On the Path to Health, Wellbeing, and Fulfilment [1 ed.] 1527574768, 9781527574762

This compelling book on health, wellbeing, and fulfilment investigates the scientific basis of what we think we know abo

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On the Path to Health, Wellbeing, and Fulfilment [1 ed.]
 1527574768, 9781527574762

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On the Path to Health, Wellbeing, and Fulfilment

This book explores health from a variety of perspectives. Interpreting scientific studies and communicating the findings in an easy to understand way is a gift that keeps on giving. To Your Health will help readers appreciate the importance of research, genetics, environment and lifestyle factors in everyday life and when working through complex medical conditions. —Beth Frates, MD FACLM DipABLM President-Elect American College of Lifestyle Medicine Clinical Assistant Professor, Harvard Medical School

An insightful, timely work on what determines our very well-being. —David Robert Grimes, PhD

In To Your Health, Dr. Iris Schrijver provides insight and commentary on how the medical community often fails to effectively communicate what is known about the prevention and management of disease, and how this failure impacts health disparities by race, ethnicity, education and socioeconomic status. Dr. Schrijver takes an in-depth and science-based look at what makes us thrive in body and mind and helps us apply a critical lens to market-driven fads. A must-read for medical providers and anyone interested in sorting fact from fiction in the search for better health and well-being. —Martha L. Spiers LCSW, Executive Director Clackamas Volunteers in Medicine

In “To Your Health“ Dr. Schrijver gives thoughtful and well-documented consideration to the things in our lives that influence our health and happiness. We can’t control all these things, but Dr. Schrijver shows how we can control our responses, to our inner cravings, to the things that cause us stress, and to information (and the abundant misinformation) surrounding us in both traditional and social media – misinformation that is intended, in many cases, to make others rich at our expense. “To Your Health” is an exceptional book that is well worth your time. —Timothy J. O'Leary, MD, PhD, Adjunct Professor, University of Maryland School of Medicine. Former Editor In Chief of the Journal of Molecular Diagnostics; Former Chief Research and Development Officer, Veterans Health Administration

On the Path to Health, Wellbeing, and Fulfilment: To Your Health By

Iris Schrijver

On the Path to Health, Wellbeing, and Fulfilment: To Your Health By Iris Schrijver This book first published 2021 Cambridge Scholars Publishing Lady Stephenson Library, Newcastle upon Tyne, NE6 2PA, UK British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Copyright © 2021 by Iris Schrijver All rights for this book reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the copyright owner. ISBN (10): 1-5275-7476-8 ISBN (13): 978-1-5275-7476-2

To Karel, who illuminates the universe and makes the world turn my way

TABLE OF CONTENTS

Introduction: Setting the Stage Introduction ................................................................................................ 2 Part I: Foundations of Health Chapter One .............................................................................................. 10 A fountain of information - How barriers to obtaining accurate information shape health decisions Chapter Two ............................................................................................. 20 In the know - How knowledge is classified and how it affects health and wellbeing Chapter Three ........................................................................................... 32 Know way - How cultural beliefs influence what is perceived to support health Chapter Four ............................................................................................. 43 Under the influence - How pseudoscientific notions and cognitive biases influence which health-related information is trusted and used Chapter Five ............................................................................................. 53 Rising to the bait - How subconscious bias and advertising strategies apply to health and healthcare Chapter Six ............................................................................................... 64 So what, who cares? - How the sources of health information impact outcomes Chapter Seven........................................................................................... 75 Public relations - How the value of science can be communicated effectively

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Table of Contents

Chapter Eight ............................................................................................ 87 Healers in the making - How information, knowledge, understanding and wisdom enabled the development of the evidence-based scientific method Chapter Nine........................................................................................... 100 Science, not fiction - How the medical scientific process provides validity that can separate correct from incorrect understanding Chapter Ten ............................................................................................ 114 Windows of opportunity - How research opportunities depend on a multitude of factors, including the public perception of science, financial resources, and bias Part II: The Science of Health and Wellbeing Chapter Eleven ....................................................................................... 128 What is health? - How the fluid and dynamic concepts of health and wellbeing relate Chapter Twelve ...................................................................................... 141 The instruction manual - How genetic makeup influences health and disease, and how it compares to the contribution of environment and lifestyle Chapter Thirteen ..................................................................................... 154 Keeping it together - How the process of homeostasis works and what happens when it fails Chapter Fourteen .................................................................................... 165 The matter of the mind - How current science challenges the dichotomy between body and mind Chapter Fifteen ....................................................................................... 180 Of pills and potions - How placebos, nocebos, pharmaceuticals and dietary supplements relate to health and disease Chapter Sixteen ...................................................................................... 193 Stressfully yours - How stress affects health, disease prognoses, health outcomes, and willpower

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Chapter Seventeen .................................................................................. 207 Diet or bust! - How global lifestyle changes have altered our relationship with food and resulted in a chronic disease epidemic Chapter Eighteen .................................................................................... 219 An ounce of prevention - How lifespan and healthspan can be improved with positive lifestyle changes Chapter Nineteen .................................................................................... 233 Alternative medicine - How complementary and alternative health practices can help or harm health and wellbeing Chapter Twenty ...................................................................................... 249 Are you happy yet? - How happiness contributes to health and longevity Conclusion .............................................................................................. 264 A Time of Hope Bibliography ........................................................................................... 267 Index ....................................................................................................... 307

INTRODUCTION SETTING THE STAGE

~Vade mecum~ [Go with me]

INTRODUCTION

You, I envision, are a reader with an open mind who is curious about what (at present) is known and not known about wellbeing and health, and, perhaps most importantly, how that knowledge can be applied in your own life. My assumption is that most people share the goal of wanting to live as long as possible while feeling as well as possible. With that perspective, people should care about the prevention of illness because of their desire to enjoy life, to feel good, and to be healthy. This basic aspiration does not depend on age, gender, identification, geographic location, what or who we worship or bow to, how we were educated, or what our social status is. It is a fundamental desire that is given meaning and substance by every single one of us, in our own unique expression of being human in this world. We all live in a global culture where health and wellbeing are not systematically supported and universally embraced. And yet, if we want to be happy and live our best life, we need to learn about health and wellness and make room for personal growth. It is my sincere wish that this book empowers you to think critically and to make informed decisions about your health based on facts instead of speculation or manipulation, no matter how compelling their packaging may be. Your choices can make a big difference: it has been estimated that genetic information determines no more than around a quarter of the variation in human lifespan and only about a third of your sense of happiness. Genes alone do not determine destiny! What you do and what you know about food, physical activity, social connection and other aspects of your life and lifestyle has consequences. And although far from everything in life is a matter of choice, you can make a positive difference in your wellbeing by taking care of your body and mind as best you can. I am honored that you chose this book and that you are joining me on a journey of understanding and insight based on breakthroughs from the world of health and wellness science. In the past few decades, information has become abundant and accessible. However, the application of knowledge and wisdom has not kept up with the pace at which information is produced. In other words: being “wellinformed” has no direct bearing on whether the information that we are informed by is actually trustworthy. This discrepancy may go unnoticed for

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quite a while in the busyness of daily life, but when health and wellbeing are at risk, the stakes are high. Knowing what is for real and what is incomplete, irrelevant, inaccurate, uncertain, or just plain wrong may well become a matter of life and death. Precisely because of the spread of misinformation, some people have not participated in safe infectious disease prevention programs. As one consequence, measles has made a come-back to regions of the world where it had been eradicated. It is causing illness there once more, and a tragically unnecessary loss of lives. False information also causes people to place their trust in practices and products that are advertised to benefit health but not verified for their claims. These are not only unproven to work, but they can also cause considerable harm without the provision of disclosure of that risk. These are just two examples, but many more are covered in the book that you are about to read. Along the way, the big questions that remain and those that are newly formed are both acknowledged and explored, while claims built on quicksand are exposed. I hope that this book contributes to demystifying research and science. Research is the endeavor of systematic studies through experimentation, observation, and analysis. Science is a process too, but it develops out of the integration of novel findings with other research findings. Only then can we arrive at a more complete and advanced body of knowledge and possible application of new understanding. Science is not easy, but it certainly can be made accessible, and to appreciate exciting developments one need not be a scientist. Physicist Oliver Heaviside (1850-1925) made the point by saying: “Am I to refuse to eat because I do not fully understand the mechanism of digestion?”1

It is a good point! In order to marvel at nature’s surprises and new technology that drives the progress of our understanding, it fortunately is not a prerequisite to understand how science works. It is, however, certainly helpful to know something about the process that defines the path of scientific inquiry because it clarifies that science is not only a method of solving questions but also a way of thinking. It is a way of edging our way forward into unknown territory. It is a path with many dead ends and with ample detours, on which one encounters obstacles that stand in the way of understanding. At times, scientific discoveries result in premature conclusions and it takes the building of a strong body of knowledge before something can be

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Introduction

considered proven. Scientific uncertainty is an almost constant companion on the path to knowledge. This inevitable degree of uncertainty, which becomes proportionally smaller with growing evidence, is an especially challenging aspect to communicate. When taken out of context, scientific uncertainty may be misinterpreted as an ever-present flaw of science and, in response, solid scientific evidence may be categorically rejected (to the detriment of rational thinking, I might add). It may also be promoted nefariously as a lethal flaw, by influencers with an anti-science agenda. Tragically, this can negatively impact the health and wellbeing of many. Naysayers who maintain untenable positions in the face of overwhelming evidence to the contrary may spread their statements widely enough to draw a following of people who are unaware of the fantastic misinformation that is being pressed upon them. A review of the foundation of knowledge and the contribution of early science to the development and evolution of that knowledge enables a fresh perspective on science today. And it is important to understand that there is a difference between information and knowledge. To that, I would like to add a quote by Dr. Martin Fischer (1879-1962), who said: “Facts are not science, as the dictionary is not literature.”2

Science continues to build on what can be objectively verified and rejects anything that has been refuted. Science in any discipline is a complex process that is frequently slow but every now and then surprisingly fast. I hope that I can take away the veil that too often seems to shroud the topic, as it is exactly the sound basis of logic that should provide both confidence and assurance. I readily admit that science does not have all the answers. In part this is because it does not have them yet, and in part because (I strongly suspect) there will always be phenomena that remain unexplained. And that’s okay. Whatever the categories and classifications into which we put our knowledge today, truth is something that emerges gradually. In this continuous process, the importance of a mindset of wisdom should never be underestimated. Wisdom and its traditions also have an important role in health and wellbeing, without the need to be perceived as separate from science or conflicting with it. This, however, is a reality that is commonly overlooked. Whereas science can seem abstract, it helps shape our world and health. It provides a foundation for wise choices and gives us the tools to recognize the best insights of our time among the noise of loud and famous voices that

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offer mere opinions. By using scientific studies to assess the current state of knowledge, it becomes clear what is supported by evidence and where the gaps are. This book shines a light on information about wellbeing and health, and, as such, it is a tool that helps distinguish fact from fiction. Instead of being a “how-to” guide, the book offers a roadmap to help navigate the available information on a wide range of health and wellness topics. Along the way, it reveals the process of scientific discovery and the subsequent path of inquiry that probes whether newfound knowledge can stand the test of replication and of time. It also addresses the challenges that exist between knowledge in its scientific form and the way in which it is presented to and understood by nonscientists. If we want to understand health and wellbeing, it is important to consider what these terms mean to different people and whether these concepts change in different phases of life. There are many definitions of health, but for the purpose of this book I use a working definition of health as the largely objective state that can be measured and thereby allows comparison of one person to others. For the concept of wellbeing I use the working definition of a primarily subjective appraisal that reflects where someone is now, compared to where that person would like to be. I acknowledge that health and wellbeing can be assessed only to a degree. They are both also intrinsically subjective. The role of wisdom, culture, traditions, and personal preferences can not and should not be ignored. Thus, while we go ahead and ask the big questions, I suspect that some of your answers to them will be deeply personal. An exploration of health and wellbeing is an invitation to look at the influence of lifestyle and genetics, and at how the human body performs the miracle of continuous metabolic balancing; to explore mind-body connections, the use of medications and supplements, the influence of stress on wellness and how it can benefit or erode health; to delve into the merit of diets, look at prevention of illness, put alternative medicine in the spotlight, and to examine the role of happiness. What makes us thrive? What makes us tick? What do we factually know, and what seems plausible enough but has been refuted? It may seem ironic that a pathologist writes a book on health and wellbeing, as the traditional focus of this medical specialty (and almost all others!) is on disease, but we live in a time where that focus is, at least in part, beginning to shift. This motivated me to become a lifestyle medicine doctor. With my immersive work in medical practice and science on the one hand and the recent realization by researchers and doctors that someone’s lifestyle has major

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repercussions for the development of disease on the other, I have become fascinated by the intersection of health and disease, the tipping point between well-being and dis-ease. There is a slow but unprecedented change in medicine that is moving the focal point of medical care from the management of disease toward the improvement and maintenance of health and wellness. With that comes a greater emphasis on prevention and (partial or complete) reversal of lifestyle-driven chronic diseases that now account for the majority of premature deaths globally. The measures we can take to improve and maintain health throughout life include personal choices, but reach all the way into the social fabric of our world, including global politics and economies of scale. The book would not be complete without a critical look at contributing factors at those levels, too. This book has two main parts. In the first part of the book, I look at the foundation of knowledge in a variety of different ways. Some of the posed questions are: What constitutes knowledge? What do you know for sure? What prevents us from questioning the validity of cultural beliefs? What is the vitally important role of wisdom? How are we influenced by biased thinking? What shapes choices and preferences? Does science impact regular life, and if so, how relevant is it? And what checks and balances exist in research? The second part of the book uses the foundation of knowledge as discussed in part one to delve into questions around specific health and wellness topics. Questions covered there include: What is health? What is the contribution of nature versus that of nurture, and to what extent do genes determine fate? What, if anything, is the difference between body and mind? How are medications different from dietary supplements? How are stress and willpower connected? What does it mean to have a healthy relationship with food? Does money buy happiness? And does happiness influence health and longevity? Every chapter begins with the overarching questions it raises and ends with a summary of the key points of that chapter. Toward the end of the book, the bibliography discloses some of the many sources of the information contained in this book, as well as resources that may be the most helpful for you and other readers. Finally, I need to point out that, in illustrative stories that involve actual people, some names and circumstances have been changed to protect privacy. Just as life is a journey, health is a journey. No matter where we are today, that point is the start from which we each, and together, take the next step

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forward. On that journey, we have one day at a time. Every day is an opportunity to align our internal values and our intentions, our realities, and our potential. An intentional life is a life of purpose that includes attention to the health and wellbeing of ourselves, those we know, and even those we do not know among humans and across species. Take good care of yourself. You are worth it. And, more than that, your life may well depend on it.

PART 1 FOUNDATIONS OF HEALTH

~Non scholae, sed vitae discimus~ [We do not learn for school, but for life]

CHAPTER ONE A FOUNTAIN OF INFORMATION

How barriers to obtaining accurate information shape health decisions

·

Within the profusion of information about health and wellbeing, how do we know what is accurate, relevant, and complete?

·

What are the risks when we trust information that is not valid or applicable?

·

Why does information from doctors not always come across?

·

How can health information be communicated to be effectively heard?

It was quite early in the year and a wonderfully sunny day in Portland. Eager to emerge from the rainy winter season that is typical for the Pacific Northwest, people flocked outside to enjoy the unexpected warmth. Exactly this was my intention too. The small restaurant where I ventured to have lunch that day certainly seized the day. The tables on its tiny patio had been placed so close together that one could barely squeeze between them. This was in 2019, well before the physical distancing requirements of the COVID-19 pandemic, and the setting reminded me of my recent visit to France. There, often every square inch of a restaurant was used to maximize

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occupancy so that dining became an unintended communal experience. It was quite intimate, yet in the hustle and bustle of the cozy Parisian cafes, nobody seemed to be bothered by a lack of privacy. Next to me, two women were engaged in lively conversation. The topic: Experts. One of them, a professional woman in her thirties, talked about how she had roamed the self-help section at a local bookstore only to become frustrated by the vast offerings of what was, in her assessment, “socalled expert advice”. Apparently, it was not only bewildering in its abundance but also often contradictory in content. I admit that I was eavesdropping, and as a matter of fact did so with considerable interest, although it would have been impossible to block out their exchange in any case. “I looked at so many books and in the end I just left without buying anything,”

she said. “The typical story is that these experts went through some difficult experience. Something life-changing happened to them, and somehow they found a way out of it that worked, for them. Of course, that automatically makes them the expert…Now they think they have a calling and can apply their solution to everyone else and tell you what to do. But I am not them. As if one size fits all!”

When my friend arrived my attention refocused, but the sentiment of the woman’s confusion and her consternation about experts and their expertise stayed with me. She was overwhelmed by choice and did not know how to determine the actual substance and validity of all the divergent advice offered. It resonated with me. Especially in the area of health and wellbeing, there is a profusion of information, and trying to take it all in can feel like taking a drink from a spouting garden hose. This is not to say that there cannot be a positive outcome or genuine improvement from reading a book that is written by someone who overcame a profound personal experience and who subsequently chose to share the pearls of wisdom of this life-changing episode with others. First-hand experience can make a story much more powerful and solutions categorically compelling. And because the journey becomes a shared one, you as a reader, facing a similar issue or related questions, inevitably feel that you are not alone. My own saving grace in a period of anxiety in medical school (which, as it turns out is not uncommon, but, in my early twenties, felt pretty

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alarming and isolating) was a wonderful book: “Anxiety & panic attacks – their cause and cure”, by Robert Handley and co-authored with Pauline Neff.1 It was not only a great comfort during that difficult time but, by outlining a simple program of desensitization, it was effective in helping me manage my fears. That book was invaluable for me on my chosen path of becoming a doctor and enabled me to manage the unavoidable pressures of medical school. Finding the right resource can be quite a challenge though, as we may not see the forest for the trees. My neighbor at the Portland lunch place found that out for herself. How do we even begin to filter the abundance of advice so that we can extract information that is relevant to us, as well as accurate and complete? How do we know what of this copious information is based on factual knowledge and what is personal opinion? What constitutes experience and expertise that can be widely applied? How do we discern what is helpful versus harmful? And where does wisdom come into all this? The traditional way to receive answers regarding health and wellness is from physicians and other healthcare professionals. And even though this can be an excellent way of receiving reliable advice, there are plenty of reasons why interactions of patients with their doctors can be frustrating, causing people to seek their answers elsewhere. In a time when we have loads of information and few filters, cognitive flooding not only happens to laypeople but to their doctors, too. Physicians and other healthcare providers experience the pressures of a shortage of time, and yet face growing expectations of being able to provide instant answers. This combination results in patient-doctor interactions that often are not optimal for either party. Aware of their limited available time for each patient encounter, physicians feel pressed to be as efficient as possible within each brief time slot. One way of doing this is to determine their patient’s concerns as expeditiously as possible. Often, nowadays, a physician will have reviewed the reason for a patient’s visit in advance and is likely to assume that such notes, frequently taken by staff when the appointment was made, reflect the main motive for the visit to the doctor’s office. Of course, this could be an erroneous assumption if the patient was not comfortable disclosing the most important concern in advance and to a stranger! Doctors rely heavily on the minimal information available in advance of the visit.2 One study found that only around half of the time primary care physicians specifically asked about what brought their patient in that day. In specialty care settings, that fraction was even lower. There, it dropped down to one-fifth of patient visits, possibly because a referral to a specialist

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is more frequently focused on a well-defined medical complaint. Not eliciting the patient’s agenda during the visit, however, is at odds with basic medical training, which includes education on the importance of good communication, and addresses the fact that meaningful conversation between doctor and patient is critical to building trust. It also can be inherently therapeutic. We all have been there: being heard by a physician who is responsive to our concerns is a hope and expectation in each patientphysician relationship. The study made another interesting observation: patients were given a median of just 11 seconds to tell their story before the clinician started speaking. If that seems extremely short to you, I would agree! The study was not very large and the times ranged from three to 234 seconds overall.2 Still, it seems that in the rush to provide solutions, important aspects of patient-centered care are sometimes lost, especially with interruptions that take place very early during the conversation. Apart from time pressure during medical appointments, there is also a growing information component to each visit. Patients ask more clinical questions than in the past, and whereas in general this is a very positive development, it comes with a need for physicians to accomplish efficient and effective retrieval of relevant medical information to answer these questions. In the ever-changing field of medicine, doctors need to make sure that they have current knowledge and that they can make the most pertinent information available to their patients. Physicians report that they spend substantial additional time searching for information and that much of this searching is done online.3 Fortunately, this has not replaced traditional methods of communication: doctors still rely on consultations with colleagues, especially for complex clinical questions that require a highly specific, tailored approach that falls outside the scope of routine medical issues with well-defined solutions. In such cases, the clinical insight from a peer with experience in a particular medical area can be extremely helpful. At the same time, technology use is expanding and new methods of information delivery are increasingly utilized in addition to more traditional means of gathering knowledge. It is undeniable that a quick internet search can be very useful, critical even, for both healthcare providers and anyone in the community, but the source of the information is key: it needs to be transparent and reliable because the consequences of misinformation may be serious. Medical journal articles, frequently available online but rarely freely accessible, remain the gold standard for reputable, up to date information for physicians and, by

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Chapter One

extension, their patients. Other sources that are highly regarded by doctors include certified courses for continuing medical education and medical practice guidelines, many of which are available and accessed through various technological means as well. Unfortunately, for any given person who seeks information from a variety of sources, it can be challenging to discern the foundation and legitimacy of found advice, especially in areas for which we do not have specific training. Of course, this is why we rely on experts in the first place! Just as with general information, however, or perhaps even more so, this concern is paramount in the context of health. Which experts offer valid knowledge? Who should you trust? After all: inaccurate, irrelevant, or incomplete information can negatively impact health and wellbeing, despite the best intentions. We live in a time of continuous access to information, and yet so much of it is distracting, useless noise. As just one example of this, Dr. Daniel Levitin, author of “The organized mind: thinking straight in the age of information overload”, acknowledged that “The past generation has seen an explosion of choices facing consumers. In 1976, the average supermarket stocked 9,000 unique products; today that number has ballooned to 40,000 of them, yet the average person gets 8085% of their needs in only 150 different supermarket items. That means that we need to ignore 39,850 items in the store. And that’s just supermarkets...”4

Apart from the sheer amount of distractions in long isles of colorful cereal boxes and other areas of the grocery store designed to entice us to buy more, filtering that which is helpful from that which is not actually deserving of our attention can be a time and energy-consuming task in many activities of our daily lives. Levitin goes on to say that “In 2011, Americans took in five times as much information as they did in 1986—the equivalent of 175 newspapers. During our leisure time, not counting work, each of us processes 34 gigabytes or 100,000 words every day. The world’s 21,274 television stations produce 85,000 hours of original programming every day as we watch an average of 5 hours of television each day, the equivalent of 20 gigabytes of audio-video images. That’s not counting YouTube, which uploads 6,000 hours of video every hour. And computer gaming? It consumes more bytes than all other media put together, including DVDs, TV, books, magazines and the Internet.”4

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Considering that these data are from 2011, the relentless stream of information will be even larger today. Not that I long for years past, when information was not literally at our fingertips… I remember the days when I would go to the university library and needed to find the topic of interest on cards, in index volumes of keywords, with the help of a kind librarian, or by using a very basic computer search. It was a tedious way of finding book chapters and scientific articles and it required wading through volume after volume of hard copies of journals and books. That approach was timeconsuming too, and definitely less convenient. Nevertheless, information overload is our constant companion and good judgment is an exercise in self-discipline. Given the abundant information available on virtually any topic, there seems to be a paradoxical hunger for information on how to optimize health and wellbeing. The online offerings are vast, as are the bookstore sections of self-help literature and other books on healthy living, improving wellness, and happiness. Just over the past decade on Amazon alone, comparing 2008 to 2018, the number of books on health has tripled from 20,000 to 60,000.5 The keywords “happiness” and “diet” each result in a tenfold increase in books offered on Amazon, from about 2,000 to 20,000 and from around 3,000 to 30,000, respectively. Perhaps a robust supply and demand in the sphere of healthy living should not be surprising, given that we (need to) accumulate most of our knowledge about this in adulthood. The curriculum in schools does not usually include much practical education on health and wellness. As a result, unless we are fortunate enough to have parents who model good health-behaviors, most of us are not equipped with the tools for lifelong wellbeing early in life, when it would be most helpful to establish such knowledge together with health-promoting habits. The level of received education does come into play, but not directly: people with more advanced education and higher incomes are known to have better overall health.6 This is evidenced by many indicators, including life expectancy. According to the annual report prepared by the Centers for Disease Control and Prevention (CDC)’s National Center for Health Statistics in 2011, data from 2006 indicated that 25-year-old women and men with a Bachelor’s degree or higher had an average life expectancy of 8.6 and 9.3 years more, respectively, than those without a high school diploma.7 That is a big difference. Education level is also predictive of higher socio-economic status8 and associated with lower risk factors for poor health such as obesity and smoking. In addition, chronic conditions are less common in people who have received more education.6

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Chapter One

It would be a crude oversimplification to conclude that this positive association between level of education and health necessarily or largely resulted from more actual schooling on health issues. There is much more to that: health status and inequities depend on numerous factors, only one of which is education. They also include race, sex, early development, employment, income, degree of social integration or exclusion, and access to healthcare. According to the World Health Organization, the social determinants of health are those conditions in which people are born, grow, live, work, and age. These, in turn, are determined by how resources, money, and power are distributed locally, at the national level, and globally.9 Health literacy, generally defined as the skills and abilities to gain access to, understand, and use health-related information,10 is another factor that influences the likelihood of health and wellbeing. It is only one aspect, but it ties back to many of the determinants just listed. And whereas general illiteracy in the U.S. and other industrialized nations is uncommon, reading skills do influence how patients understand medical information. Many people struggle with this, both when such information is spoken and when it is written down. Not surprisingly, comprehension of health information is strongly linked to health outcomes11 because it involves the entire spectrum of communication between individuals and the healthcare system. Such information includes guidance on disease prevention and screening, education on health behaviors, and the explanation of a newly diagnosed disease. Patients may struggle to understand medication and treatment plans, but also be unclear on the management of a chronic disease, which in turn can hamper improvement or obstruct it altogether. For many people, the entire healthcare system is difficult to navigate. This may allude to less-than-ideal education systems, but to be fair: the health information given to patients and the general public is often simply too difficult. It is frequently issued in complex language and presented in a way that exceeds the reading proficiency of average people with a high school diploma.10 Why is that the case? Healthcare providers are not trying to do a disservice to their patients, but providing effective, actionable information at a basic level requires a skill that their training did not focus on. It takes more than time and compassion: in the fast-paced world of medical care, it actually takes additional effort to avoid jargon and to provide key information in uncomplicated layman’s terms. This is an experience Dr. Ellen Jo Baron can speak to. She is a clinical microbiologist with a tremendous passion for her work and a former

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medical director of the leading-edge microbiology and virology laboratories at the Stanford University Medical Center, where I had the pleasure of working with her. Together with her colleague Dr. Jim McLaughlin, in 2008 she cofounded a nongovernmental organization, the Diagnostic Microbiology Development Program12, to set up basic microbiology laboratory testing in Cambodia. After her return from Southeast Asia, she shared with me how challenging it had been to keep the educational content for Cambodian hospital workers completely clear and stripped of all unnecessary frills. After consulting with local hospital staff, she organized hands-on instruction by highly qualified medical technologists, and ultimately devised visual flow charts with straightforward images of the process of bacterial culture, so that infections could be identified properly. Healthcare in Cambodia has extremely limited resources, and previously even basic approaches to diagnostic microbiology were not available. Consequently, infections were often not diagnosed or not treated correctly, because the means to establish what caused the disease and which antibiotics would be able to eradicate the infectious agents were unavailable. Patients could have complications and even perish from very treatable infections, given knowledge and resources. With Dr. Baron’s efforts and her direct involvement, microbiology laboratories were established in multiple hospitals, as well as a reference laboratory service for infections that were difficult to accurately characterize. Her contribution to patient care in Cambodia has been vital to the improvement of the country’s healthcare and is inspiring. It also highlights how important it is to overcome the language barrier, which can be caused not only by speaking different languages in the literal sense, but also by differences that amount to another type of language barrier: that between those who know the medical vocabulary and those who do not. I like to think that I am tuned in to culturally sensitive patient care, but must admit that I have been guilty of “medi-speak” myself: at Clackamas Volunteers in Medicine13, the free clinic where I work to provide medical care to un(der)insured patients, I wanted to put together a handout for patients with diabetes so that they could understand the meaning of a laboratory measurement for long-term blood sugar control (HbA1C). I wrote it in what I considered easy-to-understand language, covering everything I thought would be good to know and helpful to grasp. Then, I asked our staff and volunteers, some of whom were native English speakers whereas others were not, to read it, and to let me know their thoughts. The feedback I received was kind but clear: yes, it provided an explanation of

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Chapter One

what the measurement was based on, of what happened in the body, and of how it impacted health in the long run, but it was far too detailed, with difficult words and without any visual context. Furthermore, it did not explain in a compelling way why the patient needed to take action today or should care to remember this in the future. In other words, it failed to bring home how this measurement would be important in daily life and relevant in the long term. My initial response was surprise, but when I looked at it again I realized that their comments were spot-on. Our clinic manager soon found some example images that explained the same thing in a way that was much easier to comprehend for all patients, regardless of education level or language background, and we are now using a handout she designed, unless someone wants to have more background information. As you can imagine, only a very small minority of patients shares my fascination with the chemistry that takes place on a subset of cells in the body! The bottom line is this: unless healthcare providers and healthcare facilities become true partners to patients and reduce barriers to understanding, literacy-related obstacles to improving health will remain. But health communication finally does receive systematic attention11 and it is now understood that it must be addressed beyond the written and spoken word. Signage in healthcare facilities, the environment of a medical practice, and navigation of the overall healthcare system are being evaluated as well, and hopefully will be improved. Change takes time, however. And when the medical process is perceived to be confusing, people either give up altogether or try to find information they can understand. After all, there is an abundance of information available on the internet and on social media, and finding something, anything, on a topic of interest is easier than ever. The big challenge remains to differentiate helpful from unhelpful or even perilous information. Which brings us back to experts… A few days before her 61st birthday, novelist and non-fiction writer Anne Lamott wrote down some things that she knows for sure. In her talk: “12 truths I learned from life and writing” she shared that one of these is that “Everyone is screwed up, clingy, and scared, even the people who seem to have it most together. They are much more like you than you would believe, so try not to compare your insides to other people’s outsides.”14

Her point is well-taken. Our personal work, whatever it is, is an inside job, and perfection does not exist. The celebrity status that is bestowed upon some experts, or that some so successfully project about themselves, is best viewed with a healthy dose of skepticism.

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Long before Anne Lamott’s insights, Franklin D. Roosevelt in a speech from 1942 remarked: “There are as many opinions as there are experts”15

and that, for sure, has not changed. Opinions can provide a starting point, but ultimately our goals must be supported and advanced by information that is accurate and applied in the right context. As my neighbor at the restaurant lamented, there is no solution that necessarily fits all. This is certainly the case for many dimensions of health and wellbeing. On the positive side, there is a vast sea of knowledge that, when navigated well, can inform sound decisions. Unfortunately, a lot of beacons in that sea look deceptively real, but are not going to give us safe passage through the shallows… Key points: G There is a profusion of information in the area of health and wellbeing. Some is factual and some is personal opinion. Some is spot on, but some is unreliable, not applicable, or incomplete. G Misinformation can be detrimental to health and wellbeing. G Physicians are recognized health experts, but interactions of patients with their doctors can be frustrating, confusing, or just too fleeting, causing people to either give up or seek their answers elsewhere, in information they can understand. G How well we understand and evaluate information on health is strongly linked to health outcomes. If healthcare providers and healthcare facilities reduce barriers to understanding, obstacles to improving health can be reduced.

CHAPTER TWO IN THE KNOW

How knowledge is classified and how it affects health and wellbeing ·

What constitutes knowledge?

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How can different kinds of knowledge be distinguished?

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Why is knowledge important and how does it influence health and wellbeing?

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What is the advantage of gaining knowledge and what are its limitations?

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How does knowledge change over time?

Knowledge is a funny thing. It can be perceived as an absolute and final body of understanding but in actuality it is fluid, expanding or changing as additional facts are discovered. It is something that can be tested in a person but remains elusive, intangible in its actual extent. The development of personal knowledge takes effort for each and every one of us, yet it can be lost suddenly, in an instant, or fade gradually over time when it is not maintained. Like those dark corners of a house that, when rarely visited, accumulate dust and cobwebs and no longer shine for lack of upkeep. Sometimes we can still retrieve something from a box in one such corner of an attic, but when we try to find it we do not recall exactly where the box was stored among all the other stuff we planned to organize on a

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rainy day but never did, and we don’t have the faintest idea of what else is, perhaps, inside that box, so the search takes a long time. And what is knowledge, in the theoretical and in a practical sense? Its meaning has been debated over many centuries and knowledge has been defined in myriad ways. By now, knowledge has been categorized into so many different lists that it seems unlikely that there will ever be a consensus. Those who may know the most about knowledge are epistemologists: philosophers who focus on the study of knowledge and the degree of its validation. The word itself is Greek and has two roots: “episteme”, which can be translated into science, knowledge or understanding, and “ology” which originates from the word “logos” that can be explained as reason, logic, or the study of a certain subject matter. Epistemologists study the nature and the extent of human knowledge and do so from the perspective of philosophy. Not surprisingly then, they philosophize…and exactly therein lies the challenge for the uninitiated in philosophical thought, and for everyone else who does not have the inclination to ponder and debate this particular area of inquiry at length, be it in general, or in its sometimes exceedingly abstract terms.1 A dictionary is more likely to provide something basic for us to start with. One dictionary definition of knowledge is “the sum of what is known: the body of truth, information, and principles acquired by humankind”.2

This description of collective knowledge seems straightforward enough in the big picture, although, as we shall see later, the interpretation of “truth” is complicated and the word represents a concept that is not necessarily fixed or permanent. Another definition of knowledge remains closer to the personal level with: “1) the fact or condition of knowing something with familiarity gained through experience or association”,

and “2) acquaintance with or understanding of a science, art, or technique”.2

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This makes sense as well: both historic knowledge and personal knowledge support the framework that forms the basis of how we interact with our environment and understand the world we live in. It is tempting to adopt the cynical view that this reliance on a limited personal framework of assumed knowledge may explain a lot of current events in the world, but a paucity of knowledge is not necessarily coupled with a lack of wisdom. So it is not that simple. Knowledge has been classified in numerous ways, depending on the frame of reference to which it is applied. For example, the succinct but sage list of categories that ancient Greek philosopher Aristotle (384-322 B.C.E.) put together was so influential that it became the foundation of later logical thought and remains relevant to this day.3 The practical knowledge applications that emerged much more recently, for instance out of the field of business management, focus more on specific frameworks.4 Let us have a look at four examples of types of knowledge – a priori, a posteriori, explicit, and tacit – that apply to ancient and contemporary ideas5, while realizing that other lists with many additional sub-categories could be made, and discussed, in perpetuity! These four examples help us understand the many different ways in which knowledge can be defined. They also illustrate that academic knowledge is only one part of the picture and that a more inclusive approach that fosters an appreciation of a broad variety of underpinnings of knowledge is likely to benefit both individuals with specific areas of expertise and society as a whole. Employers are beginning to tap into this idea, for example by considering workers with traits on the autism spectrum for specific technical roles.6 The first type of knowledge is called “a priori” knowledge, which finds its origin in the activity of reasoning and is based on some previous experience, but represents those things that can be known independently from current experience. For example, you can know that all circles are round regardless of whether your eyes are open or closed. Knowing this does not require use of the senses, although it certainly requires knowledge of the concept of a circle, something that of course you would have had to learn previously. Or you know that, if your aunt Betty died at age 88, she lived for more than 85 years. For this, you would need to know how to count, but you do not need additional experimental evidence to draw this conclusion about aunt Betty. As another illustration of a priori knowledge, if you have learned something about physics, you may know that the speed of light is fixed. If you did not take that subject in school and did not learn about it in some other way, you simply would not have that knowledge. You may also know

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that penguins are found in Antarctica, whereas polar bears live in the Arctic. This last example requires prior knowledge, but it does not come out of direct experience unless you had no knowledge of wildlife in the polar regions and learned this distinction only after making expeditions to these remote areas of the world. The second category, called “a posteriori” knowledge, is different from “a priori” knowledge because it requires some experience from which the knowledge then can be derived. It is empirical in nature and requires experimentation, observation, or another sense perception. It deserves to be noted that the distinction between “a priori” and “a posteriori” concepts is not without ambiguity and requires agreement regarding the definition of “experience”.1 After all, it can be reasonably argued that knowledge without any kind of experience is useful only in abstract endeavors such as pure mathematics or abstract philosophy, not in the empirical natural sciences or in daily life. Be that as it may, a posteriori knowledge could be illuminated by the fact that you know “a priori” that cloud conditions are variable and therefore can know only “a posteriori” that right now there is not a cloud in the sky where you are (you saw this yourself by looking up as you stepped out). Other illustrations of this type are knowing that your plane is descending (something you expect and notice toward the end of your flight), or that your bank account is currently overdrawn (after you see, with dismay, the unwelcome alert on the screen of the ATM and realize that you should not have bought that expensive gizmo earlier this month). The category of “a posteriori” knowledge also encompasses another branch of knowledge, namely the experimental knowledge that is derived from scientific inquiry. Out of the categories listed in this chapter, the probing process of science that serves to further our collective understanding fits into this category most readily, although not exclusively: other types of knowledge are also applied to the discipline of science. We return to this in chapter 9. A third category of knowledge is called “explicit” knowledge, which is used to indicate that the knowledge is organized and stored in some way and therefore can be easily passed along to others. This includes knowledge contained in books, databases, and movies, and basically anything that stores and communicates information in some way, from the manual of a vacuum cleaner to extensive works such as the Encyclopaedia Brittanica7 and Wikipedia, the multi-lingual, open and editable encyclopedia.8 But explicit knowledge is not limited to the written or spoken word. The recently

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conceived idea in the mind of a product designer who presents the first drawings of his notion at a brainstorming meeting falls into this category as well. Explicit knowledge is objective in the literal sense, captured in such a way that it is expressed and shared, or at the least contains that possibility. It is considered to be externalized, and therefore in principle accessible. In addition, it is structured, documented, and amenable to high volume, as in the case of big-data collection. The fact that it is contained and available demonstrates that it can be transferred. Education, in its essence, is transferred knowledge, and explicit knowledge frequently serves as one of its foundations. But a word of caution may be in order: explicit knowledge should not be equated with factual truth. It is quite possible to become extremely learned in something for which there is no legitimate basis at all. Our fourth type of knowledge on this list is called “tacit” (which means implicit, inferred) knowledge. This type is based on personal experience, but it differs from “a posteriori” knowledge in that tacit knowledge is acquired by building experience over time and cannot be communicated easily in words. It is, in effect, internalized, and thereby the opposite of explicit knowledge. There are many examples of tacit knowledge, from the “muscle-memory” of a gymnast to an example taken directly from my kitchen. My husband loves bread and took a course in bread baking. When he aimed to put what he had learned into practice, I came to appreciate how exacting the process of making the perfect hand-made baguette really is. In the weeks just after he took the course, the loaves of bread were, at times, poor reflections of his aspirations, but with practice and patience, he learned to “read” the dough and developed the ability to see and feel the consistency it needed to have. With that, he was able to determine the perfect timing for each of his steps in the bread-baking process. Because of the trade skills he gained over time, we could enjoy consistently delicious French bread regardless of the outside temperature, the level of humidity, and the legion of seemingly mysterious factors that can influence the outcome of a baker’s endeavor. These four types of knowledge are examples of the numerous ways in which knowledge can be categorized, and of the diverse dimensions that knowledge can have. The categories do not preclude a possible overlap of these dimensions. They also do not solve the existing controversy of what, exactly, belongs were. Instead, my intent is to use these categories as examples of how one can think about knowledge. The four classifications

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may not explain every kind of knowledge mentioned in this book, or encountered in our lives, but they can stimulate a different way of thinking about what knowledge (such a deceptively simple term!) may be, and why it is important. Because there is much more to knowledge than definitions and classifications, we now turn to its practical application, and look at how knowledge affects our lives. Knowledge, or even perceived knowledge, results in effects, for better or for worse. One of my favorite things that Francis Bacon never actually said but that is often attributed to him is that “Knowledge is power.”9

The more appropriate reference is an essay from 1870 by Ralph Waldo Emerson, in which he wrote: “Skill to do comes of doing; knowledge comes by eyes always open, and working hands; and there is no knowledge that is not power.”10

Regardless of who in fact said it and used it best, this perception was instilled in me early, because education was a highly held value in my family. Especially my grandmother and my mother were strong role models in this regard: both wished for me that I would have the opportunity to pursue higher education because their circumstances prevented them from realizing that dream for themselves. My amazingly resilient grandmother Anny, who lost all of her worldly belongings multiple times during her lifetime as a result of the twentieth century World Wars and Cold War in Europe, always impressed upon me to study hard, because, as she believed, “nobody can take your knowledge away from you”. She was born in 1911 into a prosperous family, and in her teenage years her father decidedly discouraged her from pursuing anything beyond basic education, because, he explained, she did not need it... She, he assured her, would be able to live off the interest earned on the family’s assets for as long as she lived. What a rude awakening it must have been to end up with little education and completely penniless after all the cruel hardships of war! Just before the beginning of World War II, Anny was married to Rudi, a successful engineer who adored her, and for a few years they enjoyed a happy life. Their bliss, however, was not to last. At the beginning of the War he became gravely ill with Hodgkin’s lymphoma, a type of cancer that can be successfully treated today, but that was incurable in the 1940s. It was a

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time when the prognosis of a deadly disease was not usually openly discussed with the patient, so my grandmother was taken into a separate room and informed that it would take only days, weeks, or at best a few months before her husband would pass away. Being pregnant and entirely unprepared to hear this, she fainted from the shock of this devastating news. Even though his prognosis was never directly discussed with him, Rudi must have sensed how serious his condition was. And although his disease precluded that he was drafted as a soldier in that ugly war, he would be a hero to anyone given how bravely he battled his illness. He sustained terrible burns from the radiation therapy that, in those days, could not be targeted with precision, yet he continued. He also suffered additional injuries from the collateral damage of the war itself, as bombs fell onto and around the hospital where he was treated. When he could no longer be moved to safe shelter and had to stay in his bed on the ward, it was always uncertain whether he would be able to survive the bombing raids. Despite all this, with a young family to live for and remarkable courage and perseverance, he surpassed everyone’s expectations and survived for almost five years, although regrettably he did not live to celebrate the end of the war. After World War II, as a young widow of German descent in Czechoslovakia, the reverberations of the German atrocities meant that Anny’s heritage became paramount and her innocence irrelevant. Her family’s wealth and reputation became meaningless. She was persecuted in the country where she had lived her entire life and became a refugee with two small children, just lucky to survive the transportation on a cattle train, followed by the harrowing conditions of the camp where they were interned. Eventually, they were released, but discrimination and other hardships continued. It was not until years later that she was able to start over, with nothing but the love of her children and the determination to make life worth living again. It gives me comfort that she was able to live in peace and freedom during the last decades of her life, and I am deeply grateful for all that she taught me. She must have decided to not openly dwell in the past as she never complained, but her life story impressed upon me to never take anything for granted and, although there are never any guarantees, to work hard on being able to support myself and others through this life. My mother Ingrid, in due course, was also deprived of the education she had hoped to pursue. Even though she had excellent grades and teachers as well as family members who were encouraging her to become a medical student after high school, that pursuit only proved to be in the realm of political possibilities if the family joined the Communist Party in, what was by then,

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communist-ruled Czechoslovakia. It was made clear that after they would do that, Ingrid’s prospects for university enrollment would be excellent as long as they would agree to serve as whistle-blowers on their neighbors and friends. That thinly veiled blackmail and the unraveling of decency it portended was a price too high for the privilege of academic education. That awareness in itself was an education of sorts nevertheless, and it remained a smoldering thread in the fabric of my mother’s life. She did well despite, and perhaps also because of, her early setbacks, and she developed knowledge and skills in various jobs over the years. Eventually, she worked her way up to success in a foreign country with only the high school diploma. But easy it was not. These illustrations from my family history shaped my childhood, but of course there are countless other families who have endured adversity and hoped that, one day, their children would have opportunities based on fairness and merit instead of on origin, politics, class, or any other barrier based on prejudice and ignorance. The strong women, in particular, in my family deserve credit for my passion for life-long learning. I was lucky to be born in the time and circumstances of the 1960’s Netherlands, which were humble but economically stable times. Most importantly, I had the privilege to grow up in a free country where people were expected to speak their minds. Like many kids, I loved to learn but I did not always like school. It was not until well into adulthood that I came to deeply appreciate learning for its own merit and realized that it was a life-sustaining, enjoyable, and fulfilling activity. Even when I preferred to be lazy in my youth, however, the kind voice of my Omi, as I called my grandmother, always reminded me how important it was to study and that became deeply engraved in my mind. Her stories, some of which were shared with me only by my mother because they were too overwhelmingly painful for Omi to recall or retell, brought home the love and urgency with which she meant it. In time, however, I came to realize that her belief that knowledge was something that could not be taken away, was only partially correct. At one point, there is the inevitable realization for all of us that memorized personal knowledge has limitations: rather than the recall of many individual facts, it is the process of learning and the integration of that knowledge that matters the most. And not (just) what exactly it was that was factually learned. It also becomes obvious that knowledge, once obtained, is rather not permanently ours and that, unfortunately, it is not something that can never be taken away. Sometimes it can disappear just as easily or

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as suddenly as worldly possessions, for example by a stroke or by a serious accident caused by a reckless drunk driver. Nothing that we are, have, or know is permanent. Does that mean that learning is not worthwhile? Of course not! The reality of impermanence permeates every aspect of our being and we all live our lives with the certainty of uncertainty, aware of the worst and hoping for the best. In the meantime, however, we live our lives, hopefully making good use of precious time. Learning is worth the effort. It is much more than a mere accumulation of knowledge because it builds upon itself. By learning more, we know more, and by knowing more, we have the opportunity to cohesively integrate different experiences and types of information, gain perspective, and thus learn even more. As such, learning can directly contribute to life satisfaction and it can empower us. Health and wellbeing are areas in which that empowerment is of vital importance. A physician knows medicine, can prescribe treatment for illness, and give advice, but only you can interpret the shared information in a personal way. Only you can fully consider it in the context of your own life and circumstances. You should be the expert on that aspect of your care and this requires engagement, as well as some knowledge and understanding. Learning about health and wellness enables you to become a more effective advocate for your own wellbeing. Learning about health and wellbeing enables better interaction with healthcare providers. It also leads to questions that are more informed. It allows you greater insight about options and the best path forward in your own unique situation. It thus enables you to become a better champion for your health. It helps you gain perspective and expands your wellness horizon. All this is of benefit over a lifetime, but developing knowledge does take some time and effort. I often wished (only as an example of one of those wishes that, if they truly became possible, one would not want to come true) that I could have a chip implanted so that I would have immediate, easy and permanent access to all the knowledge I could possibly desire. How convenient such an instant “IrisSchrijver-pedia” would be! Instead, we each have to develop our knowledge base through sometimes tedious repetition to create the essential foundation that enables us to recognize connections, integrate new insights, and ultimately gain understanding and proficiency. It takes effort to acquire knowledge, yet it can be lost so quickly. Think of the author of a book that you read only a couple of years ago, the capitals

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of some countries in the world that will just not come to mind at the desired moment, or the name of that person who was just introduced. Sometimes such knowledge was just not retained in the first place, at other times it may have been retained but cannot be recalled, and every so often retained knowledge cannot be effectively analyzed and applied.11 This does not only happen to “older people” (which, incidentally, seems to become an increasingly stretchable term as one advances through life). Students in medical school, for example, also experience that “long-term retention of factual knowledge is mediocre at best and forgetting is the unpleasant side of learning something new”,

as Dr. Marc Augustin wrote in a 2014 article on educational scholarship.12 In medical school, the main types of knowledge to be mastered are twofold: there is the vast amount of factual, mostly explicit, knowledge that presents the theoretical backbone of the field of medicine, and procedural knowledge, which represents the practical activities that doctors have to learn as part of medical practice. Procedural knowledge includes a lot of tacit knowledge, the kind that is developed with experience, and cannot be taught in lectures or books. Especially knowledge of the factual type is challenging to retain over time, even though there are mental tools that can be applied to make it stick longer. One of these tools is (self)testing during the process of learning, as opposed to taking only a single test at the end when exam time comes around. This process is especially helpful when students receive feedback after they answered questions. Another means of improving long-term retention is the practice of active recall exercises. Engaging the mind, for example by actively recalling the name of a new acquaintance, is much more successful than the passive restudying by just reading that name multiple times. One way in which I experienced this first-hand was when I decided to learn all the capitals of the countries in the world. There are, of course, many ways to do this, but one website I enjoy using is Lizard Point Quizzes, which provides free educational content in a fun way, appropriate for all ages.13 It has geography quizzes by continent. One is shown the map with countries in that part of the world, and may be asked where Lilongwe is. The task then is to recall that Lilongwe is the capital of Malawi in southern Africa and to click on the country on that map. If the answer is correct, the screen will show that Lilongwe indeed is the capital of Malawi, together with the next question. The quiz then continues, to cover all 55 capital cities in Africa.

