 mammalian endocrine system 150–1 “manifest image” (Sellars’ “The Two Images Problem”, 1963) 211, 242 market crashes 201–2 Markov blankets 173 mathematical theories 217–19, 231–2, 235 see also Dynamic Systems Theory (DST)

Matsuno's “measuring/measured entities” (2017) 175–7, 179 Mayr's Proximate–Ultimate Causation essay (1961) 126, 129 measurement, living predictive 175–7, 179, 188 mechanical force transduction by PTHrP 161–2 “mechanicism” definition 4 Medawar's mutation accumulation theory (1952) 92 meiosis 4–5, 11, 32, 58–9, 95

memory, molecular 84–5 menarche, premature 69 Mendelbrot's fractals 186 Mendeleev's Periodic Table 11, 16, 241–2 Scerri's analysis 22–3, 42

mental… see consciousness; mind mesoderm confers plasticity 86, 123 endoderm/ectoderm interactions 131 gastrulation 86, 123, 143, 150 hormonal control 86 lung 64 protostomes/deuterostomes 143 terminal additions 32 visceral conformations 143

metabolic adjustment, homeostasis 61 metabolic cooperativity and moral behavior 85–6 metabolic syndrome 123 metaphysical aspects/thinking “The Bifurcated World” 220–2, 225 flaws 221–2

Cartesian dualism 216–17 dynamic systems theory 219–20 EET psycho-organicism 215, 217–25 free agency 217 liberal naturalism concept 231, 232–3 panpsychism 170, 215 religious awareness of greater power 30, 76, 77, 78 Transcendentalist Movement 229 transfinite/complex/real numbers 232

Metazoan evolution 155 micelles 82, 106, 121, 148, 161 see also cholesterol; lipids

microbial fraction of organisms 190–1 microbiome return to the earth in death 94–5 middle ear bones in vertebrates 13 migration matrices (bacterial) 197 milieu interieur (Bernard, 1854) 60–1, 154 mind dynamically inherent 231–3 essential embodiment theory 215–17 free will/mind is a form of life 225–9 Godfrey-Smith's “Mind is life-like” 219–20 localization 49–50 mental causal power 211–12, 215–17 mental properties in Dynamic World Picture 224 mind–body problem 215–17 Reber's The First Minds (2018) 49–50, 55, 88 two different sorts 52

mineralocorticoid receptor (MR) 59, 64, 127, 162 Modern Art movement 26, 43 “molecular exploitation” (Thornton) 162 molecular memory 84–5 money analogue “bitcoin” 199–200

Moore, Henry (sculptor) 25 moral behavior 82–90 Anthropocene Period 87–8 bacterial altruism 88 free will/agency 82–90, 226, 250–1 fundamental biological principles 90 Gaia concept 157 metabolic cooperativity as basis 85–6 reasons for immorality 86–7 unicell ascribing to Laws of Nature 84–5

morphogenesis 31, 64, 93, 146 Morris's “Design for Trellis Wallpaper” (1862) 236 “mosaic formulations” (Agnati, 2009) 191 Mother Earth natural care for 156 see also Gaia concept

mouse thyroid development model 146 multicellular organisms cellular collaboration 190 cholesterol 2–3 holobionts, kin selection 88 information sharing 199–200, 248 life cycles 4–5 see also humans; individual organisms; vertebrates

muscle contraction and ATP transfer 167 music, classical/improvised 25, 43 mutations/duplications β-adrenergic receptor 65–6, 67, 75, 128, 162, 163 glucocorticoid receptor 8, 65, 66, 67, 75, 127, 128, 162 “mutation accumulation theory” (Medawar, 1952) 92 organ remodeling 65–8 PTHrP receptor 65–6, 67, 106, 128, 149 radical oxygen species 59 receptor-mediated pathways evolution 59

mutual fund financial success 196–7 “myth of control” (Prirogine, 1997) 234 N-acetylcholine receptors in lung/brain 48 Nagels’ rational intelligibility… (2012) 233 “natural determinism” thesis 226 “natural libertarianism” (Hanna, 2018) 226–7, 228–9 “natural mechanism” thesis/fallacy 226, 227, 233, 234 “natural piety” concept (Alexander, 1939) 230, 233–4 natural selection see Darwinian theory “natural self-determination” concept 228 Nazi Germany 237 NDI-NET (non-deterministic interpretation of non-equilibrium dynamics) (Prigogine, 1997) 227 negative feedback, homeostasis 61 negentropy (Schrödinger) Big Bang theory 54 cellular 176–7 external environmental entropy differential 7 intracellular 6