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I was making good progress memorizing the countries of the world when the capital cities were presented to me, but I realized after a while that I had much more difficulty recalling the name of the capital when the country name was given. The quiz did not allow quizzing oneself from that reverse perspective, and I discovered that my passive learning of the capitals had succeeded nicely, but my active recall needed work. When I quizzed myself or asked others to indulge me and quiz me by country, that part of my memory was improved as well, like a flexing muscle that becomes stronger after working it in different ways. Knowledge can solidify even further by restudying materials over increasingly long time intervals.12 I now periodically go back to the quizzes and refresh what I learned. Having mastered the capitals of the world, after years of good intentions that remained just that, I feel happy that I completed this small thing that I set out to do. It is meaningful to me, trivial as it may be. The added benefit of learning about geography is that I feel more closely connected to the planet we all call home. This feeling of connection is likely to emerge for any area to which we apply ourselves. It is no different for learning about health and wellness, which raises awareness about health and about possibilities for health improvement. It also fosters a sense of being present for your life that results in a closer connection with your body and mind. Key points: G Knowledge is fluid, expanding or changing as additional facts are discovered. G Knowledge has been defined and classified in numerous ways, depending on the frame of reference to which it is applied. Examples of types of knowledge are a priori, a posteriori, explicit, and tacit knowledge. G Memorized knowledge has limitations: the process of learning (and learning to learn) combined with knowledge integration matters the most. G Learning expands horizons and is much more than a mere accumulation of knowledge. It helps us make sense of the world and gain perspective. As such, it empowers.

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G Learning about health and wellness provides greater insight into healthcare options and enables people to become more effective advocates for their own wellbeing. G Knowledge can create opportunities based on fairness and merit in contrast to origin, politics, class, and other barriers based on prejudice and ignorance.

CHAPTER THREE KNOW WAY

How cultural beliefs influence what is perceived to support health

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What do we know for sure?

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Is that certainty based on fact, or on shared tradition and other sources that we take at face value?

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When, during development, do we become capable of critical thinking?

·

What is the role of cultural beliefs in health and what prevents us from questioning the validity of such beliefs?

What do you know for sure? This interesting question was the final one asked of Oprah Winfrey in a live Chicago television interview by film critic Gene Siskel (1946 – 1999), during the promotion of her movie “Beloved”, in 1998. Being thrown by his unexpectedly philosophical inquiry and finding herself floundering in search of a worthy answer, she later commented on this experience saying that “It could be considered among my most embarrassing moments.”1

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Years later, after thorough reflection, it inspired the writing of her book “What I know for sure”, a work in which she seems authentically comfortable with the ways in which she could answer this question today. The question of what we know for sure is profound, and something that should give us all pause. An honest look may help ground us and support articulation of our deepest values. At the same time, the necessarily personal answers might shake up some long-held, fixed beliefs; things that have become ingrained in how we see ourselves and how we interpret our lived experience. Many of the things we “just know” have been part of our internal reality for as long as we can remember. They typically became a part of our frame of reference early in life, conceivably because someone we loved and trusted shared their knowledge with us. If we had a close relationship with that person, as with a parent or grandparent, a favorite uncle, or a best friend, it is likely that we never truly questioned what we were told. And so some of what was transmitted became ingrained in our thinking. Perhaps it reflected a common belief system within the family or in our cultural framework, as present in the part of the world or context in which we happened to grow up. If it was based on past experiences of ancestors or elders it may have become integrated in our minds as historic knowledge. Thus, it may have become part of our personal knowledge because it informed our understanding of our heritage and, as such, of our collective experience and environment. Such an individual frame of reference also inclines us to how we act in the world. As with all information to which we are exposed, however, some is valid and some is not. In any event, much of it is–or should be–questionable and therefore could be questioned. Which may require courage! Sometimes information is known to be invalid by the person who shares it, as is the case when children are misled by adults intentionally. Take the Easter bunny, whose image and traditions have evolved considerably over the course of centuries.2 Knowing that it is unlikely for children to read this book I can safely say that in that case, adults know quite well that it is a Pagan embellishment of a Christian holiday, yet they choose to uphold the tradition and introduce a character to the child that speaks to the imagination. In current Western culture, the Easter bunny is a much-beloved figure for both children and adults. Its activities primarily include the hiding of chocolate eggs, which are then searched for by children...(although I have my suspicions that it remains so firmly ensconced in its cherished role because almost everyone likes chocolate). To a young child, however, the

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Easter bunny is a literal personification and its existence is not called into question until some years later, when brain development matures enough to permit the burgeoning of critical doubt. At that time, children experience the abject disappointment of intentionally having been lied to for years and they may (begin to) question the unconditional trust they placed in their parents and in the stories they tell.3 Eventually, they understand that the lie was well-intentioned, and, given how culturally accepted it is, in turn perpetuate the conservation of tradition with the next generation. Magical imaginary figures such as the Easter bunny, Santa Claus, and the tooth fairy are then brought to life again in the minds of their own children, and allow a reliving of some of the enchantment of childhood as adults. Before a child can apply critical thinking to new information, it has to understand that others can hold false beliefs. Psychology researchers Drs. Rose Scott and Renée Baillargeon described that “children must grasp, at least intuitively, the representational nature of the mind: they must realize that beliefs are internal representations rather than direct reflections of reality and, as such, can be inaccurate.”4

And although that may seem to be a tall order for a young child and was long thought impossible, an early understanding of this concept has been documented in Western as well as in non-Western cultures by multiple studies with infants and toddlers, well before their development of speech.4 An example of such an experiment is a violation-of-expectation test that was performed with 15-month old infants.5 This test incorporated the natural tendency of infants to look only briefly at events that confirm their expectations, as opposed to events that breach that expectation. The latter events are kept in view for a longer time as if the infant were thinking, “what the heck?!?” In this way, it can be tested whether such a young child would expect a person to search for a hidden toy (for example) based on that individual’s belief about the whereabouts of the item, even when the infant knew that the toy was moved and therefore no longer in that same location. Such experiments can be carried out in a variety of ways. One example is a study in which infants first see how Person 1 hides a toy in one of two boxes. Thus, an infant and Person 1 would both know where the toy was hidden. If the infant stayed in the room and the person who hid the toy left, then another individual (Person 2) could come in and, in the absence of Person 1, move the toy to the other box. Now, the infant has new knowledge that

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Person 1 does not have, but the infant does know that Person 1 must expect that the toy still remains in the original box. When Person 1 returns, infants expect that the toy will be looked for in the original box. If the person unexpectedly looks in the second box, without first checking the box in which he or she originally hid the toy, the infant perceives this inconsistency as a violation-of-expectation and reliably looks at the scene for a longer time. Studies such as this have supported that humans, as early as in infancy, can have a concept of false beliefs in other people. Such understanding gradually matures with further development of a child’s social cognition and psychological reasoning, together with information processing capabilities.4,5 In the above example, children responded to what they knew to be false beliefs. But information may be false even as the person who shares that information may genuinely think that it is factual knowledge. This takes us into the realm of held beliefs, custom, folklore, superstition, and mythology. Many of these beliefs result in practices that have roots in ancient tradition and represent concepts with a degree of plausibility, which enabled them to take a foothold in the first place and helped maintain their appeal and perceived validity. Let me highlight some examples of where perceived knowledge is not, or no longer, in line with factual knowledge. In medieval times in the Netherlands, beds were much shorter than they are today. People from the Netherlands are now the tallest people on Earth6, with a mean final height of 183.8 cm (just over 6 ft) for men and 170.7 cm (about 5 ft and 7 inches) for women, but this was not always the case. In the middle of the eighteenth century, the average height of Dutch men in the military was around 165 cm (almost 5 ft and 5 inches), which was considerably below the European average.7 Other studies of skeletal remains from the seventeenth to eighteenth centuries recorded average Dutch male heights between 166 and 167 cm (about 5 ft and 5.5 inches).8 Even though the Dutch fell below the average European height of the time, it is of note that European people’s heights substantially decreased overall after the middle ages. There appears to be a broad U-shaped trend to average height in Europe, and whereas it may never be possible to unequivocally determine why this is the case, there likely were many contributing factors. Average height may have been negatively affected by wars and other conflicts, and by an increase in income inequalities after 1500 C.E. The Little Ice Age resulted in subsistence crises, and diseases more readily spread as an unintended consequence of urbanization,

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colonization and of the local and global expansion of trade associated with these phenomena.8 In the Middle Ages, northern European people were generally taller than in the seventeenth and eighteenth centuries, although they were shorter than they are today, with an average height of 171.4 cm (5 ft and 7.5 inches) based on measurements of adult male skeletons. The Dutch ranked above that average8, so they were by no means short. Their beds, in contrast, were remarkably short...so short, in fact, that one would not have been able to lie flat, let alone stretch out. Many people in the Middle Ages had nothing more to sleep on than a burlap sack with straw or hay (hence the expression “hitting the hay” for going to sleep), but farmers often did own an actual bed. Typically, this was an alcove bed, which can be described as a bed in a closet. The usual model of the alcove bed was one with three walls, with the fourth side either closed by closet doors, or by a curtain. This sleeping arrangement was practical because it eliminated the need for a separate bedroom and by closing the door or curtains it could be easily hidden from view during the day. The other advantage of sleeping in such a small area was that no space of the house was “wasted” and that it warmed up quickly and remained relatively comfortable during the night, even when the house was not otherwise heated. Small children were often placed in a drawer below the alcove bed itself, which I imagine may have made for a rather claustrophobic experience; not that they would have had any choice. Parents and older children slept propped up against pillows in the cramped space of the communal alcove bed.9,10 This brings us to the beliefs of the time. It was generally thought that, by lying down, blood would fill the head and cause a person to never wake up again. After all, people who were stretched out were generally dead, a state that most were anxious to avoid. And one way in which one ought to be able to avert this risk was by sleeping in a partially upright position.10 It is unclear how widespread that belief really was, but sleeping in a halfsitting position served practicality, and conformed to the notion that this way of sleeping was healthier. In any case, it possibly provided the perception of a little more air to breathe in otherwise crowded sleeping quarters. Another example of a belief that is based on historical realities of life and steeped in tradition is the way in which women should behave after childbirth. One of the amazingly talented students I have had the privilege to work with was a young woman from China, whose mother stayed with

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her after she gave birth to her first child. Whereas the mother’s presence to support the young family was much appreciated, the benefit came with a firm expectation and insistence on the tradition of postpartum confinement. The belief that isolation and confinement of new mothers are beneficial for up to 40 days after giving birth is not limited to China; this tradition is also part of Cambodian, Lao, Nepalese, Thai, Singaporean, Vietnamese and Myanmar culture.11 In China, “sitting the month”, as it is called, is similar in its purpose to practices in other countries in that it aims to enable the new mother to regain her physical and emotional strength, usually with the help of family support. However, depending on how it is interpreted and applied, the practice can appear austere by Western standards. Apart from perceiving that she was effectively under house arrest, the student was instructed not to take a bath or shower after the birth, not to wash her hair, not to use her air conditioner, to rest under warm blankets and to refrain from physical activity. She was expected to abstain from all exercise and her usual routines and to adhere to a diet that excluded the consumption of cold drinks and cold foods. She told me that she was petrified by the prospect, especially after having lived in California for several years! Yet, her postpartum experience is no exception. Traditional practices based on comparable historic beliefs are still prevalent in a variety of Asian cultures, although adaptations may be taken into consideration to more fluidly reconcile tradition with the experience of modern life.11 So where does this tradition come from? Leslie Hsu Oh, an inspiring woman of Chinese descent who was born and raised in the United States and graduated from the Harvard T.H. Chan School of Public Health is a mother of four who tried “sitting the month” after the birth of her fourth child and explains the tradition in her 2017 article in the Washington Post as follows: “the ideas that one shouldn’t wash hair, take showers, brush teeth, use an air conditioner or leave the house all stem from the belief that childbirth brings significant amounts of fluid and blood loss. According to traditional Chinese medicine, blood carries chi, your ‘life force,’ which fuels all the functions of the body. When you lose blood, you lose chi, and this causes your body to go into a state of yin (cold). When yin (cold) and yang (hot) are out of balance, your body will suffer physical disorders.”12

The prevention of illness thus is at the center of the intent of the custom. And historically, at least some of it makes sense, apart from the air

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conditioning of course, which emerged as a modern addition to the rule of avoiding the cold. Postpartum confinement has a dual overarching aim. First, the restriction of movement by the mother is intended to preserve energy after the birth, so that she can optimally bond with her new child, regain her full strength, and reap long-term health benefits from an extensive period of tissue repair. Second, it seeks to minimize the risk of disease and infection in the mother and newborn in the postpartum period. In principle, these goals are laudable. Although maternal mortality decreased globally by approximately 44% between 1990 and 2015, still 239 maternal lives were lost per 100,000 live births in developing nations, versus 12 per 100,000 live births in what are considered developed ones. In its 2018 maternal mortality fact sheet, the World Health Organization (WHO) lists infections (usually after childbirth) and complications from delivery among the five conditions that account for almost 75% of all maternal deaths. Almost one-third of these deaths occur in South Asia.13 So concerns about maternal postpartum health are as valid today as they were in the past. Cultures around the world recognize the importance of rest, combined with good nutrition and adequate hydration, in the postpartum period. In addition, many cultures seek to minimize potential exposure to infections to ensure the wellbeing of both mother and child. The Chinese practice of “sitting the month” originated from a concern about hygiene in an environment where the quality of water was poor and getting cold after birth with limited possibility of heating was an added challenge. In the first weeks after childbirth, the female reproductive tract is especially vulnerable to bacterial infections, and the practice may well have been effective in limiting disease. Ironically, whereas the goal of hygiene remains the same, environmental conditions today call for a very different approach. Women who are fortunate enough to live in areas with clean and safe drinking water give birth in an environment far superior to one that can be created by staying wrapped up, immobile, and unwashed.12,14 And many of these practices fly in the face of what is considered healthy today. Being isolated and immobile can contribute to the symptoms of postpartum depression, and inactivity negatively affects cardiovascular fitness, can contribute to weight gain, and promotes a loss of muscle mass.15 There is also the concern that unregulated traditional nutrition supplements, as part of the confinement diet, are consumed and subsequently could enter breastmilk. As such, they could negatively affect the wellbeing of the mother or the newborn, or both.

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It is interesting that traditional beliefs remain in place when at least part of their basis no longer exists. In the case of postpartum confinement, the devil is in the details: its wise execution can be quite a relief to a mother during a time of physical and mental vulnerability. The phase would ideally be supported through a combination of loving and practical support that takes into account modern ways of living, present-day hygiene, and our current knowledge of health and disease. If, however, there is an imposed and rigid clinging to archaic traditional beliefs and practices, the new mother may not feel very supported at all. Quite the opposite, in fact: as a consequence of feeling constrained, isolated, physically uncomfortable, and coerced into eating a restrictive diet, the stress that was intended to be avoided may mount and her wellbeing is likely to suffer. Ultimately, the goals of the practice are best met when there is thoughtful consideration by the family on how tradition can be balanced with today’s lifestyles, regardless of whether a woman lives in her original cultural system (e.g. China) or in another (if she moved from China to, for example, the United States). And, just as important as a reasonably flexible family dynamic, is the healthcare that is provided to her in maternity. If healthcare providers are to achieve optimal management of medical issues as well as good rapport with their patients, then their service should be both medically and culturally competent. The use of current medical practice standards combined with sensitivity to the patient’s wishes, and an awareness of cultural influences, will ultimately improve the quality of care that can be provided. Postpartum confinement was originally based on health-related concerns for mother and child and the realities facing women’s lives over a thousand years ago. As such, some of the beliefs and customs associated with this practice are no longer valid. There is an interesting contrast in this regard with male circumcision, which is also associated with deep-seated beliefs but where some present-day medical reasons for the ancient practice have recently come to the forefront. This brings me to the third example of where perceived and factual knowledge are not quite aligned. Male circumcision most commonly involves the surgical removal of the entire foreskin, so that the rounded head of the penis (known as the glans penis) remains exposed. As one of the oldest known surgical procedures, it dates back thousands of years, as evidenced by well-preserved Egyptian imagery from approximately 4,300 years ago.16 Although the origin of circumcision cannot be reliably traced, it has been speculated that it was a customary practice on the Arabian Peninsula, from where it was introduced to the area of Mesopotamia, between the rivers Euphrates and Tigris, located in what is now Iraq.16

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Today, circumcision is commonly performed in many countries. According to the WHO17 it is common in Australia, Bangladesh, Canada, Indonesia, Pakistan, the Philippines, South Korea, Turkey, and the United States. In much of Central Asia, the Middle East, and North and West Africa the procedure is almost universally performed, whereas in other parts of Africa it is common in a limited number of ethnic groups. Among religious groups, circumcision is highly prevalent among Muslims and Jews. Worldwide, about one-third of males are circumcised. Interestingly, among English-speaking industrialized nations, there is only one country with a widespread presence of circumcised males: in the United States, almost 80% of adult men are circumcised and, depending on region, between 60 and 90% of newborn boys are reportedly subjected to the surgery.17 Circumcision has been performed for cultural and religious reasons, as well as for perceived health benefits. Over the long course of history and in different geographies it has been practiced for a variety of reasons. One purpose of ritual mutilation is to test resilience and courage: it has been viewed as a societal rite of passage into manhood and all that that is believed to entail in specific cultures. In other settings, it has been promoted as a means of curtailing sexual excitement and masturbation. It also has deep roots in religion and serves as a symbol of identity and faith. In addition, it has been recommended as a way to enhance genital hygiene, and it was, and still is, perpetuated to adhere to social norms.17 In a probing article on the social history of male circumcision, sociologist and educationalist Dr. Peter Aggleton writes: “First and foremost, male circumcision is an act linked to deep-seated beliefs and ideologies about the social order. It is by no means a simple prevention technology. Male circumcision is almost inevitably linked to the expression of power—be this intra-group, between old and young for example, or intergroup in nature. Its links both with colonialism and with resistance to colonialism, invasion and conquest are profound, as are its connections with overtly moral codes and conventions. Finally, far from being a trivial or routine operation, male circumcision is an act that has profound social connotations and long-lasting physical and psychological consequences.”18

Around the turn from the 19th to the 20th century, male circumcision was thought to be a panacea for a large and strikingly diverse number of ailments, such as general anxiety, impotence, asthma, bed-wetting, eczema, epilepsy, tuberculosis, conditions affecting the hip-joint, rheumatism, alcoholism, and gangrene.16,18 The latter stands out as particularly alarming, in light of the—added—risk of infection from the procedure itself in those

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days, and the acute need of therapeutic intervention in a patient with gangrene if that patient is to be saved! None of these claims have stood the test of time. This “knowledge” was not based on facts, but received an aura of validity around deeply flawed beliefs and concepts, although the individuals who shared and received the information may genuinely have thought their knowledge to be correct. Recently, circumcision has been introduced as a means of preventing HIV (human immunodeficiency virus) infection because three randomized clinical trials in Africa demonstrated that circumcised heterosexual men had a reduced risk of becoming infected, compared to men who were not circumcised.16 Because the risk of acquiring HIV was reduced by approximately 60%, WHO/UNAIDS recommendations “emphasize that male circumcision should be considered an efficacious intervention for HIV prevention in countries and regions with heterosexual epidemics, high HIV and low male circumcision prevalence.”19

The report goes on to state that “Male circumcision provides only partial protection, and therefore should be only one element of a comprehensive HIV prevention package which includes: the provision of HIV testing and counseling services; treatment for sexually transmitted infections; the promotion of safer sex practices; the provision of male and female condoms and promotion of their correct and consistent use.”

Whereas male circumcision seems to be one “simple” way of reducing the risk of HIV infection and has been reported to help prevent other sexually transmitted infections and also the development of cancer of the penis (which is a rare malignancy)16,17,18, endorsement of circumcision is not without controversy. Apart from the ethical concern that a child is unable to consent to genital modification, there is a fine line between public health and social control.16,18 Even the studies on circumcision and reduced HIV transmission cannot necessarily be generalized. In addition, as Dr. Aggleton notes, HIV related stigmatization and social division may in fact increase because of the physical and social changes created by the practice.18 Safe sexual practices and genital hygiene remain critically important to avoid a range of infections. And in terms of preparing boys for manhood, nothing can or should take the place of personal mentoring and guidance on citizenship, ethical conduct, mature behavior, and social responsibility.

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You may align yourself with those who view male circumcision as a form of genital mutilation with the potential of long-term negative effects. Alternatively, you may be among those who embrace it as a ritual that is essential to their culture or religion. In any case, the debate about male circumcision is certain to continue for a long time to come. What we do know is that some beliefs around this practice, and some ideas associated with other traditions that have ancient roots and are continued (in one form or another) to the present day, are based on rarely or poorly questioned notions. These notions may seem dubious for those who are at some cultural distance from a given belief system, but they are part of the fabric of life and of the character, spirituality, and heritage of the cultures in which these beliefs are maintained. The common ground is that we are all susceptible to this: questioning cultural beliefs, especially those that were introduced to us early in life, takes guts. It feels far safer to stay within the boundaries of a familiar identity, even when that may not have the greatest benefits for health. Key points: G Many of the things that we “just know” have been part of our internal reality since childhood and are intrinsic to our adult thinking without critical questioning. G Cultural beliefs are important influences on what is perceived to support health. G Many long-held, cultural beliefs result in health practices that continue to this day and that have roots in ancient tradition. G Cultural beliefs and practices represent ideas with a degree of plausibility at their conception, which enabled them to take a foothold and helped maintain their appeal and perceived validity. G Shared information is not necessarily factual knowledge, although the person who shares the information may genuinely think it is. This takes us into the realm of held beliefs, custom, folklore, superstition, and mythology.

CHAPTER FOUR UNDER THE INFLUENCE

How pseudoscientific notions and cognitive biases influence which health-related information is trusted and used

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Why are we sensitive to pseudoscientific ideas about health and why are they so hard to dispel?

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How are we influenced by biased thinking?

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What are the consequences of cognitive biases and repeated information, at the level of our personal psychology and on a larger scale?

My family uses a supposedly infallible charm to change the traffic light from red to green. The phrase is “dreimal schwarzer Kater”, and translated from German to English it means “three times black cat”. This charm becomes even more powerful when we (pretend to!) spit at the light three times right after the words are spoken. Indeed, I cannot deny that it is a remarkable family to belong to... But where did the charm originate? As is the case with many phrases associated with superstition and folklore, the origin of our charm is not reliably traceable. Being part of a larger incantation it dates back hundreds of years, as an element of a formula that was used by healers to avert fevers. By invoking the number three, which was considered to be holy, and the strongly mythical figure of the black cat, it was hoped that the spell would have a more powerful effect and would help stave off bad luck.1,2

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Before you, the esteemed reader, conclude that my family is as nutty as a fruitcake, I would like to point out three things. First, think back to a time when you (or someone you know) knocked on wood or tossed some salt over the left shoulder, knowing full well that there is little rationale for doing so. And yet, maybe deep down, you expected or at least hoped for a better outcome than otherwise might have been the case. Second, consider the many buildings, in the United States as well as in other countries where the number 13 is deemed unlucky, that do not have a 13th floor. Not because they do not have 13 or more floors, but because of superstitious fear of the number 13; a condition called triskaidekaphobia. This phenomenon is not indicative of a phobia that happens to have an increased prevalence among developers and realtors, but rather reflects a preventive measure they choose to take in order to avoid potential concerns from buyers, businesses and other clients.3,4 As a result, the 13th floor may be skipped and instead be assigned the number 14, with consecutive numbering after that. Or there may be a floor 12a and one called 12b, followed by a 14th floor. Alternatively, the floor may be given only a name associated with its function, such as the mechanical floor, penthouse, restaurant floor, or pool floor. In 2015, Shirley Li reported in The Atlantic that in Manhattan only 55 out of 629 buildings with 13 floors or more had a 13th floor that was named as such (roughly 9%). The other 91% had another designation for that floor.5 As a spokesperson of Otis brand elevators, Dilip Rangnekar has been reported to state that as many as 85% of the world’s tall buildings do not have a floor that is actually numbered the 13th floor.4 These examples not only illustrate that superstition is alive and well, but also that it is accommodated and that it is being incorporated into daily life through both small and far-reaching measures. The third point that I would like to make is this: just ponder the magical effect of the spell used by my family. It works! After all, the light always turns green...eventually. Thoughts and behaviors that are the result of superstition are usually easy to recognize, even when that realization does not necessarily translate into a complete and rational dismissal of the superstition itself. It becomes more challenging to recognize whether something is for real or bogus, however, when there is at least a kernel of truth, or when something seems to be plausible. Those kinds of notions are more likely to gain a foothold with a large group of people. This occurs by being repeated and shared, especially with the widespread use of social media. There are numerous examples of

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knowledge about health that belong in the category of “pseudoscience” and we will return to exploring some of these later in the book. For now, we can use the example of how just about anything is claimed to be able to give you cancer, or, for a specific example, that we should be drinking at least eight eight-ounce (about 240 mL) glasses of water each day.6 The problem with the latter claim lies not in the notion that being wellhydrated is beneficial, because that is not disputed. Actually, more concerning than drinking too much is drinking too little: some population groups, especially older adults, may not have enough daily fluid intake and are therefore at risk of dehydration. This can lead to fatigue, a decreased frequency of urination, dizziness, confusion and, ultimately, life-threatening symptoms. For the general population, dehydration is usually not a concern. And even a large fluid intake often is not problematic in and of itself: it can be perfectly warranted under certain circumstances such as in hot weather, on long flights (as long as one is able to get up to go to the bathroom), or during intense sports activities. It is also advisable in some scenarios of disease prevention and treatment. The problem with the recommendation of drinking at least eight eightounce glasses of water each day is in how generalized and yet how specific it is. It lacks nuance on the one hand, recommending an “at least” amount for everyone across the board, and it is very specific on the other hand because it expresses the desired amount of fluid consumption in the easily remembered “8x8 rule”, as the instruction is also called. In a review article from 2002, kidney specialist Dr. Heinz Valtin concludes that “the universal advice that has made guzzling water a national pastime is more urban myth than medical dogma and appears to lack scientific proof.”6,7

He also points out that, in all fairness, it must be admitted that there is no proof to the contrary either, namely that drinking less than at least 64 ounces (1.89 liters) of water each day has no negative consequences whatsoever. That said, the published scientific literature strongly indicates that “we are currently drinking enough and possibly even more than enough.”6

In the example of the 8x8 rule, the specificity of the statement and the use of numbers, suggesting that rigorous scientific research produced a definitive finding, may have resulted in adoption on a large scale. There are

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even popular drink reminder apps, such as Hydro Coach8, that motivate people to drink in order to reach a specific daily goal. Once a pseudoscientific notion is widely embraced it is quite difficult to dispel. In a 2016 article in The Guardian, Dr. Sian Townson lists several interesting cognitive biases that complicate the successful correction of a false belief.9 First, however, she points out the existence of a general bias against academics. She notes that academics are often viewed as part of the social elite and, as such, are suspect from the outset. This perception of privilege must be one pertaining to education level rather than general prosperity, given that scientists are typically not particularly wellremunerated for their efforts. Nevertheless, they appear to have a reputation problem, founded in the perception of being arrogant and of being condescending to those whose skills or knowledge are not derived from the same level of formal education. From that viewpoint of perceived privilege, a correction by a scientist of someone’s pseudoscientific belief can come across as patronizing, even though Townson points out that many scientists with whom she has interacted are anything but snobbish and their intent is far from talking down to anyone. My own experience is similar. As in any area of life there are exceptions, but many academics are incredibly passionate about their area of study and about science overall. They are equally enthusiastic about sharing what they have learned, just to get the word out. But if they are categorically viewed with a negative lens, then their arguments, however well laid out, may not be heard or taken seriously. With that in mind, let me bring up three specific cognitive biases that can lead people to hold on to a concept that simply is not correct: selection bias, the Dunning-Kruger effect, and the sunk-cost fallacy. One form of selection bias is confirmation bias, which is a powerful adversary to objectivity. The principle of confirmation bias is that ideas for which we already have an affinity speak to us more loudly than others. Among the flood of information that we need to process each day, ideas that confirm our beliefs are favored. They support what we already think and therefore are given more weight than those that do not. As such, they become more easily solidified and part of our pattern of thinking. This form of cognitive bias is selection bias because the way in which we subconsciously gather evidence is not objective. Unfortunately, selection bias often results in considerable confidence in held ideas and, because we feel that these ideas are confirmed, our capability of being open to other points of view can become limited.

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Accordingly, even when we have access to diverse information, such availability does not mean that all information is equally considered before an opinion is shaped. If that sounds all too familiar given the contentiousness often found in the political arena, then you are on to something: across research studies, there is stronger confirmation bias for political issues than for others, indicating that, especially on political matters, we seem to have the need to feel validated, instead of being motivated to arrive at a correct understanding.10 The need for personal validation of political views makes us defensive and hampers productive engagement in a respectful exchange of ideas. It leads people to oppose diverging beliefs outright, rather than to be motivated to search for accuracy. The Dunning-Kruger effect11 is another example of cognitive bias that has been repeatedly tested and measured. It is the observation that people who are competent in a certain domain tend to underestimate their skills, whereas unskilled people tend to overestimate their abilities. In other words: those who know less think that they are more knowledgeable than they actually are. In contrast to people who do have solid knowledge in a certain subject area, they fail to appreciate how much they do not know. This principle applies widely and has been confirmed in a variety of situations. It applies to social interactions, to situations that require logical reasoning, and to those that rely on intellect, including those that require emotional intelligence. There are at least two factors that stack the cards against us in recognizing our own incompetence, and likely more. For one, an inflated self-assessment combined with lack of ability results in erroneous conclusions and, based upon these, suboptimal choices. In addition, the lack of knowledge and thereby the lack of competence prevents an accurate assessment of the situation, so that people who lack knowledge in specific areas often are not aware of the fact that they are unskilled. They fail to accurately assess how well they are doing, because they are unable to assess when their judgment is accurate versus in error.11 Charles Darwin committed this thought to paper many years ago in the introduction of his book “The descent of man” that was first published in 1871. He astutely observed that “ignorance more frequently begets confidence than does knowledge.”12

A third example of cognitive bias is known as the sunk cost fallacy or the finish-the-job fallacy.9,13 What this entails is this: the fact that resources were already expended is used to justify further investment, even when the additional investment is not logically tenable. This concept can be illustrated in business, for example, when a product is being developed at considerable cost and effort. If at some point during the progress reviews it

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becomes apparent that a successful launch of the product will be impossible without additional investment of, say, a multiple of the original budget for the project, the sunk cost fallacy may kick in. The flawed logic that is frequently used in such situations is that the loss of stopping would be too great. After all, the investment would be entirely lost if the project were aborted, even if it is known that the cost of continuing is much higher than the original investment. It may be obvious that the business will need to go over budget by multiple factors of the original allocation, but it just does not feel quite as real as the imminent loss. So even though the additional cost may not be worth it from a rational business perspective, projects are often continued at this point. The perceived loss of already expended resources is higher than the not fully imagined and not yet factually known overall losses when the project is given the green light to continue. For examples on a (presumably) less dramatic scale, with most of the cost being one of time or satisfaction, we can consider how hard it is to leave a movie theater when the selected film turns out to be terrible, or how we often still take that second (and third, and fourth...) bite of a cake we just bought, even if it is a disappointment and does not deliver on expected flavor and delight. Apart from biases that cloud our thinking when it comes to recognizing pseudoscientific ideas about health and other topics, there is also the fact that certain kinds of information are much more compelling to our brains than others, and therefore much easier to believe. A comprehensive review article with the provocative title “Bad is stronger than good” detailed how negative events usually have a bigger effect than positive ones of the same kind.14 For example, criticism will have a greater impact than praise, as will losing money compared to winning it. Overall, the imprint of pain is greater than that of pleasure, at least where single experiences are compared. The authors of the article point out that people’s bad experiences were more powerful than good ones in a variety of circumstances. These included simple interpersonal interactions, relationships over time, and experiences in larger social networks. They ranged from minor everyday occurrences to major life events. Not only do we experience a greater impact by bad events, but our brains also more readily process negative information. The authors conclude that this phenomenon of tipping the balance toward the negative is not the exception in human psychology, but rather the rule. Fortunately, it does not imply that bad triumphs over good; it simply signifies that it may take multiple positive events to compensate for one bad experience.

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Psychologist Dr. Rick Hanson has popularized the scientific “bad is stronger than good” concept, which has become known as “the negativity bias”. He argues that the human brain holds on to negative experiences like Velcro and that positive experiences are not able to stick. For these, the brain is like Teflon. On his website and in a blog of the Huffington Post he explained, “All this makes human beings super-sensitive to apparent threats. Basically, in evolution, there are two kinds of mistakes: (1) You think there is a tiger in the bushes but there isn’t one, and (2) You think the coast is clear, no tiger in the bushes, but there really is one about to pounce. These mistakes have very different consequences. The first one will make you anxious, but the second one will kill you. That’s why Mother Nature wants you to make the first mistake a thousand times over in order to avoid making the second mistake even once. This hard-wired tendency toward fear affects individuals, groups (from couples to multinational corporations), and nations. It makes them overestimate threats, underestimate opportunities, and underestimate resources.”15

Negative information is more convincing to our brain than positive information, but it goes further than that. Humans are also susceptible to negatively-biased credulity, which means that they have a tendency to more readily believe information that points to hazards than to accept information regarding benefits.16 Information that points to danger of some kind is not only more believable to the human mind, it is also more likely to be retained and transmitted. Why should that be the case? Negatively-biased credulity begins to make sense when we consider that believing something carries the inherent risk of being wrong, and therefore is associated with a potential cost. This cost can be assessed in the balance between failing to believe something that is true (called erroneous incredulity) and believing something that is false (erroneous credulity). Failing to believe information that is true and communicates potential threats will, on the whole, carry a higher cost than believing something that happens to be false. This is what I would consider being in line with the “better safe than sorry” principle, which, in the absence of additional information, usually just seems to be good common sense. If someone who hurriedly walks by you on the sidewalk says that there is a robbery going on and police cars have arrived in the street that you are walking toward, then you will weigh the cost of your next actions, whether you are conscious of that thought process or not. If you believe what you were told, then you will likely choose to avoid that street, because the cost of not believing the person could be a hazard to you. The street may be

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closed off altogether, or you may be stopped by police and be told that you have to wait before you may proceed, or you could get caught in the crossfire between the police and the robbers. You will likely believe the statement made by the stranger, even if you have no additional information that confirms what you were told. On the level of society and culture, negatively-biased credulity is present as well. One offshoot of this is that we can expect to find more information pertaining to risks, than information about benefits. So “bad” is not only stronger than “good”; in terms of information sharing, it is also more frequently encountered in our lives. No matter what your chosen sources are, news feeds are slanted toward negative stories. This is not merely a matter of the news content that is chosen and presented by journalists and their employers, but rather more of an interplay between the media and news consumers, who drive at least part of this process by their preferences, demands, and choices.17 Online, these choices are easily monitored by tracking mouse clicks. Thus, demand is no longer a matter of guessing what appeals to the largest number of people. We may proclaim (and perhaps honestly think) that we prefer positive news and high-minded stories, but our clicks and propensity for distraction by clickbait tell another tale. Stories about war, attacks, scandals, corruption, murder, disease outbreaks, and disasters will be more frequently reported on and hold our attention longer than stories about baby-elephants, good deeds, joyful events, community revitalization, political progress, positive outcomes, or medical breakthroughs.17 Additionally, people who hold the opinion that the world is a dangerous place and who, therefore, perceive a higher level of threat than the average individual, may have a relatively larger influence in a population. This is likely just because people are more susceptible to the information the fearmongers perpetuate. They are able to affect cultural perceptions to a disproportionate degree. In a society that feels vulnerable because of actual or imagined threats, beliefs about hazards are thus likely to proliferate even more16. For yet another piece of bad news to be swiftly integrated into the brain’s neuronal pathways, here is something that may surprise you: even mere repetition is enough to increase the likelihood that we will find information credible! After people are first introduced to a false statement such as a fakenews headline, even just one additional exposure will somewhat increase its perceived accuracy. This is called the “illusory truth effect”. There are boundaries to that sensed plausibility, but only if the information is blatantly

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false. For example, if you heard repeatedly that it was discovered that the Moon was made of Wensleydale or possibly Stilton cheese, then that would (hopefully) strike you as fabricated and you would dismiss this “fact”. But even if the likelihood of accuracy of a headline seems low, repetition makes us more susceptible to giving it credence. The ironic consequence of this susceptibility is that even stories that are fact-checked and subsequently reported to be false, and those that are labeled as incorrect on social media, as well as those about which we actually already do know better, still gain believability just by reiteration. This effect has been observed to occur after days, weeks, and even months.18,19 One underlying mechanism of the illusory truth effect appears to be based on the increased familiarity with the story. The prior exposure facilitates easier comprehension and recollection of a statement, even if we are not aware that this memory-trigger is happening. In other words, the brain has become more fluent in processing the information19, and this fluency can become a compelling surrogate for fact and truth18. Another mechanism that builds on the fluency concept and may further facilitate the illusory truth effect is the utilization of already present coherent references in the brain. We are more likely to interpret even new statements as true if we already have a frame of reference in our memory that provides connections to the new information. In a way, if statements are processed in our memory when a scaffold of familiarity and context for the topic is already present, then our truth judgment increases.20 Although the research in this area is ongoing, the idea of the illusory truth effect is not exactly new. As Gustave Le Bon claimed in 1895: “Affirmation pure and simple, kept free of all reasoning and all proof, is one of the surest means of making an idea enter the mind of crowds.”

He added the following comment: “The conciser an affirmation is, the more destitute of every appearance of proof and demonstration, the more weight it carries.”21

Now that is something disquieting to think about! As we shall see in the coming chapters, the effects on health and wellness by superstition, biases that prevent objectivity, pseudoscientific health ideas, negative slants that signify potential threats, and sheer repetition of false claims are not to be dismissed or underestimated.

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Key points: G Thoughts and behaviors that are the result of superstition are usually easy to recognize, but that realization does not necessarily translate into a rational dismissal of the superstition itself. G When a pseudoscientific notion about health seems plausible, it becomes more challenging to recognize its lack of validity and to dispel it. G Cognitive biases (such as the selection bias, the Dunning-Kruger effect, the negativity bias and the sunk-cost fallacy) complicate the successful correction of false beliefs. G People are also susceptible to negatively-biased credulity: information that points to hazards is not only more believable, it is also more likely to be retained and shared. G The illusory truth effect entails that repeated statements receive higher truth ratings than those that have not been heard before. G All these factors influence how likely it is which health-related information is believed and circulated.

CHAPTER FIVE RISING TO THE BAIT

How subconscious bias and advertising strategies apply to health and healthcare

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What are the influences that shape our choices and preferences?

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How do marketing strategies affect our decisions?

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What circumstances can make us susceptible or leave us more vulnerable to external influences?

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How do persuasion tactics apply to messages about health and health rumors?

Cognitive biases and preconceived notions influence our choices while we are blissfully unaware that these mental processes are taking place. Our brains are attracted to the negative, we more readily pick up on and believe information that heralds crises or contains the possibility of peril, and information becomes more persuasive by the shockingly simple act of repetition. We are also biased by information that confirms our own beliefs. As if that were not enough, our judgments and choices are influenced behind the scenes by numerous other factors. With the threat of all these biases that lurk below our consciousness, your neurons may be on high alert right now because, as they say, increased self-knowledge is rarely good news!

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Although biases typically do not rise to the level of awareness, there is a kind of predisposition that is specifically called “subconscious bias”. In general, this term is reserved for the positive or negative assessment of people, groups, or things and it is based on prejudice. We are not plugged into this, so this is implicit bias. We may not even be cognizant of our more subtle feelings about things that can separate “us” from “others”, such as gender, race, religious faith, weight, and age. I recently met a man called Tobias who, out of the blue, announced to me that he hated all Muslims. Interestingly, his blunt and prejudiced opinion was not supported by any direct experience. In fact, he did not personally know a single person of that faith, but he was quite set in his discriminatory conviction. In this case, the term subconscious bias would not apply, because Tobias did not lack awareness of his categorical prejudice. His baseless bias was explicit and he chose to make it known in no uncertain terms. With subconscious bias, the process is much more insidious. It is one of those snap situational judgments that the brain makes all the time based on our history and experiences, in this case one that is preferential to one group and critical of another. Apart from the lack of awareness of our personal areas of subconscious bias, there is the challenge of denial. Many people consider themselves openminded and tolerant but, unless you are the exception to the rule, this is where we tend to delude ourselves a little. Before we look at this further, it is important to recognize that being tolerant is not the same as being accepting. For example, one may be tolerant of a co-worker’s nervous habit of chewing his pencil during meetings. He may be appreciated as a colleague and whereas the annoying habit may be distracting and kind of gross, one can still realize that it is essentially harmless. After all, apart from causing some irritation, it does not directly affect anyone, as long as he does not expect others to use his pencil. So people just put up with it. Being accepting, for the purpose of an example, is different in that it implies that we have no resistance to a situation. Someone may wholeheartedly accept a son’s girlfriend into the family, for example. Or a couple could fully accept the fact that finances dictate that their time off this year will be a stay-cation. Especially when they actually look forward to enjoying their beautiful garden instead of experiencing the complication of having to travel. We may have the general desire to be inclusive, and we may have learned to behave in a way that minimizes bias, but that does not mean that we are

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free from thoughts and feelings that lead us to plainly favor, without good reason, one perceived category over another. Founded by three scientists in 1998, Project Implicit1 is a non-profit organization that states two goals. The first is to provide a virtual laboratory to an international collaborative network of researchers in the social and behavioral sciences so that they can do web-based research and collect online data from study participants via surveys and behavioral tasks. The second goal is to educate the public about hidden biases that are largely outside of the realm of active awareness or control. The Project offers a variety of tests on implicit social attitudes after which a result is immediately returned to the test-taker, thus enabling an evaluation of automatic preferences. The test is not designed to “prove” whether one is biased against, for instance, disabled people. It is not a definitive measure. Taking the test multiple times could result in somewhat different outcomes. It does, however, provide an assessment of our automatic preferences based in part on the speed and accuracy with which we implicitly associate words and images. The thought processes that shape our choices and preferences are complex and result in an underappreciated susceptibility to influences that range from mild to manipulating. One such influence is peer pressure, which can be positive or negative, although it often has a negative connotation. A positive example is when your exercise partner kicks your butt on a day when, for no good reason, you are not feeling motivated to do your fitness routine. If you give in to the pressure, even if guilt (“you are letting me down”) or wellmeant scorn (“you are a wuss if you bow out”) is used to persuade you to participate, the outcome is essentially positive: you exercise together and you both have the benefit of doing something good for the body. In the end, you may be grateful, and you return the “favor” on another day when your buddy is not that eager to stick with the commitment. Peer pressure can be a negative social influence, however, when someone is pressured by a peer group (for example a clique of teenagers) to conform to their point of view and norms of behavior. This may include the requirement to dress a certain way, to consume alcohol, or to be unkind to outsiders. In recent years it has also gained attention in association with indoor tanning. Peer pressure is evidenced by the perception of an individual that certain expectations must be fulfilled in order to be liked or accepted. And the need to fit in is particularly strongly present during adolescence. The use of UV-emitting tanning devices such as tanning booths, sunbeds, and sunlamps in the United States is common, especially among non-

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Hispanic white adolescent girls and young women. In 2009, the use of these devices was staggeringly high: more than one-third of the high school students in this category engaged in artificial tanning for cosmetic purposes. By 2015, this had decreased from one in three to about one in seven2, possibly because of increased awareness and new public health measures. By then, numerous research publications had documented a link between indoor tanning and skin cancer, the U.S. Food and Drug Administration (FDA) had made a recommendation against indoor tanning by minors and the WHO had declared indoor tanning devices outright carcinogenic to humans. As a result, more regulations have been put in place to restrict the use of tanning devices and indoor tanning is now a recognized public health issue.3 According to a WHO report from 2017, indoor tanning accounts for approximately 500,000 new skin cancer cases per year in the United States, Australia, and Europe. Not only has indoor tanning increased the occurrence of skin cancer, but it has also dragged down the age at which these cancers first emerge.4 The skin cancers caused by this activity include melanoma, which is the most lethal type of skin cancer. When tanning devices were popularized in the 1980s, skin cancer awareness was essentially absent. I was among the early enthusiasts, not because of any peer pressure but because, like so many ignorant others, I associated being tanned with looking healthy and with beauty. I probably also just wanted to fit in with my friends who were able to achieve browner skin in the summer quite easily. All the same, I was grasping at something that was out of reach. As a redhead, my translucent fair skin simply did not tan in the sun. I spent hours of my teenage vacations basking in the sun and drinking lots of carrot juice to increase the healthy glow I was hoping for. But instead of a tan, I developed small blisters, for which after-sun cooling gels were readily available in the stores. I guess I was not the only one plagued by this sunbathing “nuisance”! When a friend bought a sunbed and allowed me to use it, I thought that this would be the way to enhance my chances of success. I exceeded the recommended time per tanning session (against her sage advice) for quicker results, which, of course, never came. Eventually, I gave up and decided to accept my pale looking skin. Now, many years later and knowing better, I can hardly believe how much of a risk I exposed myself to. In my teenage years, however, neither children nor their parents knew better. We were not educated about the risks of UV light exposure and did not know that the considerable associated risks are

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even greater with exposure early in life. Ironically, when I traveled to Vietnam as an adult and, along my journey, visited the rural Buddhist temple of Bai Dinh, I found myself surrounded by giggling young women who could not repress the urge to touch the skin of my arms to see whether this whiteness was real. When they discovered that it was indeed genuine, more giggles followed, as well as cell phone pictures. And during another trip to Asia, when I was looking for a Mother’s Day gift in the Japanese city of Kyoto, the salesperson recommended a skin bleaching facial cream, assuming that, like many Japanese women, my mother would appreciate a product that promised to lighten her skin tone. Given that she loves tanning by sunbathing to this day, despite having been treated for a type of skin cancer called squamous cell carcinoma, it was an oddly peculiar experience to me. We humans seem to admire and want what we do not have, and the grass is always greener on the other side. Just like other industries that seek financial gain from our personal interests derived from social norms, the indoor tanning industry uses marketing practices to attract customers and to keep them coming back. Similar to the tobacco industry, some claims by the industry are misleading if not false. The U.S. House of Representatives Committee on Energy and Commerce noted that indoor tanning marketing strategies were targeted to those potential customers who were especially vulnerable. Another similarity with the tobacco corporations is that health risks were downplayed, specific subgroups in society were targeted for advertising, and positive effects were overstated. These touted effects range from social desirability of a certain beauty standard to increased feelings of wellbeing and enhanced production by the body of vitamin D.5 Although vitamin D indeed is low in many people, it is easily increased through supplementary dietary means. Exposure to cancer-causing radiation hardly is a safe way to augment it! In case you think that such manipulation is reserved for the young, think again. Adults are manipulated in their judgments in many ways, and although they may think that they have awareness around their choices, reality tells a different story. Decisions are much more often a mix of rational deliberation and influences that persuade at a subconscious level. Sometimes people are successful at “manipulating” themselves, for example when dieting. When they make the conscious decision to put the candy out of sight, to eat off of smaller plates, and to keep a food diary, they are likely to consume fewer calories overall.6 Frequently though, people merely think that they are in control of their choices, while in fact these are shaped in subtle yet powerful ways. In an interesting study of free will in the context of magician’s tricks, researchers

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explored how study participants were influenced by skillful “forcing” as carried out by a magician during a performance. Forcing, as they explain, “occurs when the magician influences the decisions made by the audience, without their awareness.”6

One such technique is physical forcing: objects are handled in such a way that a particular choice becomes more likely than another, for example by spreading a deck of cards in a certain way. With mental forcing, in contrast, the magician may say something about home improvement projects that brings to mind certain images. If someone is subsequently asked to think of a tool, then a tool that was mentioned or associated with the mental image is most likely to spring to mind first. The authors conclude that study participants “can have subjective free choice without objective free choice.”6

This technique is less obvious or direct than the social influencing of, for example, peer pressure, yet it also enhances the likelihood of one outcome over another. Our individual choices are determined by a multitude of factors, some of which reach the level of awareness, while others remain hidden. These choices, in turn, have an impact on how the world around us interacts with us. One example of that is reflected in the news content we receive. I already addressed how we preferentially click on and read stories of fame and shame, as well as disaster and war. The more we give in to that urge, the more we can expect the presentation of news stories to be slanted in those negative directions. But it is not the whole story. Stanford faculty member Dr. Angèle Christin became curious about the extent to which digitally tracked audience metrics have changed journalism in different parts of the world. In 2018, she published a study in which she investigated this question.7 She chose to focus on one news website in the United States, where clicks by the consumer directly reflect the traffic on the site and thereby record the public’s interest in a news story. These mouse clicks strongly influence online advertising revenue.8 The other online news publication was located in France, where advertising pressures are much less pronounced because the government provides strong financial support to the news media. Because of these differences in market pressures, she expected to find that clicks associated with the news articles in France would have a smaller influence on the work of journalists than in the U.S. Interestingly, it was not that straightforward.