living state within boundary conditions 186–7, 247–8 physiological principle 4 summary 82, 174, 175 see also first principles of physiology (FPP)

nematodes, contracting pharynx 45 Neo-Darwinism 30, 75 neoteny (retention of juvenile features) 32, 33 networked genes, electrochemical fields 76 neuregulin epidermal growth factor pathway 47, 53, 77, 163 new wave organicism 210–42 biology as a continuum 213–14 causal-processual mechanisms of biological evolution 213 conceptual developments 1923–1980s 237 conscious mind emergence 214–15 definition 212 dynamic systems theory/dynamic world picture 217–25 first waves 231–9 after World War I 235

free will problem solutions 225–9 mind–body problem solutions 215–17 science/philosphy mismatch after 1950 231–9 second waves 240–1 singularity and nature 212–13 Thoreau and transcendence of cell–cell communication approach to evolution  229–31

The New Yorker Magazine “How to be Good” article (Parfit) 83, 157 Newtonian physics biology/physics interrelationships 118 living state within boundary conditions 186–7 Newton's Third Law 99, 174 relativity supercedes 26–7, 30, 43

niche construction cells to human city construction 188–9 endogenization activity 97, 154 Gaia theory 153–4, 155

Nicholson's “biological mechanisms” (2011) 213 nicotine 5, 48, 63 Niemann–Pick disease 47 Nkx2.1/TTF-1 gene expression 144, 146 noise in time-stretch mechanisms 193–4 non-deterministic interpretation of non-equilibrium dynamics (NDI-NET, Prigogine, 1997) 227, 234, 235 non-equilibrium dynamics 227, 237 non-localization Bohm/Hiley 169–70 consciousness 14 physics/biology 11–12 quantum phenomena, ATP transfer for muscle contraction 167

non-null probability of backtest overfitting 195 non-reductive physicalism 216 numbers, transfinite/complex/real 231–2 nutrient restriction 123 observer/participant status ambiguity 175 Occam's razor principle 34–5, 36

O'Connor's Wayfinding (2019) 154–5 olfactory reception and quantum phenomena 166, 167 On the Origin of Species (Darwin, 1859) 202 “One” vision (Greek philosophers) 242 ontogeny fractal process 13 recapitulates phylogeny 62, 149, 155, 230 thyroid phylogeny/ontogeny 144–6

open texture of natural laws 227, 228 optimality, principle of 178 orchestrated objective reduction model (Orch OR) 171 organ remodeling 49, 64–8, 103, 108 organicist modernism 235–6, 240–1 organicist philosophy see new wave organicism origin of cosmos see Big Bang/Singularity The Origin of Species (Darwin, 1859) 151, 168 out-of-body experiences 108 overconfidence in financial trading 197, 198 oxidative stress theory of aging 92 oxygen, atmospheric 93, 146, 160–1 PAA (pituitary–adrenal axis) 66, 132–3, 150, 163 pain, “seeing red” in association with 107–8, 214–15 panpsychism 170, 215 paracrine regulation 5–6 paradigm shifts 35–6, 212, 214, 216, 242, 247 parathyroid hormone-related protein (PTHrP) receptor 8, 149 adrenal corticoid synthesis 67–8 aging as loss of cell–cell signaling 98 duplications during water–land transition 49, 65–6, 67, 106, 128, 149, 249 experimental deletion 10, 55 gravity effects on bone/lung cells 74–5, 149 kidney podocytes 162 lung development Phanerozoic Era 132–3 mechanical force biological transduction 161–2 physiologic stress regulation 67 vertebrate water–land transition 64

Parfit's article How to be Good (2011) 83, 157 particles, smaller and smaller, Layered World Picture 221 Pati's Bombay Stock Exchange study (2014) 201 Pauli exclusion principle (PEP) 11, 25, 76, 82, 117, 229, 249 Peano arithmetic 235 pedomorphosis 32 periodic table of biology 3 Periodic Table of elements 11, 16, 241–2 Crookes’ spiral representation 132 evolution connection 131–3 Scerri's analysis 22–3, 42, 131