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In the United States, the market-driven realities of commercial success do affect news organizations and their editors, but the journalists themselves still prioritize their professional journalistic integrity. This may help protect them from undue extraneous influences on the work they deliver, at least in the framework of this one carefully examined news website. In France, in contrast, journalists associated the clicks which their articles received with the degree of public debate and with the social impact of the news that they brought. Therefore, they regarded the clicks as highly important, even though advertising revenue was not at the forefront. This paradoxical effect illustrates how the same metric may be utilized quite differently in different settings or cultures, even though we tend to think that such metrics provide rational means to achieve transparency and objective assessment. The study illustrates that the interpretation of findings in different settings is multi-layered and therefore needs careful attention. The findings from this study, however, cannot necessarily be applied to media in general or even to other news media. Dr. Christin concluded that “it remains an open question whether the increased competitiveness of the digital media landscape, together with the expansive reliance of news websites on traffic numbers and social media platforms, actually leads to a marked impoverishment of the content offered on the web.”7

Regardless of whether we are exposed to manipulation by the media, by politicians or by advertising, the key goal of this kind of persuasion is to influence our decisions to the advantage of the manipulator. This is the case both for messages that truly serve a laudable purpose (you may recall the heartbreaking ads against animal cruelty with the ethereal vocals of Sarah McLachlan in the background) and for those with less praiseworthy intent. On the surface, either type of announcement may seem to have our personal or societal best interest at heart but it ultimately needs to serve the objectives of the puppeteer. Thus, commercials are designed primarily to be to someone else’s advantage instead of ours. Of course, there must be some perceived benefit to us, the target audience, as well, otherwise we would not be persuaded by these tactics. How, then, can that perception of benefit be maximized? Marketers have quite a toolbox at their disposal to further their agenda. One subtle way of persuasion is product placement on TV or in movies. Its efficacy goes back to the principle of repetition and the subsequent recognition of a product, even if that recognition happens at a subconscious level. If you see the Coca-Cola bottle multiple times, you may become thirsty for a fizzy drink, and the first one to spring to mind may well be that

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very brand. A movie may also evoke emotions that can become linked to a product placed in the scene. Especially happy emotions can lead to increased affinity with the product. Your on-screen acquaintance with a placed product that is less well known than Coca-Cola may make it more likely that you feel comfortable with it when you see it in the store. Subsequently, you may be more inclined to purchase it. With all these products, color schemes impact our associations as well. Red, for example, signals bright and energetic, green denotes calm, and navy blue indicates trustworthiness. Another tried and tested way to tip us toward purchasing more stuff is the tool of referencing.9 The lifestyles that are usually portrayed to us in the entertainment media are not within reach for most people. And whereas we know that movies idealize things, these unrealistic representations can lead to an internalized desire to live a similar lifestyle, by raising our expectations. Have you ever noticed that a disproportionate number of the homes in movies are exceptionally nice, even when supposedly the story is not about affluent people but about people “like you and me”? The subtle message to the comparative mind is that this is what life should look like, and based on the number of Americans who live beyond their means10, that message seems to be working. A weak wireless signal can precipitate feelings of terror and dismay, but it is exactly that ubiquitous use of the internet and social media that provides yet another remarkable tool to those who wish to influence others. Based on how readily privacy has been relegated to the sidelines, a remarkable opportunity for psychological profiling and targeting has emerged. Gathering information by capturing online behaviors to tailor messaging to the individual is not science fiction anymore, and it is not even difficult to do. It is here, and it is here to appeal to individual consumers with messages they are frequently unable to ignore, just based upon their psychological profile, social needs and general preferences. By skillfully using the gathered data about personal predilections, focused messages and products can be presented in a way that elicits “likes”: a quick and positive emotional judgment that does not require too much thinking and that will make adoption of a message or a quick purchase more probable. With personal profiles available to be used (and sold, and shared), groups with similarities can be targeted with precision for specific marketing purposes. All this profiling has one overarching goal, namely to determine weaknesses. It is not enough to know about our interests, it is also important to know what makes us tick, because a vulnerable state makes us more susceptible to outside influences. Vulnerability takes away that most-alert

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layer of our ability to think clearly and critically in order to make wise decisions. This is why it is not ideal to go grocery shopping when hungry if one wishes to enhance the likelihood of coming home with only what was actually on the shopping list and not also with the other things that looked appealing. We cannot make the most rational choices when we feel tired, anxious, insecure, or dejected. Likewise, our capacity for discernment suffers when we are in a hurry, on autopilot, distracted, or in a state of doubt. All these states make us more vulnerable because making considered choices takes time and effort and these conditions diminish our ability for both. In addition, we lose nuance and are more likely to see issues as black and white. Whereas such simplifications are rarely justified, our decisions become more black and white as well. So, while we are vulnerable, persuasion tactics will be more likely to achieve their hungry goals. One persuasion tactic is the urgency that can be conveyed by slogans such as “limited time only” or “save now!” There is a furniture store in the region where I live that, to the best of my knowledge, never has not had a “sale” complete with banners, flags, and large signs in the windows. I am sure that they would not take these visibility measures if these did not bring customers into the store (and indeed, when my husband and I were looking for a sofa we, too, did go in, attracted by the banners’ promises). Another example of marketing tactics is an appeal to our empathy with slogans such as “the greatest tragedy is indifference” (Red Cross) or “when you care enough to send the very best” (Hallmark). The goal there is to make you feel that you are a bad person if you do not feel compelled to respond to the appeal. And my guess is that virtually nobody wants to be perceived as heartless. That appears to be true even for marketers... In an online article in Entrepreneur11, successful businessman Scott Oldford makes the case that the audience to whom the marketing is directed needs guidance. They first need to become aware that something is lacking, or, as he states, that there is pain. The job of the marketer then is to reveal the solution by providing the option by which the situation can be improved. The marketer in effect serves as a guide to the individual who wants to surmount the issue. As Oldford points out, it is important to do this in an ethical way. He writes: “If you want to help your audience, you have to manipulate them; otherwise they may never ‘figure it’ out. But, there’s a right way to go about it and a wrong way.”11

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He asserts that the marketed solution must be relevant and highly valuable to the customer, and it has to be presented very often. After all, if an ad is seen everywhere, the product readily becomes someone’s most obvious first choice. Finally, it is important to gain trust and to ensure that the value to the audience is authentic. This marks the difference between a scheme in which someone feels taken advantage of later on, and the building of a loyal base of people who believe in the brand. If you follow these principles instead of preying on “their fears and insecurities,”

he argues that “you’ll ethically manipulate your audience into taking the action they need.”11

Marketing strategies and principles apply to healthcare advertising and to messages about health just as much as in other areas of life. But in the case of online health rumors, readers at first do not actually know whether they are dealing with something that is true or a hoax. Interestingly, people who are more aware of the process of knowing, and who understand that knowledge is acquired through considerable effort, are less likely to participate in online sharing of health rumors than people who view knowledge as something that is relatively fixed and easy to gain. Consequently, people in the first group are more likely to put the brakes on the rumor-machinery, whereas people in the second group are more likely to fuel it. Although hoaxes seem to travel faster than rumors that eventually can be confirmed to be true, neither of the two groups of people can easily ascertain whether a rumor is true or false.12 Health-related messages that have gone viral can proliferate angst, propagate misinformation, and grow out of proportion. This reminds me of the story of the chicken at one end of the henhouse who suddenly lost a feather and told her neighbor about it. By the time the news of this event had reached the other end of the henhouse, she was believed to be entirely bald... Key points: G Individual choices are determined by a mix of rational deliberation and influences that persuade at a subconscious level. G Cognitive biases and preconceived notions affect choices, but people are largely unaware that these mental processes are taking place.

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G The key goal of manipulation by the media, by politicians, or by advertisers is to direct decisions to their advantage. G A vulnerable state increases susceptibility to outside influences. Vulnerability reduces the ability to think clearly and critically in order to make wise decisions. G Marketing strategies and principles apply to healthcare advertising and to messages about health just as much as to other areas of life.

CHAPTER SIX SO WHAT, WHO CARES?

How the sources of health information impact outcomes

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Why is it critically important to be fully informed by trustworthy sources about anything that affects health?

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Why is it so challenging to easily determine the extent to which a piece of information can be trusted?

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Do two opposing opinions about health topics necessarily merit equal time?

The title of this chapter could have come straight out of a text balloon from Sally Brown’s mouth. As Charlie Brown’s sister, and one of the endearing characters from the iconic Peanuts cartoons by Charles Schulz (1922-2000), Sally comes up with new “philosophies” all the time. She is a little kid, so her philosophies are not necessarily groundbreakingly profound. She is discovering the world around her and is precocious for her age, but of course she cannot possibly be as brilliant as their dog Snoopy, whose wisdom, imagination, and intelligence stole the hearts of millions of readers all over the world. “So what, who cares?” applies to nonfictional characters too, because it illustrates people’s general tendency to think that the abundant information to which they are exposed does not necessarily change how they think or act. Surely, we have the ability to filter out what is important to us and ignore the rest? Or to determine whether something is communicated with epistemic authority, meaning with factual knowledge behind it, and a degree of validation of that knowledge that enables us to put trust in the

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information. It is a matter of distinguishing fact from fiction and to know the extent to which a piece of information can be trusted, generalized, and applied to specific situations. It sounds straightforward, but we probably all tend to overestimate our ability to make those distinctions...it is a tall order! Some websites are specifically dedicated to fact finding.1 One of the early online players is Snopes, which started in 1994 by investigating hoaxes, urban legends, and folklore. Over the years, with a growing demand for factchecking, it has expanded its scope to include general inquiries such as political statements and rumors that have gone viral. In 2008, for example, Snopes investigated the claim that “baby carrots are made from deformed full-sized carrots that have been soaked in chlorine.”2

Given that baby carrots are typically cut and therefore have no skin on them, anyone who has ever looked at a baby carrot could easily dismiss the first part of the claim. But what about the chlorine? The Snopes investigation may go beyond what one practically needs to know about the process of making baby carrots, but at least it is offering an informed answer to the concerning possibility that baby carrots might be marinated in a bath of chemicals that are known to cause eye irritation in public swimming pools. Snopes found that a chlorine rinse indeed is used for sanitation and disinfection to minimize the possibility of contamination and potential food poisoning, but after rinses with drinking water, the final chlorine concentration is quite low. And the same practice is allowed even for organic vegetables3 (which is not to say that one should not at least consider making carrot sticks from carrots that have not been processed in a factory). Another example of the ease with which fictitious claims can become accepted (and even celebrated) is the story of Australian wellness-blogger and book author Belle Gibson, who claimed that she had cured her terminal brain cancer by adhering to a healthy diet.4,5 Her positive, hopeful message inspired a large following and enabled the success of her global business that was entirely based on false claims about her disease, cure, and knowledge, not to mention the claim of her donations to charity that were never actually delivered. The unraveling came in an exposé by two journalists who discovered that Belle Gibson never in fact had terminal brain cancer (or any other cancer) and had mislead her followers, fans, publishers, friends, and even family.5 The fraud was a jarring experience for

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many, not in the least for the cancer patients who put their hope and trust in her expertise. I have not chosen this example to suggest that all influencers in the wellness sphere are frauds, but rather to highlight that stories of hope, and especially stories that hold the promise that we can overcome all obstacles, provide room for platforms that we would like to believe in. The unraveling of Gibson’s claims also highlights how powerfully attractive alternative cancer treatments are in comparison to conventional approaches and how badly we want to put faith in wellness personas who seem to use paths that fly in the face of established medical care. And why wouldn’t you want to be cured by adopting a healthy lifestyle? For some chronic and potentially life-threatening conditions it does work, but the decisive point of importance is knowing in which circumstances success is reasonably possible, and when such an approach is not going to be enough. The extent of the influence that can be exerted by wellness-gurus is now larger than ever because of the speed with which their health advice can be transmitted online and through social media. In an online article in The Conversation, Drs. Stephanie Alice Baker and Chris Rojek aptly observe that, “there is no commitment to independent testing procedures and results by objective, scientific methods. Rather, online metrics (such as followers, likes, and shares) validate their status.”4

In the end, however, the monetary and emotional exploitation associated with fraud in the wellness industry is particularly distasteful and in Belle Gibson’s case, it reached the level of a criminal offense. Are we just too gullible? Perhaps. But in our defense, unless we are that most cynical kind of person, we innately expect that people act with some degree of integrity. That does not mean that we naïvely think that people are always completely honest or that they necessarily know all there is to know about their declared area of expertise, but we generally do expect that they operate with good intentions and in good faith. If health information is presented with added entertainment value, such as on television, in compelling YouTube vlogs, or in print, then it can be quite seductive, especially after a long workday when comfort, relaxation, light entertainment, and distraction from the worries of the moment are all that seem to matter. Exactly this state, however, also induces less critical thinking and more vulnerability to being influenced. After all, as highlighted before, if you heard it on television, then there must be some truth to it, and

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if you heard it on television five times, then you can be convinced that it definitely must be true! In addition, if the packaging of information is enjoyable and facilitates “ease of absorption”, then obviously it is more likely to catch on than when it is presented in a dry, boring, difficult, or unclear way. Marketers know this, of course, and will do their very best to captivate attention and interest. It is their job. Take traditional “women’s magazines”, for example: bite-size pieces of information are usually presented in a compelling way, with colorful and pleasing images, and with a solution-oriented message that suggests some longstanding wisdom or solid truth behind it. Most disturbing is the certainty with which some of the assertions are made. More on that later on, in the second part of this book (The Science of Health and Wellbeing), where we take a closer look at perpetuated health claims to assess which of those are for real. While we grapple with the question of what information we can safely assume to have validity, the Romans already had it figured out 2000 years ago, when they asked, “cui bono?”, which means “who benefits?”. It can be used as a legal question, indicating that the person who stands to gain the most from a criminal act should be at the top of the list of suspects, but in English it has been generalized to mean that one should always wonder who stands to gain the most from any action. Which brings us back to the purpose of persuasion. In business, the goal is generally twofold. First, marketing should enhance profits by influencing brand recognition and sales in the short term. Second, it should pay off in the long term. By building demand for a product over time and by augmenting sales, advertising can result in an increasingly viable business. It is clear that advertising is primarily used to benefit a business rather than society. But it would be an oversimplification to leave it at that. Whereas marketing information is frequently promotional, it ideally provides a benefit to both the business and the customer. Along with being promotional, marketing also can be principally informational. This kind of marketing uses messaging that does not intend to sell a product, but chiefly aims to inform and explain, using many of the same tools that are used in promotional advertising. In healthcare, educational advertising is part of public health campaigns, such as those that inform about the risks of using tobacco or alcohol and messages that focus on diabetes prevention or breast cancer awareness. In these examples, the mass-marketed informational content is designed first and foremost to benefit society at large.6

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When promotional and informational advertising are combined in a single message, the “cui bono?” may be less transparent. This combination is typically seen in advertisements for medication. Interestingly, the U.S. is one of only two countries with firm regulatory frameworks (the other is New Zealand) in which pharmaceuticals can be marketed directly to potential customers, in newspapers and magazines, by direct mailing, and on the radio, on television and online. There are three basic types of these ads.7 The first kind is informational, without the naming of a specific drug. It simply highlights a medical condition and encourages people to talk to their physician. The second type mentions the product as well as specifics about the medication itself, such as its strength and how it should be taken, but it does not include claims or discuss what the medication is actually for. The strategy behind this kind of marketing seems less straightforward because people would already need to know what the indication for the medication is, or else be intrigued enough to look up whether this cute pink pill would solve their medical problems. Not surprisingly, the third type of advertisement is the most prevalent. This entails the most complete type of marketing, because it mentions the medication together with its indications as well as its claimed benefits. Direct-to-consumer (DTC) advertising is big business: in the United States, DTC marketing was the most rapidly increasing branch of medical marketing overall, growing from almost 12% (2.1 billion U.S. dollars) of total medical marketing spending in 1997 to 32% (9.6 billion U.S. dollars) in 2016.8 There are numerous pros and cons to DTC marketing of pharmaceuticals, and good arguments have been made on either side of the debate.7,9 Advantages could be that consumers become empowered to be engaged more directly in their own healthcare because they are more informed, and able to receive information about their condition and potential treatments from multiple sources. It may also encourage consultation with their physician, which can enhance the relationship between patient and doctor. This, in turn, may strengthen trust and increase treatment compliance once a therapeutic plan has been agreed upon. In addition, pharmaceutical advertising helps destigmatize conditions that can be perceived as embarrassing, which is helpful because shame can decrease the likelihood that patients discuss an ailment with their doctor in the first place. Such conditions could include psoriasis, depression, genital herpes, or incontinence. By making these issues more visible and by helping to remove associations of shame, some patients may finally feel encouraged

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to seek medical care. DTC advertising may thus reduce underdiagnosis and undertreatment. On the flipside, DTC advertising may lead to overdiagnosis and overmedication, and to inappropriate prescribing. Even if the latter does not occur, it can pose a challenge for the physician to convince a patient that the requested medication is not suitable for treating the condition as it presents in that patient, especially if the patient comes in with preconceived notions about the benefits of a medication without knowing the nuances of risk, side effects, and efficacy. Moreover, such a discussion occupies time that could otherwise be spent in discussing more appropriate treatment modalities, such as another type of medication or lifestyle adjustments. It can be frustrating for doctors to be put into a gatekeeper position instead of being able to focus on optimally taking care of their patients by using evidence-based medicine that is tailored to specific medical needs.7 The major concern about pharmaceutical DTC advertising is that it carries the risk of misinforming patients. This can happen in several ways, some of which are a function of patient characteristics and some of which are based on the goals of the pharmaceutical industry to persuade, and thereby create new customers. Patients who do not have a background in medical training may lack the ability to thoroughly interpret the presented information. This includes the indications for a certain drug, as well as its side effects, toxicology profile, and contraindications for taking it. But the concern about misinforming patients goes further than that: just as with most general healthcare information, the text of DTC drug advertisements is often presented at a level that exceeds the eight-grade reading level recommended for messages aimed at the general public, and may hamper proper content evaluation because it is too complex. Oversimplification, however, is just as much of an issue. If the information in an advertisement is presented in a compelling way, then patients may believe that they are fully cognizant of what they need to know. Ironically, such a belief reduces the likelihood that all aspects of the text will be carefully read and assessed, and it also decreases people’s motivation to seek out additional sources of information that may be less biased. After all, commercial advertisements are by definition not impartial. Even though pharmaceutical companies are required to refrain from false claims, manipulation of “the message” is often easy to spot. Advertising

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may not be the most desirable vehicle to communicate information about adverse effects in any case, but such information usually also is not provided quite as effectively as are the advantages of taking the featured medication.9 The communication of risks and side effects is, at times, literally minimized. This can take the form of small-font text, of using medical jargon, of giving these aspects much less visibility than the benefits, and of omission. It is simply not in the drug company’s interest to mention alternative options, such as dietary changes. By offering a pill as the solution to a medical problem, other interventions that either support or altogether replace medication treatment may seem superfluous. On the radio and on television, information about side effects is often either provided by someone who seems to have inhaled helium and won a fast-speaking contest, or the side effects are presented so cheerfully that it makes you wish you could enjoy some of them, as well. Have you ever noticed how the industry succeeds in presenting potential adverse effects in the most delightful and appealing way? The risk of hair loss, bleeding, erectile dysfunction, nausea, and stroke never sounded so attractive! If we wish to maximize the benefits and minimize the risks of DTC pharmaceutical advertising, reliable and objective communication is paramount. It is the only approach that is fair to a patient, especially given the premise of DTC pharmaceutical advertising that patients deserve the opportunity to make their own informed choices. We can at least agree on that. Patients deserve nothing less. Why is it so important to be fully informed via trustworthy sources and to be conscientiously educated about anything that affects health and healthcare? Why do I keep coming back to this point? Because thinking that we know something that we do not actually understand and acting upon it is risky business, especially where health and wellbeing are concerned. Let me provide just a few more examples from divergent areas of healthcare and with separate areas of concern. The first example goes to the notion that dietary supplements are harmless. After all, they often give the impression that they are natural substances and if something is “natural” then people are immediately inclined to think that they are doing something wholesome for the body. And supplements are tremendously popular. Based on surveys, it has been estimated that about 50% of Americans and 20% of Europeans use herbal and dietary supplements10, and in the United States alone, supplement sales in 2014 amounted to nearly 37 billion U.S. dollars. In recent years, however, there has been an increase in associated toxic effects on the liver.

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Drug-induced liver injury is a known phenomenon associated with a variety of prescription medicines. When such medications are prescribed, liver values are usually monitored by regular blood tests to make sure that liver damage does not occur. It may be surprising to learn that approximately 20% of drug-induced liver injuries in the U.S. are the result of herbal and dietary supplements, compared to a whopping 70% in South Korea and Singapore, and 13% in Spain.10 The risk of liver damage is not disclosed and these cases are not necessarily mild. They have been linked to an increased risk of poor outcomes, such as the need for a liver transplant and compromised survival (yes...that means death). The second example is a story of fatal consequences from manipulation by a craniosacral “therapist” of a previously healthy three-month-old infant. It is a heartbreaking story, all the more devastating because alternative medicine therapies such as craniosacral manipulation have the implied connotation of not being harmful and of being at least potentially helpful. That may well have been the assumption of the parents of the little girl. They placed their trust in the hands of the manual therapist and hoped for help with some minor restlessness of their child. During the session, the child at first cried. The therapist turned her on her side, folding the entire spine forward so that her body was bent and her chin touched her breast bone. She was held in this position for several minutes. The crying stopped, and at first, some loud breathing noises were heard. The therapist informed the parents that these sounds represented a state of deep sleep, as was expected with this kind of therapy. When the child was turned on her back after approximately ten minutes, her lips were blue and despite efforts of the father to resuscitate her, she ultimately could not be saved. The deep and prolonged forced flexion of the spine had caused damage to the spinal cord and her brain had suffered a profound lack of oxygen.11 Whereas infant injury and death from manual therapies are rare, this is not an isolated case. Three additional deaths have been reported in the English language scientific literature, all following treatment by nonchiropractic manual practitioners.12 The third example illustrates the risk of refusing to take an action that is known to be safe and can save numerous lives, in this case, vaccination for Human Papillomavirus (HPV). HPV is a sexually transmitted virus that is very common all over the world. It is best known for causing cervical cancer, but it can also cause penile, anal and oral cancer, vulvar and vaginal cancer, and genital warts. The association between HPV types 16 and 18

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and cervical cancer is not subtle: together they cause 70% of cervical precancerous changes and cancers. And whereas cervical cancer can be cured as long as it is diagnosed early, globally in 2018 still approximately 311,000 women died from it. Vaccination against the most common high-risk HPV types is available, highly effective, and safe. It has been approved for prevention in many countries and it is recommended as a public health measure by the WHO.13 Yet, there is tenacious misguided opposition against the vaccination of young people by two main constituencies.14 One group favors sexual abstinence over vaccination, based on an unsubstantiated fear that vaccination might result in promiscuous behavior. In fact, there is no difference in the level of sexual activity between vaccinated and unvaccinated groups, but the vaccinated group is more informed and health-conscious, thus less likely to be surprised by other sexually transmitted diseases or pregnancy. The second group consists of individuals who have been persuaded by emotive concerns about vaccine safety, however unfounded they are. Regrettably, fearmongering is highly effective, and on the surface it may appear to be more compelling than hard data. Who doesn’t want safety for their children? But the HPV vaccine has been extensively studied, administered widely, and monitored closely for any adverse effects in recipients. Apart from generic vaccination complications such as fainting or temporary pain at the injection site, the exceedingly large data set has borne out none of the claims about “vaccine-damage”.15 Scientist, cancer researcher and physicist Dr. David Grimes does not mince words. In a 2017 article in the Irish Times, he wrote: “Whatever their motivations, groups and public figures who peddle antivaccine nonsense ultimately condemn young people to preventable deaths.”15

But what really gets lost in copious misinformation is the excitement we should all sense about the breakthrough of having a vaccine to prevent infection with this common virus. Whereas the Pap-smear enables early detection and treatment of cervical cancer, the vaccine enables the prevention of this potentially deadly disease. Dr. Grimes underscores this when he says that “We stand on the cusp of a new era where we finally have the means to prevent an entire class of cancers. It would be a tragedy if ancient antivaccine falsehoods were to hobble this.”15

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One thing that sustains claims that have been thoroughly debunked is the notion that different opinions deserve equal time. It is consistent with the belief that “the truth lies somewhere in the middle”, that is, between two opposite ends of the spectrum. This stance may mask as fair journalism, but is in fact the opposite. By providing a platform for bogus arguments, misinformation has the opportunity to grow and metastasize. This phenomenon is also called the balance fallacy.16 It is a fallacy because it assumes that two different opinions are of comparable value and therefore deserve equal time even when one of the two is (or should be) known to have little merit or no merit at all. This can happen when one opinion is backed by abundant substantive data whereas the other is pie in the sky, expressed by a person or by a group lacking accurate topic expertise. The balance fallacy ignores the possibility that an argument that is the polar opposite of another may very well be the one that is valid. Of course there is also the possibility that neither one of two extreme opinions is correct, and that the truth is not found in the middle but rather in an opinion that has yet to be presented. By giving undue attention and time to a fringe position, a viewpoint that cannot be supported by facts is over-emphasized and feeds controversy where there really should not be any. Like Roman gladiator fights, this practice may attract spectators who are out for blood and entertainment, but ultimately it is a disservice that misleads the public and obscures the truth. Cui bono? Think about it: in such a case “cui bono” is not you! Whereas everyone is entitled to think and say what they please, it does not follow from this that clearly incorrect and unsubstantiated views warrant continued attention and propagation. Key points: G There is a general tendency to think that we can easily determine the extent to which a piece of information can be trusted. But it is important to consider who stands to gain the most and who stands to lose the most. G Public health campaigns make use of educational advertising. Their mass-marketed informational content is intended first and foremost to benefit society at large.

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G When promotional and informational advertising are combined in a single message, such as in direct-to-consumer pharmaceutical advertising, it may not be transparent who benefits the most. G Being convinced of knowing something that is not actually wellunderstood and acting upon it is risky business, especially where health and wellbeing are concerned. G Unsubstantiated views are propagated by the balance fallacy, which assumes that two different opinions are of similar value and therefore deserve equal time, even when one of the two has little or no merit.

CHAPTER SEVEN PUBLIC RELATIONS

How the value of science can be communicated effectively ·

What shapes public opinion about science, scientists, and scientific institutions?

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Can the gap between ideas about science and actual understanding be minimized?

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How can excitement about scientific breakthroughs be shared?

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How can the value of science be communicated in an inclusive way?

It happens all the time. When people ask me what I do and I tell them that I am a doctor, they often ask, “What kind of doctor?”. I can mention my certification in lifestyle medicine, and add that lifestyle medicine is the evidence-based practice of assisting individuals and families to adopt and sustain behaviors that can improve health and quality of life.1 Generally, people can imagine how the medical discipline may apply to their health journey, and some are so interested that they want to become my patient. However, when I add that I am a doctor who specialized in clinical pathology and in clinical molecular genetics, the response is different. These terms are a mouthful and, not surprisingly, they do not mean much to most people. At that point, either they conclude, “So you see dead people!”, or I

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get a puzzled look. I explain: I do not see dead people, although some anatomic pathologists do, especially those who perform autopsies or who completed additional training in forensic pathology. And I tell them that a pathologist is a specialist physician who diagnoses and interprets changes caused by disease in the body’s tissues and fluids2 and that a clinical pathologist is one who is specialized in laboratory medicine. Laboratory medicine entails much of what people associate with general internal medicine, but instead of seeing patients, clinical pathologists focus on the laboratory side of things. Specifically, we determine the cause of diseases based on what can be tested in a clinical laboratory, but we also assess the physical and functional manifestations of disease in the body. In other words: we examine disease development and its consequences. Laboratory medicine is something that is not very visible to a patient, but it is a critical part of almost all patient workups. When Mr. Smith says that his doctor diagnosed his disease then it is highly likely that the condition was in fact diagnosed by a pathologist or, at the very least, that the pathologist could narrow down the list of possible diagnoses assembled by the patient’s doctor during his initial assessment. This is why pathologists are sometimes called “the doctor’s doctor.” Because they primarily communicate and interact with other physicians, they remain out of view for most patients. In the past, pathologists often literally worked in an outlying area of the hospital and remained behind the scenes. There is still that old joke that the definition of an extroverted pathologist is one who looks at your shoes instead of his own, but this stereotype no longer holds water, and perhaps it never did. Nowadays, especially with the advent of advanced diagnostic methods such as genomic testing, pathologists do not remain behind the scenes but instead are right at the table during patient care meetings, together with other doctors and additional members of the healthcare team. Such meetings help ensure good communication between the different medical specialists who take care of the same patient. They also improve the coordination of that care. Pathologists have become more integral than ever to a patient’s care, for example in the case of cancer. They work directly with oncologists, radiologists, and other care providers to present the most accurate diagnosis and explain it on the level of the body (macroscopic) and the cells (microscopic), and on the molecular (genomic) level. This helps ensure that a patient’s cancer is correctly diagnosed and subtyped. The latter provides an extra level of detail that is important for how the cancer can be treated.

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In the case of breast cancer, for example, subtyping determines which specific type of breast cancer it is, out of multiple different possibilities that differ on the cellular and molecular level. Such a thorough analysis also means that relevant information about the patient’s prognosis can be shared. Moreover, a pathology-based prediction of treatments that will work for that specific cancer type makes it possible that a patient can be treated accordingly, instead of suffering the side effects and cost-burden of a chemotherapy that would decrease the quality of life without being effective. And finally, once certain molecular details of a cancer are known, patients can be monitored for minimal residual disease or for early cancer recurrence, well before cancer relapse might become obvious because of symptoms. By combining specialty training in laboratory medicine with clinical molecular genetics, I was able to conduct genetic testing on cancer patients as well as on people with inherited genetic diseases, such as hearing loss, intellectual disability, and cystic fibrosis (CF). Together with my superb colleague, mentor, and friend Dr. Jim Zehnder, I directed the clinical molecular diagnostic laboratory at Stanford. I also had a research laboratory, where I explored new questions about diseases and their causes. The work in my research laboratory was not diagnostic but was instead conducted to advance clinical knowledge with the goal of eventually improving how we diagnose and treat patients. My research was not part of my medical practice, and my role in that aspect of my career was not that of a doctor but that of a scientist. This distinction is important because diagnostic genetic testing is a medical service, whereas research entails informed consent by people who choose to participate in a study with an understanding that there may not be a result that can be communicated back. This type of work, therefore, is performed at no charge to participants and aims to answer questions that go beyond what thus far can be tested for in a clinical setting. One of the things my research team and I aimed to accomplish was to level the landscape for non-white patients with CF. CF is a relatively common, potentially fatal genetic disease that classically manifests early in childhood with failure to thrive, problems in the digestive system, respiratory infections, and lung disease, with breathing difficulties as the disease progresses. It occurs all over the world, but more commonly in white people. In each affected child it is caused by two mutations (gene changes) in the CFTR gene, but the specific combination of the two changes varies because there are many possible mutations in this gene.

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In white people of northern European descent, there is a relatively small number of frequently identified mutations, and these are the ones most commonly targeted for genetic testing. The problem, however, was that patients of all ethnicities were typically tested with this same test and that the test was originally designed based only on the most common gene changes carried in white individuals. Because the mutations in other ethnic groups are often different, it is not surprising that many non-white patients were left without a known complement of two CFTR gene changes, even after genetic testing. Putting it plainly: If a test can only identify A, B, and C, then it will not find X, Y, or Z. But knowing the details of the two changes is important, even for an initial diagnosis. Early on, CF is not that easy to diagnose based on symptoms, and ideally the diagnosis should be made before it is obvious that the child has CF. If the disease is diagnosed through newborn screening or at an early stage, then emerging symptoms can be effectively treated and the child can be comprehensively supported, resulting in better long-term health and survival. A genetic diagnosis is also valuable for genetic counseling of the family, for prediction of the severity and course of the disease, and even for treatment. By studying non-white CF patients from all over the U.S., our research was able to identify the most common mutations in non-white ethnic groups. We illuminated that the most often used mutation panels were not adequate for non-white patients and that other types of genetic testing would be able to improve the likelihood of arriving at a genetic diagnosis, and thereby improve patient care.3,4 This is just one example of how science can go from “bench to bedside”, or, in other words, how research can be translated into diagnostic and treatment progress. Returning to when people ask me what I do, you will now understand that I could answer that I am a physician or that I am a scientist or both. But depending on my answer, I have noticed an interesting difference in the responses that I generally receive. When my answer includes that I am a scientist, just at the mention of the word science, a subset of otherwise perfectly intelligent people seem to have an immediate visceral response that results in an absent-minded look, even though polite conversation continues. Where does that come from? To explore this some more I started with an admittedly non-scientific, small-number experiment, and asked some friends who are also scientists whether they could relate to my experience. As it turned out, their

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observations were quite similar. One friend described it as the worried look of “too much information may be harmful to your health!”. I made sure to specifically ask people who are not prone to giving overly lengthy explanations of their work and of whom I knew that they were quite capable of explaining their research in non-expert language, so there seemed to be something just in what science tends to evoke. Next, I asked a handful of well-educated people who are not working in an academic setting to name some living scientists. As it turned out, scientist trail far, far behind movie stars and other public figures, despite the fact that they may make life-changing, fascinating, publicized breakthroughs. After physicist Dr. Stephen Hawking (1942-2018) passed away, coming up with the name of even a single living scientist proved difficult. How come? And why is science not among those topics that bring about intense curiosity and excitement? It seems fair to say that there may be a bit of a public relations problem... As we shall see, consideration of the public perception of science and scientists can shed some light, although it is not the whole story. For one, there are few scientists who become celebrated like Stephen Hawking was. If given the opportunity (typically after writing many proposals for grant funding) most scientists are driven to dedicate themselves to what they do best and to what they are most interested in, namely their research. The reward comes in discovering something the world has never known before, and in publishing those findings, as well as communicating them to peers at scientific conferences. The following day, they usually just take the next step forward by going back to the bench! There are few scientists who charismatically share science news with the general public. One name that came up in my question of “can you name a living scientist?”, was Dr. Neil deGrasse Tyson, who is an astrophysicist by training and the head of the Hayden Planetarium in New York City. Whereas he is not in fact working as a scientist, he has become a highly successful science communicator and has brought excitement about the cosmos to millions of people. But although he and a limited number of others have been very successful at breaking down barriers between science and general audiences, these barriers still do exist. For many people, science evokes school years with unpopular science classes. Perhaps they entailed experiment demonstrations that repeatedly failed, or left a sense that the immediate relevance of what was taught was lacking. Science is also perceived as being difficult. I am not arguing that it

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is not challenging, but with that preconceived notion, it becomes harder to remain open to the ideas of new discovery, and to the excitement of understanding something new, let alone appreciating its impact. Public perception of science and scientists is fraught with the potential for discord. One factor that continues to cause dissonance is the traditional model of science communication as a didactic endeavor. That premise takes people back to their school days and the differences (in knowledge, status, and power) between teachers and students. It implies, on the one hand, that the general public has a knowledge deficit which is an inadequacy that needs to be corrected, and, on the other hand, it betokens that scientists are somehow outside of public discourse, excluded, as if they were non-citizens. Both these notions create a sphere of opposition where there need not be one. Compounding this issue is the shortsighted idea that there is a single public of “equally ignorant nonentities,”5

whereas in fact, it would be more appropriate to use a term that allows for a recognition of the diversity of culture and knowledge. The term “publics” has been used to acknowledge that social groups are based on shared characteristics and that the public does not fit that mold, being far too diverse to make sweeping assumptions about. But beyond arguing about terms, successful communication requires insight, including the realization that science communication as a didactic endeavor also misses that scientists themselves are part of the public, especially outside their own area of expertise. Hence, science communication should be didactic when the goal is to teach and should be a matter of mutual engagement in the public dialogue when science-related matters of public interest are to be shared.5 Another factor that influences how scientists and science are perceived is the degree to which scientific institutions are effective at communicating what it is they do and why they do it. In a study of predictors of trust in the research of U.S. federal agencies, it was noted that, “their success at these tasks influences the extent to which the public trusts the work they do—and to which policy-makers consider relevant scientific findings in policy-making, citizens incorporate scientific knowledge into their life decisions, and institutions secure long-term funding.”6

Trust, in this context, has two main components: the first is perceived competence and the second perceived character. Perceived competence

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reflects the extent to which there is confidence in the technical ability to carry out the work. Perceived character speaks to the degree to which there is confidence in ethical conduct when the research is performed, so that integrity and public interest are kept at the forefront. I suspect that it is that perceived character that causes the most doubt among members of the public(s). If communication is ineffective, then trust in research integrity is not cultivated in the first place and the existing process of checks and balances on scientific publications (more about that later) is poorly understood. Without that trust, scientific organizations such as research agencies and universities may be considered less trustworthy, which may negatively affect the impact they are able to make with their work. After all, trust is an integral part of meaningful communication. The concluding and self-evident statement in the study on trust in the research of federal agencies was this: “Only after both parties develop trust in each other can outreach efforts effectively inform scientific research and public policy.”6

It deserves to be noted that scientific organizations are not equal to science as a whole, even where public perceptions are concerned. It is perfectly possible that someone has trust in scientific methods and principles, but questions the integrity of some scientific institutions.7 To determine whether there is a difference in how scientists and science are perceived among members of the public and among scientists across disciplines, the Pew Research Center (a nonprofit, nonpartisan, and nonadvocacy fact tank) explored the views on science and society in each group. Such studies are useful not only because they assess whether there is any difference in perceptions around science between the public and the scientific community, but also because if there is a difference, they can highlight where and how it occurs. The conducted surveys on which the 2015 report was based included a canvassing of 3,748 U.S. based members of the American Association for the Advancement of Science (AAAS) and a representative survey of 2,002 other U.S. adults.8 There were substantial differences in perception across the board, both for the biomedical and the physical sciences. For example, there was a difference of 51 percentage points between AAAS scientists and the general public when asked whether the consumption of genetically modified foods is safe. Of the scientists, 88% thought that it is generally safe to eat these products as compared to 37% of the general public. The statement that climate change is mostly due to human activity created a 37 percentage point gap. Of the scientists, 87% agreed with this notion, compared to 50%

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of the general public. The perception was shifted in the other direction when asked about increasing the practice of offshore drilling. Only 32% of scientists were in favor of this idea, as compared to 52% of participating citizens. Whereas scientists as a group seem to differ from nonscientists in the opinions explored in this study, differences between individuals also depend on political ideology and world views. In the United States, partisan differences and political polarization appear to strongly influence general and policy debates around science-related topics such as climate change, stem cell research, genetic testing, space research, and evolution. Political positions and advocacy certainly contribute to the shaping of public opinion in relation to science and technology. However, public opinion also depends on core beliefs. These form the foundation on which the political and media communications that adhere to specific frames of reference are constructed. The results of a study on Americans’ support for embryonic stem cell research indicated that, together with religion, general beliefs about society and science had a greater impact on public opinion than political partisanship, because they reflect an individual’s long-term belief system. That system also has a more lasting influence than media coverage of current events that receive brief bursts of visibility, but otherwise are given only fleeting attention.9 It turns out that in the process of forming opinions, humans are “cognitive misers”: they collect only a small amount of information on which to base their opinions. This attempt at efficiency is borne out of a desire to arrive at a position quickly, given the limited time and attention that can be expended on carefully weighing the pros and cons for each one of numerous complex societal issues that need to be processed along with personal ones. And, perhaps contrary to what one might expect, particularly the better educated make use of (over)simplification. They are also better at remaining ideologically consistent and at arguing their held positions. Thus, during debates and public discourse, the polarization between Democratic and Republican politicians with a college education tends to be more pronounced than that of less highly educated politicians.9 In the context of science, it follows that both conservatives and liberals are more likely to be distrustful of science, of scientists, and of the organizations in which research is conducted, when specific research topics are perceived to have ramifications that could threaten their respective world views.6 Although there still is a long way to go in reducing the gap between public perception and scientific understanding, some organizations contribute

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much to opening minds to the value of science. Take TED,10 for example, a not for profit organization that has recognized the power of ideas. It is dedicated to spreading them across disciplines and cultures through conferences that foster interaction, connection, and collaboration. It can thereby effect positive change. Best of all, the short presentations that are the hallmark of every TED gathering are made freely available to the general public. TED originated in 1984 as a conference that focused on technology, entertainment, and design (hence the acronym). Over the years, the organization has broadened its scope that now encompasses a wide range of topics, including medicine and other sciences.11 Like many other viewers, I always learn something new from TED talks. However, it seems that even those venues that are able to convey excitement about science sometimes choose to do so in a somewhat indirect way. If I could change one thing about this organization, it would be its name. I doubt that the organizers would be receptive to changing their well-established name from TED to TEDS with the S standing for science, but by doing so they could inclusively acknowledge the range of their topics and the existing diversity in their collection of inspiring talks. After all, if we can have “publics” then we should be able to have “TEDS”, and at least TEDS does not cause an infraction involving an uncountable noun! Suggestions aside, as an organization TED has been quite influential in highlighting and communicating new ideas across the breadth of science. Even though TED talks often reflect the opinions of their presenters and should not be confused with vetted scientific publications, TED has been exceptionally successful at making scientific ideas accessible to an interested audience from all walks of life. Notwithstanding the trail-blazing initiative by the organizers of TED, it is only one venue. There is a lot of room for improvement in communication about science elsewhere, and overall. In order to engage general audiences, it would help to make outreach efforts using culturally inclusive communication and to keep various ethical, religious, and ethnic perspectives in mind. Such efforts would be enhanced by diverse approaches that invite multidisciplinary participation from universities, other research organizations, industry, scientific and trade associations, government agencies, foundations, interest groups, faith-based initiatives, and other segments of the general public. This could accomplish more dialogue and enable ongoing engagement, even with those groups who may have deep-rooted reservations about the scientific endeavor.9 Dr. Bart Penders, who studies the co-evolution of facts, knowledge, and norms, points out that scientists cannot and do not work in

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and that science must “embrace the social elements it already contains.”12

The image of the scientist who is fueled only by curiosity and accountable solely to herself disregards the social fabric in which science takes place. Whereas scientific, fact-based results do not have politics, scientists and their efforts are subject to social and political influences, especially regarding the likelihood of project support and funding. In other words, what is stimulated and funded for study is not independent from external factors. The difference between science and its facts on the one hand, and the communication and acceptance of those facts on the other, further highlights the difference between science and the business of science. Which brings me back to the idea that clear communication is at the center of any true dialogue. Effective communication about complex scientific facts can be accomplished. One example of where an inclusive, sensitive, multidisciplinary approach has been highly successful is with genetic testing among orthodox Ashkenazi Jews. In this population, several fatal genetic diseases occur with a higher frequency than in other ethnic groups. Most of these diseases have their onset at birth or in early childhood. Tay-Sachs disease is one example. It is a neurodegenerative condition caused by an inherited enzyme deficiency. At first, an affected child will develop normally, but typically between three and six months of age, the child will gradually lose motor skills and continue to deteriorate. Blindness and seizures occur as the disease progresses to intellectual disability, paralysis, and finally complete incapacitation and death, often before the age of four. This disease is devastating, not only because of its natural course, but also because there is no cure.13 In 1983, the charitable non-profit organization Dor Yeshorim14 was founded to address this issue and to prevent the agonizing grief for parents that results from losing children to this disease. Because Tay-Sachs disease is genetically recessive, the parents are completely asymptomatic carriers of a small genetic change. The Dor Yeshorim initiative, galvanized by Rabbi Josef Ekstein, required extraordinary consideration upfront: genetic testing that might result in abortion is prohibited in the orthodox Ashkenazi Jewish community on religious grounds. Yet, the organization was effective by providing a highly

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successful premarital genetic screening program that has drastically reduced the occurrence of affected births in this population. The genetic testing is performed at highly regulated diagnostic laboratories and remains confidential and anonymous, indicating only whether a couple is genetically “compatible” or not. If both members of a couple are carriers of the disease, then they receive genetic counseling. With this approach, couples maintain their privacy and autonomy, while they have the benefit of receiving leading-edge testing and are able to adhere to their world view.14 Dor Yeshorim required the building of bridges between unlikely allies, but it was well worth the effort. I believe that this is often the case, even though hurdles are undeniably present when divergent groups need to navigate potentially contentious issues. But science builds knowledge, and knowledge enables the consideration of a range of possibilities. In turn, when people can understand and clarify their options, informed decisionmaking is facilitated. In the example of Tay-Sachs disease, it becomes clear that it is possible to respect people’s right to know as well as their right not to know, and to act in a culturally sensitive way that helps alleviate suffering. Despite the orthodox religious framework in which the Dor Yeshorim testing initially exclusively took place, individuals are provided with information that helps them make decisions based on facts; decisions that are well-informed, yet may remain congruent with their beliefs and culture. This is possible in other communities too. It is time (if I may be so bold) that we, scientists and nonscientists alike, take back our power. And it is high time to see where interests between different constituencies overlap, where collaboration is possible, and how validated information can be made available widely so that it can be utilized for the practical questions of daily life. It is time to cut through the nonsense. Without factual knowledge and without understanding how that knowledge is generated, we are like leaves blowing in the wind. Key points: G The field of science does not excel at public relations and is not prominent in the public eye. G The general perception of science is that it is difficult and not accessible or relevant to everyone.

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G Core ideas about society, religious beliefs, and political leanings all contribute to how science, scientists, and scientific institutions are viewed. They also contribute to the degree to which each of these is trusted. G Successful initiatives of bridge-building between different groups are characterized by dialogue instead of purely didactic communication. They require a culturally responsive, multidisciplinary collaboration that is respectful and goal-oriented.

CHAPTER EIGHT HEALERS IN THE MAKING

How information, knowledge, understanding and wisdom enabled the development of the evidence-based scientific method

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What are the differences between information, knowledge, and understanding?

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What is the role of wisdom?

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How and when was medical progress made?

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How did the evidence-based scientific method come about?

There is a fundamental difference between information and knowledge, which is not always appreciated in our time of information overload. Consequently, mere information is often confused with knowledge. But what exactly is the distinction? I like to think about it this way: whereas raw data can be distilled into information, the recipe for knowledge requires additional ingredients. First, we need to develop a process of assessing the information that can be extracted from the “ones and zeros” of raw data sets. That evaluation leads to a basic understanding. But this level of understanding still does not warrant the label of knowledge.

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Dr. David Weinberger, whose work at the Berkman Klein Center for Internet & Society at Harvard University explores how the internet affects ideas, communication, society, and knowledge, described the distinction in the Harvard Business Review. He wrote: “We get to knowledge—especially ‘actionable’ knowledge—by having desires and curiosity, through plotting and play, by being wrong more often than right, by talking with others and forming social bonds, by applying methods and then backing away from them, by calculation and serendipity, by rationality and intuition, by institutional processes and social roles. Most important in this regard, where the decisions are tough and knowledge is hard to come by, knowledge is not determined by information, for it is the knowing process that first decides which information is relevant, and how it is to be used.”1

Knowledge cannot be developed without an input of information, as we all know from the process of learning something new: in order to know how to read, for example, you first need to see the letters of the alphabet and be taught what they mean. But developing knowledge is a process that requires much more than information alone. Information and the basic understanding of that information form the foundation of knowledge, but they need to be augmented with the right amount of analysis and a modicum of experience. Only then can the whole evolve into a deeper understanding and consolidated knowledge. And whereas information may be free, knowledge is not. Even if one does not have to pay for it in the literal sense, it requires resources. It requires an investment of time and effort (and yes, it may require money too) in order to arrive at the point where newly learned material can be successfully integrated in a meaningful, functional way. The latter may require an additional dimension: this is where wisdom comes in, as a final but critical element that provides us with the insight and ability to determine how our knowledge can be applied most constructively. The past two decades have seen a new interest in the history of knowledge and, with that, an increase in research that has knowledge itself as the main focus, where before the emphasis was primarily on other contexts, such as society or science. It has been argued that a major impetus for this development is that the state of human knowledge has become increasingly disputed. On the one hand, the economy and politics both rely on knowledge institutions while, on the other hand, some political leaders brazenly dismiss long-established facts and promote so-called “alternative facts”. By studying

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knowledge throughout the course of history, scholars now aim to increase their understanding of the function and fluidity of knowledge as it plays out in individual societies and human life at large.2 Over the ages, knowledge has evolved and increased dramatically. Unfortunately, the way in which its history is communicated often demonstrates a relatively narrow focus on the western world and, specifically, on men in western cultures. There are many reasons for the selective representation of history. In addition to the almost exclusive attention on the male, the omission of entire cultures and continents is rooted largely in the exertion of authority by power and politics. It has been influenced also by auxiliary historic obstacles to information sharing. Yet, western knowledge is deeply indebted to the insights it received from other countries and cultures. In this chapter I, too, will mostly adhere to the western framework, but only because I want to address the connections and distinctions between knowledge and science and illuminate how the scientific method of knowledge generation came about, a process that initially largely took place in Europe. As this is a book about health, the main focus is on the history of science in medicine, which is characterized by a long and winding road with early forays into experimentation, but also happenstance and tragedy. Given the vast history of world knowledge and science,3 the examples provided should be viewed only as illustrations, because they are necessarily simplifications of an ongoing endeavor that, up to this day, took many centuries and numerous dedicated minds all over the world to move forward. When we consider the development of knowledge, Aristotle (384-322 B.C.E.) cannot be ignored, because (together with Socrates and Plato) Aristotle was one of the greatest thinkers of ancient Greece.4,5 Aristotle’s contributions reflect his all-encompassing interests and his intense passion for learning. The first to use systematic examination, he is credited with comprehensively categorizing human knowledge as it existed in his time. His efforts enabled a standardized approach to the collection and analysis of information and that became instrumental in the advancement of knowledge and the development of structured education in many disciplines. Aristotle studied and taught biology, meteorology, physics, logic, ethics, psychology, politics, poetry, and drama, among other things. He was a philosopher, a master at reasoning, and the father of logical thinking about the physical world. In the Middle Ages, he was still so revered that his authority was accepted by Christian as well as Muslim schools of thought.

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The irony is that, whereas Aristotle was a man who questioned almost everything, his authority remained unquestioned for many centuries after his death. That such blind acceptance is flawed became clear only much later, when plenty of what he subscribed to turned out to be incorrect.6 Nevertheless, Aristotle’s contributions to humanity have been tremendous and his impact continues: he more than succeeded at creating the solid foundation on which scholarly activity is based to this day. Can we say that Aristotle was a scientist? By any reasonable definition for the time of Antiquity indeed he was. However, he lived in a preexperimental era when science as we view it today did not yet exist. His careful observations enabled the development of otherwise untested theories, such as on human reproduction and childbirth.6 He also performed explorations into territories where no or little knowledge yet existed. For example, Aristotle’s curiosity induced him to undertake dissections of many species of animals, which was unusual for the time as it went well beyond the realm of theoretical reasoning into the territory of physical examination. This kind of investigation enabled him to learn about embryology and zoology and to categorize the differences he observed between species. Dissections on human bodies, however, were not part of his fact-finding quest. That would have been a serious breach of cultural boundaries, especially because the human corpse was considered a pollutant, but also because of the cultural importance of intact skin, and the prevailing views about violating that sacred skin by cutting into the human body. It is a little vexing that in all of Antiquity only two men, Herophilos (~335~280 B.C.E) and Erasistratos (~325-~250 B.C.E), who made their mark about one century after Aristotle, took advantage of somewhat less restrictive circumstances that made the dissection of human cadavers not as much of a taboo. Quite disturbingly, in all likelihood, they also performed vivisection on both animals and condemned criminals. Possibly they thought that different observations could be made and additional things could be learned from beings who were still alive, and from organs that still had blood flowing through them.7,8 Cruelty and controversy notwithstanding, their work represents the only body of knowledge of systematic exploration of the human body by dissection before the Renaissance, almost two millennia later, and as such their discoveries became the very basis of human anatomy.7

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In the second century (C.E.), Greek physician Galen of Pergamon (~129~216 C.E.) built on the work of Herophilus and Erasistratos, although Galen never performed a human dissection. He was a prolific writer on logical reasoning, on medicine in general, and on anatomy and physiology specifically. His extensive and detailed work became the framework of medical knowledge that was used until the sixteenth century. It was predicated on his exploration of anatomy by animal dissection, careful clinical observations, and experimentation. Whereas Galen was a vocal proponent of logic and reason, he simultaneously put everything he saw in the service of his religious faith. To Galen, the overarching purpose of his findings was confirmation of a “Higher Truth.” This belief considerably limited where his experiments could lead him. To him, hypothesis and fact appeared equally valid and this prevented him from doing the multiple and varied experiments that could have comprised a valid scientific data set with which hypotheses could be refuted or confirmed. Correspondingly and paradoxically, his work both pushed and stifled progress. We should not judge Galen too harshly, because his approach was simply a sign of his times: speculation and attribution to divine purpose were an accepted complement to logical reasoning.9 Surgeon and writer Dr. Sherwin Nuland (1930-2014 C.E.) described it as follows: “...he often drifted off course, veering from the direction in which more experiments might have taken him. His process is comparable to attempting to draw a graph with too few proven points scattered diffusely along it, and with the further handicap of having decided beforehand what the graph is to look like. Galen’s greatness lay in the beautifully designed experiments that provided the data for each point; his failure lay in the scarcity of the points, the ways he joined them, and the ways he extrapolated from them.”10

Sometime after Galen’s death, turmoil resulted from the disintegration of the Roman Empire and persisted during the rise of the Byzantine empire. And while the pursuit of scientific investigation was relegated to the back burner, the Christian church gained increasing influence and power. During that time, Galen’s work was elevated to a virtually definitive status and he became the “Medical Pope of the Middle Ages.”9 Galen’s work also reached the Arab world and was revered by scholars there. Ebn Sina, better known as Avicenna (~980-~1037 C.E.) was an eminent Persian intellectual with scholarly activities in an astonishing range of topics that included medicine, philosophy, alchemy, theology, mathematics, poetry, astronomy, geology and logic. Working as a Muslim physician, his

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writings connected and integrated the works on natural philosophy by Aristotle and the contributions to medicine by Galen.11 Eventually, Avicenna’s work reached as far as the West. His contemporary scholars there, however, were now found mainly in monasteries. The centers of learning were focused almost entirely on scriptures and religious dogma, instead of on logical thought and investigation. In this historic context, the collective intellectual contributions by Aristotle, Galen, and Avicenna were not further advanced; they remained firmly established as the authoritative and indisputable body of medical knowledge for centuries to come. In order to appreciate how deeply-entrenched beliefs can change over time, we have to understand the following: individual discoveries that signify progress tend to stand out in a timeline of events, but advances are rarely made in a vacuum. Instead, knowledge is a commodity that is built on the cumulative work of those who came before. The context in which new discoveries take place should not be overlooked. Knowledge is built gradually and its trajectory is not linear, because the parameters of possibility are influenced by the attitude and culture that constitute the fabric of society at any given period in history. It is not wholly surprising then, that a renewed interest in scientific inquiry and a more critical stance toward established medical doctrine arose in an environment in which other doctrines, including those of the Church, were increasingly questioned as well. Change requires an environment that is primed for creative engagement and in which curiosity is, at a minimum, not discouraged. This does not mean that the conditions are such that thinking “out of the box” can truly flourish, but at least a consideration of issues from more than a single angle must be tolerated. The sixteenth century in Europe saw a large enough shift in that direction, during a time when the ideas of Antiquity enjoyed a revival. This set the stage for figures such as Paracelsus (1493-1541 C.E.), one of the few iconoclasts of the time. Paracelsus was a German-speaking physician and alchemist who chose to write in his own language instead of in Latin. He thoroughly rejected the unquestioned authority of Aristotle, Galen, and Avicenna.12 Being strongheaded, he did so in a way that made him many enemies. This antagonism was in part fueled by his lack of diplomacy (to put it mildly; he was known for angry outbursts and book-burnings) and in part caused by his forceful opinions that went against the views and practices of the time. Paracelsus may not have been a “people-pleaser” by any stretch of the imagination, but his contributions to medicine cannot be denied.

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For example, Paracelsus is credited with bringing chemistry into medicine, and with appreciating the importance of dosage. Thus, he augmented therapeutic options while monitoring toxic effects. He also applied a scientific approach to his endeavors, something that was not typically done at that time. And whereas the modern methods of investigation were not available to him, many of his concepts have stood the test of time. He aimed to reform medical education for physicians and he stressed character and virtue as two essential ingredients for practicing medicine with integrity. Apart from medicine and chemistry, theology and philosophy also had his interest. Being a man with a degree of humility despite his volatile personality, he realized that, “the universities do not teach all things,”13

and that knowledge needs to be complemented with experience before one can become an expert. Even if that seems evident to most of us today, it was quite controversial at the time. Another ground-breaking figure of the sixteenth century was Belgian physician Andreas Vesalius (1514-1564 C.E.). He was a trailblazer because he had the courage to search for answers when he realized that a good part of established medical knowledge was based only on inference. Seeking knowledge and innovation, he managed to become an expert at anatomy by his diligent study of bones at the cemetery and by performing thorough dissections of human cadavers in Paris. Contrary to the practice of the times, however, he chose to carry out these studies by himself because he realized the importance of hands-on experience for surgical procedures on patients. Vesalius obtained his medical degree from the University of Padua in Italy. He demonstrated the errors of Galen, and published his seminal work “De humani corporis fabrica libri septem” (which can be translated as the fabric—or construction—of the human body in seven books).14 The work was enhanced by beautiful woodblock prints and by novel techniques of typography and production. With illustrations by a disciple of Titian, it represents one of the most influential books in medical history and it was the most comprehensive, accurate, and visually appealing book on human anatomy published until then. Shortly after presenting his book at the royal court, he was appointed personal physician to Roman emperor Charles V. Just consider the impact of this man on the advancement of medicine through his dedication to revealing details of the human body that had never been documented

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before...What is even more amazing, is that Vesalius accomplished all this impressive work well before he turned 30 years old!10 Both Paracelsus and Vesalius lived in a time known as the Scientific Revolution, when questions in the natural and social sciences were finally approached in a more structured way. This was the time of burgeoning experimentation and of a new line of reasoning that was based on results instead of on dogma or foregone conclusions. Knowledge of anatomy enabled the development of new medical techniques, and facilitated gradual improvements of the practice of medicine overall. It was the beginning of an exciting age of active exploration in science and medicine, where each discovery propelled new ones and baby steps became the springboard of giant leaps forward. Out of necessity for brevity, some of the most prominent medical specialties and names in all of medicine must be omitted here, but a whirlwind tour of historic medical advances can still highlight the vast progress that has been made. Medical history of the past few centuries is full of “firsts”, brimming with numerous assertions of one or another development being “arguably the greatest discovery of medicine” and many assignments of “he was the father of....” In reality, however, there were often multiple fathers to the birth of the same, or similar, or partial discoveries, the entirety of which culminated in an actual breakthrough. This comes back to my earlier point: the development of knowledge is strongly influenced by external factors and science is almost always a team effort. It also happened sometimes that a major discovery was not recognized for its value so that some bright minds were condemned to obscurity or were not recognized for their contributions until long after they made them. Or that, in addition to the discovery of some important piece in the puzzle of knowledge, other pieces were added that reflected ideas that later turned out to be plain wrong. Nevertheless, there were some great triumphs. The seventeenth century saw the functional elucidation of the human heart and blood circulation by William Harvey. But one critical piece was missing. A more complete understanding of circulation became possible only after the discovery by Marcello Malpighi, in the same century, of the tiny blood vessels called capillaries that connect the arterial and venous blood systems.10 Critical technical improvements of the microscope by the largely autodidactic Antonie van Leeuwenhoek enabled the first accurate description

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of red blood cells, allowed the observation of single-cell organisms such as protozoa, and made possible the discovery of spermatozoa.15 The microscope, by the way, provides only one example of the importance of instrument development. From the humble thermometer to genomic sequencing instruments, scientific tools have been paramount enablers in the progress of medicine as in other sciences. In the eighteenth century, Giovanni Morgagni transformed how medical diagnoses were made.10,16 He correlated the clinical findings observed in hundreds of fatal cases with their pathological findings in individual organs at autopsy. Such a methodical approach to the analysis of diseases may seem a no-brainer today, but in his 1907 book “Makers of modern medicine”, Dr. James J. Walsh reminded us that in hindsight many things seem selfevident. He wrote, “Morgagni’s investigations in pathology consisted in tracing side by side all the clinical symptoms to their causes as far as that might be possible. This looks so simple now as to be quite obvious, as all great discoveries are both simple and obvious once they have been made; but it takes a genius to make them, since their very nearness causes them to be overlooked by the ordinary observer so prone to seek something strange and different from the common.”16

The work by Scottish physician James Lind was also remarkable for the eighteenth century because he was an early advocate of occupational health and prevention. He was among the first to conduct what today, albeit with a different set of standards, we would call a “trial”: a systematic comparison of multiple potential treatments. The malady that captured his interest was scurvy, a disease that is caused by a lack of vitamin C and that could be successfully prevented by including citrus fruit in the diet of sailors during long voyages. He also found a way to distill fresh water from seawater and recommended measures that improved hygiene on navy ships.17 As a final example of movers and shakers of the eighteenth century I include John Hunter, whose claim to fame is that he was one of the (brave? reckless?) physicians in history who performed self-experimentation in order to further the understanding of diseases. He inoculated his penis with pus from a patient with a sexually transmitted disease, not realizing that the patient had both gonorrhea and syphilis. Hunter studied his own symptoms and responses to treatment for years afterwards, and understandably but mistakenly thought that the two diseases were based on a single infection,

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just manifesting with different symptoms over time and in different body parts.10 In the nineteenth century, Renée Laennec invented an early version of the stethoscope, a medical instrument without which we cannot imagine medicine as practiced today. With this instrument, he was the first to clinically examine the chest by listening to human organs in a way that was previously impossible. He proceeded to investigate the sounds of the heart and especially the lungs, which led to his classification of lung diseases. In an ironic trick of fate, he passed away from a lung disease himself: he had cavitating tuberculosis, a fatal condition that could be accurately diagnosed because of his own great invention.18 One of the most illustrative examples of the bumpy road to medical progress in the nineteenth century is in the discovery of various aspects of infectious disease processes. In that story, Ignác Semmelweis was a genius innovator who became a tragic hero.10 Semmelweis worked in obstetrics in a Viennese hospital, which had two maternity wards. One of these was directed by midwives, whereas in the other patient care was provided by medical doctors and their students. The latter ward had a high maternal mortality rate due to childbed fever, now known in medicine as puerperal fever. This is an infection in women after giving birth. At the time, it was attributed to external causes such as illnesscausing vapors. The numerous deaths both greatly puzzled and pained Semmelweis. He began to compare the differences between the two wards by considering religion, climate, and the number of admitted patients.19,20 After his colleague, pathologist Jakob Kolletschka, sustained an accidental cut from a scalpel (it was used by one of his medical students during an autopsy) he became feverous and died from this illness with symptoms that were very similar to those of childbed fever. It triggered a lightbulb moment for Semmelweis, who began to suspect that Kolletschka died from “cadaverous particles” that had been present on the knife. Likewise, he thought, the infections on his maternity ward might be caused by such particles, transmitted via the hands of the doctors and students who examined the women who were hospitalized there. He realized that only doctors and students also worked in the autopsy room, but midwives did not. With that conclusion, infection control became his life purpose. He devised an aggressive and tedious hand-cleaning method with a substance similar to today’s household bleach and the mortality rates on the maternity ward dropped dramatically.

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Semmelweis had it right and his meticulous hand-hygiene practices produced results that should have been convincing, but his discovery was not well-received. He was not taken seriously, and instead of being recognized for his keen observation and the successful solution he proposed, he was demoted and ridiculed. After all, the “gentlemen doctors” of the time could not possibly have hands so dirty that they caused preventable infections in their patients, could they? And everyone already “knew” that childbed fever was caused by bad air, perhaps with an additional influence by other factors intrinsic to the affected women themselves. The possibility of healthcare-associated infections was basically rejected. It did not help matters that Semmelweis had a militant and selfrighteous streak and that he had no proof other than his epidemiology (which later developed into an entire field of medicine that focuses on the incidence and distribution of diseases and on ways to limit them). The results that were achieved by the infection control methods that Semmelweis implemented should have been ample evidence that he was on to something, but the medical world was not ready to accept his inconvenient truth. It might have been easier had he known what the proposed particles were or why they would wreak such havoc, but he did not pursue this aspect with scientific inquiry. His great contribution to medicine was only realized years later, after his mental state had deteriorated and he had died, institutionalized, at the age of 47.10,19,20 Semmelweis was not the only one who went against the current in the nineteenth century and then was largely ignored. John Snow, who discovered that cholera was transmitted by contaminated water instead of by “bad air” or “bad blood”, created detailed maps of London based on whether water supplied from the Thames river was relatively clean or was obtained from an area that was close to sewage. Even though Snow’s work was controversial, he was at least able to persuade the authorities to remove the handle of a contaminated well. By that simple action, many lives were saved as the incidence of cholera dropped precipitously in that area.21 Just like Semmelweis, however, the true appreciation of Snow’s contributions to medicine and to the burgeoning field of epidemiology only came after his death. Later in the same century, additional discoveries transformed the understanding of causes of disease, through which medicine was revolutionized. Among the outstanding minds who made this possible was Louis Pasteur, a French chemist with a special interest in microbiology (and later the study of vaccines), who postulated the germ-theory of infectious disease after he

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discovered that tiny organisms, not visible without the aid of a microscope, could cause specific diseases. He was one of the first to make the leap from observation to experimentation, and he carefully applied quantitative methods in the design of his experiments. Among other things, this enabled him to demonstrate that microbes are responsible for spoilage of foods and that spoilage could be prevented by sterilization.22 Joseph Lister, an English surgeon, took this knowledge a step further and pioneered the early principles of antiseptic medical practice. He applied a disinfecting agent to treat infected wounds, but also used it for prevention of infection by applying it to the skin before surgery, thus reducing both morbidity and mortality in his patient population.23 A decade later, German physician Robert Koch, despite the distractions of his intense rivalry with Pasteur and other colleagues, discovered the bacillus that causes anthrax, a serious and often fatal disease of both livestock and wool sorters in those days. He learned how to grow isolated bacterial colonies on plates and identified the causative microorganisms for cholera and tuberculosis.23,24 Eventually, vaccines were developed, and a new era of microbiology had begun. Why were the contributions by Pasteur and Koch received with interest, whereas those by Semmelweis and Snow met with overwhelming resistance? One might argue that the adoption of new principles simply takes time, but that would be too easy. The fundamental difference was that Pasteur, Koch and contemporary colleagues realized that observation, however carefully made, was not enough. They embarked on a path of experimentation and scientific publication. They used meticulous experimental design, tested their findings for reproducibility, included large numbers of samples and controls, and considered the possibility of biases. They were deliberate and conscientious with respect to their scientific approaches. And the design and the analyses of their experiments were thorough and methodical. With this new dedication to uncompromising scientific rigor, they had embarked on what may have been the greatest revolution in medicine of all: they developed the evidence-based scientific method. And the rest...is history! Key points: G There is no knowledge of the material world without the input of information, but developing knowledge is a process that requires much more than information alone. Wisdom is critically important in the application of knowledge.

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G The Scientific Revolution of the sixteenth century heralded a time when questions were approached with a new interest in experimentation and with reasoning that was based on evidence. G In the nineteenth century, Pasteur, Koch, and contemporary scientists conducted health-focused experiments that were meticulous and thorough in design, execution, and analysis. G Uncompromising scientific rigor resulted in what may have been the most profound revolution in medicine: the introduction of the scientific method based on experimental evidence. G Individual discoveries tend to stand out in a timeline of events, but advances are rarely made in isolation. They are founded on preceding work and interpreted in the context of society and culture. G Science almost always is a team effort.

CHAPTER NINE SCIENCE, NOT FICTION

How the medical scientific process provides validity that can separate correct from incorrect understanding

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Does science impact daily life, and if so, how relevant is it?

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How does the scientific process work and what is the role of research publications?

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How can scientific insights change with time?

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What are the advantages of being able to make decisions based on facts instead of fantasy?

When I was in medical school, the emphasis of the curriculum was not on how research takes place at the forefront of medicine, but rather on comprehensive medical training so that the students would become good physicians. Nevertheless, it was expected that we, aspiring doctors, gained some experience with scientific inquiry. We could do this either by joining a research laboratory to learn how to perform laboratory experiments in the context of a specific research project, or we could perform clinical research by, for example, investigating which of multiple surgical procedures for a gynecological condition had the best long-term outcomes. Even though virtually all our training was built on scientific discoveries, we did not really think about it with this mindset while we focused on our

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fast-paced courses and practical training. Frankly, the world of science seemed somewhat separate and daunting. Most of us perceived it as important work, but very few of the students were keen on pursuing it. For me, the realization that I could feel excited about patient care and about answering scientific questions did not come until later, after I completed my medical school training, moved from the Netherlands to the U.S., and pursued the remote possibility of working in the laboratory of Dr. Uta Francke. She was a highly distinguished, trailblazing physician-scientist, and her dedication to scientific excellence in the rapidly growing field of genetics was widely known. Once upon a time, she too had moved to the U.S. from Europe and, in a moment for which I will be forever grateful, she was willing to give me a chance. I started as a lowly postdoctoral fellow. I say lowly because, in contrast to many much more experienced fellows in the lab, I had to first learn quite basic laboratory techniques to effectively conduct my benchwork and, accordingly, my pay was diminutive. When I began my research project, I had the intent to make a useful contribution and to learn something new, while bridging the time to the first opportunity to apply for residency training. To my surprise, however, I fell in love with the work. Everyone who worked in the Francke laboratory had an individual research project, so we were not competing with each other as is the case in some research environments. Rather, we could reach new insights in our own research area, in the rigorous scientific environment that she demanded. The lab consisted of a group of international people, including postdoctoral fellows with MD or PhD degrees or both, and graduate and undergraduate students from all over the world. This diverse atmosphere was stimulating, although at times the language barrier resulted in funny situations. For example, one of the postdocs, whose name was Johannes, was introduced to a young student from Asia. She was impressed with his experience, but unwittingly took her admiration a step too far because she was not familiar with his name in her own culture and simply misheard. For several days after the introduction, she kept calling him “Your Highness”, which quite amused him! Once we clued her in to the practical joke she had sparked, we all had a good laugh about it. What excited me most about doing research was hardly a groundbreaking but, to me, newly-found perspective. It finally clicked in my mind that the practice of medicine is entirely based on and continuously improved by scientific research. By this insight, I understood that the scientific endeavor

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that previously seemed so opaque and esoteric, was acutely and practically relevant. I use the words research and science almost interchangeably. I should clarify, however, that research is but one aspect of science: research is the systematic effort of observation, of designing and performing experiments, and of analyzing results. Science is bigger than research because it encompasses the overarching process of taking new research findings and integrating them with previously published research results. This allows the body of knowledge on a topic to grow. Because science integrates new knowledge with existing knowledge, it also advances the application of research findings. My research at the time focused on Marfan syndrome, a genetic connective tissue disorder that affects multiple organ systems in the body. The most serious manifestation that occurs with progression of this disease is a weakening of the wall of the aorta (the largest artery of the body). If the ensuing enlargement remains unrecognized, the aorta can rupture with fatal consequences. I worked on finding changes in the DNA sequence of the gene (FBN1) that is associated with Marfan syndrome and performed other experiments that enabled me to study the consequences of mutations on the protein that is encoded by this gene. With the combined results from this research, it became possible to explain which regions in the gene were the most important for protein stability. We could make correlations between the type and location of gene mutations and resulting effects on the protein, the connective tissues, and patient symptoms. Were they relatively mildly affected or did they need to be evaluated frequently to prevent a catastrophic outcome? The findings moved us toward understanding this complex disease. But I made progress one small step at a time, during very long days of meticulous work. Research is a demanding mistress, but there is something very special about being in the lab and looking at the result of a long and tedious experiment and suddenly realizing that you have the privilege to learn something that has never before been seen by anyone. That is the precious moment when you can begin to understand connections between things that previously seemed unrelated and disjoint, until you found the missing link. I am sure that I am not the only researcher in such a moment to have done a private little dance in the laboratory late at night! It was also rewarding to know that, one day, this work could make it from the bench to the bedside and be relevant to patients’ lives. For example, this work could contribute to a more nuanced prediction of the course of the

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condition, instead of merely being able to provide the general diagnosis of Marfan syndrome without an associated patient-specific prediction of how the disease was likely to develop over the years to come. Through the ages, science has been advanced by the persistence of numerous people who shared a sense of curiosity and inspiration. Scientific research provides us with answers, and in return gives us other questions. And, when its reach is recognized, it inevitably instills a sense of awe and wonder. What science has given us, among other things, is the opportunity to look past our own experiential existence and to become aware that we do not exist outside of nature but rather are inseparable from it. We are part of, surrounded and sustained by numerous networks, each part of which helps to support and stabilize the whole. And the material out of which the human body is made literally reflects the content of the Universe and follows its history.1 Atoms that were recently generated by cosmic rays that crashed into the Earth’s atmosphere, as well as those that originated billions of years ago in colossal explosions, are the very substance of not only our body but also of all living things around us, thus literally and authentically connecting life as we know it to the mystifying Universe. It is a humbling thought. There are many other fascinating facts that have been discovered through the process of science. For example, if we could line up the DNA from all the cells in our body so that it became one long string, we could wrap it around the Earth two million times and let it make about 333 return trips to our closest star, the Sun, which is hanging in the sky at a whopping distance of 93 million miles (150 million kilometers) from Earth!1 For another example that may surprise you: with an estimated 100 to 400 billion stars in our Galaxy and approximately three trillion trees on Earth, the trees on our small planet outnumber stars in the Milky Way by a thousand to one.2 As a third case in point: the technique of carbon dating enables us to know that cells in the human body are replaced, on average, about once every seven to ten years, which means that our body is rebuilt time and again over its entire lifespan. What we think of as our age has very little to do with the actual age of individual cell types. In other words, we each are a remarkable system of maintenance and regeneration that allows us to keep going throughout life. What logically follows is that there is no permanent “self”, but rather that the body is like a pattern that, although ever-changing, more or less persists over time.

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You may read this with amazement and (hopefully) think that it is fascinating to learn about, but perhaps it does not appear to be directly relevant to you. Certainly, science can be interesting and entertaining: there are various online outlets that showcase science for anyone who wants to be wowed by new discoveries or science-related imagery, such as, for example, the astronomy picture of the day.3,4,5 The popular Astronomy Picture of the Day website5 has been around since 1995 and features a daily greeting card from the Universe. It is available in 20 languages, has large followings on Twitter, Facebook and the like, and boasts more than a million visitors daily.6 Scientific research impacts our lives, however, and much more profoundly than we generally appreciate. Considering the wide-ranging benefits, science is not just for scientists. Research discoveries are often translated to tools and applications down the road, usually without reference to the original science behind them. Without science, we would not have electricity, antibiotics, clean water, cell phones, nutrition labels on food products, eyeglasses, cars, cancer therapy, microwaves, vaccines, or pacemakers. And these are just a few examples! You get the idea...Science is vital to daily life. All science-driven advances are brought to “a theater near you” by scientists. But what makes a scientist? Dr. Stephen Hawking (1942-2018), himself a household name among both scientists and the general public, asked himself about the iconic Dr. Albert Einstein (1879-1955), “Where did his ingenious ideas come from?”7

He mused: “A blend of qualities, perhaps: intuition, originality, brilliance. Einstein had the ability to look beyond the surface to reveal the underlying structure. He was undaunted by common sense, the idea that things must be the way they seemed. He had the courage to pursue ideas that seemed absurd to others. And this set him free to be ingenious, a genius of his time and every other.”7

Whether we are scientists or not, we all shape our world through our thoughts. Scientific analysis gives us tools, the means to understand the world we inhabit, and a way of interpreting whatever we encounter during our lifetime. Some scientists make science more accessible by increasing the public understanding of both science and the scientific method. Such understanding could reduce implicit bias and change how decisions are made.

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Dr. David Grimes is just one of the scientists who actively make such efforts. When he advocates for the general public, he explains scientific data in ordinary terms and debunks pseudoscientific claims. As such, he enables nonscientists to make decisions based on facts instead of on fiction and when this happens, both individual people and society as a whole benefit.8 Dr. Michael Greger is another such example. He is a lifestyle medicine physician who puts (often contradictory and confusing) nutrition information to the test. He and his team provide a science-based, non-commercial public service by analyzing the latest nutrition research and presenting nutrition and health research in a way that is easy to understand, and, above all, factually correct.9 Looking at life’s questions through a scientific lens does not mean looking at all things in a sterile, dispassionate way or giving up gut feeling or intuition. Rather, using this lens enables us to engage our intuition in a way that is not random or haphazard. We consider things with logic and reason, just as Aristotle taught. We also now, however, have a major advantage compared to him: we can base our decisions on a lot more evidence. It is the sorting and evaluating of all the evidence, that poses the biggest challenge. In medical practice, for example, the amount of information that may contain useable evidence can seem overwhelming: PubMed is a widely used resource that contains more than 29 million entries of biomedical literature from MEDLINE, life science journals, and online books.10 But not all evidence is created equal. The 1990s saw a concerted effort toward the use of evidence-based medicine, first to educate clinicians so that they would understand and make better use of the published literature to optimize the care of their patients, and later to meet three additional main principles. First, the practice of medicine should be based on the best available evidence. Second, to arrive at a summary of the best evidence, the entire body of evidence needs to be evaluated and not only a selection thereof that supports any particular claim. Finally, in medicine, evidence is essential but not by itself sufficient to arrive at an optimal clinical outcome. Effective decision making requires consideration of patient preferences and values, as well as context and environment. The evidence-based medicine movement developed a methodology for generating systematic reviews and practice guidelines, which represent a standard of care. The impact was substantial: in contrast to how medicine was practiced in years past, medical practice was no longer only empirical, based on physician observation or experience, but instead it was placed on

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a solid scientific foundation. And even though keeping up with the literature may seem a tall order, clinicians can keep up to date in their area of expertise by reviewing 20 to 50 articles from the medical scientific literature per year, provided that critical techniques of appraisal are used. There are resources for physicians that make this feasible, amounting to a “noise reduction” of well over 99%.11 It is important to note that evidence-based medicine does not diminish the importance of clinical judgment. Instead, it adds the results of systematically evaluated, reproducible research studies to expert judgment in patient-centered clinical decision making. And as such, it contributes to the use of the best available evidence to guide patient care. Before using “the scientific lens”, it is helpful to understand that the scientific endeavor is a well-defined process. It requires a toolbox that contains logic, hypotheses, targeted questions, a well-designed experimental process, appropriate research boundaries, technological means to conduct the research, careful and competent interpretation and statistical analysis, reproducibility, effective communication, and more. For nonscientists, effective communication likely is the most relatable part of this list, but that in itself does not necessarily reveal what of that communication is based on opinion as opposed to what has been investigated. And if it has been investigated, then how can one know that the results are valid? One important aspect of this process is the peerreviewed literature, which serves as the collective public body of knowledge in science. Once a research question has been explored and progress has been made by answering that question to a degree that constitutes a substantial increase in understanding, a science team may write a scientific article about the work and submit it to a journal for publication. Such publications are important for researchers. First and foremost, they are the primary way to disseminate their work. Whereas researchers may also attend conferences and present their research there, the work will be regarded as preliminary unless it has been published in a peer-reviewed journal. Second, the number, as well as the quality of publications (in part measured by the importance of the journals in which they are published, quantified by what is called the impact factor of a journal), are a measure of success and productivity. Hence, they contribute to how a researcher is evaluated for academic standing, promotion, and funding. In the past, the manuscript review process could be based upon just one person, such as an editor or, in the more distant past, a president of a scientific association. Nowadays, a journal editor will typically assess

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whether a manuscript is of potential interest to the journal to which it was submitted. If so, the manuscript will be sent out to several professionals who work in the same field but are not collaborating with the science team that submitted the paper, in order to minimize the risk of a conflict of interest. The reviewers do not work for the journal and are not paid for their service. It is an expectation that everyone in the scientific community who benefits from the reviewing efforts made by others, returns the favor to the community when a journal editor approaches them with the request to serve as a reviewer for a submitted manuscript. Multiple reviewers are recruited independently and they usually remain anonymous throughout the reviewing process. They also do not know of each other’s assessment until the journal editor aggregates and shares all reviews with the authors of the article and informs them whether the manuscript will be rejected, would be reconsidered pending major or minor revision, or is accepted without changes. The latter, by the way, is exceedingly rare. Scientific reviewers have a clear role: they are tasked with assessing the merit of a manuscript by evaluating all aspects of the reported study, except those on which they lack expertise. This can happen when, for example, a study has a clinical focus in the reviewer’s field but also contains a highly specialized bioinformatics approach for data analysis. In such cases, additional reviewers with that kind of expertise have to be involved. The assessments will include an evaluation of study design, to ascertain whether the correct type of study was used. Reviewers also need to determine whether a study was sufficiently powered to allow for meaningful results. What that means is this: when a manuscript describes a single case, such as in a case study, it can be illustrative by highlighting unique and interesting findings, but these findings cannot be generalized to a large patient population. It could be a report on a 99-year old chain smoker in perfectly good health, and if you read no larger studies, you could get the impression that smoking enhances longevity, which is a far cry from the truth. To counter this particular case report I could write one about my cigarsmoking grandfather who developed throat cancer and had to have his voice box removed in a life-saving operation, to be left with a tracheostomy: a surgically-created opening in the throat to his windpipe to provide an alternative route for breathing. The malignancy is directly linked to smoking, but not all people who smoke will eventually develop this type of cancer. Put another way, both stories are compelling but neither gives us information about the risks of smoking when extrapolated to a large

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population. Thus, in general, appropriately designed and conducted studies involving many people are much more powerful. Manuscript reviewers also evaluate the used methods and assess whether the study was conducted within the boundaries of current ethical standards. They are tasked with reviewing the results of the study, determining the validity of the findings and the interpretation, and with appraising the added value of the research given the existing literature. In addition, they need to determine whether all the information is provided by the authors to repeat the experiments (at least in principle). All of this requires solid expertise in the applicable area of research. Over the years, researchers have become increasingly specialized. In light of the continuous (and in some areas exponential) growth of research activity over the past century or so, scientific journals have proliferated as well. They surged in number and became more and more focused on pertinent (sub)disciplines, just as the researchers and clinicians who read them. Does the scientific publication process ensure that what we read in the peerreviewed literature is true? This is an important question, both for researchers and the public, and it requires a nuanced answer. Researchers analyze their observational and experimental results and put them in context with previously published research in the field. The conclusions that can be drawn from this evidence, however, are tentative and contingent upon new data from additional and future research because the interpretation of research findings is always limited by what we know up until that time. That does not mean that research findings cannot be trusted or that they are never conclusive, but any scientist would acknowledge the possibility that findings may lead to an incorrect interpretation as long as there is a possibility that some critical piece of information was not known. Science does not equal certainty, and researchers must always keep in mind that it is not possible to be entirely sure to be either correct or wrong. In fact, proving something to be not true is far easier than proving something to be true! The dilemma is succinctly summed up on Wikipedia, where it is explained that “It is thus an irony of proper scientific method that one must doubt even when correct, in the hopes that this practice will lead to greater convergence on the truth in general.”12

This attitude is not only applicable to the findings of an individual researcher and her team, but also to published data, even in view of systematic

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reviews and other methodologies of evidence-based medicine, which considerably reduce the risk of erroneous conclusions but cannot entirely eliminate the chance that they exist. Scientists live in the ever-abiding knowledge that their research contributions may “expire”, when the conclusions from their work need to be fine-tuned or even rejected altogether. This can happen after new methods become available and additional insights are developed. For example, before it became possible to identify differences between cancers at the molecular level, it was thought that all cancers that originated from a certain tissue type were alike. With the advent of genetic testing, however, more refined distinctions had to be made. It was discovered that subtle but important differences reveal how a tumor will behave over time. Such differences are also critically important for cancer treatment because they determine whether a tumor is likely to respond to a specific therapy. As a result of the fact that research findings may become outdated, the scientific endeavor is a poor fit for those with a big ego: integrity demands critical skepticism, with continued testing and refuting anything that does not hold up over time. Readers of the scientific literature should practice due diligence as well. They are required to take into account the quality of the research study, the standing of the scientific journal in which the research was published, and the extent of the review process to which that journal adheres. In addition, it must be taken into consideration whether a research question was explored by multiple different, independent methods. Evidence becomes stronger when reproducibility of results is not only achieved with different sets of laboratory samples or research subjects but also (and especially) when the same research question was investigated with different tools. A reader has additional things to consider: how do the findings of a newly published study fit in with the extant literature on the topic? Who financed the study? Is there literature that supports the findings, or are the findings contradicting published work? It is in itself not unusual to find literature that seems incongruent with new findings. That does not necessarily mean that the conclusions of one or the other are wrong, although it may. It often simply means that additional analysis is necessary because there are more layers of complexity or areas of uncertainty. Are we comparing apples to apples or apples to chestnuts? It is important to determine whether seemingly inconsistent studies were

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designed to answer the same question in comparable research populations, as there may be confounding factors. Technology also plays a role in this, in both the research setting and in clinical medicine. In my role as director of a clinical diagnostic laboratory, I encountered the following conundrum: on occasion, we would receive a sample from a patient whose disease-causing gene mutation had been missed by another diagnostic laboratory. In such a case, it is wise to first determine which analytic instrument was used in the other laboratory. It is also important to find out whether a more limited analysis was applied by which the mutation could not have been identified. Only if it becomes clear that the used instrument and the technological method should have been capable of picking up the mutation, can one conclude that there was an error that prevented the mutation from being detected. Apparently discrepant research studies warrant another critical question: were the researchers prepared to reject their initial hypothesis when the data pointed another way? Or, staying with the fruit analogy, were they cherrypicking data to confirm their hypotheses while aware of their bias (which is a breach of integrity that, once discovered, would lead to disgrace) or perhaps unaware (I talked about subconscious bias in chapter 5). Systematic reviews and meta-analyses (an assessment of separate studies on the same topic to draw conclusions based on a body of research) can be very helpful because they comprehensively review and integrate the published data on a specific topic. Whereas the scientific literature has its share of discordant studies on a wide range of topics, the body of knowledge is refined as more data become available and more research groups investigate how things work and why something is observed. Science, over time, is an effective self-correcting system. Ultimately, progress is achieved by testing hypothesis after hypothesis and by exposing that which is inconsistent. It will be obvious by now that research is a long-term activity. A game of patience and persistence. It begins with a superficial understanding that becomes gradually deeper as the “layers of the onion” are one by one removed with ever-sharper tools. It requires perseverance, a mind open to surprises, and good “hearing” with a willingness to move when opportunity knocks softly. The discovery of penicillin is an example of a fortuitous confluence of events when luck meets opportunity. When Dr. Alexander Fleming, Professor of bacteriology at St. Mary’s Hospital in London returned from his vacation in 1928, he checked in on his petri dishes on which colonies of bacteria had been grown. One of the dishes had become contaminated in the culturing process and he saw that

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mold was present on it. To his surprise, the area located immediately adjacent to the mold was clear, whereas areas of the dish without the mold still showed bacterial colonies. It looked as if the mold had secreted a substance that prevented bacterial growth...Fleming then conducted a series of experiments that indicated that a wide range of disease-causing bacteria could be inhibited with this mysterious stuff. Unfortunately, it turned out to be difficult to purify the active component from the mold, and once Fleming’s assistants succeeded, it proved to be unstable, as well.13 When this original work was published in 1929, the reference to the potential benefits of penicillin was almost casual, because experiments in connection with its potential value in the treatment of infections were still in progress. It seems that Fleming preferred the immediate, experimentally proven use for penicillin over speculation about the future, as he simply wrote: “In addition to its possible use in the treatment of bacterial infections penicillin is certainly useful to the bacteriologist for its power of inhibiting unwanted microbes in bacterial cultures so that penicillin insensitive bacteria can readily be isolated.”14

It would take until 1945 in the United States and until 1946 in the United Kingdom before penicillin became available to the general public.13 Science is a community activity, and little private dances of individual researchers at midnight notwithstanding, nothing happens in a vacuum. Science is a team sport, albeit with often strong competition between the players, as in many team sports. One example of this is the fierce race toward completion of the human genome project, during which the publicly funded team of Dr. Francis Collins at the National Institutes of Health competed with the privately funded team of Dr. Craig Venter at Celera Genomics. Ultimately, Venter and Collins joined forces and in June of 2000 declared that they had deciphered almost all genes in the human DNA sequence.15 Researchers stand on the shoulders of all others who advanced their field in the past, and they are dependent on their research associates, on collaboration with colleagues in their own field and in complementary disciplines, and on resources provided to conduct the work. The days that any one person could know everything there is to know in the world, or even in his or her own general area of learning, are long gone. Research also has become increasingly specialized, and highly interdisciplinary.16 Boundaries between areas of expertise evolve. Collaborations become more fluid, more international, more technology-

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driven, and more diverse. This is a positive development because it enables the formation of an expert team that is not limited by location. It allows the brightest minds to contribute their skills and to interact, to work together, and to complete a compelling research project as a group, with fewer hurdles related to the institutional breadth of expertise and local resources. It thus facilitates open communication and effectively pushes the frontiers of knowledge forward. Systems biologist Dr. Uri Alon emphasizes the need for open communication between scientists for additional reasons.17 He compares science to improvisational theater: both pursuits operate by a well-defined set of rules to be successful, but some of these rules are not necessarily transmitted by mentors early on. They then have to be learned through trial and error. For example, it will be obvious that both science and improv theater require creativity, but in both cases that creativity is not only needed to come up with interesting angles. It is also essential to breaking free from being stuck. When we are stuck, we tend to retreat to approaches that are familiar and we gravitate to doing what feels safe. But fear of leaping into the unknown narrows the mind and can become the kiss of death for both activities. Unfortunately, in contrast to improv theater, the periods of being stuck can last very much longer in science. When stuck, researchers may become discouraged because, whereas virtually every researcher experiences times when experiments will not work, these stressful times are not readily shared. After all, at conferences and in publications one only learns about results, all too often selectively biased toward the successful ones, and not about the sometimes long, tedious, and circuitous process of arriving at a valid research finding. The things that are communicated give the impression that there is a straight line between the original research question and the answer to that question, with a series of successful experiments in between.17 As if the outcome were predictable and the path a straight line. In reality, however, science does not work that way. At the boundary between the known and the unknown, one has to be prepared for the unexpected, count on setbacks and surprises, and harness the courage to forge entirely new paths. There are many examples of scientists who went against common practice and broke the mold of their time, only to made groundbreaking discoveries by doing so. Two such examples are Drs. Caldwell Esselstyn and Dean Ornish, who treated patients with advanced heart disease. They independently demonstrated in multiyear studies that lifestyle changes can be more powerful than conventional

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treatments with medication and surgical intervention. In contrast to the conventional approaches, intensive lifestyle changes can stop disease progression and reverse even severe disease!18,19 Often, at least at first, a scientist may stand alone as peers critique, perhaps even ridicule, the work. The results of the quest, however, will be all the more worthwhile. In this chapter, I have aimed to lift the veil of the scientific process, because so much of it remains hidden from view to anyone who is not engaged in scientific work. The process of science is not easy, and it is by no means perfect. But ultimately it provides the reward of a level of proof that enables a separation of fact from fiction. It is that very contribution that is of great value to us all. Key points: G The practice of medicine is entirely based on and continuously improved by scientific research. Research provides answers, and it offers new questions. G Science is not just relevant to scientists. Instead, science profoundly impacts daily life, in many more ways than generally appreciated. G When decisions can be made based on facts instead of fantasy, both the individual and society as a whole benefit. G The peer-review process and evidence-based systematic reviews of published data reduce the risk of erroneous conclusions, but cannot entirely eliminate them. Independent follow-up studies do eventually catch and rectify them, though. G Research findings are limited by what we know up until that time and contingent upon new information from additional research as knowledge evolves and matures. G Ultimately, the scientific process provides validity that helps separate correct from incorrect understanding.

CHAPTER TEN WINDOWS OF OPPORTUNITY

How research opportunities depend on a multitude of factors, including the public perception of science, financial resources, and bias ·

What is the significance of opportunity in scientific progress?

·

What are some of the factors on which such opportunity depends?

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What checks and balances exist in scientific research that create the opportunity to get it right?

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Can nonscientist learn about scientific advances and gain science knowledge?

One day in the mid-nineties I was on a plane to Denver to attend a conference. As we were waiting on the tarmac for the plane to take off, I looked outside at the typical San Francisco morning fog and wished that I could bring some immediate sunshine to my day. I turned to the colleague sitting next to me and said, “wouldn’t it be great if we could make an entire playlist of songs about sunshine?”. She considered it briefly but then shrugged at my idea. “You are neurotic!”, she laughed, and we have been friends ever since. My idea bubbled up well before the days of iTunes, Pandora, or Spotify, and it was just a fleeting thought. A desire, removed by many degrees of

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separation from anything like an actionable plan. It was something I would never pursue, as I had neither the skills nor the interest. But I certainly hoped that somebody would have a similar wish, think about this too and see its potential, because surely I was not the only person who would like to easily organize songs by theme? Years later, when these services became available and my wish was indeed granted, I realized that there probably had been many people thinking along the same lines. It was just a matter of the right time and place; a time at which ideas, technology, and opportunity converged. At another time, a different colleague and I were talking about our dogs. We had both adopted our dogs from rescue organizations and we had no information about their pedigrees beyond the way they looked. As we talked, we conceived of what we thought to be a great idea, not knowing that this idea was already close to being actualized somewhere else. What if we would find a way to examine the DNA of individual dogs, find unique breed sequences, and thus be able to determine the mix of breeds in any mutt? We were sure that there was a market for it, and given that we were both geneticists we were fairly certain that we had the capability to pull this off if we set our minds to it. It was fun to imagine what the service would look like and to think about how we would go about designing an accurate test. We were intrigued and we enjoyed playing ideas off of each other from time to time, but given our lack of spare time in our demanding academic environment, in which we focused on diagnostic genetic services for humans, we did not seriously explore our “start-up company” idea any further. Perhaps only six months after we had our idea, the first DNA test for dogs became available. We had been “scooped”...Or had we? Being scooped is a researcher’s nightmare. It happens when you work toward the publication of your findings, only to see with immense disappointment that similar work performed by another science team has just been published in the peer-reviewed literature. At that point, it feels as if all is lost. Granted, there is value in independent confirmation of published data by another method or in another patient population but, truth be told, nobody enjoys coming in second when the project seemed to be original and promised to offer an important, novel contribution to the field. In the case of dog genotyping, my colleague and I clearly were not factually scooped, because we had only been entertaining the idea (and even that rather lightly) without actually working on it. We were both amazed, however, at the fact that this service was launched so soon after “our” idea. Our humble conclusion? Great minds think alike!

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These two stories illustrate that ideas alone are not enough to make something come to fruition. Success requires that things come together in the right way and at the right time, in a process that has many moving parts. Nobody knows this better than U.S. Airways Captain Chesley (Sully) Sullenberger, who, together with co-pilot Jeff Skiles, made a successful splash-landing on the Hudson River in New York after their airplane struck a flock of Canadian geese soon after takeoff, and lost power in both of its engines. In this event that became known as the “miracle on the Hudson”, all 153 passengers and crew aboard the aircraft survived. In a 2009 interview with CBS News anchor Katie Couric, Captain Sullenberger shared his take on the reasons for the extraordinary outcome. He said, “One way of looking at this might be that, for 42 years, I’ve been making small regular deposits in this bank of experience: education and training. And on January 15, the balance was sufficient so that I could make a very large withdrawal.”1

During an interview that commemorated the tenth anniversary of the emergency landing, he commented: “I think about not only what we did but what everybody else did. All the pieces had to come together. This group of strangers had to rise to the occasion and make sure that they saved every life.”2

This insight highlights that the pieces that have to come together often are quite diverse. The emergency landing required alignment of Sullenberger’s experience, the various teams, and internal and external factors. But the special and rare moments in which things come together and beautifully work out are not limited to heroic level-headedness and competence during flight emergencies. They occur in all realms of life, science included. All these situations share commonalities that enable a fortunate alignment of circumstances: education and training, certainly, complemented with a variety of other factors including aptitude, vision, courage, preparedness, technology, teamwork, and determination. In any case, however, there is one major prerequisite to success that we tend to overlook, but that should never be underestimated. That prerequisite is opportunity. Opportunity is a core element in the foundation of knowledge and, as such, it is critically important to achieving any goal. Unfortunately, the obstacle course of life presents a variety of barriers to the materialization of

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opportunity. I will give some examples that pertain to science, and specifically to the possibility of making scientific progress. One obstacle to realizing research goals is the difficulty of obtaining funding for specific projects. Principal investigators (who are lead researchers and head up scientific research projects) need to bring in funds to support the work because their institutions usually do not cover these costs. Depending on where they work, a grant proposal to a funding agency may or may not need to include a budget for their own time percentage dedicated to the project. It typically does need to include budgets to support students and research associates, the cost of supplies (such as chemical reagents in a health sciences laboratory) and equipment. Depending on how a grant opportunity is formulated, it also could include a request for funding of travel to a conference to present the work, and for the cost of publishing the results. Funds can be made available by a variety of funders, including large research agencies such as the National Institutes of Health (NIH) in the United States. Other possibilities include smaller foundations that are dedicated to research on a specific disease, and funds from academic institutions, private funders, and industry. An investigator needs to ensure that research integrity is maintained and that results can be published freely, regardless of the findings. Only then would the research results remain unbiased. In order to obtain funding from any source, the researcher is required to write a proposal that describes exactly what will be done, why it is important, and how the research plan will be carried out. The funding organization, in turn, will have its own (not always transparent) goals and will prioritize proposals that best meet its needs. Usually, there are far more applications than could possibly be funded, especially when the funding environment is tough, as increasingly is the case in the U.S., for example. And that has consequences that reach far beyond individual researchers. Whereas historically the U.S. has had the global lead in new scientific discoveries, its commitment to science and, with that, its willingness to invest, have decreased in recent years. As a result, the U.S. share of global research funding decreased from 57% in 2004 to 44% in 2012.3 At the same time, the share of life science patents declined. With less funding, there is less possibility for innovation, and in light of global trends, it is increasingly likely that the U.S. may lose its front position in driving innovation unless the funding environment improves.3

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Research funding, and with that the opportunity to work on research projects, is influenced by institutional, local, national, and international politics. In the increasingly crowded, ambitious terrain of striving for limited resources, competition simultaneously is an incentive for innovation and a barrier to success, because cutting-edge ideas that leap-frog over others may be perceived as too much of a risk to fund or, for that matter, to apply for. And it can be frustrating: it is not uncommon for a principal investigator to write an average of ten proposals before a single one of these is funded, and that typically for only a fraction of his or her time. Given the level of detail in complex proposals, and the amount of preliminary results that is required in order to be persuasive to a funder, proposal writing requires a large time commitment and experience, not to mention the ability to market the proposed research ideas effectively. It takes time away from actual research and its publication. One hidden but associated consequence may be that data sets that either confirm the findings of other researchers or present “negative results”, which are those that show that something did not work or did not lead to novel insights, are less likely to be published. This is not a recent phenomenon, however. In 1904, Nobel Prize-winning chemist William Ramsay (1852-1916) already noted, “Progress is made by trial and failure; the failures are generally a hundred times more numerous than the successes; yet they are usually left unchronicled.”4

Confirmatory and negative results are less exciting than new findings, but they are important. In cases of independent confirmation, they provide additional support for published findings. In cases of negative results, a publication could prevent other researchers from going down the same rabbit hole. However, there is little glory in such publications, and researchers may choose to not put the effort into publishing their “uninteresting” data at all. When rates for acceptance of proposals for funding drop below 20%, as is the case for many (meritorious) proposals submitted to funding agencies in the U.S., eventually at least half of the active researchers are predicted to be driven away from federally funded research5, if not from conducting independent research altogether. To make matters worse, the process of evaluating grant proposals is usually not blinded, and, as in many aspects of society in general, it is influenced by implicit biases against women and minorities.6 Such biases further limit the likelihood that a window of opportunity will open.