The Periodic Table… (Scerri, 2019) 42 peroxisome evolution 10 peroxisome proliferator-activated receptor gamma (PPARγ) 100 Phanerozoic Era 132–3 phase separations 165–6

phase transitions 175 phase-space consciousness theory 172, 173 phenomenal consciousness, qualia 52 phenotype as agent aging process 95 epigenetic marks 58–9, 249 error in viewing the phenotype as ‘object’ 122–4 extended mind manifestation 55, 56 Gaia concept 154–5 unicellular state 78

“phenotype verb not noun” 32–3 phenotypic acquired characteristics see epigenetic inheritance phenotypic evolution, regression 111, 112 phenylethanolamine-N-methyltransferase (PNMT) 66 philogeny as fractal process 13 Philosophical Investigations (Wittgenstein, 1953) 232, 237 philosophy ambiguity recognition 7 history of “transcendence” references 229, 230 Locke's 17th century concept 210 new wave organicism 231–9 Reichenbach's The Rise of Scientific Philosophy (1951) 210 revolutions history 240–1 science–philosophy schism 212 Sellars’ “The Two Images Problem” (1963) 211 Transcendentalist Movement 229

photosynthesis and criticality theory 166, 167–8 phylogeny history of organisms 3 ontogeny recapitulates phylogeny 62, 149, 155, 230 thyroid 144–6 lamprey/hagfish 144–5

vagus nerve 147

physicalism, reductive/non-reductive 216 physics physics/biology interface 117–20, 165–80, 241–2 relativity theory (Einstein) 7, 26–7, 43 second law of thermodynamics 6–8, 86, 93, 96, 174, 247 see also Newtonian physics; quantum mechanics/phenomena

physiology Big Bang origins 73–4 commutative principle (maths) allows wide range of adaptation 151 cosmology/physiology intersection 131–9 deep integration with consciousness 78 evolution, cell–cell communications 2–3, 9–10 fractal view 12–14 stress regulation and PTHrP 67 see also first principles of physiology (FPP)

Piaget's human development perspective (1936) 123 pineal gland 9, 52 Pinker's “right and wrong” concept (2011) 83 pituitary–adrenal axis (PAA) 66, 132–3, 150, 163 PKA (protein kinase A) pathway 103, 146 plant consciousness theory (Trewavas/Baluska, 2011) 112

plants and gravity 147 Plato's repetitive themes 186 Plattner/Verkhratsky's calcium signaling theory (2018) 112 The Plausibility of Life (Kirschner & Gerhart, 2005) 62 pleiotropy 11, 12, 32, 53 PNMT (phenylethanolamine-N-methyltransferase) 66 polyploidy 62 Porges’ “polyvagal theory” (1995) 77, 147 possibilities, superimposition of 170, 178–9 PPARγ (peroxisome proliferator-activated receptor gamma) 100 precocious puberty 69 prediction/predictive laws biology 3, 36, 37 cells/humans 204 dynamic system states 218 Matsuno's difference between measuring/measured entities 179

premature menarche 69 price fluctuations and “trader's fallacy” 195 Prigogine's End of Uncertainty (1997) 227 “Principle of Biological Attraction” (Agnati, 2009) 200–1 “principle of optimality” (Igamberdiev/Shklovsky-Kordi, 2017) 178 Prirogine's “myth of control” (1997) 234 “Prisoner's Dilemma” in kin selection 89 probability theory 195–7 problem-solving 7, 156–7, 192 Process and Reality (Whitehead, 1929) 235, 237 “process theory” (Whitehead, 1978) 56 protein kinase A (PKA) pathway 103, 146 protostomes/deuterostomes development 142–3 Proust's Remembrance of Things Past 14–15, 25 proximate causation 9, 126–9 Proximate–Ultimate Causation essay (Mayr) 126, 129 psycho-organicism 215 puberty, precocious 69 pump function, hearts 13, 46, 47, 128 punctuated equilibrium 12, 203 QBism (quantum Bayesian system) 178 qualia (intrinsic self-referential quality) 52, 55, 74 quantum Bayesian system (QBism) 178 quantum mechanics/phenomena bird migration 166 cellular physiology integration 76, 78 coherences ATP transfer for muscle contraction 167 biology/chemistry/physics 118, 165–80, 249 Darwin's Origin of Species 168

contextuality 176 non-localization 11–12 Pauli exclusion principle 11 unicellular consciousness 111