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Even though there is more attention now, compared to past decades, to the need to increase diversity and equality in medicine, as in science in general, biases continue to exist and they can manifest in insidious ways. Several of my colleagues of color have shared that they, specifically, were approached at events and conference centers with questions by fellow attendees, the only difference being that these were white. The questions ranged from “can you tell me where the bathrooms are?” to “can you please clean up the coffee that was spilled over there?” One particularly telling and disturbing instance of implicit but all the more jarring race-based bias happened to a fellow physician who works in a highly regarded medical specialty. This colleague is professional, articulate, and impeccably dressed. She also happens to be a person of color. Stepping into the elevator one morning at a hotel, on her way to the scientific session that she planned to attend in the adjacent conference center, another person in the elevator noticed her name, followed by “MD”, on her conference name tag. The elevator passenger proclaimed, “oh, I am from Maryland too!”. It was painful to me to hear this story and it served as an eye-opener: clearly, it had not even crossed the person’s mind that the MD on the name tag indicated the physician’s medical degree. There was an implicit bias that a person of this sex and color could not be a physician, let alone attend a conference about the leading edge of medicine. This example highlights the harm that is inflicted by the limited views that result from a narrow perception of possibilities. In a world with continued macro- and microaggressions against people who do not conform to traditional expectations, such notions, especially when they affect young people, may prevent the availability of opportunity altogether. And even though the story was shocking to me, my colleague said that she could fill a book with experiences along these lines. She had already mused about a book title, she said casually. It was “No, I am not from Maryland”. Opportunities for research depend on many factors. Last but not least, something that strongly factors in the emergence of opportunity is the public understanding of science, because it ties in with politics, public interest, and the overall support of funding. The crux to the perception of science, however, is how it is taught and communicated, just as is the case with any other field of information. Muriel Cooper (1925-1994), who was a trendsetting designer and the first tenured female professor at the Massachusetts Institute of Technology (MIT) Media Lab, described this critical point as,

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In science, there are several points to consider when communication is to succeed. For one, there is the scientific literature, which is an important tool for researchers, but not generally accessible to lay readers. There are two main reasons for this lack of access. First, scientific publications are often available only by subscription or via academic libraries, even though in recent years there has been a major push toward free and open access, a concept that has been proven feasible and is gaining ground. Open access enables a wide distribution and a readership that is independent of affiliation and economic constraints. Second, the lack of access to scientific information is also caused by the way in which scientific publications are written. Here we must take into account that they are not intended for the general public, but rather for researchers in a specific scientific field. These publications, therefore, usually address highly specialized research questions and may use jargon, the meaning of which may escape everyone but the initiated in that area. As a result, these articles are neither practically accessible for a general audience, nor for the majority of researchers who are not working in that particular field of interest. Moreover, the scientific literature is very concise and terse, which has its roots in the cost of print publications. Although there is, of course, a progressive shift toward digital publishing, where page limits should not matter much. Still, journals often prescribe a compact format for their published articles. Interestingly, it was not always this way. In the days of Ancient Greek physicians and centuries later when Galen of Pergamon wrote his famous treatises, communications of autobiographical comments and observations of contemporary society, religion, and philosophy were commonplace.8 More recent historic scientific literature did not meander to quite the same extent, but it still waxed poetic. For example, Charles Darwin who published his book “On the origin of species” in 1859, and produced one of the most famous and beautiful concluding sentences in all of science, wrote: “There is grandeur in this view of life, with its several powers, having been originally breathed into a few forms or into one; and that, whilst this planet has gone cycling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.”9

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Of course, sometimes the literature was less poetic and really merely waxed, albeit in an amusing way, as was the case in a text by Thomas Huxley (1825-1895), published in 1857. He clearly was quite excited about the reproductive abilities of the humble aphid, when he wrote that “...a single impregnated ovum of Aphis may give rise, without fecundation, to a quintillion of Aphides. I will assume that an Aphis weighs 1/1000th of a grain which is certainly vastly under the mark. A quintillion of Aphides will, on this estimate, weigh a quatrillion of grains. He is a very stout man who weighs two million grains; consequently the tenth brood alone, if all its members survive the perils to which they are exposed, contains more substance than 500,000,000 stout men—to say the least, more than the whole population of China!”10,11

And the epic narrative goes on...As charming as this reading is, and with the disclaimer that I do not tend to venture into contemporary aphid science literature, it would seem virtually impossible to have such a text published as part of a modern scientific manuscript. If the conversational storytelling element of scientific literature is all but lost, we cannot expect wide dissemination of scientific discoveries without their “translation” into popular science, by press releases, blogs, and articles by journalists and scientists, or by other popular science writings. These ways of communicating science are vital because they create a bridge between the scientific endeavor and the people who can benefit from new discoveries. Popular science is essential in creating shared interest, fascination, and enthusiasm for the relevance of research and its findings. Sometimes that relevance may not be immediately obvious, especially in areas of science that work on the development of basic understanding, where practical applications may be years into the future. But even there, results may uncover something really neat or beautiful that can stimulate curiosity, and may motivate a child to become interested in science overall. One of the most challenging aspects of translating science into a popular format is the communication of scientific evidence in the framework of remaining uncertainty. When scientific uncertainty is taken out of context, research results may be misrepresented or misunderstood, and solid scientific evidence may be rejected outright. An example of this is the denial of HIV (human immunodeficiency virus) and AIDS (acquired immunodeficiency syndrome), which is the late stage of HIV infection.

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Infectious Disease specialist Dr. Mark Crislip shared his frustration about this, and about the general denial of germs as a cause of disease, in a 2008 online article in Science-Based Medicine, where he explained that, “There are 191,000 plus articles on Pubmed concerning HIV research. The astounding accumulation of data to support HIV as a cause of AIDS and the benefits of applying that understanding to the treatment of AIDS is triumph of the modern medical-industrial complex. It is why I have one AIDS patient die this century after a decade of AIDS deaths. Application of germ theory saves lives. Millions and millions of lives.”

Then he turns cynical and adds: “Of course, that is just what they told me to say.”12

This is not only an issue that lives at the fringes of society: former SouthAfrican president Thabo Mbeki, who, from 1999 to 2008 held office as the second post-apartheid president of the country, publicly denied that HIV causes AIDS. He restricted access to antiretroviral medications that can treat the infection and can prevent transmission from infected mothers to their babies during childbirth. A study authored by Harvard-educated physician-scientist Dr. Pride Chigwedere and colleagues estimated that between the years 2000 and 2005 more than 330,000 lives were lost because of the abject leadership failure to implement a timely treatment program for HIV patients in South-Africa. Moreover, 35,000 children contracted AIDS at birth, because prophylaxis to prevent mother-to-child transmission of HIV was not put in place.13 How, then, should we understand scientific uncertainty, so that on the one hand unwarranted mistrust and on the other hand false confidence can be avoided? A look at some of the sources of scientific uncertainty may be useful in this regard, so that it can become clear why they even exist. Scientific measurements have variability for several reasons. For example, when blood is drawn and the sample analyzed in a clinical laboratory, the result statement will indicate a normal range for each substance that was tested. The values that are considered to be normal are expressed in a range, because everyone is different and also because values can be higher or lower on any given day in the same person. Apart from biological differences within and between people, however, there is known variation within and between the instruments that are used to make the laboratory measurements. If the correct value is 5 watchamacallit units, and the same instrument and sample are used for a

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certain test multiple times, then it may give a measurement result of 5 units at one time, and, for example, 5.2, 4.9, 5.5, and 4.7 at subsequent times. In this case, we can observe that the results are always close to the correct measurement, which indicates good accuracy, but there is a little variation around the actual number. So precision (repeatability) is not as good. With another instrument, the measurement of the same analyte may be 7, 7 again, 7.1, and 6.9 units in sequential testing. In that case, precision is much better but the value is off, and accuracy is not as good. This makes it obvious that it is necessary to adhere to the standard practice to reduce any risk of error by including known positive and negative controls during testing, to know whether the instrument is behaving properly. Nevertheless, some variation between instruments is a given, and clinical diagnostic laboratories go to great lengths to carefully validate all their laboratory tests and to ensure that the reported results will be as accurate and precise as possible. In addition, in both clinical laboratory testing and scientific experiments, outliers cause scatter, which indicates occasional randomness when numerous measurements are taken. These outliers are flukes that are easily recognized. Scientific uncertainty becomes more tricky when, in some types of research studies, estimates are made about things that cannot be observed and tested directly, such as is the case with events in the distant past or future.14 Accuracy, precision, randomness, and other types of variability can be quantified and taken into account when results are interpreted. This is why, in scientific publications, statistical tools are used to determine the range of variability. Findings are reported after an assessment of standard deviations around the mean and with an indication of confidence intervals.15 It is critically important to both the reviewers and the readers of these manuscripts that sources of uncertainty are openly acknowledged, so that they can be taken into consideration for decisions based on the reported results, and for the design of new experiments.14 The measures that need to be taken to optimize the validity of research results depend on the type of study. In clinical trials, for example, the risk of bias can be minimized by using a blind study design, where neither the researcher nor the patient knows whether the drug used is the drug to be tested or a placebo. The assignment of the patient into the therapeutic or into the placebo part of the study remains masked until after all the testing is completed. Regardless of study design, however, communication and disclosure are key factors in the entire research process. Once all the data and potential sources of uncertainty are transparent, scientists may still disagree on the

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meaning of data sets and conclusions drawn from them, but when the methods of analysis are clearly reported and described, there will be less risk of incorrect interpretation based on experimental error. It is tempting to assume that scientists get up in the morning, formulate a hypothesis, work on experiments that prove or refute the hypothesis, arrive at a satisfying result, go home and have a beer. But the reality is usually different. After all, science is the long-time and often indirect process during which humanity is breaking new ground, and, as innovator, educator, and artist Dr. Michael Hawley once mused: “the most exciting expression isn’t ‘Eureka!’ It’s ‘Huh?’.”16

In all this work it is paramount how and why the research is conceived, designed, conducted, and applied. And it is equally important that, as noted in an article on evidence-based medicine, “scientific evidence should reflect knowledge that is publicly shared and easily understood by all qualified professionals in the field.”17

Replicable, transparent research practices are characterized by integrated quality assessment, quality assurance, ethical conduct, and control measures. Nowhere is this underscored more than in studies that influence patient care. Before the era of evidence-based medicine, harmful medical interventions were, at times, widely adopted even though they were based on biased research that turned out to be incorrect. Examples include categorical hormone replacement therapy for postmenopausal women to reduce the risk of cardiovascular disease, the advice to place infants on their stomachs to sleep, bone marrow transplants in women with breast cancer, and prophylactic use of drugs that prevent irregular cardiac rhythms in patients who have suffered a heart attack.17 In (too much) time, these serious and consequential mistakes were identified, but for many patients, they could not be corrected. Erroneous practices such as these make the case for evidence-based medicine all the more urgent, compelling, and powerful, because its prudent application can avoid such errors in the first place. When checks and balances are in place, research can improve the lives of individuals and enable developments that benefit humankind. But, as we have seen, success in research is conditional: it requires opportunity and a

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confluence of the right effort at the right time. When that happens, however, it can work magic. We can witness health advances, such as the cure of some types of cancer, and the emergence of diagnostics and treatments that are able to transform other types of cancer from a death sentence to a chronic disease with a more benign course. We can marvel at recent advances that enable a patient to receive the best treatment at the correct time followed by close monitoring of treatment results, and that allow for the possibility of early and effective intervention in the case of relapse. This is what is called precision medicine, which emerged as an outflow of human genome research. Such improvements in patient care lead to better personal health, a higher quality of life, and enhanced life expectancy. Science also propels technological advances, like those that realize the practical use of cleaner forms of energy. It helps meet basic human needs, such as the availability of clean water, and can contribute to improvements in regional standards of living. In some instances, science drives economic growth while it also illuminates how to rationally use natural resources in a framework of sustainability. All in all, it holds extraordinary promise, creating a new dawn in a great variety of disciplines, one discovery at a time. Effective communication that demystifies the process of science and provides an understanding of how science helps shape our world may well be one of the most crucially important endeavors in the coming years. Science is a method, an approach to explaining the world in which we live, a mechanism to tackle big questions and to solve problems, and a way to fulfill human needs and interests.18 Because science influences our lives in social, economic and environmental terms, it is not a distant entity that helps quench the thirst for knowledge of nerdy maladapted people in some far-off corner behind concrete academic walls, but, more accurately, it realizes the conditions that encourage free thinking and offers a marvelous toolbox to be used and applied widely. Ultimately, an inclination toward science helps people and societies flourish. Key points: G Opportunity is central to building knowledge. As such, it is a critically important prerequisite to achieving success. G Scientific progress requires that things come together in the right way and at the right time, in a process that has many moving parts.

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G The emergence of opportunity depends on many factors, including the presence or absence of financial resources, bias, beliefs, and chance. G Research opportunity depends on the perception of science because this ties in with politics, public interest, and overall support for funding. How science is taught and communicated is critical to how it is perceived. G Replicable, transparent research practices are characterized by quality assessment, quality assurance, and ethical conduct. When such checks and balances are in place, research can improve lives and enable developments that benefit humanity.

PART 2 THE SCIENCE OF HEALTH AND WELLBEING

~Mens sana in corpore sano~ [A healthy mind in a healthy body]

CHAPTER ELEVEN WHAT IS HEALTH?

How the fluid and dynamic concepts of health and wellbeing relate

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What is health?

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What is wellbeing?

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Are they purely personal?

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How does the concept of health compare to wellbeing?

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Can a general definition suffice?

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Do health and wellbeing change for a person over a lifetime?

Imagine Shirley: she is a woman in her late eighties. She is sharp, interested in everything and everyone around her, and she delights in every new day. With a twinkle in her eyes, she will tell you what she thinks of the latest news about celebrities and British royalty, or will inform you about the prevailing sentiments surrounding a new development in town. She never fails to inquire about your kids, your dog, or your vacation plans. When you ask her whether she feels well, she gives you a bright smile and says, “well yes, I suppose I do! I have everything I need and I am happy to be alive”.

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By the medical definition of health, Shirley has enjoyed an aboveaverage lifespan, and her cognitive function is excellent. However, she depends on medication to counter chronic heart failure, her mobility is quite limited after she recovered from a broken hip three years ago, and she needs regular assistance. On balance: she feels well, but is she healthy? And then there is the example of, let’s say, Omar. Omar is a salesman in his fifties. He recently saw his physician, who ordered some laboratory tests with the annual check-up. The numbers looked good and he received a clean bill of health. Omar has gained some weight recently, but he tries to stay away from junk food most of the time, and walks as much as he can during the day to maximize his step count. What he did not mention to his doctor was that he has not been able to maintain a social life after his wife died from cancer within weeks of the diagnosis. He misses her terribly, and even though he tries to do everything the way it was before, he dreads his routine and he does not have the energy to start anything new. Omar feels numb, lonely, and left with a big gaping hole in his life. He does not sleep well and sometimes sees no purpose in continuing this way. Even though he was offered grief-counseling just after his wife passed away two months ago, he dislikes what he thinks of as “the touchy-feely group meetings” that were suggested to him. His work productivity has suffered, which brings him down even more. Would you consider Omar to be well and healthy? Let us also look in on a fictional Kate. Kate is an ambitious young woman. She is in her early twenties and works two jobs to pay for her college tuition and cost of living. Kate studies hard toward her business degree. On the weekend, she likes to party to relieve stress. A few months ago, Kate was offered cocaine at a dance party and realized that it could keep her going without the need to sleep or eat much. It made her feel euphoric: she felt energized, alert, and very “up”. She has heard about risks but she is pretty sure that for her, the benefits outweigh those risks. Kate is slim, active, and has been able to keep all her balls in the air. She has not told anyone about her drug use. Although lately she has noticed negative moods, irritability, and the urge to use more frequently, she feels confident that this is temporary and that she has the situation under control. She is young and independent, and she believes that she deserves to feel great while pursuing her goals. Is Kate well? Is she healthier than Omar or Shirley?

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In this chapter, we’ll explore what health may look like for individuals and populations. This leads to the question of whether it is feasible to create a unifying definition of something like health that is a mix of objective and subjective elements. When someone asks you, “What is health?”, a first response may well be, “I think I know it when I see it”. But the examples of Shirley, Omar, and Kate illustrate that health might be, in fact, a relative thing with some aspects that can be measured with biomedical assessment tools and other elements that are in the eye of the beholder, where even your own assessment may differ from that of someone else. In this context, I am reminded of a patient who did not have any physical complaints until, during a routine colonoscopy, a polyp in his colon was removed and found to be malignant. All of a sudden, this man carried a diagnosis of cancer and his world was turned upside down. Was he healthy the week before the colonoscopy? Given that tumors tend to develop over a timespan of years before becoming apparent, either as a finding during a physical examination or because of symptoms, one cannot maintain that he was healthy by any medical definition, but he certainly may have felt that there was nothing wrong. What, then, is health as compared to wellbeing? Is one more important than the other? In the search of possible answers to such questions, we can begin by considering some definitions of health. The constitutional document of the WHO that was originally adopted in 1946 defines health as, “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.”1

This definition was a critically important departure from traditional interpretations of health, which largely focused on the ability of the human body to carry out its normal functions. But the WHO definition, broad as it is, has been subjected to criticism because it appears to indicate that wellbeing cannot be perceived or exist when health is any less than perfect. The main concern is with the word “complete”. Apart from the fact that complete health cannot be practically measured, by this definition, it may well be that the majority of today’s world population would have to be excluded because it cannot meet such a strict criterion. In other words, the definition describes an unrealistic absolute that is beyond reach for any person and at best can be achieved for relatively brief periods at a time. People often complain about minor ailments in the category of “PHAT” (not an official diagnosis!), which simply stands for “pain here, ache there”, and

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is my affectionate term or sympathetic acknowledgement that indicates that life indeed does include discomfort. It encompasses all the minor aches and pains that come and go, for anyone, in the course of normal living. Do these inconvenient realities of life point to a lack of health? The WHO definition of health leaves no room for these small bothers, or for older adults like Shirley, for example, who perceive an overall state of health and wellbeing, find purpose in life and live quite successfully with age-related physical limitations and chronic disease. Of course, we have to bear in mind that in the decades since the conception and adoption of the definition, life expectancy has risen considerably. Life expectancy has increased as a result of multiple factors, one of which is that the medical treatment of diseases has improved. With a longer average lifespan, however, health issues have increased as well. Noncommunicable diseases increase with age and result in a wide range of disabilities. They ultimately account for approximately 73% of deaths worldwide.2 Conditions such as hypertension, diabetes, osteoporosis, thyroid conditions and some types of cancer are now managed as chronic diseases because they have become much more treatable than in the past, when they were frequently more debilitating or outright fatal. And although this transformation to chronic disease status largely applies to non-communicable diseases, it is applicable to some infectious diseases, such as HIV, as well. If the WHO definition were to be viewed as something to aspire to rather than an impossibly idealistic definition of a state required to be perfect, then it would remain valuable, although it has been argued that even under those relaxed circumstances it falls short. Aside from the fact that it does not take into consideration disabled and ageing populations who have been capable of adapting to certain limitations and of managing their conditions in ways that may not have been feasible in the middle of the twentieth century, additional omissions and exclusions have been perceived. Given the lack of consensus on the matter, the debate about which elements should be included in a useful definition of health continues. In 2017, for example, a group of indigenous peoples, medical anthropologists, and physicians from culturally diverse areas of the globe proposed that additional parameters should be integrated into a comprehensive definition of health. They argued for the inclusion of three main concepts.3 First, they pointed out, it should be taken into consideration that the health of someone’s environment influences the individual’s state of health. The

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health of a person, a community, and civilization at large is closely intertwined with the degree to which natural systems are able to thrive. The second concept is that of spirituality, which is especially ingrained in some indigenous cultures regarding factors that are thought to contribute to health and disease. More widely and across faiths and cultures, they noted, spirituality is viewed as a source of energy that can provide the means for acceptance and growth on someone’s path of overcoming the negative ramifications of adversity. The third concept is that of adaptability to changing circumstances. This is a crucial skill because, after all, impermanence is one of the few certainties we have in life. Resilience, autonomy, and maintaining the capability to function in one’s community are all part of this concept. Their loss may affect the very survival of an individual and, depending on the impact of losing that individual, may become a threat to the community that he or she belonged to. In this view, health is seen as a resource for daily living and expressed as a process rather than as a fixed state. The three main points raised by this very diverse, international group of authors converge in one overarching idea: we are not individual entities independent from our environment, but rather inseparable from it, and the same is true for our health.3 As such, they augment the interpretation of the description by the WHO. Many other perspectives on the definition of health have been offered over the years, either together with newly forged definitions, or just with a plea for revision of the widely used WHO definition. Because apart from the troublesome use of the word “complete”, the use of the not otherwise defined term “well-being” is also problematic. Saying that health is a state of wellbeing makes the definition somewhat circular, after all... Perhaps a single definition of health cannot be accomplished because any such definition needs to be tailored to its targeted scope of use. And, whereas some such definitions may be dubious because they are altogether incompatible with clinical and scientific applications that make use of biological data points4, it indeed may make sense to consider health in multiple different contexts. Examples of such contextual definitions are mental health5, which would be one aspect or category within the overall health of an individual, or rural health, as relating to a set of identified perceptions about health in a specific geographic and cultural setting.6 The perception of health by individuals is one important context in which to consider health. One study7 describes this as “the lay perspective on

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health” and notes three universal qualities: wholeness, pragmatism, and individualism. Wholeness refers to health as a phenomenon that is intrinsically interwoven with all aspects of life, including one’s environment and personal values. Pragmatism refers to health being relative, depending on what someone finds realistic to expect, given, for example, advancing age. Positive aspects of life may be able to offset the loss of functional ability or symptoms of a disease, so a person may have some physical limitation yet may not feel encumbered by it. Individualism acknowledges that values are personal and that strategic health improvement approaches can be expected to be most successful when they are individualized. In addition to the personal or lay views on health, there is all of that which can be measured objectively. This can be very useful to quantify certain aspects of health. Such measurements are typically made in the context of healthcare and provide snapshots in time, but when monitored over a longer period they do provide indispensable and quantitative information about improvement versus deterioration and about the risk of developing disease. These assessments provide a scientific basis for health decisions, an advantage that does not even take into account the health benefits of having access to and developing a relationship with a healthcare provider who can answer questions, alleviate concerns, treat illness, and advise on optimizing one’s health. Regardless of definitions or specific contexts in which health is considered, I would contend that health is not a “state”, but rather an assessment of a fluid, dynamic concept. Thus, the degree to which we are healthy keeps changing in minor and major ways throughout our lifetime. And although a single definition of health may have remained elusive as yet, it is generally recognized that a functional definition would be useful given the implications at the level of the individual and at the level of entire systems. An agreed-upon framework could apply to personal wellbeing, patient care, healthcare institutions, health promotion, illness prevention efforts, public health, and the development of local or global policies. The WHO recognized and addressed this during the first international conference on health promotion in 1986. In what became known as the Ottawa Charter for Health Promotion, they determined that “Health promotion is the process of enabling people to increase control over, and to improve, their health. To reach a state of complete physical, mental and social wellbeing, an individual or group must be able to identify and to realize aspirations, to satisfy needs, and to change or cope with the

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Chapter Eleven environment. Health is, therefore, seen as a resource fo[r] everyday life, not the objective of living. Health is a positive concept emphasizing social and personal resources, as well as physical capacities. Therefore, health promotion is not just the responsibility of the health sector but goes beyond healthy lifestyles to wellbeing.”8

This definition of health still includes the word “complete”, but dares to innovate by incorporating the creative concept of health as a resource, making room for additional areas of common ground. Where opinions diverge is whether the listed dimensions suffice or whether they should be augmented. In proposed expansions of the definition, a stronger emphasis on the environment or on adaptability are two commonly recurring concepts3,4,8,9,10,11, which are worth a closer look. Inclusion of the environment would recognize that humans are interdependent with all life on earth and that we cannot pretend to exist in biological isolation. However, our interconnectedness extends further than biology, given that wellbeing also depends on inanimate Earth systems, such as climate, which are coupled to the biosphere.11 The environment also includes smaller parts of the whole, such as communities. In an editorial article of the medical journal The Lancet, this point was made very well with the argument that “dimensions of suffering, especially at the community level, are measurable and often severe. Science has not eradicated suffering, despite its enormous power to deliver technologies to improve health. Being more humble about the experience of individuals, rather than simply drawing up reductive report cards of their health status, opens up the possibility for a more realistic understanding of what it means to be healthy. The fact is that one cannot be healthy in an unhealthy society.”11

Advocates of an increased focus on the concept of adaptability argue that this would facilitate an inclusive and dynamic view of health that can be modified with changing circumstances over a lifetime. It would incorporate the inevitable need to cope with and bounce back from physical and emotional stressors, and acknowledges the advantage of resilience and autonomy. Such autonomy also invites a proactive partnership between patient and doctor in determining and delivering health needs.9,11 As a result, the optimal management of disease can become a means to greater health and wellbeing, rather than remain a (sometimes distant) goal.2 Definitions of health can become ever more granular, but that includes the risk of a less than pragmatic approach on the one hand and, on the other

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hand, the risk of conflating determinants of health with the elements that define it. Such melding of characteristics appears to be rather widespread, and it muddies the waters. This observation does not intend to diminish, in any way, the weight and importance of the broad spectrum of determinants of health: economic, political, societal, environmental, moral, ethical, religious and other factors indeed all do influence the likelihood of good health and longevity. Socio-economic hardships, for example, tie in with poor diet and with smoking and go against the prospects of a long and healthy life. A social network of family and friends can influence health because it may help or hinder healing. Living in an unsafe or hostile environment such as occurs in war, perhaps combined with manmade famines like those caused in Sudan or Yemen12, and the witnessing or experiencing of atrocities of war, are all likely to result in emotional difficulties and negative effects on health in both the short term and the long term.9 But these elements contribute to health and disease. They do not provide the definition or meaning of “health”. Because health is influenced by an interwoven system of factors that shape how we (can) live, our own choices and actions matter. The circumstances in which our lives unfold, however, are important as well. Our health and happiness are affected by and contingent upon our situation, including the extent to which we encounter inequality, inequity, poverty, violence, oppression, discrimination, and other disadvantages.4 With such a plurality of influencing factors, we may well need to make room for the coexistence of multiple views in order to minimize the risk of oversimplification in any attempt to define health. Nevertheless, as physician and philosopher Dr. Piet van Spijk pointed out, “Health functions as the aim and guiding principle of medical practice and thereby takes on significant practical importance.”13

Van Spijk made the argument that, without a thorough understanding of the term “health” by itself, medicine is at risk of losing its focus.13 My review of the literature, together with the diversity of answers that I received to the question of “what does the term health mean to you?” made it abundantly clear that any attempt to arrive at a universally accepted definition of health would be presumptuous, if not impossible. After all, if there is this much controversy about the breadth and boundaries of one single word after more than 70 years of discussion, such a quest would seem doomed to fail. Nevertheless, flawed as it may be perceived, a definition of

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health is also something that belongs in this book, even if it were only used as a working definition to provide a framework around its content. While I pondered this idea in the lone company of my computer within the space within which I write, I concluded that my articulation of a working definition of health and wellbeing, together, at a minimum, will help inform the chapters that follow. I did not attempt to create an all-encompassing definition of health and also chose to refrain from defining health in the purely analytic sense that has been accused of being reductionist. Rather, my aim was a pragmatic and practical statement of health and wellbeing, as pertaining to an individual person. In the context of how health and wellbeing are discussed in this book, I therefore defined these terms as follows. x Health and wellbeing are dynamic concepts that are influenced by multiple external and internal determinants. x Health is the largely objective state that can be measured and thereby allows comparison of one person to others. x Wellbeing is a primarily subjective evaluation that reflects where someone is now, compared to where that person would like to be. x Both health and wellbeing can be assessed by observation and measurements, but only to a degree. They are each also intrinsically subjective and dependent on perspective. This working definition leaves room for the objective biomedical assessments that can be made of certain health indicators, integrates the various systems of the human body, and takes into consideration the subjective perception of one’s quality of life. It includes one’s own sense of living relatively unburdened by physical and mental limitations or by being differently abled. This definition also recognizes the complexity of the simple statement “I am well”, in that it may pertain to what goes on in the body at the molecular level or extend to the entire human body and beyond, to populations, society, or the environment. By accepting that health is fluid and always evolving within a person between different time points, my working definition does not imply that “I am well” indicates a permanent state, but rather that people who say it experience that they feel well most of the time, or at least at a given time when the question is asked. They express a sum of the moments in which

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they perceive wellness.10 If they have a headache one evening, that can be taken in stride. It also takes into account our response to life events, such as the death of a partner as we have seen in the example of Omar, earlier in the chapter. Omar was deeply affected by the death of his wife after a brief but devastating period of illness and is in the midst of the sorrow that is a normal part of the grieving process. It will take time to come to terms with his loss. He does not experience wellbeing after this negative life event and his health may not be as good as it was before, but it would not be correct to think that his present response signifies a major loss of health per se. In fact, Omar’s current state may well reflect a sense of reality that is appropriate. If he did not feel emotions associated with the loss of his wife after many happy years of marriage, and if he were to express excellent wellbeing despite it, then that could reflect a loss of health because his sense of reality might be impaired.4 We may expect that Omar’s sense of wellbeing would gradually improve with time. If his current state were to continue without improvement, if he were to withdraw from social activities for an extended period of time, if he were to continue to suffer from insomnia and would feel an increasing loss of purpose, and if he continued to gain weight because he did not take care of himself, then the determination of a loss of health could be made. His loss of wellbeing should not be dismissed, but we just should not cross that line too soon. If we subscribe to the idea that wellbeing is defined by someone’s own interpretation and based on individual perceptions, then we need to allow for opinions and priorities that are not necessarily leading to an optimal state of health as it would be defined by the medical establishment. This is not always easy to accept, because patients may well express preferences that are known to not improve their condition, thus negatively affecting their prognosis. Sometimes such preferences are caused by a lack of factual knowledge and the belief in something unproven or disproven (“this herbal supplement will cure my diabetes”) and sometimes there are other factors that play a role, such as inertia or fear of short-term discomfort (“exercise makes me feel worse”). I encountered a patient who refused to take medication for his hypertension. He claimed, “I just feel better with high blood pressure”. His blood pressure, however, was dangerously high, which predisposed him to catastrophic consequences such as a massive stroke. What was going on? When faced with such strong resistance to treatment, digging deeper to unearth underlying reasons becomes part of caregiving.

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Does the patient not fully understand the potential consequences of not taking the prescribed medication? Do the medications have intolerable side effects? Is he clinically depressed, feeling that his life has no value? Or can the patient not financially afford the medication? It is often worthwhile to consider what is gained by staying with the status quo, for example when a patient seems less than motivated to recover (“I dread going back to the job I dislike”). In the example of Kate, who has started to use cocaine, a difference of opinion with her physician regarding her health and wellbeing would almost certainly exist. After all, she feels well. Here, it is especially important to have an honest conversation about what is happening because Kate is on the downward spiral of addiction. She does not seem to realize that her negative moods and increased urge to use drugs are withdrawal symptoms and indicate that she is on a very slippery slope. Kate’s drug use could easily escalate and destroy her bright future. Cocaine can alter brain structure and function, can cause hallucinations and psychosis, and increases the risk of stroke or sudden death from cardiac arrest or a seizure. Users can die from an overdose or from cocaine that is adulterated with additional harmful substances to increase the profits of drug dealers.14 In Kate’s case, simply ignoring or accommodating her current drug use in a health plan would be poor care indeed. Even in this case, however, it is imperative to start a dialogue, assess where she is at, and work with her toward health-improving circumstances. Healthcare for Kate, as for any person, should start with her current specific health situation and take into respectful consideration the preferences, values, and points of view of the individual. In many cases, developing a plan for care is an iterative process, because health improvements are more likely to materialize when they are tailored, personal, and collaborative. Improving and sustaining health is a process. It unfolds one day at a time, just like life itself. Health is complex, and there are many ways to look at it. Health-centered science, for example, is a field that encompasses a large number of disciplines and areas of expertise, but it is unified by a common goal: increasing the understanding of the nature and function of body and mind under conditions of health and disease, in order to improve health and wellbeing. Medicine, which is one of the practical applications of knowledge derived from health-centered research, aims to cure illnesses, to alleviate disease symptoms, to rehabilitate, to ameliorate the effects of long-

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term diseases, and to prevent the arising of illnesses for which a patient is at risk. Caring for patients and caring about health, however, requires more. For one, it requires an open, inquisitive mind that keeps integrating new information; information that is held to sound scientific standards. Health processes and indicators must be objectively assessed to determine whether a person’s body is able to carry out its functions. These measurements and evaluations can only be optimally effective when they are integrated with the entire patient, with an evaluation of determinants of health, lifestyle choices, and with the unique subjective experience of each patient. In order to accomplish that, healthcare providers need to embody a skillful combination of knowledge, competence, and compassion. Patients, in turn, need to be active participants in their care, which is aided by a mindful, proactive approach to their own health and their wellbeing, whenever and to the extent possible. It is important to realize that this engagement is not only relevant to patients. Anyone’s health requires attention and is amenable to improvement. If healthcare is delivered in a way that is less prescriptive and more interactive (a dance between patient and provider rather than a top-down delivery of orders), then medicine has a better chance of accomplishing healing through lifestyle changes and additional therapeutic modalities, as necessary. Health and wellbeing are central to the prevention of disease and they are at the heart of resilience throughout a lifetime. More on that to follow in the coming chapters. In a way, health and wellbeing are integral to embracing life, something that the French call “joie de vivre” (the joy of being alive). As I see it, our personal health is a journey. It is a journey of love. I do not use that word lightly. The journey is one of development toward care (healthcare and selfcare) that aims to enhance the conditions of living. Never stagnant, it evolves over a lifetime and can reach its full potential only when we do not neglect individual elements but take care of and successfully integrate all of its seemingly separate parts. American writer, poet, and civil rights activist Dr. Maya Angelou (19282014) was an inspiration and a wonderful teacher who frequently mentioned this process in her writings, expressing it as part of her profound wisdom. She said: “Living well is an art that can be developed. Of course, you will need the basic talents to build upon: They are a love of life and ability to take great pleasure from small offerings, an assurance that the world owes you nothing

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and that every gift is exactly that, a gift...Life is pure adventure, and the sooner we realize that, the quicker we will be able to treat life as art: to bring all our energies to each encounter, to remain flexible enough to notice and admit when what we expected to happen did not happen. We need to remember that we were created creative and can invent new scenarios as frequently as they are needed.”15

Just like life, health is an art that can be developed if we bring our energies to it. The fruits of this labor are well worth the effort. Key points: G Health and wellbeing are fluid and dynamic concepts. The degree to which someone experiences health and wellbeing keeps changing in minor and major ways over the course of a lifetime. G Agreement on a single comprehensive definition of health has been elusive. However, it is generally recognized that a functional definition would be useful given the implications for individuals and at the level of entire systems. G For the practical purpose of this book, health and wellbeing are defined at the level of the individual person: health as the largely objective state that can be measured and thereby allows comparison of one person to another, and wellbeing as a primarily subjective appraisal that reflects where someone is now, compared to where that person would like to be. G Personal health is a journey of development toward healthcare and self-care that aims to enhance the conditions of living. It can reach its full potential only when all of its seemingly separate parts are taken care of and successfully integrated.

CHAPTER TWELVE THE INSTRUCTION MANUAL

How genetic makeup influences health and disease, and how it compares to the contribution of environment and lifestyle

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How does the genetic code encrypt what needs to be accomplished in the body and how is that carried out at the right time?

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How does our DNA affect health and disease?

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How large is the influence of DNA in someone’s overall picture of health?

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What is the contribution of nature versus nurture, of the initial inherited state versus the influence of environment and lifestyle?

She called me from Australia. An educated mom, living in a remote area with limited direct access to healthcare. She had seen several doctors about her daughter’s hearing, but she had to travel to the city each time. She said, “I received the result from the genetic test that was done on my daughter Chloe. It is very technical. I talked to my doctor about it, but I am not sure that I understand his explanation. Can you tell me why my child is deaf?”. She paused. It does not happen often that I receive a call from Australia about a clinical matter. There are excellent geneticists in Australia, but

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unfortunately, this mom had not been referred to one and was left without a clear explanation from her primary care doctor. Thus, she decided to research the internet on her own. Given that the genetics of hearing loss was a clinical and research interest of mine on which I had published multiple times, she had come across my name and affiliation in her online search and had decided to give me a call. Unconventional as her step may have been, what did she have to lose? Direct contact with patients is a welcome reality in the practice of laboratory physicians today, but that is a big shift compared to the past. We more often fulfill the role of what has been called the doctor’s doctor, providing important information to other physicians, so that they can best treat their patients. Whereas previously patients received almost all of their medical information from their doctors, today they are much more informed and proactive, using the internet to find information before and after their medical appointments. They also use it to communicate about genetic and other diagnostic findings in social support networks.1 Most likely, only a subset of these individuals will be alert to the fact that a google search can lead to excellent answers or to a wild goose chase. The outcome is contingent on the quality of the information accessed, and that, in turn, depends on the mission, ownership and support sources of a consulted website. It also depends on whether a site is updated in a timely manner and whether the information is sourced from authors with appropriate expertise. These factors represent some of the key distinctions between information and actual knowledge.2 At a minimum, however, an internet search can provide an avenue to a medical specialist, anywhere in the world. I asked the caller to read me the result from the genetic testing laboratory where the test had been performed, and she shared the two genetic changes that had been identified in her daughter. They were present in the GJB2 gene, which encodes a protein (called connexin) that is critical to normal hearing. Most of the changes in this gene are very small and inherited in an autosomal recessive way. That means that carriers of a single gene mutation have a normal auditory function with completely normal hearing. Partners who each have such a change, however, have a one in four chance with each pregnancy of passing along both these changes to their offspring.3 A child with a change in the gene that was inherited from the father, as well as in the gene that was inherited from the mother, will be affected with hearing loss. In Chloe’s case, the result was unambiguous. She carried two GJB2 changes and both have been well-documented to be harmful. The

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parents could benefit from genetic counseling and could consider additional genetic testing to determine which change came from which parent, but it would not change their daughter’s diagnosis, which was “autosomal recessive sensorineural hearing loss with two pathogenic mutations in the GJB2 gene”. One might think that hearing this would have distressed the mom, but in fact, she expressed a tremendous sense of relief. She finally found answers after what had been a frustratingly long time. This mother already knew that her child was deaf, but she had not been able to understand why, or whether anything could be done about it. Now she knew that it was caused by the configuration of Chloe’s genes, that Chloe had been born this way, and that it was not something she herself could have prevented or avoided during pregnancy. And in fact, there was good news: with the kind of hearing loss affecting her two-year-old daughter, there was the option of receiving a cochlear implant. This is a small electronic device, part of which is surgically placed in the inner ear with the placement of another, external component behind the ear. It stimulates the auditory nerve, which then sends signals to the brain. Because a cochlear implant functions like a sound processor, the device can partially restore the sense of hearing, especially if it is implanted before the development of speech. As such, it has the potential to improve communication and to enhance the overall quality of life for people with hearing loss, as well as for their families. Knowing that Chloe had this specific type of hearing loss provided certainty, a course of action, and, just as importantly, hope. Genes are often called our blueprint. They are made of DNA (deoxyribonucleic acid), and all of the DNA in a cell combined is called the genome. DNA carries genetic information that is more like an instruction manual than a blueprint. You can compare it to the manual that comes with an unassembled lawn mower, telling how to put it together, how to operate it, as well as how to maintain it. Humans have roughly 25,000 genes that encode proteins but, surprisingly, 98.5% of our DNA is not translated into proteins. Although initially it was thought that much of that unexplained material was “junk DNA”, it has become clear that about 70% of our genome is transcribed into RNA (ribonucleic acid), which, in its various forms, serves as a functional molecule that contains vital information for all the processes in the body.4

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The DNA and RNA molecules are part of an astonishingly intricate machinery of transcription into messages and translation of some of those messages into the proteins that build and run our bodies. Our genome carries the instructions for the messages that encode building blocks, as well as information about how the blocks are to be assembled and about the regulation of an entire spectrum of associated tasks, collectively called gene expression. In a way, the process could be likened to a combination of road construction and maintenance: there are workers and supervisors and their superiors, and every person has one or more roles in building, maintaining, and regulating a functioning road system. In the human body, the regulation of gene expression changes over time and depends on many factors, including the state of our tissues, organs, or the body as a whole. Thus, there is no easy answer to the question of how much our genes contribute to overall health and disease. The expression of genes differs between individuals but also between different cell types within a single individual. Which raises the question: how are our genes told what and how much needs to be done, and when? The activity of genes can be tuned in a highly coordinated process that involves a lot of “on” and “off”, but also “a little more oomph please” and “hold your horses for the time being”. It is an orchestra of regulating players that include transcription factors, on-off switches, “volume-control” modulators of gene expression, and other modifying and stabilizing influences, some of which leave indirect instructions. These can, for example, be based on the way our DNA is coiled or on chemical adjustments to the DNA. All in all, human life depends on the highly reproducible, organized, and ordered generation of a large variety of different cell types such as cells in the heart, lung, brain, skin, and blood. And in fact, even each of those has subclasses. Once generated, the identity of each cell type needs to be stable and, during any cell divisions that may follow, order must be maintained.5 Much of this intricate process has been unveiled in recent years but it remains a very active area of scientific research, with much yet to be discovered and understood. After birth, the growth of a child’s body continues through the combination of cell division and enlargement. The increase in cell number and size is accomplished by genetic, hormonal, nutritional, and environmental factors that all interact and influence each other. Although we may marvel at the myriad changes during the development of a baby into a child and,

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eventually, into an adult, we rarely consider what is required for that transformation on a molecular and cellular level! The body needs to accomplish a particular pattern of rapid growth in early life, followed by a gradual deceleration of that growth rate with age until, sometime after the growth spurt in puberty, final body size is reached.6 The numerous influences that go into the variation in human height remain on the sidelines of our consciousness and we may never even wonder about them, except perhaps when we encounter someone with obvious growth failure or overgrowth. Nevertheless, the body needs to know when to stop growing. This is necessary up to adulthood, but it also remains relevant throughout life, when cell division must remain regulated. After all, one of the mechanisms leading to cancer is a new DNA mutation that changes this regulatory system in the cell, so that the usual brakes on cell division come off and cell proliferation proceeds unchecked and out of control. In normal growth and development, after the growth-promoting genes are highly activated (expressed) early on, gradual downregulation of the expression of these genes takes place, which is a really complex process.6 Natural growth is slowed down through growth-limiting genetic programming, which allows coordinated growth deceleration that results in a completion of growth while body proportions are carefully maintained. Thus, under normal circumstances, people do not end up with enormous ears, bones that are of widely differing sizes on the left versus the right side of the body, or tiny lungs. A body like that would not only defy our expectations, it would also be unlikely to be able to sustain itself. The importance of the DNA instruction manual should not imply that human bodies are formed according to genetic templates only. In early human development, a fetus is also affected by the conditions in the womb, which are shaped by, for example, the nutritional status of the mother, infectious diseases, and exposure to toxic substances such as alcohol and other drugs. These factors are environmental; they are not intrinsic to the fetus. Because they influence whether or not a fetus will develop normally, they become part of the cards we are dealt, if you will, and part of how we are born into this world. In medicine, there is a word for any abnormality that is present at birth, whether it is genetic or not. Any such finding that is existing at or dating from birth is called congenital.7 At birth as well as later in life, health is influenced by a multitude of factors. Our genes are inherited from our parents and, as we have seen in the case of Chloe, gene mutations can cause differences in ability and can result in

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medical conditions. These, in turn, can be monogenic (one gene is responsible), polygenic (multiple genes play a role), or multifactorial. The latter conditions are caused by a combination of genetic and environmental factors. The environment influences the degree to which we can be healthy. Our social and economic environment, as well as our physical environment, have an impact. Our behavior and lifestyle also contribute to our potential for health. Physical activity, dietary habits, and smoking, for example, all influence the internal and external environment of the body. In life, things are rarely black and white and there is no exception for the genome and the environment: genetic makeup and environmental factors both influence the likelihood of staying healthy, and the probability of getting a disease such as type-2 diabetes, for instance. Someone who is genetically susceptible will be more likely to become ill when there is a triggering environmental condition8 and, conversely, someone who has protective genetic factors may remain healthy despite environmental factors that would negatively impact the health of most people. From this, it will be clear that the claim that “it’s all in my genes!” is not valid when we are faced with a few extra pounds after the winter holidays. But how much weight (pardon the pun) do our genes really carry in our overall picture of health? What is, in fact, the contribution of nature versus nurture, and are we able to accurately tease this out? One way of looking at the contribution of the environment in health and disease has been through studies of identical (monozygotic) twins who grew up in different settings. If their circumstances were different, then the contribution of genetic factors, which should be the same for both individuals, and the contribution of the environment, which differs for twins who were not raised together, should be measurable. Such twin pairs can also participate in research as genetic controls: given that they have a common genotype, anything that is different between them theoretically could be attributed to the environment, at least largely. Identical twins arise when a single embryo splits soon after fertilization, and not, as is the case in so-called fraternal (dizygotic) twins, when two egg cells instead of a single one are released in the same menstrual cycle and each one of these eggs subsequently is fertilized by a separate sperm cell. Monozygotic twinning occurs in three to four births per 1,000 births worldwide (so about 1 in 250) and is fairly constant across populations.9,10 Monozygotic twins are thought of as genetically identical and therefore are of the same sex. As with anything in biology, however, taking this

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similarity as an absolute would be erroneous. The historic view of identical twins, first recognized by closely similar appearance (phenotype, with “pheno-” having its roots in Greek for “to show” or “to display”) and later determined by finding the same DNA sequence (genotype), is too simplistic. Recent discoveries have toppled the notion of “identical twins” and illuminated differences between monozygotic twins, especially in gene expression. Even though the genetic code itself may be virtually identical, the way in which genes are expressed turns out to be different in twins who spent less of their lives together, who differed in lifestyle, and who were already older at the time of the study. Drs. Manel Esteller and Mario Fraga and their team discovered that twins with these characteristics had more differences in the expression of their genes, based on how the genes were regulated, than other twins with less or shorter separation from each other. From that, they concluded that environmental factors played an important role in translating an identically-shared genotype into a different phenotype.11 These findings underscored that genetically similar individuals really are unique and, even more surprisingly, that their gene expression patterns evolve and remain dynamic over time.9,11 The neatly constructed twin studies of the past were not as straightforward as was thought, after all. There, then, it is again: science progresses as it builds on previously established knowledge and as new tools of investigation become available. In twin studies, the emphasis is now shifting away from attributing differences in traits between twins solely to their respective environments. In contrast to years past, scientists now have the opportunity to pursue additional research avenues. They can augment their understanding of the reasons for the differences between twins through the discovery and analysis of genetic elements, and of other molecules that influence how genes are expressed. Gene expression factors themselves, however, are tweaked by external forces such as lifestyle and environmental exposures. As a result, nature versus nurture has become a distinction that is not only difficult to tease out, but that may be much more intertwined with genetic regulation than previously thought. All that is studied in the field of epigenetics (“epi” originated from Greek and means “upon” or “above”). Epigenetics is one of the most intriguing and puzzling areas of current research in genetics. The study of epigenetic phenomena has received much attention in both the scientific and the lay press and has captured the imagination of researchers and nonscientists alike.12 Let us have a closer look at this, in order to better understand what it is and what it is not, and to

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dispel some pseudoscientific notions that have arisen out of tempting speculations and misperceptions. Epigenetics refers to the field that studies changes in cells that directly affect and can alter the expression of genes, but that do not change the DNA sequence itself. Some epigenetic modifications are transmissible from one generation to another while others are not.4 The term epigenetics includes some characteristics of gene activation (that is, whether the gene is turned to “on”) and expression (how and to which degree it manifests its code) that can be inherited, but more typically it refers to long-term alterations, in the gene transcription of cells, that are not passed on to a next generation.4,12 Epigenetics is thus a term that describes the ability of cells to remember how their genes were regulated. In their essay on epigenetics, cellular memory and gene regulation12, Drs. Steven Henikoff and John Greally explain this concept by giving the example of a calico cat, whose coat color shows a patchy pattern of black, orange, and white. In the early embryonic development of the cat, genetic events take place that determine the coat color in cells. A specific color is maintained in all the cells that originate from the cell in which that color was first established, through all the rounds of cell division that follow. Thus, all the cells that came from that one cell with its specific programming will express the same fur color. Epigenetics should not be viewed as a literal kind of memory, but rather as a program that is maintained in a specific line of cells throughout the life of the animal, even though the initiating event itself was transient. The definition of epigenetics is broad, allowing the inclusion of a diversity of events that initiate maintained programs, some of which may be necessary steps but not sufficient on their own, whereas others appear to mediate the maintenance of cell states in some organisms but not in others. Despite being broad, the definition is also narrow enough to exclude processes that require the persistent presence of a signal. Even though effects of that nature may be additional influences on gene expression, they are less likely to have a key initiating role in gene activation events. I should make clear that all of the epigenetic effects I mentioned so far are contained within a single organism during its lifetime. But much attention has been given to the idea that some of the mechanisms that cause persistent cellular memory within one living being could also be transmitted across generations. Henikoff and Greally point out that such a mechanism was indeed experimentally confirmed to work in worms, but that in mammals the molecular processes that could contribute to transgenerational epigenetics

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are, as yet, unclear. Nevertheless, the idea that variability of traits and disease risk could be caused by stressors in one generation with transmission to future generations is thought-provoking and makes for a pretty interesting story. It just is one of those things that is not the entire story, and in fact, it may not be the correct story at all, as is especially highlighted when the reasons for such events are misconceived. Henikoff and Greally describe the peril of jumping to conclusions as follows: “Misconceptions abound. For example, the popular press has touted as epigenetic the evidence that the children of men exposed to the 1944-1945 Dutch ‘Hongerwinter’ [in the final phases of WW II] during gestation tended to be overweight like their fathers. But this transgenerational interpretation overlooks the researchers’ own explanation, that parents control the food and influence the eating and exercise habits of their children.”12

So epigenetics may not be the reason for this phenomenon: it is just not that simple. The fact that something speaks to our imagination is no substitute for scientific investigation and for meticulously building a verifiable knowledge base. In any case, we can be sure that there is more to come in the story of epigenetics, because the molecular details of the indirect modifying effects on people’s genetic material, especially during development and differentiation, remain a hot area of research. Given that the mechanisms involved in the regulation of gene expression are highly complex and that much remains to be discovered, it should be evident by now that there is no easy answer to the question of how much our genes contribute to overall health and disease. There are many estimates, but an accurate one-size-fits-all answer would be foolish to defend. Nevertheless, some answers have emerged. It just depends on the exact question being asked and on the context in which one asks it. As we have seen in the case of Chloe’s deafness, and as is the case with many inherited genetic conditions, changes in a single gene can determine whether a condition will or will not occur. Many of these inherited conditions are uncommon and some are exceedingly rare. So rare, in fact, that for some inherited genetic syndromes with a specific constellation of symptoms only a few individuals have been described worldwide! Changes in single genes are not only associated with a “yes” or “no” for diseases; some such changes instead are linked to disease susceptibility or the likelihood of developing a certain disease at some point in life.13 These

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specific changes are not deterministic in that their presence definitely leads to disease, but they are associated with an increased or decreased risk. Genetic predisposition to breast cancer, for example, can be caused by mutations in the BRCA1 or the BRCA2 gene. Breast cancer is an example of a disease that has an increased likelihood to develop when changes in one of multiple separate genes are present, although most types of breast cancer do not appear to have an inherited genetic basis. Having a disease does not necessarily depend on single genes; it can be influenced by multiple genes. More often than not, and especially in the case of relatively common health conditions, the cause will be multifactorial, either determined by the contributions of multiple genes, or by environmental factors, or by a combination of both, in a range of complex interactions.14 Researchers aim to separate these individual factors. This work, painstaking as it is, ultimately provides the detailed information that is needed to assign cause and effect. It also furnishes hope for targeted prevention, mitigation, and treatment of illness. But differences between healthy people are important, too. Researchers are not only interested in understanding the causes of genetic diseases, but also in the reasons for variance in physical capacity. Take the example of the relative tolerance of low levels of oxygen in native peoples living at high altitudes.15 Compared to most people who dwell at lower altitudes and are prone to shortness of breath and altitude sickness when they travel to high altitude regions, the native peoples in Chile and Tibet were reported to be much more resistant to the effects of reduced oxygen levels in the air. Although a genetic basis likely contributes to their tolerance, there is currently more evidence available for developmental effects that help the body adjust to the low levels of oxygen in the air, such as adaptive growth and modeling of the lungs early on in life. Understanding the factors that contribute to traits of the human body under physical duress also provides a window onto other intriguing differences, such as superior athletic performance. Not to mention the quest for a healthy old age and extended longevity (more about that in chapter 18). My mother has suggested that “really useful research” (and when will I start working on that?) would reveal the complement of factors for a long lifespan, as she is planning to reach a hundred years of age while living an active life. I applaud her intention and banter back that, on average, the cells in our body are replaced every seven to ten years so what is she complaining about, she is still a spring chicken...

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Of course, my mother is not exactly alone in her desire and curiosity. Inheritance plays a role in determining lifespan, but so do lifestyle and the environment in which people live their lives. It has been estimated that genetic information determines around 25% of the variation in human lifespan. People who live longer than most may have certain protective factors in their genetic code that others lack, so that the factors that contribute to disease risk are dampened in their negative effects. Until the age of 70 or 80, however, lifestyle appears to surpass genetics in importance for health and longevity.16 One area of investigation with a high impact on the health of the general population is the study of chronic diseases. The risk of acquiring a chronic disease typically depends on a person’s DNA (the genome) as well as on the environmental exposures throughout life (also called the “exposome”), plus the interactions between them. Conditions such as diabetes, rheumatoid arthritis, dementia, asthma, irritable bowel disease, chronic obstructive pulmonary disease, depression, and cancer are all in the category of chronic diseases.17 Coronary artery disease is one such chronic condition that tends to develop over the course of years. It can be insidious, without symptoms, until the event of a heart attack or death from heart disease. Coronary artery disease remains the leading cause of death worldwide.18 In 2016, a large and comprehensive study of 55,685 participants was able to demonstrate that both genetic factors and lifestyle contribute to the likelihood that someone develops heart disease. It had been known for a long time that genetic factors influence the likelihood of heart disease. The relative risk of coronary artery events for people with high genetic risk is 91% higher (so almost twice as high) than for those with a low genetic risk burden. The main research question that was formulated for this study, however, was whether and to which extent a healthy lifestyle can reduce coronary artery disease, regardless of genetic risk. Initially, the researchers posed that “genetic risk might be attenuated by a favorable lifestyle,”18

but to thoroughly and scientifically test that hypothesis they had to meticulously analyze large data sets.18 The healthy lifestyle behaviors that were assessed included not smoking, avoiding obesity (defined as a bodymass index below 30), regular physical activity, and healthy dietary habits.

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Upon conclusion of the study, the authors were able to put numbers to the respective influence and interplay of genetic and lifestyle risk factors. They found that genetics and lifestyle were independently contributing risk factors for the development of coronary artery disease, but interestingly they also discovered that a healthy lifestyle was able to substantially reduce the risk of heart disease by the same relative amount, regardless of whether participants were in the high, intermediate or low genetic risk category. What that means is that even though we cannot change the genetic risk factors we inherit, we can all reduce our personal risk of coronary artery events by almost half if we adhere to a lifestyle that supports health.19 And that is a very substantial difference! Not only does this support the usefulness of advocacy efforts for a healthy lifestyle for everyone, but it also unequivocally shows that for the major health threat of heart disease, just as for many other ailments, genes alone do not determine destiny. Genome sequencing has been what is called a “disruptive technology” in genetic medicine and in research. It is disruptive—meaning upsetting business as usual—because its scale and speed are unparalleled. It has allowed the leap-frogging over other approaches that, eventually but at a much slower pace, might have revealed the sequences of the genome. Reports on the first drafts of the human genome were published in 2001, after years of massive, tedious, detailed DNA sequencing efforts. Since then, new frontiers have been explored and have shifted forward as our understanding of health and disease has expanded rapidly. One major goal, which has become a realistic aspiration, is to illuminate the molecular pathways that influence disease processes so that these diseases can be treated more effectively. Knowledge of these pathways can result in treatments that are based on a patient’s specific gene changes. It can also lead to treatments that can be broadly applied, independent of individual genotypes. This has been especially successful in cancers, such as leukemias, lung cancer, malignant melanoma, and colon cancer, to name a few. Some cancer types that used to carry an ominous prognosis and basically presented a short-term death sentence have now been successfully transformed into chronic diseases. Dr. Eric Lander is a pioneer of the Human Genome Project and of the molecular characterization of cancers, which typically carry various underlying gene changes that are not inherited but rather occur in the genome during the course of life. He pointed out that predictions of disease risks for individual patients are partial at best, and cautioned,

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“there are likely to be fundamental limits on precise prediction due to the complex architecture of common traits, including common variants of tiny effect, rare variants that cannot be fully enumerated and complex epistatic interactions, as well as many non-genetic factors.”

This observation in no way diminishes the tremendous impact and promise of genomics, it simply states that our genome, our DNA, our instruction manual, by itself, is only part of the story. Key points: G DNA carries genetic information in the form of genes. Humans have about 25,000 genes that encode proteins. Most of the genome is not translated into proteins but transcribed into important information that guides body processes. G Instructions for development, growth, and cell division are provided by the genetic template and from there through highly regulated gene expression, which differs between individuals but also between different cell types. G Given that the mechanisms involved in gene regulation are complex and that much remains to be discovered, there is no accurate answer to the question of how much, exactly, genes contribute to overall health and disease. G Even though inherited genetic risk factors cannot be changed, the personal risk of acquiring chronic diseases such as heart disease (the leading cause of death) can be markedly reduced through adherence to a healthy lifestyle. G Genes alone do not determine destiny.

CHAPTER THIRTEEN KEEPING IT TOGETHER

How the process of homeostasis works and what happens when it fails

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How does the human body keep everything in check in order to keep going?

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How does that process function under normal conditions, as compared to acute and chronic illness or extreme situations?

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And what causes that vexing difference in temperature perception between men and women?

It is said that, in traffic, we admire the patience of the driver behind us and loathe it in the driver in front of us.1 Traffic is tricky. Not only because it may stir up emotions about the competence of fellow drivers, but also in terms of its flow and the design of underlying traffic networks. Who has not waited at a red light on an intersection where nobody was driving or seemed to have a green light, in any of the directions? And when an accident has happened or when road work is done, the flow dynamics of traffic change. In all the braking and maneuvering that ensue from those events, we can appreciate that traffic flow is like a wave, yet not a linear one, and that a slightly increased density may cause the cars to move in a stop-and-go pattern.

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People have studied traffic flow ever since there have been enough cars on the road to warrant our interest. Numerous traffic models have been derived by mathematicians and transportation engineers, but from this one driver’s perspective, we seem to be far off from solving the problem of traffic congestion...It is a complex problem, of course, depending on many things such as the concentration of cars and other traffic, the unpredictable choices of individual drivers, infrastructure and road conditions, even cloud cover, and whether the sun blinds us. Every one of these elements impacts speed, density, and flow.2 What we would really like to see is a state of dynamic stabilizing feedback, in which there is a relative adjustment between the various unique but interdependent factors, so that the system as a whole can function efficiently and we can travel to our destination without delay. In the human body, we have our own traffic systems. These systems include the blood vessels and other infrastructure that enable the carrying of substances from A to B. They also, however, encompass mechanisms that work to find the best way to accomplish this, like the navigator in a car that can avoid traffic jams, point out detours, and make sure that one continues on the fastest route. The body depends on all these kinds of systems in order to function and to support the vitally important process of homeostasis. In the realm of health, homeostasis is commonly viewed as the maintenance of relatively stable internal physiological conditions under fluctuating environmental conditions. In a different context, it can be defined as “the process of maintaining a stable psychological state in the individual under varying psychological pressures or stable social conditions in a group under varying social, environmental, or political factors.”3

In plain language, homeostasis simply means that body and mind have to keep it together in order to function and survive. It is important to point out, however, that the processes that maintain homeostasis change and adjust continually. The body is constantly in flux as it needs to rapidly adapt to changes in the external and internal environment on an ongoing basis. It does not have the luxury to remain fixed at a certain set point. One example of this is the highly regulated circadian rhythm of day and night: if our waking hours are not alternated with sufficient sleep, we cannot continue to function. And whereas the sleep-wake cycle is a biological rhythm, the body needs to adapt to unexpected changes, as well. Whether you use your weekend to run a marathon or binge-watch your favorite television series, whether you are walking in the bitter cold of

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winter or find yourself in conditions of oppressive heat, whether you eat food with excellent or dismal nutritional value, and whether you are in a place where you are received with kindness or are subjected to hostility, your body and mind will do their best to keep everything in check to keep you going. Homeostasis is vital because it maintains a physiological state that is compatible with life. That sounds basic, perhaps, but is no small task. After all, the body has to contend with a staggering number of variables while it keeps its chemical and physical conditions within the homeostatic range in response to changing circumstances. Just to give a few examples, it has to regulate blood pressure, the fluid balance, blood sugar levels, core temperature, ion concentrations, blood gases (oxygen and carbon dioxide), the acid-base balance (pH), and it needs to manage cell loss and regeneration in individual organs and tissues. The extent to which tissue repair can be successful depends on the species. In humans, tissue repair can only restore injuries to a point, but other creatures such as spiders and some reptiles can grow back entire body parts. Although all the regulatory actions of the human body are customized to each individual process, there are common roadmaps. The body has a messaging system that includes receptors that sense changes in their environment. Such sensor-receptors can detect, for example, when the target value for core temperature, which is 37 degrees Celsius or 98.6 degrees Fahrenheit, is “off”. These numbers are not rigidly adhered to, because body temperature and many other parameters fluctuate somewhat in the course of night and day; they are subject to circadian rhythms. Even so, they should remain within the normal range. The sensor-receptors pass along the message to an integrating control center, which then gives directions to an effector system that will aim to rectify the situation as quickly as possible. In such complicated processes, corrections are usually carried out via self-regulating negative feedback loops that return signals to the control system when a situation has been remedied, so that further corrective action is inhibited. For temperature control, such feedback loops are also used. The temperature control center is in the hypothalamus, a small but mighty centrally located structure of neurons at the base of the brain. From there, a lot is orchestrated, as it also regulates several other feedback loops and hormone release programs. If we are too hot, a signal is sent from the brain to the blood vessels in the skin so that heat can radiate out as the skin becomes flushed. And when our

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sweat glands are activated, the evaporation of sweat from the skin helps us cool off further. We tend to breathe more heavily when we feel hot and we even lose some heat via respiration. When we are cold, in contrast, the distribution of blood to our core is favored over that to our arms and legs so that we diminish heat loss. Our muscles start to contract to generate heat by shivering, and several hormones are released to boost metabolic activity. This leads to an increase in heat.4 We also get goosebumps, caused by contraction of the tiny muscles at the base of our hairs. This is a valiant but feeble effort to create more warmth because most humans do not have enough hair all over their skin to create an effective extra layer of insulating air between the hairs. In animals with fur or feathers, however, this mechanism is quite useful. Women and men may be of the same species, but I have long had the distinct impression that women tend to feel cold much more often than men. Overall, women seem to have a more frequent (and sensible, I might add) desire to wear a sweater, there is more purposeful seeking of warm feet to snuggle up against in bed, and women feel a greater level of comfort with higher temperatures at home and in the workplace. This, as we all know, can lead anywhere from a respectful agreeing-to-disagree to passionate and vocal antagonism stemming from clashing views on who should control the thermostat. What causes that difference in temperature perception? Is it because women carry two X chromosomes whereas men carry one X and one Y? Are women just more sensitive? Or do those body hairs make a difference after all? One non-biological factor to consider is office dress code, which is less of a factor now than some decades ago when many men were expected to wear business suits to work. Differences in attire continue to exist, being more pronounced in certain sectors and some counties, but these in themselves cannot explain the gender difference in temperature response. Differences in physiology are more compelling. Men usually have higher body weight and more lean muscle mass and strength, which is associated with a higher metabolic rate: more calories are burned to fuel the extra muscle tissue. This, in turn, increases blood flow to the arms and legs and generates heat, which is evaporated from body surfaces but also trapped between the skin and clothing. Thus, the male body is naturally kept warmer, and the difference in temperature sensation is a real thing. And its relevance extends well beyond personal comfort levels...

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It was recently discovered that cognitive performance by women on arithmetic and verbal tests is positively influenced by higher temperatures.5 When temperatures between 16 and 33 degrees Celsius (about 61 to 91 degrees Fahrenheit) were tested, female participants performed better toward the high end of that temperature range, especially in the number of answers submitted but also in the number of questions answered correctly. In male study participants the opposite pattern was observed. Their achievements on these tests were better at lower temperatures, but the divergence in performance at different temperatures was less striking than in their female counterparts. Of course, there are individual differences and some men and women will not fit this trend, but given that ambient temperature affects productivity and cognitive performance, the experiment suggested that, at the very least, differences between men and women should be taken seriously if optimizing work performance is a goal.5,6 It just does not help to be freezing all the time! For the U.S. military, the question of gender differences in temperature tolerance came to the fore when, in 2013, women were allowed to fill combat positions. With that change, the armed forces became interested in analyzing differences in thermoregulation between men and women. The goal was to maximize physical performance in different environments, and in particular in extreme warfighter conditions. When this was studied, it was confirmed that, for both men and women, physical exercise performance suffers when body temperature increases. Of note, the differences under heat conditions were small overall despite usual gender differences such as the amount of sweat production, which is lower in women. Assessments during cold stress demonstrated more dissimilarity: for the same degree of cooling, women exhibited a lower core temperature and less shivering capacity than their male colleagues. As a result, they generated less body heat, especially in cold water as compared to cold air. The report on this study concluded that “there is still uncertainty in where these sex differences would limit or benefit women’s ability to accomplish certain tasks, as the specific demands and environment must be taken into account to better assess the physical and mental outcomes of men and women.”7

What this study importantly was able to demonstrate, however, is that the use of male control equations to predict female body responses is inadequate.

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Projected onto a larger scale, temperature preferences and the energy consumption they require are of interest not only for scientific investigation, but also for business and policy making.8 Energy-efficiency for buildings is increasingly taken into account during building design to reduce thermal costs and to combat climate change. Still, the envisioned energy-efficiency of a building can be derailed if occupants make adaptations after the fact to improve their comfort. In order to prevent that from happening, it is important to predict energy needs. Energy-consumption can only be predicted effectively if occupant demographics are kept in mind. After all, indoor climate requirements will be different for a nursing home that houses senior residents, and for a sports center that is designed for physically active teenagers. Until recently, differences between females, males, children, and seniors were not typically considered when buildings were developed. But it makes sense to use a biophysical approach to building design. Consideration of factors such as metabolic rate, tissue insulation, and body composition in light of age, sex, and individual variation could more accurately predict and support decisions about the thermal regulation of a building, or of spaces within that building.8 Even though it is not possible to be entirely accurate in view of subjective perceptions of comfortable temperatures, a biophysical approach has the advantage of flexibility that is based on differences in demand. And it opens up the possibility of equity, by recalibrating temperature standards based on diverse populations that were not previously given much deliberation. This example illustrates that the principle of homeostasis affects more than the human body alone and that its effects have ramifications ranging from individuals to groups and to bigger systems, such as society and climate. Back at the level of the individual person, in your own body, homeostasis in all likelihood continued inevitably and flawlessly while you were reading. So, whereas one can become aware of the astonishing complexity of the juggling act that the body continually performs, the numerous automatic processes that are required for homeostasis largely escape notice. It is not surprising then, that instead of being in awe, people tend to take them for granted, at least until something goes wrong. In disease states, the normal physiology of the body is disrupted and the usual homeostasis of one or more processes cannot be maintained. Thus, one becomes ill. One symptom that accompanies a variety of illnesses is fever, which has been defined as a core temperature of 38.3 degrees Celsius (about 100.9 degrees Fahrenheit) or above.9 Because it is a symptom rather than a cause, it should not be seen as a disease in itself, but rather as

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something that develops with many different conditions, including infections, cancer, injury, and as a reaction to medication. Fever occurs when the body receives a signal from the hypothalamus, the temperature control center in the brain, to raise its temperature. Then, core temperature begins to exceed the normal and minimally fluctuating daily range. The body further complies with this signal by conserving heat, so chills, shivers, and goosebumps arise. Being wrapped in a warm blanket feels good (or at least a little better) until, eventually, the fever breaks, the set point returns to normal and all that extra heat is lost by sweating. Fever seems to make people more miserable than would seem desirable, but the increased thermal set point usually is protective. It is the result of a complex response by the nervous system, the hormone-producing endocrine system, and the immune system. This response is triggered by external and internal factors, such as, respectively, bacterial toxins and substances secreted by various immune cells. Overall, its purpose is to defend the body against infectious and non-infectious health threats.9,10 Especially in the case of infectious diseases, fever can be a blessing-indisguise that enhances survival, because an elevated temperature inhibits the replication of microorganisms, improves the efficacy of many classes of antibiotics, and kicks the immune system into higher gear.9 Regrettably, sometimes the protective mechanism goes awry and becomes life-threatening itself. A very high fever of more than approximately 41 degrees Celsius or 106 degrees Fahrenheit can develop when the normal temperature feedback loops are overruled. Instead of hitting the brakes, a continuously stimulating positive feedback loop is put in motion, and body systems become trapped in a runaway process that, if that vicious cycle is not interrupted, can lead to organ damage, confusion, seizures, and death.11 It all depends on the combination of timing and magnitude of inflammatory and anti-inflammatory effects that range from the level of cells to the whole body. At the level of cells, very high temperatures cause direct damage, for example to cell membranes and organelles within the cells. In fact, cell death occurs at a temperature close to that of protein denaturation, which is the point at which proteins lose their normal shape and structure. This is one of the main reasons why high fevers are so dangerous.9 Whereas high fevers are typically associated with acute illness, chronic diseases are precipitated by a failure of homeostasis as well. One example of such a disease is diabetes mellitus, a serious chronic condition that affects at least 422 million people worldwide.12 According to numbers from 2015,

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9.4% of the population of the United States had diabetes (about 30.3 million Americans).13 Diabetes mellitus is generally divided into two categories: type 1 (which affects approximately 1.3 million people in the U.S.), in which the insulinproducing cells of the pancreas are attacked and destroyed by an autoimmune reaction of unknown exact causes, and the far more common type 2, in which blood sugar levels remain high because body cells have developed insulin resistance. Obesity is strongly associated with type-2 diabetes, but it is not the only factor, considering that some patients with type-2 diabetes are not overweight. As with many chronic diseases, there is an interplay between genetic and environmental risk factors, including being overweight, inactive, and older. Race, family history, high blood pressure, abnormal blood cholesterol values, and personal medical history additionally influence the risk of developing diabetes.14 Regardless of the factors that come to bear in individual patients, all people with type-2 diabetes are unable to optimally utilize their insulin, which is critical to the processing of sugar in the body. Insulin is the key hormone that is released by the pancreas, after which it circulates in the bloodstream and allows sugar (in the form of glucose) to enter the cells. In healthy people, blood glucose levels are stable but not constant: they remain within the range of homeostasis but they do fluctuate throughout the day. It is normal for blood sugar to rise with every meal, but that increase is balanced out by the uptake of glucose by cells that need it for energy while the rest of it can be stored in the form of glycogen for future use. When that mechanism does not work properly, blood glucose levels remain too high, which can lead to serious acute symptoms and to long-term complications from permanent organ damage. Thus, diabetes is an example of a disease in which a normal feedback loop, in this case the one for insulin, is broken. As a consequence, blood glucose is not maintained within the normal range. Patients may need to take insulin or other medications to restore homeostasis, although sufficiently intensive lifestyle interventions have been shown to be capable of the same effect. This is very encouraging. Lifestyle changes that include a whole food, plant based eating pattern and moderate exercise can reverse the disease in at least half of the patients with type-2 diabetes.15,16 In the case of an illness such as diabetes, the boundaries of normal functioning are breached and the body no longer can maintain homeostasis for one or

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more critical functions. But it will have tried, and tried very hard, to return to an internally acceptable state before the system failed. Apart from acute or chronic illness, the boundaries of normal functioning can be reached under a variety of circumstances. The body may reach the limit any time it needs to perform at extremes, for example under conditions of starvation. Sometimes extremes are voluntarily pursued, as in the case of daredevils (my description, not theirs) who seek to push their body to the max. Two such people are extreme athlete Wim Hof and investigative journalist Scott Carney, who trained hard to achieve active physical and mental conditioning so that they could adapt, over time, to increasingly drastic exposure to the elements. For example, they expose themselves to conditions like icy water and snow, without the use of protective layers of clothing. This would have grave consequences for most people. Under the mentorship of Hof, Carney incorporated cold showers, specific training techniques and breathing exercises into his fitness regimen, and recounts his experience in his book “What doesn’t kill us: how freezing water, extreme altitude, and environmental conditioning will renew our lost evolutionary strength”.17,18 Whereas I admire the effort and enjoy experiencing their ambitions and the rigorous training and triumph vicariously, I would not recommend that people try this at home. The conditions they expose themselves to are harsh and could easily lead to disruption of the homeostasis of physiologic body processes. The difference between life and death in this case is a gradual adaptation over an extended period of time, instead of an abrupt exposure that the body is not prepared to cope with. With these adaptations in place, the short-term homeostatic processes have a better chance of success. This does not make the achievements by these endurance athletes any less admirable, but it does at least reduce the risk of imminent death! Different phases of life come with their own challenges to homeostasis. During critical times in early development, for instance, the nervous system makes connections between individual neurons, the cells that carry electrical pulses. The neural circuits that are formed by these connections are vital for communication between the neurons, without which one would not be able to think or act. Similar to other processes in the body, neural networks require a degree of stability that is achieved by operating in a dynamic range around a set point that appears to be developmentally regulated.19 But sometimes things go wrong, and either the set point erroneously changes or the homeostatic range cannot be maintained. Conditions such as epilepsy, which is characterized by neuron over-activity and best known for recurrent seizures, can have their origin in such events.

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Another phase in life during which people are more vulnerable to disturbances of homeostasis is in advanced age. With ageing, body systems have a greater failure rate and the ability to maintain homeostasis is no exception. The body gradually becomes less resilient and has a harder time dealing with fluctuating stressors, even the minor ones that in and of themselves are not toxic or damaging, but do require a response in the form of a temporary biochemical or regulatory adjustment. This reduced ability to cope with changes in the external or internal environment factors into the development of age-related disorders, such as Parkinson’s disease, osteoporosis, osteoarthritis, and age-related macular degeneration.20 Ageing may be risky business, but let’s not forget that from the earliest stages and throughout an entire life survival depends on homeostasis in all kinds of body functions and tissues. Tissue homeostasis, specifically, is a “process involved in the maintenance of an internal steady state within a defined tissue of an organism, including control of cellular proliferation and death and control of metabolic function.”21

In order to sustain this balance between cell production and demise, stem cells that turn into specialized cells within an organ must be accurately regulated, and the connective tissue that supports the organ structure has to be maintained. The tissue types within living beings have their own requirements and regenerative capacity. That comes into play after injuries, when structures need to be repaired. Salamanders, for example, are able to regenerate severed limbs; a very practical feature that unfortunately does not apply to organisms of higher complexity, including humans. The less dramatic regeneration that goes on in daily human life, however, is just as deserving of attention: it has been estimated that the consequence of an imbalance in liver cell production over cell death by just 1% would, after six to eight years, result in a liver that weighed as much as the entire human body!22 All these examples converge to this: the body is a wondrous and extraordinary structure, with countless ways of keeping things in motion, yet stable. It is fascinating that, whereas the processes that occur in different people are essentially the same, they are never exactly the same. The ways to support homeostasis and ultimately health are not identical for everyone and there is some fortunate redundancy in the variety of pathways that can get us there. If there is a roadblock in one direction, the body may be able to find an alternative route. In any case, it will be darned if it does not try.

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We all have to function under different stressors and with different supplies. We may eat a heavy meal or a light one, or have diverging eating habits overall, and yet our body will manage most of the time, and for a long time, to extract the nutrients it can use from different types and amounts of input. The body will keep us warm, it will make sure that we do not lose consciousness, it will help us get oxygen to all our tissues, and it will make sure that our cells remain appropriately hydrated. For sure, and despite any flaws that we may perceive, the body is something to deeply appreciate, and worthy of our utmost respect and care. The body does its very best to stay within bounds, but our behavior can push it out of the desired range. The mind needs to work with, not against, the body on which it so depends. Key points: G The processes of homeostasis enable the body to maintain a physiological state that is compatible with life. G Homeostasis can be maintained via self-regulating negative feedback loops, but it is not a fixed state. The body is continuously changing as it needs to adapt to fluctuations in the external and internal environment. G In disease states, the normal physiology of the body is disrupted and the usual homeostasis of one or more processes cannot be maintained. Thus, one becomes ill. G In extreme situations, the difference between life and death can be gradual adaptation over a period of time, as opposed to an abrupt exposure. G The ways to support homeostasis and ultimately health are not exactly the same for everyone. People have to function under different stressors and with different supplies. G There is some redundancy in the pathways of homeostasis, and variation in the availability of compensatory mechanisms.

CHAPTER FOURTEEN THE MATTER OF THE MIND

How current science challenges the dichotomy between body and mind

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What is the difference between body and mind?

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Do they influence each other?

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Is the division between mental health and physical health warranted or artificial in light of current science?

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Can a more integrated approach be helpful given that body and mind together affect everything that people think and do and feel?

When we talk about health, we tend to parse it into a variety of subtypes, including emotional health, spiritual health, and even financial health. The two most commonly used categories, however, are physical health and mental health. Mental health, when described as a separate entity, encompasses our psychological, emotional, and social wellbeing. It influences how we manage stress, how we interact with others, and how we make choices. Mental health problems can affect mood, but they also shape behavior and patterns of thinking. Among the contributing factors to mental health problems are biology (including genetic predisposition and brain chemistry), life experiences (such as traumatizing events), and family history. Contrary to popular belief, mental health issues are not uncommon and they can occur at any

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stage in life. According to data from 2014 for example, approximately one in five American adults experienced a mental health problem that year.1 Physical health and mental health seem to be divided so firmly that we hardly question whether or where, exactly, a boundary exists. This separation is also adhered to in healthcare. When health concerns are first presented in primary care, they are quickly assigned to one category or to the other. In this chapter, I explore whether such a separation makes sense, and, if it does, whether there are areas where a less exclusive or segregated path could be helpful. At the very least, the dichotomy between physical and mental health raises questions: as science reveals an increasing number of direct connections between the brain and the rest of the body, it has become quite clear that body and mind mutually influence each other. This insight has important consequences for how we think about wellbeing. If we use my definition of wellbeing as “a primarily subjective evaluation that reflects where someone is now, compared to where that person would like to be”, then a comprehensive approach to health would seem appropriate. After all, shouldn’t we acknowledge that both body and mind are essential to our health because together they affect everything we think and do and feel? Is the division between mental health and physical health always warranted? Is it artificial, or perhaps even obsolete in light of current science? To investigate these questions, it may be helpful to better understand some of the context and history around this dualistic thinking. One way in which the world of health has been divided is into physical and mental properties.2 The physical properties such as weight, size, and electric nerve impulses are thought of as those that are measurable with scientific techniques and instruments and, as such, they are in essence accessible to an external observer. With mental properties, that does not appear to be the case. Here, one can think of things such as emotional states (joy, anger, and so on), being conscious of a texture (perhaps a fabric or a food), or what an image looks like to one person as compared to another. Other examples are personal beliefs, thoughts, the long-term memory of personal knowledge (termed semantic memory) and the experience of pain. Pain cannot be directly or exactly shared, and it remains one of the most subjective and therefore challenging symptoms doctors need to assess during the interactions with their patients. Pain, just like all the other examples of mental events are private to a person. Only you can feel your pain directly, just as only you know what you experience when you taste

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licorice, or whether you perceive turquoise as a shade of blue instead of green (my husband and I have strongly differing opinions about that). Mind-body dualism has been most firmly associated with French philosopher René Descartes (1596-1650), who argued that mind and body are radically different. Because he viewed them to be closely-linked but separate entities, he contended that one could exist without the other and that no direct interface between mind and body needed to exist. This argument enabled Descartes to remain largely congruent with the predominant religious sentiment of the time: his philosophy conveniently provided a basis for both the soul and for immortality, and, as such, it supported Christian doctrine.3 This was beneficial to him because it remained quite important at the time to reconcile new ideas with the framework of the politically powerful Church. Descartes, however, also wanted to learn about mind and soul, at least within the framework of philosophical discourse. This interest in worldly investigation was far from being embraced by church authorities. It truly was a “Janus-faced age”: the seventeenth century saw a progressive movement toward modern thinking while the prescriptive ties to medieval convictions remained.4 Nevertheless, the excitement of independent reasoning and exploration of novel ideas is almost palpable in the written works from that time, and philosophers grappled with concepts in ways never quite expressed before then. This resulted in philosophical arguments and counter-arguments, such as those made by critical thinkers Pierre Gassendi (1592-1655; philosopher, mathematician, and Catholic priest) and princess Elisabeth of Bohemia (1618-1680; philosopher and Lutheran abbess in her later years), who corresponded with Descartes and wondered how something immaterial like the mind could bring about physical, voluntary movements if there were no surface or other direct contact between the body and the mind.3,4,5 It was a valid point that challenged Descartes because, until then, he had not fully considered it. The conundrum became known as the “mind-body problem”. And whereas Descartes eventually did concoct a philosophical solution, it did not stand the test of time and the problem persisted! To this day, the mind-body problem has not been completely worked out. People still debate the fundamentals of the relationship between body and mind by considering whether mental and physical states are distinct, or whether all mental states are physical versus the other way around. Among the many proposed models, the “mind-brain identity theory” has gained traction over time with contemporary philosophers and scientists

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alike.6 It asserts that the mind (consciousness) is a function of the brain or of the central nervous system, which consists of the brain and the spinal cord together. This view acknowledges that human beings are organisms with complicated physiology, but proposes that a research-based understanding of neural processes will ultimately be able to explain mental activity. If that cannot be accomplished yet, it is likely to be successful in the future, when more is understood about the vast complexity of cognitive mechanisms. In other words, the hypothesis contends that mental states are brain states. Dr. Bryan Chambliss, whose work has focused on the philosophy of mind and cognitive science, explains that once upon a time, we discovered that lightning is a kind of electrical discharge and that it is likely that, similarly, the developments in the neurosciences will discover mind-brain characteristics of different kinds, as well.6 Our various mental states would then be shown to be different elements or possibilities in the large spectrum of brain states. Nonetheless, it remains conceivable that we will not ever give up thinking of mind and brain as somewhat distinct, although that has its basis in history and in culture as much as in medical understanding. And in any case, that idea at least does not preclude that they are intimately connected and function hand in glove. As part of larger cognitive systems, mental states are shaped by the system of which they are a part. The advent of the computer has enabled cognitive psychology to use network analogies, for instance in the comparison with information processors and by promoting the notion that individual people differ in their thinking because they essentially run different software programs. But these terms, however tempting they are, risk oversimplification. According to Dr. Chambliss, “...scientific accounts of consciousness seek to explain a range of psychological processes including the integration of information, the focus of attention, the deliberate control of behavior, the ability of a system to access its own internal states, and the ability to report on one’s mental state. Each of these phenomena pose scientific challenges, but there is no reason to doubt that we might eventually explain each in terms of their underlying computational and neural bases. The real problem of explaining consciousness arises in explaining phenomenal consciousness, sometimes called qualia, the introspectively accessible what-it-is-like-for-me aspects of experience.”6

It is highly likely that certain aspects of mental states will remain a mystery for a long time to come. Somehow, to me, even as a curious scientist, that is a comforting thought. Notwithstanding the considerable

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recent progress in the neural sciences, we still have our own individual experience and subjective perspective, on which intentionality and conscious thinking are based. The question of what brain states and mind states really are and whether they are distinct has been considered by philosophical reasoning and, once they became available, by scientific research tools of ever-increasing precision. The same applies to the question of causality: much recent research interest has focused on whether and how mental states influence physical states and vice versa.2 This is a less abstract question because it is something with which we have direct experience ourselves, something that we can relate to in daily life. Even though in general, perhaps, we may view our own body and mind as separate and as functioning independently from each other, we all have been in situations where our mind state has had physical effects. Perhaps it was a dinner appointment with an old friend you really looked forward to seeing, and he did not arrive. At first, you waited patiently, then you texted or called and there was no answer. You started worrying, imagining all kinds of serious reasons for why he did not show up. You paced and fidgeted, waited longer, feeling a slight headache arise. After a while perhaps you grew impatient, and your worry changed to increasing irritation. How could he stand you up? Just like that? You swallowed hard a few times, felt flushed as you became annoyed and noticed that you were clenching your jaw. Eventually, you gave up on waiting for him, suddenly feeling abandoned and alone, convinced that he did not care about you at all, and probably never did, and in fact nobody ever loved you. You were probably not lovable anyway. Your shoulders slumped forward and you left the meeting place, dejected, without the usual spring in your step and not feeling hungry at all anymore... This scenario may not reflect your experience, exactly. It is (hopefully) a rather dramatized version of what might have happened, but I will take a wild guess and assume that most people might recognize themselves in at least some of the emotions, behaviors, and body responses. Another example of the dynamic relationship between body and mind is the experience of public speaking, which can have positive effects on both body and mind when it is perceived as something positive that energizes us, and (hopefully) our audience. It also, however, is said to evoke more fear than the thought of death.7 Jerry Seinfeld made this sentiment famous in his stand-up comedy performance, by saying:

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Regardless of its ranking on the scale of fear, the thought of public speaking causes feelings of terror in many people. There is something about needing to get up in front of a crowd that can cause anxious thoughts beforehand, which, well before the event, may result in nausea or diarrhea. Then, when it is time to speak, one may feel self-conscious and nervous instead of confident, so one stands there with trembling hands, sweaty palms and shortness of breath, a dry mouth and a pounding heart, feeling dizzy. All these symptoms are the physical expression of anxiety around the possibility of failure, which in essence is a common social phobia. The physical response is based on how the body deals with fear, even if, during the obligation of public speaking, that stress reaction occurs at the least opportune moment and in the most unpleasant and intensely-felt way. An acute stress response can be triggered by public speaking and by many other situations of real or anticipated danger. When this happens, several biological systems kick into higher gear, rapidly sending around signals via distinct pathways in the body. The autonomic nervous system, which is important for homeostasis and which controls involuntary visceral functions such as digestion and the rate of breathing, orchestrates much of our perception of stress and the resulting physical events. These include the delivery of extra energy that enables a fight-or-flight response. The fight-or-flight response entails a series of biological reactions that include the release of adrenaline by the adrenal glands, which are located directly above the kidneys, hugging their tops. Collectively, these reactions are intended to keep us safe during threats and emergencies. They are so automated, however, that they can work against us, as in the example of public speaking when this response rather gets in the way of the composed, relaxed, and collected impression we may try to make. During stress-reactions (more on these in chapter 16), the interplay between mind and body can result in an amplifying spiral, where the physical symptoms that result from anxiety can cause more anxiety, which leads to more and stronger physical reactions, and so on. Importantly, however, the stress response usually presents a critical survival mechanism that allows us to become acutely aware and alert with sharpened senses. It also supplies enough physical energy to execute that split-second decision to jump out of the way of an oncoming car. And that might just save your life!

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Additional hormones, directed by the hormone-driven endocrine system, are important as well: once a stress signal is received in the brain a “high alert” message is sent to the hypothalamus. The hypothalamus accepts the request for help by starting a cascade of chemical messages to the pituitary gland and from there, through blood circulation, to the adrenal glands that then secrete the hormone cortisol. This hormone supports the autonomic nervous system in its acute stress reaction. Under normal circumstances, it will only remain at increased levels until it is safe to relax.9,10,11 In medicine, the interaction between body and mind has long been recognized, albeit not in the way one might expect. Only decades ago, the term “psychosomatic” (stemming from the Greek words “psyche” for mind and “soma” for body) was almost exclusively reserved for conditions that were thought to originate “between the ears”, so in essence consciously or subconsciously made up by the mind. Patients with illnesses designated as such were often not taken seriously. Stress or internal conflict were seen as the cause of psychosomatic conditions and a physical basis was thereby dismissed. How utterly frustrating it must have been for those patients, who were basically thought of as being irrational or malingering! Although there still is much to learn and change in how healthcare is delivered, doctors and other healthcare providers have come a long way in improving their understanding of how mind states can have very real effects on the body, and, conversely, how physical conditions can influence mental health. There now is an interdisciplinary field of psychosomatic medicine, that “is concerned with the interaction of biological, psychological, and social factors in regulating the balance between health and disease.”12

It forms the basis of research into psychosocial factors that influence any kind of medical condition, promotes the integration of psychosocial assessments in medical examinations, and uses psychological approaches to enhance disease prevention and treatment. It also advocates for a revision in the organization of healthcare, so that patients may benefit from interdisciplinary care with fewer traditional boundaries of medical services, some of which focus on single organs.12 Does that mean that, if one has a medical condition that affects a single organ, for example, a leaky heart valve, one should not see a cardiologist and not consider surgery to have the valve replaced? Fortunately, it does not imply that at all. It simply means that a heart valve is not the whole person

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and that in the treatment of the heart problem, the whole person should be considered and engaged. The incorporation of mind-body approaches does not translate into the dismissal of biomedical approaches in any way. Instead, the vision is to improve care by integrating one with the other. And there are good reasons to do so: some of these approaches benefit physiologic function and improve health outcomes. Scientifically supported by numerous research studies and by randomized controlled trials, they are medically useful and cost-effective methods with minimal side effects, that can serve alongside with conventional biomedical healthcare.13 Mind-body approaches such as relaxation techniques, meditation, or the combining of psychological techniques with patient education have been especially effective in the treatment process of conditions as wide-ranging as chronic low back pain and headaches, insomnia, and coronary artery disease. They are also helpful in managing the symptoms and treatment effects of cancer and benefit patients with urinary incontinence or arthritic joint disease. In addition, integration of biopsychosocial methods, such as relaxation exercises in the preparation of patients for surgery, has produced positive effects on surgical outcomes.13 This insight has caused quite a shift in medicine, and yet it may take some getting used to. After all, we can draw on direct experience when we are frightened and feel our heart pound, but the realization that depression and other negative emotional states can impair the functioning of the body and affect physical health is a bigger leap. A variety of mind-body approaches can be used to improve healing and rehabilitation by harnessing the power of the mind. But scientists have also investigated the influence of mind states on the body separately, outside of the context of treatment or other medical interventions for specific diseases. One area of investigation involved the question of how mind-body practices such as mindfulness training, yoga, and breath regulation affect gene expression patterns and how these molecular changes might influence general health. A review14 of 18 studies that were designed in a variety of ways indicated that such practices downregulate genes and pathways that become activated when cells and the immune system react to potentially harmful triggers such as stress, infectious agents, and UV radiation (yes, as when sunbathing or in a tanning salon). The observed downregulation of the genes that play a role in inflammation suggests reduced inflammation in the body overall. Inflammation can occur

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in response to an infection, but there are other causes too: it occurs whenever an immune reaction is set in motion and the body activates its defense mechanisms. Some of the triggers of inflammation can contribute to chronic inflammation, which is one indicator of less than optimal health (as explained in detail in chapter 18). So when pro-inflammatory genes are less active, it is a good thing. The authors, however, caution that the results are preliminary: the number of studies is as yet too small and some studies are not set up rigorously enough to compare the molecular benefits of mind-body practices to other health-promoting activities such as a physically active lifestyle and healthful eating, which we do know for sure to make a positive difference.14 In the medical literature, there is a wide range of studied mind-body practices on the one hand and a considerable variety of research study designs on the other. This results in a patchwork of findings that are difficult to integrate with confidence until such findings are replicated and verified through long-term, carefully designed studies that address the current shortcomings. Nevertheless, and even though cause-and-effect relationships are not yet clear, the studies together do convincingly link mind-body practices with biological events. In particular, mind-body practices are associated with a variety of beneficial molecular and cellular changes in the immune response. Effects on brain structure and function that enhance emotional stability, attention, and learning have also been documented. One fascinating finding is that subjective experience, which is exactly that which is associated with the “private” mind rather than with the “public” biology of the body, must be taken into account and, in fact, is critically important for the interpretation of mind-body studies. If someone feels lonely, it is that sense of being socially isolated that counts and that correlates with biological changes that may have a negative impact on health. Thus, some associations may be revealed only by asking about someone’s subjective experience and would remain hidden if, for example, only the objective size of someone’s social network were to be considered. All in all, even though the underlying molecular mechanisms still require further investigation, the current literature supports the adoption of mindbody practices in the toolkit for wellness.15 If body and mind are so interconnected, one might expect that a person with mental health problems has a greater risk of other illnesses, as well. That notion has been explored especially in relation to cardiovascular disease.16,17

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There is a firm connection between heart disease and depression, as well as between heart disease and traumatic stress, such as experienced by people with post-traumatic stress disorder (PTSD). Chronic anxiety and chronic psychological stress, which, for instance, can be caused by loneliness or problems at work, have also been found to be toxic to the heart.16 But does the negative impact on heart-health occur before or after the fact? Interestingly, it works both ways. Mental health issues come into play after receiving a diagnosis of cardiovascular disease and after the dramatic, life-changing events of a heart attack or stroke. It would be reasonable to assume that the physical aftereffects of an acute event like a heart attack and the direct confrontation with the possibility of death could contribute to depression and anxiety. And indeed, this is supported by the numbers: about one in five patients with heart disease is depressed, which is at least three times more than what is seen in the general population.14 In these patients, poor mental health may exist together with poor general health because of new physical limitations, and because of a reduced quality of life. And their mental health issues remain risk factors for adverse events and poor outcomes in the future. But that is not the whole story. There is now ample evidence for a role of mental health conditions even before the stroke or heart attack. Mental health problems are a risk factor for the development of cardiovascular disease in the first place. Unfortunately, it is not straightforward to determine the exact mechanisms through which they contribute, because poor mental health often prevents people from taking good care of themselves. Mental health issues may go along with detrimental lifestyle behaviors such as smoking, poor food choices, use of alcohol or drugs, not exercising, and spotty compliance with medical treatment plans. They also coincide with increased inflammation in the body overall, which can damage blood vessels and injure heart function in the long run. In the case of chronic anxiety and stress, they can result in changes within the autonomic nervous system that harm the cardiovascular system over time. So, whereas we may not always know exactly how different factors affect each other causally or over time, it is quite obvious that treatment of the underlying mental health issues as well as other risk factors and the biological changes that contribute to and result from heart disease, would support patients’ overall health and wellbeing. Thus far, I have mostly described how mind states influence the body. This is where most of the research has focused, but studies that look at the mutual

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relationship and at the effects of the body on the mind are emerging, as well.17,18 Of particular interest in this regard is the recent appreciation of the human microbiome, which encompasses all the microorganisms that live on the skin and inside the body. The majority of these bacteria and other microbes live in the gut and most of them are good guys with important jobs, like helping us digest our meals and protecting against their bad bug colleagues that make people sick (more on this in chapter 17). As it turns out, communications between the gut and the brain go back and forth in rapid succession, and the microbes themselves do some of the calling! All of this happens via a variety of signaling pathways that involve hormones, immune cells, chemicals, and nerves. The central nervous system can influence the complement of microbes in the gut of animals and people under a variety of conditions that produce mental and physical stress. Examples of this are early separation from a mother, exposure to excessive heat or loud noise, and hostile social conditions.18,19,20 Just as we have seen earlier with the stress response, cortisol is secreted by the adrenal glands after they receive signals via the hypothalamus and the pituitary gland in the brain. This cortisol has effects on the cells of the immune system throughout the body, but also in the gut: it can alter the local barrier defenses of the gut against toxins and it can even change the composition of the microbial populations that live in the digestive system.18 Moreover, when people are stressed, their colon movements may slow down and that, too, can contribute to a balance-shift with a reduction in the number and diversity of good guys on which everyone depends for healthy digestion. Conversely, gut microbes can act upon organs, including the brain. They influence brain activity by sending messages through neurons, by modulating the amounts of certain chemicals and by changing the levels of circulating immune system components.15,18,19 Of course, it was already evident that some form of communication takes place between the digestive system and the brain, given that when we eat, we eventually realize that we feel full and satisfied. However, recent studies have revealed that there is much more and quite intriguing interaction between the two. The specific microbiome we carry with us plays an important role in the state of our health and wellbeing. The discovery that gut-brain communications can influence mood and behavior was a true paradigm shift that opened up lots of possibilities for

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potential medical treatments, ranging from new purposes of probiotics and antibiotics to fecal transplantation (yes, really).20 One example of a mood-enhancing message from the gut is an observed elevation of the chemical tryptophan in the bloodstream, courtesy of a type of bacterium that likes to live in the bowel. This increase in tryptophan can increase the central activity of the neurotransmitter serotonin. As one of the chemicals that can transfer signals from one neuron to the next, serotonin has gained a reputation as a “feel-good” chemical, even though it has a variety of biological functions.19 At least theoretically, mood can be enhanced in a natural way by having a good amount of the specific tryptophan-elevating microbes in one’s gut. Whereas this particular alteration could result in a positive effect of gut microbes on mental health, disruption of the normal intestinal environment can wreak havoc, as illustrated by the story of one Canadian town.19,20 It was in the spring of the year 2000 that heavy downpours washed away farm run-off and contaminated the drinking-water supply of Walkerton, a small town in Canada. From a population of 5000, at least 2300 residents fell ill with acute bacterial dysentery and six lost their lives as a direct result of the infection. Over the eight years following this tragedy, researchers aimed to learn about the after-effects. One of the things they investigated about this large and well-documented waterborne outbreak was irritable bowel syndrome (IBS). IBS is a common condition that affects at least one in 20 people overall and is characterized by abdominal pain, diarrhea, bloating, and constipation. Symptoms tend to come and go over time and can last for days, weeks, or months at a time. Among other risk factors, acute gastroenteritis is a wellknown contributor, but before the Walkerton analysis only smaller and shorter studies of post-infectious IBS were reported. What emerged was that almost one in three study participants developed IBS as a complication of the infection. Eventual improvement and resolution occurred in many patients, but after eight years approximately one in seven still had IBS symptoms. That meant that the prevalence of IBS remained significantly increased. The long duration of symptoms correlated with having had a more severe initial infection that was accompanied by fever and weight loss, but also with other known risk factors for IBS, especially being younger and female. As is often the case in people who suffer from IBS, and coming back to the effects of the gut on mental health, anxiety, or depression coexisted relatively frequently. Together with the mix of microbes in the gut, altered gut-brain communication appears to play an important role in IBS.19 IBS

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patients have stronger responses to visceral pain, an elevated cortisol response, and increased levels of immune substances in the blood that are seen with inflammation. Although it remains to be resolved how increased bowel permeability, chronic inflammation, and changed neuromuscular functioning play a role in post-infective IBS, the Walkerton research importantly demonstrated that acute dysentery can trigger chronic symptoms and can have long-term physical and mental health effects.21 Looking into the ongoing dialogue between the brain and the gut has given me an even greater respect for the human digestive system. Until recently, it was unknown that there is a sophisticated communication network in the belly that influences mood. The term “gut-feeling” suddenly gained a whole new meaning! Despite the many questions as yet unanswered, the diverse scientific directions in which mind and body are being explored are showing us one thing very clearly: there is a newfound degree of interconnectedness between body and mind that is fundamentally important for human health. And with solid scientific evidence to support the existence of mind-body interactions that are vital from birth to old age, exciting possibilities follow, spanning prevention to treatments to general wellness. Just one word of caution: this realization should never be misconstrued as “mind over matter” or become a way to blame ourselves when we become ill. In the week during which someone was challenged by a job-interview his immune system may well have been weaker, but that does not mean that he is now responsible for the fact that he caught a nasty cold. Life just is neither that simple, nor black and white. I find it much more fruitful to recognize that some of the ideas about mind-body connections (such as found in yoga) have been passed down as ancient wisdom and that, at last, there are ways to discover physiologic correlates. Integrating mind-body considerations with the process of healing and using them in the support of general health seems more pertinent than ever. It can no longer be ignored that a multifaceted mind-body interchange is part of the human condition. All these lines of scientific investigation, however, do face considerable challenges. Many underlying mechanisms remain unclear and even though it is now known that a broad range of critically important mind-body interactions exists, it is still not known exactly how these influences occur and which approaches are most useful in different clinical situations. It will be essential to figure that out in order to integrate mind-body practices into healthcare and self-care in the most effective (including cost-effective) way

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and to empower people to more actively engage with the optimization of their own health. Perhaps it is general relaxation, no matter how it is achieved, that will turn out to restore beneficial neuronal, hormonal, and immune responses. Rigorously designed and conducted studies that involve interdisciplinary teams will be required to make the next leaps. Such teams that, at first glance, appear to be polar opposites currently rarely cross paths, so new dialogues will need to be forged to achieve collaboration. Only then can biomedical data be meaningfully correlated with psychologic and social findings. The final big challenge in this is funding, given that mind-body interventions may well result in a reduction of medication use, which makes support from pharmaceutical sources unlikely. Overall, the closely intertwined existence of body and mind (if we want to maintain that separation given how integrated they seem to be) provides a message of tremendous hope. In this era of precision medicine, in which we have unprecedented tools to analyze the human genome, provide targeted therapies, monitor disease and health at the molecular level, and can begin to optimize medical treatments while avoiding the use of medications that will not help, it is indispensable to integrate psychological, social, and behavioral dimensions into the care of each individual. If we fail to do so, we may risk missing the immensely worthwhile goal of personalized medicine as a way to improved health and healing, and instead end up with a depersonalized, pale semblance of what could be possible.12,22 Key points: G The two most commonly used categories of health are physical health and mental health. Mental health encompasses psychological, emotional, and social wellbeing. G The dichotomy between physical and mental health is rooted in history and culture but raises questions as science reveals that physical and objectively measurable aspects of the human body on the one hand, and subjective states of mind on the other, mutually influence each other. G The interdisciplinary field of psychosomatic medicine targets the interaction and integration of biological, psychological, and social factors in health and disease.