“quantum superimposition of possibilities” (Goswami, 1990) 170 radical oxygen species (ROS) 49, 59, 64, 65, 108, 127

rapamycin (TOR) gene 75, 100 random probability theory 195–7 range-bound trading 203 gene 119

rational intelligibility… (Nagel, 2012) 233 rationality in information sharing/handling 201–2 reactive oxygen species (ROS) 49, 59, 64, 65, 108, 127 real numbers 231–2 Reality is Not What it Seems (Rovelli, 2014) 111 reasoning after-the-fact 112 Age of Reason 35–6 rationality in information sharing/handling 201–2 teleological fallacy (Roux, 2014) 106

Reber's The First Minds (2018) 49–50, 55, 88 receptor-mediated pathways 8, 9, 32, 59 see also individual receptors

reciprocation biological homeostasis 37 cooperative behavior 89 dynamic systems theory causality 219 human economic behavior 186, 187 negentropy 187 phase-space consciousness theories 173

The Red Queen (Alice in Wonderland, Lewis Carroll) 78, 95–6, 111, 230 reductive physicalism 216, 232 Reichenbach's The Rise of Scientific Philosophy (1951) 210 Reid, Robert G. B. 60 reiteration 12–14, 186, 187 relativity theory (Einstein) 7, 26–7, 43 religious awareness of greater power 30, 76, 77, 78 see also metaphysical aspects/thinking

Remembrance of Things Past (Proust, M.) 14–15, 25, 214–15 remodeling of organs 49, 64–8, 103, 108 repetitive themes (Plato) 186 reproductive phase of life 94, 96, 98 reptile lung development 150 resonances cellular decision-making 204 cell–cell signaling 250 chemical bonding 186 human economics 187 multicellular life 248 self-reference 171 wisdom of crowds 188 see also reciprocation

retro-causal action-reaction 176–7 reverse development 33 Rhapsody in Blue (Gershwin, 1924) 26 “right and wrong” (Pinker, 2011) 83 The Rise of Scientific Philosophy (Reichenbach, 1951) 210 risk management/taking 195–7, 198, 201

ROS (radical oxygen species) 49, 59, 64, 65, 108, 127 rosiglitazone 100 Roux's teleological fallacy (2014) 23, 45, 106, 126 Rovelli's Reality is Not What it Seems (2014) 111 rules of behavior see moral behavior “running as fast as it can” (life as “The Red Queen”) 95–6 Rutherford/Bohr's atomic theory 221 Rutherford's “biology is stamp-collecting” 26, 30, 43 Sagan's “we are all stardust” 42 “saltationism” (Larson) 168 sample size and “trader's fallacy” 195–6 scalarity of evolutionary biology/physics 7 SCAP (sterol regulatory element-binding protein cleavage-activating protein) gene 47 Scerri's The Periodic Table… (2019) 22–3, 42 Schindewolf's “Hopeful Monster” theory 168 Schopenhauer's consciousness definition 53, 106 Schrödinger's “continuity view” (1944) 220 Schrödinger's negentropy see negentropy (Schrödinger) Schrödinger's What is Life (1944) 237 Schwann cells 6, 53, 77, 127 science–arts schism 41, 42–3 science–philosophy schism 211–12 scientific method controls/subjectivity 24, 42–4 definition 211 empiricism as common ground with the Arts 42–3 Explicate to the Implicate Order 27 importance 43–4 limitations 211–12 Matsuno's difference between measuring/measured entities 179 new wave organicism 231–9 science–arts schism 41, 42–3 Sellars’ “The Two Images Problem” (1963) 211, 242 yeast and holistic view of consciousness 74

“scientific naturalism” definition 211 scientific/manifest images of rational human beings 211, 242 Scott's Seeing Like a State (1998) 239 second law of thermodynamics 6–8, 86, 93, 96, 174, 247 second messengers 9, 32, 85–6, 230 Seeing Like a State (Scott, 1998) 239 “seeing red” in association with pain 107–8, 214–15 self-control, illusion of (Konnikova, 2013) 198 self-determination, natural 228 self-identity 189, 199 self-organization dissipative-structured dynamic systems 218–19, 227–8 instantiating point of reference 72–3 stigmergic 191

self-reference cells/organisms/human economics 190 choices

ambiguity 87 Gaia concept 156–7 inevitable information incompatibilities 177–8

definition 187–8 evolution of biological forms 248 negentropy/homeostasis 176–7 physical recoil as reaction 72–3 qualia (intrinsic self-referential quality) 52, 55, 74 self-organizing criticalities 171

Sellars’ “The Two Images Problem” (1963) 211, 242 semi-permeable membranes chemiosmosis 248 cholesterol 13 evolution 14, 42, 47 micelle formation 82, 106, 121, 148, 161

senescence see aging “sense-awareness, universal” (Whitehead, 1920) 170–1 sharp features distinction in anamorphic stretch transform 193–4 Shewanella loihica PV-4 metal-reducing bacterium 168 Shubin's Tiktaalik quadruped fossil 134, 148, 162 signaling see cell–cell communications/signaling simplicity is best 34–5 simplicity of life 111, 112 single-celled organisms see unicellular state Singularity of technology (Kurzweil, 2005) 110 Singularity, the see Big Bang/Singularity skin 47, 48, 53, 163 skin–brain hypothesis (Holland) 47, 53 sleep and homeothermy suspension 77 slime mold (Dictyostelium discoideum) 75, 122 small-for-gestation birth 69 Smith's “basic economic principles” (2010) 189 Smocovitis, V. B. Unifying Biology (1996) 126–7 smoking 5, 48 Snow, C. P. The Two Cultures (1959) 41–4 social contagion theory (Christakis, 2013) 153–4 “social ecology” concept (Bookchin, 1960s) 85 “social engineering” (Scott, 1998) 239, 240 solid–liquid–gas systems 165 soma/body 50, 92, 96 Space, Time, and Deity (Alexander, 1920) 235 space/time aspects of imaginative literature 25 cell division homology with Big Bang/Singularity 124 embryogenesis/development 31 gravity stretches 149 non-localization 11–12 transcendence to understand consciousness 52–6 see also relativity theory

The Spandrels of San Marco essay (Gould/Lewontin, 1979) 128 spiral image for the Dynamic World 223–4 sport, shot selection 25–6 “stamp-collecting” (Rutherford about biology) 26, 30, 43

statins 100 statistics and “trader's fallacy” 195 Steward's conception of the human person (2012) 240 Steward's “task of understanding free agency” (2012) 225 stigmergic signals 191, 200 The Strategy of the Genes (Waddington, C. H., 1957) 62, 63 stress-stimulated access of conserved processes 107–8 stretch domain, anamorphic stretch transform 193–4 stretch-regulated surfactant systems 47, 55, 66, 146, 161, 162 stretchable matrix experiment (Bohm) 22, 24, 42–3 stromalites 189 subconsciousness theories 171, 172 subjectivity Fuchs’ wave functions as Bayesian probabilities 178 scientific method 24, 42–3 “seeing red” in association with pain 107–8, 214–15 subjective idealism 216

Suel's study of bacterial altruism (2015) 88 superimposition of possibilities 170, 178–9 surface criticalities 165 surfactants lung evolution 160 stretch-regulated formation 47, 55, 66, 146, 161, 162 swim bladder/lung homology 23–4, 46–9, 64, 65, 127–8, 148, 162 see also cholesterol

survival of the fittest see Darwinian theory swim bladder/lung homology 23–4, 46–9, 64, 65, 127–8, 148, 162 PTHrP expression 149 Shubin's Tiktaalik quadruped fossil 148, 162

symbiosis 97, 190–1, 192 symmetry breaking theory 117–24, 169, 172 symmorphosis (Weibel, 2015) 48–9 taxonomical approach see descriptive biology Tay-Sach's disease 47 teleological fallacy (Roux, 2014) 106 temperature control, homeostasis 61 terminal addition aging and loss of most recently acquired traits 94 evidence of singularity 8–9 key aspect of evolution 32 new validity 33 Nkx2.1/TTF-1 gene expression 144

termites 191 The First Minds (Arthur Reber, 2018) 49–50, 55, 88 The Periodic Table: Its Story and Its Significance (Eric Scerri, 2006) 22–3, 42 theory proliferation 34 thermodynamic phase-space consciousness theory 172 Thoreau's dictum “When one man…” (1960) 212 Thoreau's “transcendence of cell–cell communication” approach 229–31 Thoreau's Walden (1854) 228

Thornton's “molecular exploitation” 162 thyroid 144–5, 146 see also parathyroid hormone-related protein (PTHrP) receptor