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G Mind-body approaches can be medically useful, cost-effective methods with minimal side effects that supplement conventional biomedical healthcare to benefit body functions, and improve health outcomes.

CHAPTER FIFTEEN OF PILLS AND POTIONS

How placebos, nocebos, pharmaceuticals and dietary supplements relate to health and disease

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What are the placebo and nocebo effects, can they be useful, and how do they work?

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What does it take for a prescription drug to come to market?

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What are the uses, costs, risks and benefits of prescription drugs?

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How are medications different from dietary supplements?

Do you know that feeling of tension and discomfort that starts in your neck and gradually becomes a headache? When you have one of those headaches, especially if you have them from time to time, you know quite well that “this too shall pass”, as common sense tells us, but in the meantime it can intensify and morph into a pounding, most bothersome headache that interferes with your plans. You could wait it out, take it easy, and perhaps lie down, but sometimes that is not a realistic option. When it happens to me, even though generally I refrain from taking medication unless truly warranted, I may decide to take something just to be able to get on with my day.

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One time when I had such a headache, I decided to take pain medicine for it and went back to my activities. An hour later my husband asked, “how is your headache?”, and I replied, “thank you, much better!”. He then pointed at the glass of water standing on the counter, the medication still at the ready right next to it. Apparently, I had not taken anything! I felt silly, but my headache really had vanished. Was this just the natural course of the headache that day, or was it the power of suggestion? Was I susceptible to the placebo effect? The placebo effect has been defined as “a beneficial health outcome resulting from a person’s anticipation that an intervention—pill, procedure, or injection, for example—will help them. A clinician’s style in interacting with patients also may bring about a positive response that is independent of any specific treatment.”1

So a placebo can be a variety of things that in and of themselves are not effective medical treatments. They do not cure. If the placebo is a pill, it may look like the real thing but in fact be made from an inactive substance such as starch or sugar. And although the look-alike treatment is not an actual medicine, taking it may relieve symptoms, at least temporarily. It seems that when we have the expectation that some intervention will help, mind and body align to perceive positive effects. Thus, one could say that the placebo effect is an anticipation effect. That this can work the other way around, as well, has been recognized much more recently than the positive placebo effect. If the expectation is one of a negative experience, and there is an anticipation of not feeling well, patients may report a worsening of symptoms or side effects such as nausea, anxiety, or headaches. This can happen when they are taking an actual medication but also if all they are taking is an inert pill, for example if they have been warned about unpleasant side effects by what their doctor said, or even just by their doctor’s body language. This type of expectation effect has become known as the nocebo effect.2 The nocebo effect has not been investigated as thoroughly as the placebo effect, because it does not have a benefit for patients. Clinical trials designed to investigate the nocebo effect would not live up to the medical ethics standard of “first, do no harm” and therefore would not pass muster. Nevertheless, learning more about the nocebo effect is important in order to better understand how treatment sometimes increases the burden of an illness. Treatment may heighten patient worry, potentially leading to noncompliance and to new complaints that may not only have negative effects on the patient, but also increase healthcare costs.2 This much is clear:

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for both the placebo and the nocebo effect, verbal and nonverbal communication between patients and physicians has considerable influence. Placebo treatment is most commonly used in clinical trials, which are critically important studies that are set up to demonstrate whether a new pharmaceutical drug or other treatment has beneficial therapeutic effects. They also assess potential side effects, benefits versus risks, and whether the treatment is widely useful or only in a specific subset of patients. If a patient is eligible for participation based on pre-established criteria, the doctor and patient discuss the trial. Once the trial has been explained and the patient’s questions have been answered, the patient can choose to participate by giving consent, or decide against participation and receive other treatment. In clinical trials, patients with a medical condition that is expected to improve when a new drug is taken are typically assigned either to a treatment group, or to a control group which will receive a placebo. If another therapy is already on the market for the same condition, a comparison to that existing treatment is usually also made. Comparisons of the new drug to a placebo or an older drug serve as controls for the trial. Controls are important in any research study, and clinical trials are no exception. The evidence derived from studies that incorporate appropriate controls is much more clinically relevant and robust. This approach also minimizes the potential for bias by both patients and their doctors. In a randomized controlled clinical trial, neither doctors nor participants know whether an individual patient is taking the new drug or a placebo.3 That is why these studies are called double-blind. They have become the gold standard for the clinical evaluation of treatment efficacy. In the United States, a drug cannot receive approval from the Food and Drug Administration (FDA), and would therefore not come to market, without the use of controls. The control design is explained to patients in advance so that it is clear that they may not at all directly benefit from participating, especially if they are assigned to the placebo side of the study. It is not a given, however, that the other group will benefit either: even if a patient is assigned to the treatment side of the study, it is possible that the tested drug has unanticipated negative effects, or that it simply does not work. Because this is drug testing in a research phase, all such information must be disclosed to patients so that they can either give informed consent to their participation in the clinical trial, or decide not to participate as a volunteer study subject.

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Whereas randomized controlled clinical trials are the cornerstone of the drug pipeline today, they had a colorful beginning that dates back to the year 1784. It was a year when complaints about the methods of a German physician, Franz Anton Mesmer (1734-1815)4 reached the French court of Louis XVI (1754-1793) and a royal commission was convened to determine whether the methods of the charismatic Dr. Mesmer were, in fact, the reason for his patients’ improvements.5 Mesmer had left Vienna earlier under a cloud of controversy and was not even granted a license to practice medicine when he settled in Paris, but he set up shop with a licensed associate and “mesmerized” his French clientele for the next five years by practicing what he called animal magnetism. He viewed it as a force that supposedly only he and his trainees could manipulate and that put patients in a state of trance during long sessions with elaborate procedures. Mesmer’s treatment sessions often resulted in a dramatic climax that included fainting spells or convulsions, after which the patients reported feeling better. The royal investigative commission was chaired by Benjamin Franklin (1706-1790)6, then ambassador to the French court for the new republic of the United States, which he had helped create. Before then, though, he had made far-reaching contributions to the understanding of electricity and it was his standing as a scientist rather than his statesmanship that was of key importance to the commission. Other prominent commission members included French chemist Antoine Lavoisier (1743-1794)7 who had revolutionized his field and was known for his meticulous experiments, and French physician and politician Joseph-Ignace Guillotin (1738-1814).8 The latter became best known for proposing the guillotine as a (perhaps) more compassionate alternative to the methods of execution in those days. Ironically, only about a decade after the Franklin commission was convened, both the king and Lavoisier were executed with this very device. But I digress... The Franklin commission set out to test Mesmer’s methods by a diverse and carefully designed set of experiments. Importantly, they focused on evaluating the efficacy of Mesmer’s method, not on whether the effects experienced by the patients were real or not. After all, they reasoned, the beneficial effects on individual patients could well be real, even if factors other than animal magnetism caused them. Part of their trial was literally blinded, as they used a blindfold on patients to assess whether they responded to the purported force of magnetism through the actions by their doctor, or to what they believed that doctor to be doing at the time but could not see. Consistently, they responded to the latter. When patients were

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blindfolded, what the doctor was doing made no difference in the patient’s experience. There simply was no correlation. But the commission did more. They also used placebo controls, namely objects that had not been subjected to the asserted energies of animal magnetism. Patient responses to such objects, of which they believed they were magnetized but had not been manipulated, and their responses to objects that indeed had been treated were pretty much the same.9 Ultimately, the commission conclusively demonstrated that animal magnetism had no basis and that the curative effects were produced by the minds of the patients. They also, however, realized that in the many patients who found relief with Mesmer, the expectation of healing may have given an unintended boost to nature, which, in time, heals many ailments anyway, even without medical treatment.3 Placebos are important components of randomized controlled clinical trials, and they can have psychotherapeutic value, as well.9 Yet, moraleboosting beneficial effects notwithstanding, there is something inherently and profoundly problematic with the idea of misleading patients to think that they are taking an actual medicine if all they receive is an inactive substance or procedure. If physicians were to be deceiving their patients by prescribing sugar pills, it would not only be an egregious abuse of trust, but they would act like charlatans. Still, if the placebo can be effective and less harmful than other drugs in the treatment of, for example, pain or nausea, then how can we make use of them in an ethical way? One of the leading researchers in this area is Harvard professor Dr. Ted Kaptchuk, who directs the Program in Placebo Studies and the Therapeutic Encounter at the Harvard Medical School. He studies the placebo as a “key to understanding the healing that arises from medical ritual, the context of treatment, the patient-provider relationship and the power of imagination, hope, expectation and empathic witnessing. Although our biomedical healthcare system often considers these humanistic dimensions of care as secondary to the administration of pharmaceuticals and procedures, the emerging field of placebo studies is producing scientific evidence that these more intangible elements of medicine may fundamentally contribute to the improvement of patient outcomes.”10

In one of his publications, Kaptchuk and colleague Dr. Franklin Miller address whether placebo effects can be harnessed ethically by prescribing them openly when patients are informed that they are receiving pills that contain no medication. They report on results from four small clinical trials that involved people with irritable bowel syndrome, chronic low back pain,

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cancer-related fatigue, and episodic migraines. Interestingly, even under these fully transparent prescribing conditions, the placebo did evoke meaningful therapeutic benefits, and many patients were prepared to try placebo treatments when they were honestly prescribed.11 More research needs to be done in order to assess how long the effects of candidly prescribed placebos last, which patients respond and to what degree, and how to optimally present this unorthodox possibility to patients. The authors note that placebos can be useful for health concerns with selfreported outcomes, as has been demonstrated for fatigue, pain, and nausea. Importantly, however, they caution that placebos do not actually alter underlying medical conditions. For example, placebos do not shrink cancer tumors, fight a malaria infection, or reduce high cholesterol levels.11 The placebo effect is a fascinating phenomenon overall, but the central question of how it works remains. Neurobiological pathways and the closely intertwined connections between body and mind are likely (part of) the answer. Thus far, several neural and neurochemical pathways, as well as gene changes, have been found to influence the strength of the placebo effect. In this field of study much remains to be discovered and many different research directions are being pursued, but the use of high-throughput technical advances such as genome sequencing is especially likely to facilitate the identification of molecular contributors to the placebo effect. Genome sequencing enables a big-scale look at this on the systems level, so that many genetic factors that play a role, each perhaps with a small individual effect, eventually can be characterized and documented in what may become known as the “placebome”.9 Multiple links in various signaling pathways, such as those involved with pain and reward systems, influence what happens within the brain and in the rest of the body when placebo treatment is used. And some of people’s responses to placebos can be visualized by brain imaging. At this stage, the specific contribution of particular neurobiological, genetic, and behavioral factors is not yet well-known, but it is clear that the placebo effect and the nocebo effect are complex reactions that are determined by a constellation of gene changes, genetic messages, protein effects such as enzyme levels, and additional diverse biological and psychological factors. One intriguing aspect of scientific studies of placebo effects on the one hand and of drug responses on the other is that it seems increasingly probable that the two work along the same biochemical pathways, and not through separate processes as was previously thought.3,9

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Before a pharmaceutical drug can be used to clinically treat patients, it is extensively evaluated and approved by regulatory agencies. During this evaluation, it is important to be aware of possible influences that may make the drug seem more or less effective than it actually is. One of these influences is the anticipation effect. This effect, which is observed with the use of placebo treatments, also plays a role when patients take actual medication. However, it is not the only confounding factor for the evaluation of drug treatment efficacy. Several things can cloud or confuse observations. Sometimes a health issue improves by itself, without intervention. Or symptoms fluctuate over time as part of the natural course of a disease, with periods of remission and exacerbation. It is also quite common that people use a variety of different approaches to deal with a health condition, often not disclosed to the physician or in the study, each of which at least potentially contributes to improvement or deterioration. This is why it is vital to assess as objectively as possible whether a medication is safe and has a pharmaceutical effect on the condition for which it is intended. The first step is experimental laboratory testing, followed by animal research, and finally, safety and effects are determined in stringentlyconducted clinical trials that include control groups that are as similar to the treated groups as possible. It is a long process by which the majority of new pharmaceuticals are rejected along the way. In the end, it may take more than a decade before a successful drug finally comes to market. And the cost of the drug pipeline is staggeringly high. In 2010 it was conservatively estimated that, taken together, the large pharmaceutical companies alone spent 50 billion U.S. dollars on research and development, and that for these companies the rapidly rising average price tag of bringing a new drug to market was approximately 1.8 billion U.S. dollars12, although it is not clear how much of that cost is dedicated to market analysis, publicizing efforts and general advertising. The total worldwide spending by the pharmaceutical industry on all phases of research and development was reported to be 186 billion U.S. dollars in 2019.13 But sales and profits more than make up for these costs: in 2020, the ever-increasing pharmaceutical industry market was valued at about 1.27 trillion U.S. dollars globally, with the United States as the leading market in this sector and China as the largest emerging market in pharmaceuticals. China, therefore, has been called a “pharmerging” market.14,15

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What does that mean for individual people? The CDC tracks this information for the United States. Between 2011 and 2016 almost every second person used at least one prescription drug over the course of a month, and based on data obtained between 2011 and 2014 almost one in four (23.1%) used three or more prescription drugs.16,17 Drug therapy was also used broadly: prescription medication was part of the treatment plan in around three quarters (73.9%) of physician office visits. The most commonly prescribed kinds of drugs overall were pain medication, lipid-lowering (anti-cholesterol) drugs, and medicines for skin conditions.16 Keep in mind, however, that this is a generalization because the most frequently prescribed types of medication differ by age group. Not surprisingly, the use of prescription drugs increased with age, ranging from 18% under the age of 12 to 85% for people of 60 years and older. But it also depends on race. All ages taken together, prescription drugs were significantly more frequently used by non-Hispanic whites than by Hispanic, Asian, or black people.17 In another set of countries that (as a collective) have a standard of living comparable to the United States, we can look at data from the European Union. It conducted a health interview survey between 2013 and 2015 in its (then) 28 member nations. The survey included self-reported medicine use by people aged 15 and over, over the two weeks prior to the survey.18 Just as in the U.S., prescription medication use was somewhat higher in women than in men and increased with age. But differences between countries were considerable, ranging from more than 50% of people in Belgium, the Czech Republic, Finland, France, Germany, Luxemburg, Portugal, Spain, and the United Kingdom, to less than 40% in Bulgaria, Cyprus, Italy, and Romania. Education level also played a role, with an inverse relationship between education level and prescription drug use: a lower level of education was associated with higher use of prescription drugs. Interestingly, the opposite was found regarding the use of over-thecounter medication, vitamins, and other supplements. Whereas the extensive and widespread use of prescription drugs in itself gives ample reason for concern, we should remember that the isolation of chemical compounds and the creation of synthetic compounds for the development of pharmaceutical treatments have had a major positive influence on human lives. In the big picture, prescription drugs have been game-changing agents, increasing both lifespan and quality of life. They enabled increasingly sophisticated treatment of medical conditions including infections, heart

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disease, diabetes, and cancer, all of which were drastically life-limiting only a century ago. Of course, these remain serious conditions that can be lethal, but many can be managed with medication for a long time as chronic, treatable diseases. The irony is that with longer lifespans, the ageing process itself will make the manifestation of additional diseases ever more likely, and this contributes to an increase in the number of drugs that are prescribed. So an ageing population definitely is a boon for big pharma. Having a large number of pharmaceutical options at the ready, however, comes with all too often underestimated risks. When multiple medications are taken, there is more to consider than the side effects of each individual drug (which is one of the important tasks of the pharmacist). There also is a risk of adverse drug interactions, which can be so debilitating that a thoughtful and cautious elimination of drugs from someone’s prescription list may bring considerable relief and health improvements. Especially in elderly patients, the list of prescribed drugs tends to become strikingly long. A few of the drugs on the list may manage the original medical conditions, but then, in retrospect, it becomes obvious that the majority of medicines were added to counter side effects such as nausea, constipation, dry eyes, or itchiness. Those additional medications each have their own possible side effects and contribute to potentially dangerous drugdrug interactions. That risk not only exists with prescription medications, but also with over-the-counter medication and supplements, the use of which is not always disclosed. Another risk of having a wide range of pharmaceutical options is that drugs may be prescribed too quickly. Overuse of antibiotics, for example, has resulted in the rise of resistant bacterial strains so that standard antibacterial treatments are becoming ineffective. This now is a major public health concern worldwide19,20. And the over-prescription of pain medication has resulted in habituation, addiction, and an unprecedented number of overdoses and opioid-related deaths in what has become known as the “opioid crisis” in the United States.21 Overuse of prescriptions also occurs when other, non-pharmaceutical options would be appropriate to use. This overuse is motivated by both doctors and their patients. After all, a prescription is a fast, effective, and easy option for both parties, especially when it is compared to more timeconsuming treatment methods. These may involve dialogue and education, extra support such as is desirable when the dose of a habituating drug is gradually reduced, and paving of the path to lasting lifestyle changes, which can result in disease reversal, rather than chronic disease management.

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Doctors are compelled to prescribe because they are often pressed for time and know that medication is likely to be effective in the short term. A prescription addresses the problem at hand, and it does so efficiently. Correspondingly, many patients have come to expect a pharmaceutical fix, with a prescription from the doctor as a validation for their medical concern or as evidence that something “real” will be done to cure their symptoms. But improving symptoms is not the same as curing disease. Many drugs prescribed today are used exactly because it is easier to pop a pill than to make decisive lifestyle changes toward better health. Unfortunately, in contrast to positive changes in lifestyle, drugs often have unintended side effects. Even more importantly, drugs mask the normal response of the body to a toxic state that was precipitated by poor health behaviors. Prescription medications may be seen as a solution to counteract the health consequences of, for example, obesity and of the inactive lifestyle that often contributes to becoming obese. Medications for high blood pressure, high blood sugar (prediabetes or diabetes), high lipid levels, and gastric acid reflux are all frequently used in overweight people. The health issues that these medications seek to remedy, however, can be viewed as (often reversible) complications rather than as primary diseases. Although moving the needle of the lifestyle compass toward health and wellbeing certainly is not effortless, it is a well-worth process that ultimately beats the alternative. It improves health and wellbeing at the core, instead of creating a constant need to correct the issues that arise with poor general health. As an added benefit, health-supporting lifestyle adjustments can dramatically reduce the need for prescription medications, through disease prevention as well as disease reversal. A healthy diet can also avert nutrition gaps that are targeted by a multitude of supplements on the market. Speaking of supplements...Walking into a grocery store or a health food store these days, the large amount of space that is dedicated to vitamins and other dietary supplements is striking. It seems peculiar, to say the least, that a large part of a store should carry fresh fruits, vegetables, and other carefully resourced and mostly healthful foods, while a comparable space is dedicated to pills and potions that supplement that nutrition, with lots of promised health benefits. The subliminal signal appears to be that, if you shop for food at that kind of a store, you need to buy vitamins and supplements in order to avoid deficits in your diet! Of course, this is a misperception.

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Interpreting the combined presence in a store of healthy foods and dietary supplements as needing to complement each other would be incorrect: the placement of these products in health food stores has more to do with a health-conscious target customer group, which for health food stores is slanted toward relative affluence and an interest in health products, than with the direct need for supplementation of an already relatively healthy diet. In any case, one can appreciate the irony. By all indications, the market of dietary supplements is thriving, with strong demand from consumers. Cleverly promoted products promise to deliver where food sources are implied to fail. But do they actually deliver the claimed and implied benefits? In the United States, prescription medication is strictly regulated. It cannot be marketed and offered unless it has received the stamp of approval from the FDA, which occurs only after safety and efficacy have been established. That process is thorough but not perfect, and sometimes previously unrecognized or undisclosed negative effects only come to light after a drug has been on the market for a while. Exactly that was the case with Vioxx, for example, a drug that was introduced to treat the pain associated with osteoarthritis but turned out to introduce an unacceptable associated cardiovascular risk. It was taken off the market in 2004, five years after it was launched.22 Opportunities for improvement of the pharmaceutical regulatory system notwithstanding, dietary supplements such as vitamins, enzymes, herbs, amino acids, and minerals are not regulated via this system at all. Instead of being treated as medications, they fall under the umbrella of food products and “the FDA is not authorized to review dietary supplement products for safety and effectiveness before they are marketed.”23

These products “are not permitted to be marketed for the purpose of treating, diagnosing, preventing, or curing diseases”23,

so a dietary supplement is not allowed to make specific claims about lowering high cholesterol, for example.23 Still, manufacturers have clever marketing strategies that make these products look appealing. When a product is labeled to be “natural”, for example, people tend to assume that they are safe, and who would not want to use something that “supports health” or “supports the immune system”? The fact that such

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statements are followed by a disclaimer of the FDA that spells out that these statements have not been evaluated by the agency is easily overlooked in the fine print.24 Unfortunately, the side effects of these complex products have not been established, and it has not been demonstrated independently whether these products even remain chemically intact until they reach the place in the body where they are supposed to be of benefit. Whereas production facilities are periodically inspected by the FDA on good manufacturing practices and labeling, the manufacturers and distributors of dietary supplements themselves are responsible for ensuring the safety of these products before they are sold, and their effectiveness is neither regulated nor verified. Thus, whereas some supplements may be useful, your personal wellbeing calls for an awareness of potential risks and limitations. A qualified and knowledgeable healthcare provider can help determine which, if any, supplements may in fact contribute to better health.24 Overall, health and wellbeing are much more supported by a healthy diet than by a combination of individual supplements, because whole foods (such as fruits, vegetables, and whole grains) come in natural “bundles” of nutrients, vitamins, and minerals. Supplementing individual nutrients can not fully mimic, compare to, or compete with the wholesome combination already present in real food.25 Finally, a brief note on the cost of healthcare services, if only because the cost of medical care affects the extent to which it is practically available when needed. Access to care directly impacts the degree to which we can maintain our health and wellbeing. And whereas healthcare has a price tag everywhere, in comparison with various other high-income countries there is one outlier: The United States towers far above others in healthcare spending, both when measured as a percent of gross domestic product (GDP) and when considered per capita. This gap with other nations shows an increasing trend despite the fact that the overall use of prescription medication is not markedly different.27 In her incisive book “An American sickness” Dr. Elisabeth Rosenthal points out that “The rules governing the delivery of healthcare in the United States have grown out of the market’s design. The type of healthcare we get these days is exactly what the market’s financial incentives demand. So we have to get wise to them, and be smarter, far more active participants in this ugly, roughand-tumble world.”28

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If we just focus on prescription drug spending, which is a substantial component of healthcare costs, prices paid by purchasers and consumers in the United States are considerably higher than in other countries and people have higher out-of-pocket costs with less financial protection through insurance. Contributing to these differences is the fact that other countries employ more stringent price control strategies such as centralized price negotiations and price caps based on studies that assess cost-effectiveness and the relative added treatment value of new pharmaceuticals. Of course one should not overlook that the promise of profitability in the United States also appeals to investors, and motivates a larger industry effort toward research and development. But if the goal is that medications can be used, they first must be available to those who could benefit from them, and not only to a fortunate few who may be able to pay a large sum to obtain them. Key points: G The placebo and nocebo effects respectively are based on expectations of positive and negative effects of treatment. G The expectation of healing may give a boost to nature, which, in time, heals many ailments, even without medical treatment. G Placebos can be useful for health issues with self-reported outcomes, such as fatigue, pain, and nausea. Importantly, however, placebos do not actually heal underlying medical conditions. G The placebo and nocebo effects are complex responses determined by gene variants, genetic messages, protein effects, and diverse biological and psychological factors. G Pharmaceutical innovation has had a major positive influence on human lives, increasing both lifespan and quality of life. However, (over)use of prescription drugs is associated with considerable risks and costs. G Dietary supplements are not regulated in the same way as prescription medications. Their side effects, drug interactions, chemical robustness, safety, and effectiveness are often not determined or disclosed.

CHAPTER SIXTEEN STRESSFULLY YOURS

How stress affects health, disease prognoses, health outcomes, and willpower

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What is stress, what types of stress occur, and what are its effects on body and mind?

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What influences the effects of stress?

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What are the main causes of stress?

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And how are stress and willpower connected?

Stress!!! We all know days similar to the one that I imagine Paul is experiencing. But for him, this is one stressful day in a long series: Paul had not been able to fall asleep until hours after midnight and consequently overslept. He jumped up. He had to get to work! He quickly brushed his teeth, took a two-minute shower, and left his house in a hurry, only to abruptly stop the car before turning out of the driveway. In his haste, he had forgotten to take his laptop. Once he made it inside, he grabbed his extraneous brain (without which he could not function). He rushed off, only to find himself in a traffic jam just minutes away from the office because some ill-guided powers-that-be prioritized routine roadwork over common sense during rush hour traffic. Surely this could not be happening. Was he even going to make it to his critically important meeting? When he finally reached the office, the

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elevator was out of order. Of course. Not amused, he ran up the seven flights of stairs and when he finally reached his floor he felt hot. So much for being calm and centered! The administrative assistant did not crack a smile. Instead, she raised a meticulously shaped eyebrow and curtly notified him that the boss wanted to see him. His heart sank. Was he going to lose his job? The company was in the midst of major restructuring, which had taken on a “slash-and-burn” vibe. And with Michelle being pregnant, the weight of the world seemed to rest on his shoulders... There it was again: that tight feeling in his chest. He felt nauseous but then realized that he had not had time for breakfast or coffee. Too bad. First, he needed to focus on his negotiations. It was essential, now more than ever, that he would clinch the deal. These Japanese clients were just so hard to read. Would they accept his proposal? After the meeting concluded he walked over to his boss when his phone rang. His father said: “Son, we are in the emergency room. Your mother fainted this morning and hit her head. They are doing some tests”. He sounded worried. Paul said: “Oh no, dad! Is she going to be okay?” His father replied: “We don’t know yet. Can you come over?” He promised that he would come as soon as possible and called Michelle, who would be able to drive to the hospital before he could. “By the way,” she said, “I just left the doctor’s office. Everything is going well with the pregnancy but the echo showed an unexpected finding”. She paused. “Guess what,” she said, “we are going to have twins!” Clearly, Paul was having a stressful day with lots of unplanned twists and turns. But let us part with him there, leaving him to manage his rollercoaster kind of a day without us following along, at least for the moment. Instead, we shall direct our focus onto stress itself. Stress, after all, affects us all and is a fact of life. Stress can be mitigated but not avoided and it influences everyone in minor and major ways, depending on its underlying causes and severity, as well as on our coping capabilities.1 It also comes in many guises: there is the minor stress of daily life related to common activities (like being late for an appointment, being in heavy traffic, or being excited about a date), the acute stress caused by sudden changes (such as intense worry about an injured family member), and the traumatic stress that occurs in case of real danger of serious harm, for example in the course of a natural disaster. The examples above illustrate that stress can be associated with positive or negative feelings. Positive stress (eustress) is associated with wanted events, such as the desired move to a new location or the excited anticipation of the wedding of a daughter. Both are positive life events, but they may be

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preceded by a very busy time of planning and organizing, not to mention expenses. A move to a new area can be appealing, but the cost of that opportunity is a disruption of familiar routines and social ties. And before a wedding, there may be somewhat unrealistic hope for an absolutely perfect day shared with family and friends. So even though a change or an event can be desired, it still causes stress that may manifest, for instance, as a nervous preoccupation or sleepless nights. The counterpart to eustress is negative stress (distress). This type of stress may include sudden health challenges, the loss of a loved one, being laid off, and having financial troubles or family problems. Some of its causes are common to everyone over the course of a lifetime, whereas others may be caused by exceptional but drastic situations such as a major car accident or experiencing violence of any kind. Chronic stress is the most insidious type of distress. It occurs when the underlying reason is present for an extended period of time, such as with constantly-high pressure at work or with the loneliness of social isolation. Stress is a biological response during which stress-induced hormones (including adrenaline, cortisol, and norepinephrine) are released to give the body a boost so that it can deal with an unusual situation. Normally, this is a temporary physical and psychological reaction that subsides once the stressor is no longer there. With chronic stress, however, the body does not go back to baseline and this ongoing strain can be harmful, both physically and mentally. Through mind-body connections, stress can increase heart rate, raise blood pressure, and induce metabolism changes. The reaction to stress is not exactly the same from person to person, but the various reactions have in common that they carry the risk of affecting the functioning of one or multiple body systems. For example, chronic stress may disrupt the immune, digestive, reproductive, and sleep systems. What this means in terms of symptoms is that someone under chronic stress may be more susceptible to whatever infection is going around, may experience diarrhea, constipation or an upset stomach, may notice a change in sex drive, may feel tired all the time, and may be more accident-prone. In the long term, serious health problems may develop. Stress contributes to high blood pressure, heart disease, asthma, obesity, and diabetes. It can reduce the capacity to fight infections and increase the risk of developing cancer. In other words, chronic stress is bad news. There is an increased risk of up to 60% for heart disease and stroke in people who experience substantial work-related stress or stress in their private lives.2 And although smoking, high blood pressure, high cholesterol, being

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overweight, and having experienced multiple severely stressful experiences during childhood are each risk factors with even greater individual effects on health than stress itself, stress can contribute to the development of these risk factors for cardiovascular disease and make them worse. If someone already has advanced narrowing of the blood vessels, for example, stress can trigger a first heart attack. Overall, stress is an important factor in disease development. It also influences prognosis and outcome once disease is present.3,4 In an interesting turn of events, amid mounting evidence of the harmful effects of stress, some researchers began to question whether stress inescapably interferes with good health. They discovered something that challenges the notion that stress is necessarily bad.5,6,7 In her TED talk, health psychologist and Stanford University lecturer Dr. Kelly McGonigal explained what was so exciting about these studies.8 The first study that made her rethink her approach to stress involved 29,000 people. About one third (35.3%) of the participants reported experiencing a moderate amount of stress and approximately one fifth (20.2%) reported a lot of stress in the preceding year. The investigators also asked the participants whether they thought that stress was bad for their health and recorded the answers. Eight years later, they reviewed death records and determined how many of their participants had died. The big surprise was that premature mortality was neither related to the amount of stress alone, nor just to the perception by the participants that stress is bad for your health. So just having a lot of stress did not, by itself, increase the risk of dying. Negative thoughts about stress did not move the needle either. However, people who reported a high amount of stress and also perceived that it was bad for their health were much more likely to have died in the intervening years: in this group, the risk of dying was increased by 43%!5 “You can see why this study freaked me out,”

McGonigal said, “here I have been spending so much energy telling people stress is bad for your health...So this study got me wondering: can changing how you think about stress make you healthier? And here the science says yes. When you change your mind about stress, you can change your body’s response to stress.”8

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If one is in a stressful situation but reappraises the body’s response as being functional and useful, for example by seeing it as a helpful reaction that provides the support of strength and readiness, then the heart and blood vessels reflect a physical state of motivation and courage, instead of one that is typical of fear. In that reappraised situation the stress response itself is not automatically dampened, but cardiovascular function remains much better. That means that, whereas the pumping of the heart may still occur at a high rate, the overall constriction of blood vessels in the body that typically develops during threatening situations is not pronounced and the circulation system overall remains relatively relaxed.6 With this research, it was highlighted that stress does not have to be bad by default, and that optimizing a response to stress is possible. This insight has fostered two main approaches to stress management. One is to achieve a better response to stress and the second, more traditional approach, is to reduce stress where possible. In order to know how to reduce stress, however, it makes sense to look at some of the main factors that cause stress to build in the first place. In his acclaimed book “Why zebras don’t get ulcers”, Dr. Robert Sapolsky, professor of biology and neurosciences at Stanford University, explains that for most beings on Earth “stress is about a short-term crisis, after which it’s either over with or you’re over with.”3

He gives the example of a zebra and a hungry lion chasing it. With chronic mental stress, however, the stimulus persists and can be made better or worse by several critical variables. Whereas stress will mount if there is no outlet for frustration, it can be mitigated by activities that distract from the stressor, such as engaging in a hobby, walking in nature, or taking a kickboxing class. Social support is another variable. Feeling alone with a stressful situation makes things worse, but social support is protective, even to the degree that people who are in a relationship or have close friendships have a longer life expectancy. Not knowing what might happen next is another variable that influences the building of stress, because uncertainty is unsettling. Predictability, however, helps reduce stress, because information about upcoming stress, or about the likely duration and intensity of ongoing stress, provides an opportunity to plan how one can cope. For example, someone with a fear of flying might be helped by knowing that the flight time in the air is exactly an hour so that the changes in airplane sounds and movements associated

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with taking off and landing can be anticipated and interpreted correctly when they occur. The person may also decide to read a magazine in that hour to minimize the tension he knows will arise. Having no control over what is happening is often perceived as being stressful. It follows, therefore, that a modicum of control is another source of relief. A situation in which one is somewhat empowered is likely to cause much less distress than a situation in which one feels entirely helpless. If medical treatment is necessary, for example, it can help to know the options and to make an informed decision about the way forward. Finally, the perception that a stressful situation is improving generally reduces stress, whereas the opposite, when things seem to become worse, can add fuel to the fire, bringing spirits down and increasing the risk of developing stressinduced health issues.3 Reducing stress where possible requires an understanding of the major sources of stress today, beyond the above-mentioned variables that can modulate the stress response. In a 2018 report by the American Psychological Society, the biggest stressors for adults in the United States were work and money (mentioned in 64% of cases each), closely followed by health-related concerns (63%). Perceived stress levels were also assessed and scored on a scale from 1 to 10. For adults overall, the average reported stress level was 4.9. However, older adults (defined as 73 years of age or above) had the lowest score at 3.3 while Millennials (22-39 years old) scored the highest at 5.7 out of 10.9 Among the myriad possible sources of stress over a lifetime, one, in particular, stands out in economically developed nations. It is (the sense of) busyness, which is especially paradoxical because being busy has become something to aspire to, more or less as a status symbol. The question “how are you?” commonly receives a response along the lines of “busy”, “crazy busy”, or, delivered with a semi-tortured smile, “pressed for time, I have no life!” instead of a simple “doing well, thank you”. In reality, these answers are what have become known as humblebrags: they sound like regret, and the person legitimately may feel overwhelmed, but at the same time these answers convey social status and, let’s be honest, self-importance. The notion that working around the clock deserves a badge of honor is prominent in modern western society, especially in the United States. In the past, however, wealth and social standing were more commonly associated with people who had abundant leisure time. This remains the case in some

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countries, such as Italy, where some of the “modern values” have not been as widely adopted.10,11 It has been hypothesized that the change from leisure to busyness as a status symbol may be driven by economies in which knowledge has emerged as a major resource. Individuals who possess the skills that are most desired by employers in such settings will be the most sought after. Thus, by lamenting how busy they are, people signal that they are productive, of value, and in demand, which these days does more to increase social rank than the flaunting of luxury products. In other words: the Maserati may still provide some status, but will not comprehensively persuade because the most valued scarce resource today is not disposable income, but time.11 Unfortunately, the fact that staying busy by being overscheduled, available at all times, and tethered to the virtual reality of electronic devices is in part a choice is often lost to awareness. One would think that the time poverty that comes with values attached to perpetual busyness could be offset, at least in part, by the conveniences of modern life. After all, the days of tediously doing the laundry on a washboard, of chopping heaps of vegetables by hand and of mowing a meadow by using a scythe are long gone, at least in industrialized nations. But personally, I do not know a single person who actually perceives the increased amount of time that is freed up by such advances. Technological progress has gradually charmed us with new ways to spend our time. These now seem as indispensable, and, at times, just as demanding as doing the laundry in the olden days. Time is still easily filled, in line with Parkinson’s law, which asserts that tasks simply take up the time we make available for their completion.12 With rapid and almost continuous access to the internet, the line between personal and professional endeavors becomes more fluid and, therefore, harder to define. This dovetails with another factor that influences stress levels: the time available to take a real break. Whereas economic development may result in a larger amount of money per household, the time to spend it is not increased simultaneously. It is not uncommon that vacation time is not used up because of work pressures. In addition, vacation time between different countries differs considerably.13,14 Based on data from 2016, the countries of Chile, France, Germany, South Korea, Spain, and the United Kingdom, for example, all have a statutory minimum of 30 days or more of paid leave and public holidays. The United States pales in comparison with 10 public holidays and no minimum paid days of annual leave. I remember the first year my husband took employment

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in California and recall my surprise that he did not have any vacation days that year at all. In Europe, this would be illegal, but in the U.S. people tend to just “drink the Kool-Aid” and join the mentality of prioritizing work over wellness. It is remarkable that in the decades after, not much seems to have changed for workers in the United States. After one year of employment, the distribution is as follows: 8% of workers are entitled to less than five days of paid vacation, 30% receive five to nine days, 38% have 10 to 14 days, 16% have an allotment of 15 to19 days, and 2% are granted more than 24 days of vacation time.13 The price of not stopping is high, not only for people who push themselves to (or over) the limit but ultimately also for employers who generally welcome and perhaps expect that their workers make personal sacrifices to climb the ladder of success. Burnout, according to the 2019 revision of the International Classification of Diseases by the WHO, is, “a syndrome conceptualized as resulting from chronic workplace stress that has not been successfully managed.”15

Burnout has been given three dimensions: emotional exhaustion, a disengaged and cynical outlook about one’s job, and reduced work performance. The term as defined by the WHO specifically applies to the context of the workplace. It is described as an occupational phenomenon and not classified as a medical condition. Which in no way should be taken to mean that it cannot make someone ill. Burnout is a global phenomenon that is seen across all layers of the workforce. However, especially people earning at the low and the high ends of the spectrum are working the most hours. In Japan, work culture often dictates that employees dedicate an excessive number of hours to their jobs to prove loyalty to the company for which they work, even though productivity cannot possibly be enhanced when workers are exhausted. Japanese employees, on average, also use less than half their earned vacation time. The health risks that result from this have become painfully clear. Deaths from suicides, heart attacks, strokes, and other conditions brought on by overwork were recognized as a problem decades ago. The phenomenon even has its own designation (karoshi). Nevertheless, only in 2014 has it received legislative attention, with a call to action directed at the Japanese authorities, employers, and the workers themselves. Regulation is slowly

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but surely phased in, but changing the culture will be a gradual process that requires buy-in and sustained support at all levels.16,17 There is more to the development of burnout than only the influence of excessive work hours on mental and physical health: the feeling that one has little influence over one’s work-life contributes as well. This applies, for example, when people do not have input on decisions that affect their work, if they do not have the support to make a meaningful difference, or if they lack control over how they do their work.18 And this affects low-wage workers as well as corporate leaders. In the end, after all, everyone has a boss, even if that should be the board of the company! Compared to the overall population, individuals with professional degrees do have a lower risk of burnout, but the level of education is not necessarily protective. Burnout among physicians, for instance, is high and continues to increase. In the United States, burnout symptoms are more common among doctors than in any other professional group. The frustrations and practice pressures that precede physician burnout are largely precipitated by the healthcare system and the changes it has imposed on the practice of medicine. These changes include increased administrative requirements such as the use of electronic medical record systems, and shorter appointment times to see patients. So pressures have increased while the relative autonomy that physicians used to enjoy has dwindled over the years. Given that physicians consider patient care as the most important and most rewarding aspect of their profession, they typically prioritize the quality of their work over personal wellness for as long as possible. Even so, the trend of dissatisfaction is quite concerning. Burnout symptoms are reported to affect one third to two thirds of physicians, depending on the scope of published studies, physician specialty, and practice setting. As such, physician burnout is an underappreciated healthcare crisis with costs on the personal, professional, institutional, and societal levels. And there are repercussions on the delivery of care: in order to optimally work with their teams and to effectively help their patients by fostering the conditions that facilitate recovery from illness, physicians must be well themselves. If that is not the case, there will be a ripple effect throughout the whole system.19 For anyone affected by burnout, regardless of occupation, the personal cost can be enormous. Burnout depletes energy and leads to attrition, but it can also precipitate poor overall health, result in substance abuse, lead to relationship problems, and increase the risk of suicide.