Tiktaalik skeleton 134, 148, 162 time dynamic systems theory includes 219 see also space/time

time-stretch mechanisms 193–4 timelessness, evolution 119 “tinkering” concept (Jacob, 1977) 59 tissue–tissue interactions see cell–cell communications/signaling top-down/bottom-up approaches 6 “Tortoise-Hare” adaptive fitness 197 Tractatus Logico-Philosophicus (Wittgenstein, 1981) 223 “trader's fallacy” concept 195 trading back-test overfitting 194–5 cellular collaborative functioning 199 herd instinct 201 human economics 185–92 cellular cooperation connection 192–203

market crashes 201–2 range-bound trading 203

transcendence 229–30 Transcendentalist Movement 229 transfinite numbers 231–2 Trewavas/Baluska's “plant consciousness” theory (2011) 112 Triver's “life is full of deceptions” idea 8, 21, 83, 86 Turing machines, real world 232, 233, 235 Turing-compatible algorithms 235 Turritopsis dohrnii jellyfish 33, 122, 125 The Two Cultures (Snow, 1959) 41–4 “The Two Images Problem” (Sellars, 1963) 211, 242 type IV collagen isotypes 9, 18, 128, 129 ultimate causation 9, 126–9 Ulysses (James Joyce, 1922) 25 uncertainties see ambiguity; deceptions Uncertainty Principle (Heisenberg) 25, 76, 84, 118, 249 unconscious mind 220 unicellular state 55 consciousness continuation 111, 112 quantum mechanics 111

existence for 3.8 billion years 189 Gaia concept 154, 155 origins 2 perpetuality 249–50 phenotype as agent 78 prehistory 83, 84–5 proximate-ultimate causation 9, 126–9 return to during life cycle 95 see also zygotes

Unifying Biology (Smocovitis, 1996) 126–7

“universal sense-awareness” (Whitehead, 1920) 170–1 universe point source see Big Bang/Singularity uranium 22–3 vagus nerve 77, 147 valence bond theory 186 vascular system adrenal medulla 77 β-adrenergic receptor duplication 66, 163 development/homeostasis 64, 65 water-land transition 59, 65 see also hearts

vectoral origins of Periodic Table/Evolution 131–9 vertebrates evolution brain 47 cell–cell communications 9–10

middle ear bones 13 see also humans; water–land transition

virtual reality, moral behavior 87 vision, human 167 Waddington's “diachronic perspective” 12, 62–3, 78 Walden (Thoreau, 1854) 228 warm-bloodedness see endothermy water-land transition 8–10 adrenal corticoid synthesis 67–8 aging as loss of cell–cell signaling 98 deuterostome morphogenesis 93 endothermy evolution 77 five attempts 163 Goodpasture syndrome 9, 128–9 Hobson & Friston's brain cooling concept 105–6 homeostasis 64 iodine-rich seas to iodine-poor land 145 lung/kidney evolution 13, 47, 106, 127–8, 162–3 organ remodelling 65–8 PTHrP signaling 49, 65–6, 67, 106, 128, 149, 161–2, 249 stretch-regulated surfactant system 47, 55, 66, 146, 161, 162 see also parathyroid hormone-related protein (PTHrP) receptor

wave functions, Fuchs’ Bayesian probabilities 178 wave/particle duality 12 Wayfinding (O'Connor, 2019) 155 weather systems 224 Weibel's “symmorphosis” (2015) 48–9 What is Life (Schrödinger, 1944) 237 Whitehead's concept of nature 212 Whitehead's “consciousness” 170 Whitehead's Process and Reality (1929) 235, 237 Whitehead's “process theory” 56 Wholeness and the Implicate Order (David Bohm, 1980) 22, 42, 110 empiricism 42–3

William of Occam 34 Williams’ “antagonistic pleiotropy theory” (1957) 92 Wilson's “consilience” (1998) 1, 3, 16, 136, 241

Wingless/Int expression, aging loss of homeostatic control 99–100 The Wisdom of the Body (Claude Bernard, 1963) 60–1 Wittgenstein's “logical space” concept 223 Wittgenstein's Philosophical Investigations (1953) 232, 237 Wolpert's “importance of gastrulation” 86, 123 World War I 235 World War II 237, 240 world-views “The Two Images Problem” (Sellars, 1963) 211 see also The Bifurcated World; Dynamic World Picture; Layered World Picture

wound healing 24, 43 Xenopus lung 128 Xeno's Paradox 230 yeast 74, 75, 122 zygotes aging process, phenotype as agent 95 epigenetic marks 64, 120 retention/disposal 193–4, 197

information sharing/handling 194 phenotype as agent  6 protostomes/deuterostomes 142–3 unicellular recapitulation reframing 193 see also unicellular state