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Burnout is the consequence of stress in the workplace, but long-term stress can occur in any dimension of life. Lasting mental stress taxes or surpasses adaptive resources and influences how safe people feel, their flexibility, and their outlook. It is the result of things that people would have rather avoided, something over which they may not have much control, and that potentially impacts physical and mental health. Chronic stress threatens people’s wellbeing and may trigger unwelcome emotions such as fear and anger. The psychological burden of chronic stress can also cause fatigue, irritability and a diminished ability to concentrate. If uncertainty and frustration drag on, depression or anxiety may develop and feelings of hopelessness may arise.1 After all, people are not usually in a position to just quit their jobs, move away from a bad neighborhood, carry on as before when a partner is ill, or return their children like mail-ordered goods! Somehow, we all have to cope with the vicissitudes of life when things do not go our way. With chronic stress and the slowly building physical and mental exhaustion it feeds, changes in behavior are common. Long-term stress and fatigue both influence the capacity to make sound choices. People may overeat or lose their appetite and, as a consequence, unintentionally gain or lose weight. They may not take the time to exercise, rest, and relax when in fact these activities would help in dealing with stress. They may also withdraw socially and spend less time with the people who matter to them most. Their world becomes constricted, and still, it will not help. Model, entrepreneur and actress Iman has been quoted to say: “Eliminating the things you love is not wellness. Wellness feeds your soul and makes you feel good.”20

Wise words, indeed. Wellness is a quality that is broad and reaches deeply. It is not just what feels good for a short time. It has a richness to it because it encompasses all dimensions of life and it is inclusive, not isolating. This is in stark contrast with the automatic defense mechanisms that, like a shadow, accompany chronic stress. They may seem to offer protection but upon closer examination, they turn out to be incompatible with actual wellness. People may try to mentally escape a stressful situation, at least temporarily, by smoking, overeating, drinking, or using drugs. But none of these actions, whichever way one looks at it, actually benefit health or, in the long run, soothe the difficult state of feeling overwhelmed, because they do not change the situation for the better in a constructive way. They only

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highlight the presence of another complication: stress does a number on willpower. In his tragedy “Othello”, English playwright William Shakespeare (15641616) gave life to the words: “Our bodies are gardens, to the which our wills are gardeners.”21

Despite the somewhat dated language, it is clear that the phrase implies that willpower is a key ingredient to taking care of ourselves. This is affirmed in the book “Willpower”, co-authored by social psychologist Dr. Roy Baumeister, who has published on this topic extensively, and journalist John Tierney.22 Self-regulation, as psychologists prefer to call willpower or self-control, consistently has been shown to provide the most promising avenue to a better life. Unfortunately, most people list a lack of willpower as one of their greatest weaknesses! This is probably rooted in the circumstance that it is hard to notice just how frequently willpower is used throughout the day. Willpower is required to go to the gym before work, to decide what job task to tackle first, to remain professional with that gossiping colleague, to choose what meal to select in the cafeteria, to handle the toddler who throws a tantrum, to weigh how much to spend on that good cause, and to not yell at the spouse who went to the grocery store with a shopping list but bought the wrong kind of mustard...again. Human beings seem to have a finite amount of willpower that becomes depleted as it is used throughout the day for both self-control and decision making. This helps explain why someone who is trying to lose a few pounds can easily resist the cupcakes offered at work in the morning but will have a harder time withstanding the temptation of that tub of ice cream in the freezer after a long and harrowing day. Moreover, the same source of energy is used for all kinds of self-regulation and decision-making tasks, regardless of whether they are enjoyable or not. Willpower may be taxed less for enjoyable things, but, as Baumeister and Tierney point out, even deciding where to go on vacation can deplete the supply. With the fundamental shift in psychology, just decades ago, toward a neuroscientific model that recognized that the mind is part of human body biology, it became possible to link physical events with mental states. For example, it was discovered that having low blood sugar (hypoglycemia) negatively influences willpower and reduces the capacity to make good decisions. When there is not enough fuel to expend, self-control suffers and it becomes more challenging to keep emotions in check.23 Being sleep-

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deprived, being mentally exhausted by chronic stress, and being low on blood glucose (which is the fuel that powers the brain), all lead to a state of resource depletion. The effects on people of such “ego depletion”, as the state of “diminished capacity to regulate their thoughts, feelings, and actions”22

is called, were very clearly measurable and reproducible in various tests of human behavior. However, what throws a real wrench into the mix is the fact that the depletion of willpower does not come with clear subjective signals and symptoms. The only thing that researchers reliably found (but is difficult to recognize unless one really focuses on noticing subtle changes) was the general presence of fatigue and negative emotions, with no single emotion that stood out. If anything, it seemed that emotional reactions were simply stronger. Both positive and negative feelings, as well as desires, became more intense. A sad story, for instance, would provoke more sorrow, and eating chocolate provoked stronger cravings to keep eating more of it than would be the case otherwise. Ego depletion, therefore, causes a double hit: not only is self-control reduced, cravings and emotions become more intensely felt. It is the perfect storm... How, then, can levels of stress be reduced in order to minimize the negative effects on willpower? According to Baumeister and Tierney: “You could sum up a large new body of research literature with a simple rule: The best way to reduce stress in your life is to stop screwing up. That means setting up your life so that you have a realistic chance to succeed.”22

That, of course, is rather easier said than done. It is a gradual process that provides both a challenge and an opportunity. But strengthening the “muscle” of willpower is one feasible step toward that goal and the strengthening can be done over time, with practice. It is an endeavor with practical and far-reaching consequences that provides solid benefits for life and health. The positive effects of improved self-regulation manifest in interpersonal interactions, in patterns of spending and saving money, in the commitment to physical exercise and healthy eating, in efficiency and effectiveness at work, in the reduction of procrastination, and in overcoming cravings and addiction. Dr. Kelly McGonigal has made the observation that negative stress and willpower are incompatible on their biological basis alone.24 That means

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that the biologic effects of chronic stress interfere in a direct and physiologic way with the capability to muster willpower. Conversely, however, stress reduction is one of the most powerful ways to improve willpower. Physical exercise and meditation each support both willpower and stress reduction. In fact, they can improve both at the same time, which is great news for anyone who likes to maximize outcomes with efficient, targeted effort! Even taking a few deep breaths and remembering to tap into a place of inner calm can help to reduce stress and boost willpower. Improving willpower is not easy (after all, it takes willpower to decide to make changes toward it), but knowing something about what challenges us helps make sense of why virtually everyone, on some level, struggles with stress and with a lack of willpower. If knowledge is power, this can be a first step forward toward a better state of mind. By the way, here’s the follow-up on our friend Paul. His mother fully recovered. Paul and Michelle have become proud parents of two healthy baby girls. And Paul successfully completed his transaction with the Japanese clients. He was not laid off during the reorganization of his company, but he realized that his continuously high work pressure was not sustainable and that the personal cost of chronic stress was too high for him. Because Michelle was in a well-paying job she loved, they decided that Paul would stay home with the twins until he figures out which career direction he will be excited to pursue. Or, at least, that is what I would like to have happened. Key points: G Stress affects everyone. Its effects depend on cause, severity, and duration, as well as on someone’s resilience. G Stress is an important factor in disease development and also influences prognosis and outcome once disease is present. However, by optimizing the response to stress, negative effects can be mitigated. G For many people, the most valued scarce resource today is not disposable income, but time. Paradoxically, busyness has become a status symbol and something to aspire to.

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G Lasting mental stress taxes or exceeds adaptive resources. It influences how safe people feel and affects their flexibility as well as their outlook. It can lead to changes in behavior and it diminishes willpower.

CHAPTER SEVENTEEN DIET OR BUST!

How global lifestyle changes have altered our relationship with food and resulted in a chronic disease epidemic

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What does it mean to have a healthy relationship with food?

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Why is the relationship with food so troublesome for many people?

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What factors contribute to overweight and obesity?

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What is the role of diets?

Do you have a healthy relationship with food? People who have a sound connection with what they eat and drink nourish their bodies in a way that benefits their being. The wisdom of the body informs their food decisions and they can be mindful of their choices without having to rely on an extensive list of external rules. Although they may have some “do’s and don’ts” that support their choices, austerity measures such as the categoric denial of favorite foods are not going to be on the menu. These individuals are able to tune into the signals from the body and they honor them as a natural part of taking good care of themselves. For example, if they are hungry between meals one day, they may have a snack instead of denying that nagging “hungry” signal. They do not feel the need to resist food merely based on clock time, and therefore they will not be confronted with the unpleasant consequence of either feeling faint until

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dinner time finally arrives, or, and probably more likely, going on a binge at four pm. Eating with joy and for sustenance means not having to be afraid of being hungry, as is the case for many dieters. If people who have a healthy relationship with food are hungry, they just eat something: end of story! Importantly, their snack most likely will be something that provides energy for some time, such as nuts, rather than a rich caloric treat with little nutritional value, such as a cookie (or four), triggering glucose level spikes without staving off hunger signals for long. A healthy relationship with food also means being able to stop when “sufficiently replete”, as one of my friends describes it. That means to not keep eating once comfortably full. It is a matter of listening to the body and acting on its cues, which gradually change during the course of a meal. With mindful and unhurried eating, these signals can be clear and helpful. Of course, it also does not hurt to start with a plate that has a regular portion of food on it, instead of one that could feed an army! Does this sound as if people who have a normal relationship with food are always models of restraint? Rest assured, they are not: they may well enjoy overly large helpings of cake on special occasions, but such escapades are balanced out easily without drastic efforts. Most importantly, such people are able to enjoy their meals without being very restrictive, without constantly thinking about how their food could tip the scales, without eating in secret, without regularly using food for emotional compensation, and without the feelings of guilt that are imposed by diet culture.1 Their relationship with food is uncomplicated. Food is neither the scapegoat nor the fix for the challenges they face. In much of today’s world, however, these people are becoming rather less common. Even though the term “emotional eating” is used to indicate a problematic relationship with food, one could argue that all eating is emotional on some level. According to registered dietician Abby Langer: “Normal eating has everything to do with our relationship to food and nothing to do with our actual diet. Everyone’s diet is different, but normal eating isn’t the food we choose, it’s how and why. Normal isn’t the same as healthy, or some version of ‘calories in, calories out.’ It doesn’t mean eating tons of vegetables, or complying with any official nutrition recommendations. It’s about our emotional relationship to food and eating.”2

Langer points out that, whereas babies and toddlers have an innately normal connection to food, many people lose that connection later in life

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because of outside influences. Their relationship with food may become overshadowed by anxiety, guilt, suspicion, and shame around eating and around the imposed ideas about what a body should look like. When that happens, the simple enjoyment of food, the satisfying feeling of nourishment, and the social aspects of having a meal may become colored in such a way that the natural connection is lost. One may almost forget that food is a wonderful, fundamental cornerstone of being alive. Food nourishes body and mind and it provides pleasure by making our taste buds “dance”. It can be comforting and can evoke happy memories. And it can take us to different places, such as back in time to the days of childhood or to a favorite vacation spot. Nothing spells winter to me like the scent of “poffertjes”, a heap of small traditional Dutch batter treats, made in a cast-iron pan and served hot, straight from the pan, dusted with sugar and served with some melting butter. It used to be such a welcome indulgence on days when it was freezing outside! The memories are probably far better than the treat would taste to me today, but still... Last but not least, food can unite. It can help us flourish by bringing people together to join in social interaction and the relishing of flavors, and it can stimulate the sharing of diverse cultures. At the most fundamental level, however, the purpose of food is to support the function and health of the human body. Before food can reach the places where it provides actual sustenance, it first has to be digested and absorbed in the intestines. As mentioned in chapter 14, the food we consume is as critical for the microbiome that lives in the gut as it is to us, because the microbiome exists in a reciprocal relationship with the body. Unique to each individual in both composition and diversity, the trillions of microbes that cohabitate in the dark tunnel of the human digestive tract snap up the passing food, sort of as if it were a sushi train in a Japanese restaurant. What we eat maintains these microbes and, in turn, enables them to carry out essential biological actions that benefit the body. Among the spectrum of functions performed by the microbiome is the production of enzymes, vitamins, and essential amino acids. But it also offers protection from diseases by a direct physical barrier and by immune system interactions, and it manages the orchestration of a plethora of refined metabolic processes that accomplish communications with the human brain. By enhancing the processing, absorption, and availability of ingested nutrients, the microbiome has a profound impact on host physiology, a function that has become increasingly appreciated and studied in recent years.

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Together with other elements of health, a well-functioning microbiome is one of the foundations of child development, adult health, and healthy ageing.3,4 One of the aspects of the symbiotic relationship between humans and gut microbes (and one that is becoming increasingly clear) is that the food that people eat influences how well their “home team” of microorganisms can carry out its functions: food facilitates function. In addition, mixed into what people eat and drink, some substances can further enhance body function and performance. An example of this is caffeine. Not only does it help the majority of adults wake up in the morning, but its stimulant effects are also recognized by athletes. Among the performance-enhancing effects of caffeine is the increased release of endorphins, which are molecules that reduce the perception of pain and bring about positive feelings. Caffeine also improves neuromuscular function, increases alertness, and reduces the perception of effort. As such, it is one of only a few (allowed) nutritional supplements that are acknowledged to have robust evidence of efficacy in sports.5,6 At some level, everybody knows that food provides the fuel for their engine and that the choice of foods is an important variable that influences health. But doing the right thing can pose a challenge and not simply because of the notion that (at least according to the writing by Mark Twain), “The only way to keep your health is to eat what you don’t want, drink what you don’t like, and do what you’d druther not.”7

Everyone likes food, but for many people the relationship with food is complicated. Food has become an adversary instead of an ally. Why is it that something so fundamental is often so troublesome? Let us delve into a few of the numerous factors that contribute to what, when, and how much we eat, first from a global perspective, and then with a lens on the western world. One major factor that has changed over time is the way in which food is produced. Because of innovations in agriculture, the overall capacity to produce food has increased considerably. That, together with the globalization of food production and distribution, has expanded the diversity of available foods and decreased the dependence on seasons. Just as an illustration: when I was a child (in the northern Europe of the seventies), berries would not be available in the winter, pineapple was a canned fruit at any time of the year, and virtually nobody had heard of exotic things such as quinoa, arugula, and hummus. Together with the changed availability of food, income levels worldwide have tended to rise while the overall price of food has dropped.8 Between 1969 and 2001, global calorie consumption increased by almost 400 kcal

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per person or, roughly, some 25%. This was the result of food becoming less expensive in both developed and developing nations, combined with a shift in eating patterns. Whereas a calorie increase was beneficial in areas of the world where calorie-driven malnutrition was prevalent, it is a reason for concern in areas where calorie consumption was not low to begin with. Changes in food consumption were partially driven by population moves from rural areas to cities. Whereas changes to which foods were consumed were wide-spread, they remained linked and somewhat specific to countries and their cultures. Nevertheless, the overall shift entailed a move away from staple foods such as grains and tubers and a turn toward dairy and meat, vegetable oils, and sugar. As such, traditional staples were substituted by products that had become more affordable than before and were also more readily available than in the past. Unfortunately, many of these products replaced fresh high-fiber foods with processed alternatives with long shelf lives. These new goods were produced using more salt and sugar and contained more fat. In other words: these replacements were high in calories but low in fiber and not necessarily nutrient-dense. The worldwide impact of these changes, taken together, is undeniable. There is a steep global increase in nutrition-related noncommunicable diseases, a loss of biodiversity, a large-scale negative impact on other aspects of the environment, and a widening gap in diet as well as health between socio-economic groups.8 In the western world, but also increasingly in less affluent countries, the shift in food consumption can be understood in light of present realities. Time pressures, for example as caused by long commutes and work hours combined with the strains of raising children in a setting where the extended family is no longer a natural part of child care, leave less time and energy for home-cooked meals. Family members each have a busy schedule of individual activities and families share fewer meals together because they are not necessarily in the same place at the same time. In a culture of haste, breakfast is the meal that is skipped most frequently. In the United States, for example, approximately 20-30% of adults omit the morning meal. Across the world, the skipping of breakfast is observed primarily in adults who are younger, use tobacco, drink alcohol, eat dinner later, exercise infrequently, and consume more calories per day.9 And, whereas on the surface it may seem that skipping breakfast would lead to a slim waistline, the opposite is the case. Skipping breakfast is associated with diets of lower nutritional quality and with a higher risk of obesity, diabetes, unfavorable blood lipid profiles

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(such as cholesterol values), high blood pressure, and heart disease. A 2017 scientific statement from the American Heart Association noted that “time constraints limit meal planning and preparation, leading to increased use of convenience food items (eg, fast food, vending machines) and haphazard eating supported by an environment with readily accessible food options. What results is a poor-quality diet with large portions that are often energy dense but nutrient poor.”9

Vendors and marketers of fast food, convenience foods, and highly processed products know what sells. Many consumers want quick satisfaction and they want more for less. It logically follows that eating on-the-go usually results in the consumption of meals that entice by low cost and instant gratification because they are salty, fatty, sweet, caloric, and large. The fact that they may lack protein, fiber, vitamins, and other nutrients can easily go unnoticed. As if that were not enough, portion sizes have gradually changed in such a way that they have become deceptive. One muffin, sandwich, or pizza may be sold as a single serving unit, but in fact it may be twice the size and caloric value compared to the same item a couple of decades ago. And when portions are larger, people unknowingly eat more.10 It is worthwhile to mention that portion size is but one variable among many that influences how much we eat. For instance, the visual appeal of restaurant foods and the size of plates and utensils also play a role. And for foods sold in stores, the packaging, labeling, advertising, and unit size are all likely to contribute their share to how much food ultimately is consumed.11 Urbanization has had yet another consequence: lifestyles have become much more sedentary. Private and public spaces are now designed to be “energy-efficient”, in that they minimize the need to move around and thus curtail people’s physical activity. In addition, there is an ever-increasing number of technological conveniences such as garage door openers, selfdriving vacuum cleaners (not to mention self-driving cars!), remote controls, and electric lawn mowers that reduce the need to expend muscle power or, indeed, to get up and move at all. Passive modes of transportation bring commuters almost door to door, with minimal requirements for physical effort. Moreover, many jobs have changed. There has been a shift away from physical activity toward work that requires prolonged sitting. This, as has become clear over time, is detrimental to health. The issue of inactivity extends beyond the work sphere into leisure time, due to the often lengthy periods of sitting for the purpose of “screen-time”, for example when

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watching television, playing computer games, or during other uses of electronic devices for reading, social media, or video calls.8,9,12 All these fairly recent lifestyle changes affect large swaths of the world population and go a long way in explaining why overweight and obesity have become such major public health concerns. They also illuminate why, for many people, the relationship with food has become much more convoluted. Food consumption is influenced by what is available, by what is accessible, and by personal preference. And the latter, motivated by consumer attitudes, is profoundly influenced by marketing and advertising.8 Effective messaging plus convenience appear as irresistible as the ultra-processed ingredients contained in a multitude of readily available foods. In the midst of all this muddle one cannot help but wonder: when did the humble banana fall off of the list of convenient foods? Knowledge is an important condition for disentanglement, but being aware of the issues is not necessarily enough to effect change. For Ramona, just like for many others, changing to a healthful diet is not easy. She is a remarkable, socially-engaged, intelligent, and educated woman in her fifties, who spends much of her waking hours taking care of premature babies and their parents. She is overweight and a few years ago she was diagnosed with type-2 diabetes. She now takes daily medication to stabilize her blood sugar. Ramona has been informed about the potential consequences of her diagnosis. She has received educational materials about how to improve her lifestyle, but she admits that, so far, nothing has “clicked” and prompted her to make lasting changes. She explains that she has a demanding job and a loving but at times dysfunctional family. She emphatically states that she loves eating (“a diet is just ‘die’ with a ‘t’ at the end”) and that she has little time and support to change her way of cooking. Ramona rolls her eyes when I ask her about exercise. She tells me that she feels fat and self-conscious in exercise clothing and that it never feels like fun. She shares that she has tried many diets, to the point that she is ready to give up. But then a new week or month comes around and she tries again. Or she learns about a new and promising diet formula on late-night television. She finds out that, incidentally, it is available on sale at her favorite discount conglomerate. Maybe, just maybe, this is “The One”. At least, she feels, it is worth a try... Do you think she will be successful? Before you judge Ramona, think about the people you know (including yourself): her story is by no means

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an exception. Obesity is as rampant as people’s struggle to lose weight. In the United States, the overall obesity rate is now over 40%.13 The body mass index (BMI) is a measure of body fat based on height and weight, that applies to adult women and men. Normal weight is reflected by a BMI of 18.5-24.9, overweight corresponds to a BMI of 25-29.9, and obesity is defined as having a BMI of 30 or above.14 Based on long-term data from 1975 to 2016, overweight and obesity have increased worldwide and in 2016 more than one third of the population was overweight in three major geographic regions: the eastern Mediterranean (49%), Europe (59%), and the Americas (63%). In that year, not counting small island nations, people above the normal BMI or truly obese were most prevalent in Kuwait at 72% and 38%, respectively, with the United States following close behind at 70% and 36%.15,16 And the trend continues in the years after 2016. Interestingly, worldwide, with the exception of some parts of Asia and Africa, more adults are now obese than underweight.17 Where did this begin? The global increase in obesity over the past half-century was first seen in prosperous states, although many middle-income countries soon followed. Today it affects low-income nations too. Within a given country, city-dwellers with relatively high incomes and socio-economic status typically have the highest initial rate of obesity because they can afford novelty-goods.18 Over time, with greater distribution, these products become more economical and turn into an affordable convenience for the majority of a population. Dr. Matthias Blüher at the University of Leipzig in Germany works on research and treatment of obesity and its consequences. He summarized that “obesity represents a major health challenge because it substantially increases the risk of diseases such as type-2 diabetes mellitus, fatty liver disease, hypertension, myocardial infarction, stroke, dementia, osteoarthritis, obstructive sleep apnea, and several cancers, thereby contributing to a decline in both quality of life and life expectancy. Obesity is also associated with unemployment, social disadvantages, and reduced socio-economic productivity.”17

It is ironic that a condition that started with increased economic prosperity now often and disproportionally affects people of lower socio-economic status. It has become one of the major negative consequences of inequity and disparity.

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Caused by an imbalance between energy intake and energy expenditure, obesity is a condition that develops when more calories are consumed than used. Although genetic factors play a role in individual predisposition to obesity, they simply do not explain the dramatic rise in obesity prevalence over the past five decades. Human DNA has not changed much in that short time frame, but our food habits and mobility have. And whereas obesity in principle is preventable, personal choice by itself certainly is not the whole story either. More accurately, the interactions between individuals and their environments, as caused by the changes in global food production and more sedentary lifestyles, all contribute to this troubling phenomenon of largescale increases in calorie consumption, and consequently in weight. Obesity is a condition that comes about after a prolonged period of energy imbalance and it is preceded by increasing overweight. The remedy, therefore, may seem as straight-forward as eating less and moving more, but it is not quite that simple. At its core, the notion of eating less and moving more to remedy obesity remains correct, but it is not an easy, unfluctuating, or short-term fix. Weight loss is definitely possible and it is critical to improving health and to reducing the risks of developing additional disease. However, multiple barriers need to be acknowledged and taken into account if effective and lasting weight reduction is to be achieved. Overweight and obesity cause changes to human body metabolism that hamper weight loss and stimulate additional weight gain. It is as if the body were fighting back with all its might to maintain the status quo and it does this in several sneaky ways.19 For one, calorie restriction alarms the internal workings of the body and sends it into survival mode, which manifests in a slower rate of metabolism to conserve energy, combined with an outpouring of hormones that signal “hunger!”. These hormones have one purpose: to stimulate food-seeking behaviors. In addition, in obese people the aggregate bacteria in the gut may process food in a way that is less advantageous for weight loss, slowing down digestion and constraining its functionality. Moreover, for overweight and obese people, exercise is considerably harder than for individuals of normal weight. The difference in overall energy level, muscle mass, and exercise capacity impedes the burning of a large number of calories by increased physical activity. Addressing barriers to weight loss may involve a review of not only what is eaten when, but also what a person drinks. It may include discussion about how the quality of life could be enhanced, an assessment of all medications and supplements currently taken (some of which may promote

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weight gain), and a consideration of diverse options that support the individual person in their environment and that increase the odds of success, including medications and procedures that can help counteract weight loss barriers. Unfortunately, overweight and obesity are still stigmatized, both within medical settings and by society at large. And for an obese person, eating high-calorie foods may be one potential emotional coping strategy, albeit one that only works to reinforce the spiral of ever more weight gain.18 Stigmatization can be experienced in multiple ways, such as in receiving less than optimal care, being the target of discrimination and shame, or fear of all of the above.20 As a result, one line of scholars advocates the view that obesity should be considered independent of health and that weight loss should not be a goal of medical care. However, this position sidesteps the reality that obesity is a risk factor for a multitude of health issues. Denial is nothing but a poor strategy. Obesity is now recognized to be a chronic and progressive disease that can cause disability and can shorten life expectancy by five to 20 years, depending on its severity and complications.18,21,22 This classification as a complex medical problem acknowledges, finally, that the obesity epidemic may only be halted by individual responsibility combined with effective interventions. These must involve public and private sectors and range from government policies to responsible and transparent food labeling. All involved sectors need to get behind the sustained shaping of conditions that support people in living healthy lives. Access to a healthy lifestyle should not be an exception, but could become available widely. And it can be done, although it will take a coordinated effort. True support of public health will be evidenced by comprehensive action and will be substantiated by two main changes: increased availability of healthful foods, and opportunities for more physical activity. Both must become easy, affordable, and realistic choices for everyone, across all layers of society.21 So, does all this mean that diets do not work? Diets actually do work, initially. If a person follows the guidelines of almost any diet out there, it is quite likely that that person will lose weight. Diet plans are designed to reduce calorie intake per day, and people will eventually lose weight when calorie consumption is limited. In addition, most diets curb the consumption of highly processed foods and with that, excess sugar, salt, and fat. Diets, however, are not solutions that foster lasting change. Diets are conceived for short-term effects in the form of relatively rapid weight loss. When someone needs to lose more than a few pounds, specific restrictive diets

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become too hard to stick to in the long run (and, in most cases, it is not a good idea to try that). Another problem with diets is that they do not change deeply ingrained habits. Because of the absence of sustained lifestyle changes, it is not the losing of weight that is the biggest problem. For many people, the biggest challenge is keeping it off. Diets have no answer for the days, months, and years after the initial weight loss. Thus, it should not come as a surprise when all too soon the hard-fought weight loss is erased as weight is just gained back. The possibly most frustrating common outcome of dieting is that more weight is gained back than was originally lost. So, on it goes, back to dieting, in a cycle that is known as the yo-yo effect.23 After all, there always seems to be a new diet that entices with promises that are unlikely to be kept! In parallel with the pandemic weight gain of the past half-century, the dietindustry has flourished. New diets are promoted as the saving grace. Often, however, their food philosophies are more likely to divide than to unite people, regardless of whether they are rooted in fact or in fantasy. Faced with the diet flavor-of-the-month and with promises of bikini-bodies, how can one distill merit? If the claims on some magazine covers were true, one could lose 50 pounds in a month. Easily! Conveniently, however, these prominently placed headlines omit to mention that a person, if that weight loss were in fact completed in a single month, also could well be...dead. As they say, if it sounds too good to be true, it probably is. But manipulative advertising can be extremely powerful. The number and variety of pseudoscientific diets and the zeal with which they are promoted are united by one thing: the desire to make money, and lots of it, by largely empty promises of short-cuts to a smaller waistline. These diets may be part of the wellness industry, but many have little to do with wellness or wellbeing. A nutritious human diet is not a temporary fad. Instead, it is what one eats every day and what remains healthful over a lifetime. It helps foster a normal relationship with food. And it certainly does not require a loan to pay for special products! Healthy, predominantly whole-food plant-based eating is achievable, sustainable, and enjoyable. It nourishes body and soul and it promotes health and wellbeing. It supports (the return to) a healthy weight. It supports life.24,25,26,27

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Key points: G Fundamentally, the purpose of food is to support the function and health of the human body. The choice of foods influences health. G For people who have a healthy relationship with food, eating and drinking are part of taking good care of themselves. Their relationship with food is relatively uncomplicated. G For many people the relationship with food is complex and food has become an adversary instead of an ally in healthy living. G In the past half-century, lifestyles have become much more sedentary and traditional staple foods increasingly have been substituted by highly processed foods that are often high in calories but low in nutrients. G Obesity and overweight are as wide-spread as the desire to lose weight. Obesity is a chronic, progressive condition that increases the risk of additional medical issues. G Dieting does not change deeply ingrained habits but making lasting lifestyle changes does.

CHAPTER EIGHTEEN AN OUNCE OF PREVENTION

How lifespan and healthspan can be improved with positive lifestyle changes

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Does it make sense for an individual to make efforts to prevent illness?

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Is prevention cost-effective for society?

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Which illnesses can be prevented and how?

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Are there some easy steps toward prevention that are likely to make a big difference?

Prevention sounds like one of those things that requires a lot of effort for uncertain returns. As if it were a kind of chore. Something that requires deprivation or exertion, the sole purpose of which it is to avoid adverse events that may never transpire anyway. Plus, nobody escapes death, and we all have to die of something, right? So do we really want to work on the prevention of illness so that in the end we can die healthy? It is a common argument that I hear all too often, but it does not hold water. Prevention may not sound appealing, but it certainly beats the alternative! As with many old sayings, there is wisdom in “An ounce of prevention is worth a pound of cure.”1

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Author, scientist, and statesman Benjamin Franklin wielded the phrase in the year 1735, but it likely originated even earlier. He used it to his advantage in a newspaper article in the Philadelphia Gazette, when he advocated for the creation of a firefighting organization in the city. Today it seems rather obvious that having a fire station is preferable to rebuilding a scorched city, but in those days he had to overcome public resistance. Eventually, however, he succeeded in his efforts to prevent fires from going out of control. A fire is a reasonable analogy for a health crisis: just as it is easier to prevent the start of a fire than it is to put it out, avoiding illness is often easier than correcting or curing it.2,3 For full disclosure, here is my bias: my assumption is that most people share the goal of wanting to live as long as possible, feeling as well as possible. And if that assumption is correct, people should care about the prevention of illness because of their desire to enjoy life, to feel good, and to be healthy. Whereas it is true that everybody will die, quality of life may remain high for many years and well into advanced age. And with an ounce of prevention, death is less likely to be preceded by a long period of illness accompanied by a physical or mental decline (or both). With the aspiration of living as long as possible and feeling as well as possible, a person would pursue a healthy and active lifestyle and live a fulfilling life up until the end, or until a short while before dying. This scenario is in stark contrast to the course that life may take for people whose lifestyle does not support health and longevity. In their case, protracted or chronic illnesses are likely to develop early. And any number of possible associated complications may further compound each disease. With compromised health, quality of life is almost certain to suffer. These individuals may experience many years of poor health with a gradual, relentless decline until death, which can be years premature. In my work as a physician, I have learned that most people do not want that for themselves. They generally hope to pass away peacefully during the night when they are old. It is not death itself that they fear the most, but rather the potential of pain and suffering before their passing. The most important aspect of longevity, therefore, is not just to add years, but to add healthy years to life. If lifespan is the time from birth to death, then healthspan can be viewed as the time from birth to the time when someone is no longer in good health. The healthspan concept gained scientific interest and growing traction in the past two decades, with an increase from just a few research articles before

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the year 2000 to more than 900 by 2018.4 The term implies that it is something that is well-defined and can be quantified by validated metrics, but there has been much discussion about how it should be measured and used. It is easy to agree that, considered over a lifetime, health generally tends to decrease with increasing age. Among the points of debate, however, is the notion of what, exactly, constitutes good health. As we have seen in chapter 11, the definition of good health is subject to perception and interpretation. And healthspan is not necessarily a contiguous period: a person may have a period of poor health with a lot of disability followed by a return to a healthy state. Notwithstanding the controversies about definition and measurement, the conceptual distinction between lifespan and healthspan is easy to grasp and it is straightforward to appreciate how increasing the latter could be beneficial. Dr. Matt Kaeberlein, who investigates the basic mechanisms of ageing at the University of Washington, points out that “while some would debate the ethics of research aimed at increasing lifespan, there is broad agreement that expanding the period of life spent in good health is a worthwhile research endeavor, with significant economic and social benefits.”4

In the past century, efforts have concentrated on life expectancy instead of healthspan. And major strides have been made in the increase of life expectancy. Much of that improvement has been accomplished by reducing early mortality, which was achieved with improved hygiene, access to clean drinking water, and better treatments for infectious diseases. In the year 1900, almost a quarter (22%) of people born in the United States would perish before the age of ten! Life expectancy today is approximately 81 and 76 years for women and men, respectively.5,6,7 In 2018, around 96% of babies born in developed countries could expect to live to, or beyond, the age of 50. Three-quarters of all deaths were predicted to take place between the ages of 65 and 95.5 That is a gigantic leap compared to the beginning of the twentieth century, when overall life expectancy did not exceed 50 years. Largely, this was caused by the staggering number of childhood deaths. The remarkable increase in life expectancy since then has been called a “longevity revolution”, but this upward trend has not been sustained in recent years. On average, young people today may live less healthy and shorter lives than their parents.8 As people reach more than 70 years of age, the risk for disability, frailty, and treatment-resistant fatal diseases increases rapidly, which, as age rises further, eventually has to do more with human biology than with a person’s

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health habits. As a result, the focus of public health goals is beginning to shift away from life extension alone, and toward the goal of increasing the number of healthy years in a lifetime. In the coming decades, achieving a greater healthspan may be more realistic than prolonging life expectancy much further. Such healthspan expansion can be attained by compressing, as much as possible, the period at the end of life that is affected by disabling conditions and general fragility. For the medical field, a change of focus in favor of increasing healthspan may allow a more thoughtful and more comprehensive approach to chronic diseases. Currently, these conditions are still often dealt with one by one, as if they were emerging as independent entities. Instead, however, they typically result from a suboptimal overall state of health, that predisposes to the development of a host of seemingly separate illnesses.5 With that in mind, let us have a closer look at low-grade chronic inflammation, which can trigger the development of a long list of medical conditions. Inflammation is a reaction of the body to harmful triggers, and, as such, it is one of the body’s great defense mechanisms. With acute inflammation, in response to an infection or an injury, for example, the reaction typically remains localized. There will be more blood flow to the affected area, and there may be redness, swelling, warmth, and pain. In response to local cell damage, the immune system kicks into higher gear and works toward healing the body. When that healing is accomplished, the inflammation reaction ends. With chronic inflammation, however, the immune reaction lingers and lasts. In that case, the inflammation is not just localized. Chronic inflammation is a continuing signal that something is wrong, rather than a direct and effective way to healing. The ongoing state of distress and the immune reaction that is set off in response, eventually harm organs and cells. Chronic inflammation, therefore, is one indicator of less than optimal health. The strongest evidence for a key role of chronic inflammation in the development of illness is available for cardiovascular disease, metabolic syndrome (high blood pressure, high blood sugar, an abnormal lipid profile in the blood, and excess fat around the waist), and type-2 diabetes.9 The list of diseases associated with chronic inflammation, however, also includes cancer, fatty liver disease, neurodegenerative disorders (an example is Alzheimer’s disease), fragile bones with decreased density (osteoporosis), depression, chronic kidney disease, and autoimmune conditions such as rheumatoid arthritis. Chronic inflammation furthermore erodes the capabilities of the immune system, especially with increasing age. All in all,

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it is clear that chronic inflammation, simmering in the whole body, is not a good thing! It is important to stress that inflammation is not all bad. In principle, inflammation is a very useful response of the body and it is used to activate a host of cells, many of which are part of the immune system. The immune system has a critically important function because it helps the body rid itself of health threats such as viruses and bacteria, parasites, and fungi. It also serves to detect and clean up human cells that have been damaged and need to be discarded.10 Thus, a well-functioning immune system is our hero inside that fights on our behalf: it protects against assault by infectious agents and helps the body recover and heal. The immune system is life-saving. Nevertheless, in recent decades it has become clear that some inflammatory processes and some activities of the human immune system play a previously unknown role in a range of physical and mental health issues, and that a long-lasting state of low-grade inflammation is implicated in more than half of all deaths worldwide.9 This realization caused quite a paradigm shift, because, for more than a century, the prevailing biomedical framework was that a specific disease has a specific cause. Contemporary research on chronic inflammation has shown that many chronic health ailments share commonalities, such as in the proteins that are expressed and in a host of molecular interactions. These interactions facilitate communication between and within cells, connect internal systems, and ultimately determine body function. It is now understood that a range of contributing factors can impair body functions by causing chronic inflammation. And a persisting state of chronic inflammation can have major consequences for different organs, such as the heart, the lungs, and the pancreas. To recap: inflammation can last without the immediate threat of an underlying infectious agent or obvious trauma. Through the activation of numerous feed-back loops, it can involve the entire body.10 And that is bad news. This kind of inflammatory process may be low grade, but it is far from benign. It generates signals to communicate trouble in the whole system that constitutes the human body and poses a covert and festering source of problems that can damage organs and other body parts without obvious clinical symptoms. Eventually, this type of inflammation can declare itself by increased susceptibility for infectious diseases and result in a high risk for the development of non-communicable diseases, as well.9,10

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Dysregulated inflammation has yet another effect: it speeds up ageing, in a process that is nicknamed “inflammageing”. This phenomenon serves as another indication of how chronic inflammation affects the whole body and, in fact, the complete person.10 The causes of chronic inflammation are diverse. They range from a sedentary lifestyle, obesity, and an unhealthy diet to an unfavorable composition of the microbiome in the digestive system. Chronic psychological stress and social isolation, sleep disorders, chronic infections, and exposure to toxic chemicals and pollutants such as tobacco smoke also contribute.9 Unfortunately, apart from a few general biomarkers of inflammation, comprehensive dependable clinical testing for this condition is not yet available. There are no standardized biomarkers for detection yet, because the immune system is so complex and because these insights are relatively new. Approaches that combine multiple markers of chronic inflammation are promising, but they are too new to be used for regular diagnostic testing that can be universally applied across populations, disease states, and ageranges. Before these markers can be used for diagnosis, they need to be wellcharacterized, with reliable normal and abnormal laboratory measurement ranges. Once this area of research matures, however, it holds the promising prospect that age-related disease-risk for patients can be assessed and quantified by looking at the markers of chronic inflammation. And then it will become common knowledge that the chronic conditions that constitute the major general health concerns of our time have a common denominator. Current public health threats, which are not only widespread but also represent leading causes of death worldwide, include serious chronic diseases such as heart disease and stroke, type-2 diabetes, some types of cancer, and lung diseases. Chronic diseases are commonly defined as those medical conditions that exceed one year of duration and that require ongoing medical attention, limit the activities of daily living, or both. They affect six in ten U.S. adults while four in ten have two or more such diseases.11 This statistic from the National Center for Chronic Disease Prevention and Health Promotion is alarming, but many of these illnesses are preventable because they are caused by a relatively short list of what are called risk behaviors. These, notably, mirror the causes of chronic inflammation and include tobacco use, lack of physical activity, excessive use of alcohol, and a poor diet that includes few fruits and vegetables and a lot of saturated fat, refined sugar, and salt,11 All of these promote chronic inflammation of body tissues, as do exposures to toxic substances and psychological stress.12

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Preventing chronic diseases does not mean that one has to have lived a perfectly healthy lifestyle since childhood (although it helps), but it does mean that prevention has to start sometime. Lifestyle decisions can make a positive difference at any age.12 And even if a disease is not prevented, there is some good news. Some chronic diseases can be reversed, at least partially, or managed in a way that improves the quality of life by maintaining as much health and independence as possible. It should be acknowledged that some illnesses cannot be avoided or reversed given specific underlying causes (such as genetics), the present state of medical knowledge, and the treatments that are available today. Nevertheless, it may be possible to postpone their onset or reduce their impact by adopting a lifestyle that supports health and wellbeing. In healthcare, prevention is divided into three basic groups.13,14 Primary prevention is aimed at improving overall health by preventing the onset of diseases. This can be accomplished by minimizing exposures or behaviors that could result in disease, or by increasing resistance to diseases despite exposures. Routine immunization programs for children or the annual flu shot for adults are examples of primary prevention. Not smoking is another example. Secondary prevention targets early disease detection and treatment. By diagnosing an illness before the emergence of symptoms, disease progression often can be averted. Examples of secondary prevention are mammography to screen for breast cancer or routine well-woman screening by PAP smear for cervical cancer. Tertiary prevention seeks to reduce the impact caused by a disease that is already present, after diagnosis and initial treatment. It takes into account quality of life issues, aims to support a person’s ability and function, and strives to reduce the prevalence of illnesses by improving treatments and by fostering recovery. These main categories highlight that prevention depends on several strategies: medical knowledge and practices are important, certainly, but these go hand in hand with personal choices and actions that enhance the likelihood of being able to enjoy good health. One’s state of health is a lifelong companion, making its presence known every single day. It is not static or stationary for even a moment. And it also is not a distant goal that is to be reached at the end of the road. Health is a process. It is best served when it receives ongoing care and consideration with a focus on improvement and maintenance throughout life. In that process, every person is an active and critically important participant. And whereas health is influenced by many contributing factors,

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including genetic and environmental circumstances, level of education, and social support, these important aspects are not the sole determinants. Regular disease screening, health assessments, and other components of taking good personal care such as eating healthful foods and being physically active, maintaining social connections, and nurturing mental wellbeing, all together build resilience and enhance overall health.15 There is plenty in life that we cannot control or even influence, and the realm of health is no exception. Living conditions cannot always be changed, and our genetic make-up is unique to each human being. Nevertheless, the choices made by society and individual actions do matter in the space of health and wellbeing. They matter tremendously! One can successfully argue that, even though each person is part of society, an individual alone has a limited degree of influence over a community and culture. A single person can only help shape policies and even this limited power only applies if that individual lives in a functioning democracy. So perhaps it is more productive to focus on health-sustaining behaviors that are most likely to be broadly accessible. What, then, is it that we, as individuals, can prevent and influence? Health can be supported in simple ways. That is not to say that making changes and especially sticking to them for the long term is easy, but the principles of healthy living are not difficult in and of themselves. Physical health can be supported by everything that not only sustains the maintenance of the body, but also helps it carry out its functions in an optimal way. Just like the fact that a drop of oil goes a long way in fixing the performance of a squeaky wheel, the ingredients that nurture health are basic but effective. That, unfortunately, means that there is not a lot of novelty appeal in them: there is no magic potion that can take the place of proven common-sense measures, regardless of the latest promises and claims. Of course, this message happens to be the exact opposite of the seductive assertions touted by certain weight loss methods. “Just take this pill, and keep all your current lifestyle and eating habits!” Or, “by only taking product ‘misLEADing PROmise’ the weight will come off fast!” Wait a minute...Losing weight while eating pizza all day and surfing (the web) for exercise? It is hardly a surprise that people think, “Sign me up!”. Disappointingly, generally the only weight that will be reduced over a sustained period of time is the weight of their wallet. Without the sexy novelty factor, the message of how to improve or maintain health is not as

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catchy and tends to fall on deaf ears. However, there is a silver lining, and it is bright. The reality that simple measures are effective also means that the fundamental steps toward improving personal health are in principle accessible to a very broad spectrum of people, and that virtually anyone can influence their health and wellbeing in some ways.16 Here are some examples: x Regular physical activity is a prerequisite to a well-functioning body. The guideline is a minimum of 150 minutes a week for healthy adults and an hour per day for children.17,18 In adults, the activity does not need to include vigorous exercise, and being healthy is not the prerogative of those who can run a marathon or snowboard down the slopes year-round. But moving the body by staying active is as important for physical and mental health as sufficient sleep and rest. x Nutrition is another important factor. A healthy weight is preceded and supported by an appropriate amount of balanced nutrition. As author Michael Pollan advocates: “Eat food. Not too much. Mostly plants.”19

x Adequate hygiene around preparing that food and good personal habits (such as regular hand washing, refraining from sharing utensils or other personal items, and practicing safe sex) can help prevent an assortment of communicable diseases. x Avoidance of substances that are directly toxic to the body, such as alcohol and many other mind-altering substances, tobacco smoke, or noxious hazards in the work environment, supports health maintenance. Keeping exposures to a minimum substantially influences the achievable degree of health. x Resilience in the face of life’s inevitable adverse events, even though these and their individual impacts will be different from person to person, is health-sustaining. It is built up through emotionally supportive interactions, relaxation, and stress management (so do cuddle with the cat!). x Regular health checks for cholesterol levels, blood pressure, blood sugar levels, weight, and body mass index, all support health. So do

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assessments of the need for vaccines and health screenings for cancer. Guidelines are different for children, women, and men, and recommendations depend on age, so it is important to talk about these with a knowledgeable healthcare provider. A yearly health visit can help to stay informed, current, and well. This succinct list is hardly headline news: it is widely known, honored by time, and validated by numerous scientific studies. Many people have heard at least part of this before and are likely to possess some awareness of healthy habits, even though the practical implementation of such habits can prove to be a major obstacle. It is the next level, the one that clarifies and highlights the positive effects of taking personal action toward better health, which is much less often underscored. This is unfortunate because it is a missed opportunity to specifically highlight what will be better when lifestyle changes are implemented. Changing health habits is not just about losing weight, for example, but rather about a path that leads to the many aspects of life that will be positively impacted by this weight loss. The instructions that guide people toward improving their health are often combined with brimstone predictions of illness and disability if the changes are not implemented. For a newly diagnosed patient who is already overwhelmed by the onset of type-2 diabetes, however, the possible future complications of blindness, amputations, kidney damage, and heart disease may seem far in the future and too much to think about right now. And whereas doctors know those consequences because they have seen patients with these complications or images depicting neglected diabetic illness, a newly diagnosed patient may need to hear the “what’s in it for me” in a different way. Beyond a list of complications, is there a message that can be encouraging and motivating? There sure is, and that, too, amounts to a list. One that is, in fact, brimming with heartening news: Physical fitness, at any age, positively influences outlook and emotions, and thereby improves mental health. It protects vitality and increases endurance by enhancing breathing capacity and heart function. Thus, energy level and stamina will go up. It bolsters the development and preservation of muscle mass and strength, improves body composition and flexibility, helps reduce the risk of injuries, and protects against a variety of serious health problems. Fitter people are stronger and they actually feel better!12,20 This list represents just some of the advantages...and would one not rather hear this instead of doomsday forecasts to become inspired for

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change? I know that I would, but different people respond to different messages: for some persuasion comes with the carrot, and some prefer the image of the stick. It is just that without any expectation of a carrot, becoming motivated and especially remaining it, is a Sisyphean task. Being one’s own health warrior means taking action to protect one’s health. With the recent COVID-19 pandemic, which came out of the blue and proceeded to disrupt life globally in dramatic and pervasive ways, it has become quite obvious that primary, secondary, and tertiary prevention are critical. Prevention and preparedness influence the way in which a health threat unfolds, and the extent to which it can impact communities. Fostering one’s wellbeing is important in a crisis, but it truly is a lifelong process of personal development. That process involves attention to all the various aspects of one’s health, given individual potential.11 Ideally, it would be supported by a way of life that is broadly oriented toward healthful choices, but it is not uncommon to hear stories about some personal healthscare that became a wake-up call, changed someone’s perspective, and spurred the person into action. Such transformations are to be admired because it takes more effort to dramatically improve health after a derailment than to live a healthy lifestyle to begin with. In either case, however, aligning life with wellbeing takes a joyful commitment that is renewed every day, in the realization that each day of healthy living is a gift. As the saying goes, life is a gift and that is why it is called the present! To some, no doubt, this is a banality, but to me, it rings true and serves as a reminder to be grateful. Ultimately, individuals and society at large each must weigh the cost of doing something versus the cost of not doing something. For administrators at healthcare institutions, that consideration may be driven largely by the bottom line, whereas for individual people the financial consequences of poor health are but one piece of the puzzle, and one that is often overlooked. But so is the personal cost of losing quality of life (not to mention life time), when prevention is ignored. How many twenty-five year-olds think that their health is ironclad? One example of a widely embraced prevention effort is in the area of heart disease. Coming at a cost that is estimated to exceed $200 billion per year in the United States, cardiovascular disease is not only the leading cause of death, but also a main burden on healthcare services and an important reason for the use (and costs) of pharmaceutical drugs. Moreover, it strains the economy in a broader sense due to lost productivity.21,22

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In Europe, according to data from 2009, healthcare costs related to cardiovascular disease amounted to approximately 9% of healthcare costs in the European Union, with a total price tag of about €106 billion. Not surprisingly, efforts to prevent cardiovascular diseases are not only reducing the population risk of adverse cardiovascular events (such as stroke or heart attack) but they are also cost-effective.23 Current guidelines on the primary prevention of cardiovascular disease emphasize that the most important way to prevent heart disease is a healthy lifestyle throughout life, as well as a team-based care approach that involves the patient.22 For patients with elevated low-density lipoprotein (LDL) cholesterol levels, statins can be used to lower cholesterol, and medications from this class of drugs are prescribed as a first-line pharmaceutical treatment. When my husband Karel was found to have elevated lipid levels in his blood, however, his doctor recommended statin therapy right away. I spoke to several physicians since, and most shared that they tend to prescribe statins sooner rather than later because few patients follow through on the recommended lifestyle changes. Without change, they reasoned, the risk of a cardiovascular event would remain elevated. What concerned me the most, however, was not that the doctor had recommended statin therapy, but the fact that possible lifestyle changes were not discussed at all. When Karel attended a dinner with a group of men in the same age range, he conducted an unscientific small-number experiment with a nevertheless interesting finding: the men who also had been diagnosed with suboptimal lipid profiles had been offered statin therapy right away, without exception. None had received guidance on how to improve their lipid profiles with targeted lifestyle changes before the initiation of drug therapy. My husband, who already had an active lifestyle and a normal body mass index, declined the medication and successfully improved his laboratory values by cutting back on sugary sweets and dairy and also by shifting toward whole grains and whole wheat bread. In particular, he made the fairly easy switch from cow milk to soy milk for his coffee. And whereas he could not eliminate all risk of heart disease, drugs can not deliver on that goal either. Moreover, every drug has the potential for side effects.23,24 With his laboratory values returned to the normal range, he made an important step toward prevention. Statin therapy can be necessary and valuable, but guidelines do not propose its use as a quick-fix alternative for improving diet and lifestyle.

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Prevention is most effective when it is treated like a team sport. Patients and providers must be partners in care to arrive at a desired result. The anecdote above merely highlights that patients who actively engage and ask about their options, together with doctors who take time to explain options and current health recommendations, are likely to have the best chance of a jointly designed roadmap to better health. Although a lot is yet to learn, prevention is an area in which there is a solid amount of knowledge that can be applied widely. For many common diseases, the main causes, the underlying processes, and the factors that modulate outcomes are fairly well-characterized. The challenge, however, is to translate this knowledge into effective action.25,26 To combat the obesity epidemic, for example, it may require the implementation of policies and regulations that help people choose foods with less fat, sugar, and salt. Such measures are often challenged and unpopular. But when sectors collaborate, some changes that benefit public health, such as adjustments of portion sizes, should be feasible. And behavior changes toward better health can be stimulated by education, by modeling healthy lifestyles (for example on television), and by the use of incentives (for example by employers). At the personal level, thoughts and actions either contribute to health or deplete it. Is an action nourishing or diminishing health and wellbeing? Health may not be something that can be controlled, but it is among those things in life that can be influenced to a large degree, at every age. Small positive changes do matter because they pay into the bank of health benefits and can make a large difference over time. As author Anne Lamott said about the topic of food during one of her talks, “Try to do a little better...I think you know what I mean.”27

The audience, after a moment of pause, responded with resounding laughter, because it turned out to be all she chose to say about food. And in a way, it was enough. Key points: G Avoiding illness is in many cases easier than correcting or curing it. G If you want to live as long as possible while feeling as well as possible, the prevention of illness is key.

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G Most people fear pain and suffering more than death. The most important aspect of longevity, therefore, is not just to add years to life, but to add healthy ones. G Many chronic diseases are fundamentally triggered by low-grade chronic inflammation. G The principles of healthy living are not difficult in and of themselves. The habits that nurture health are basic but effective. G The core steps toward improving personal health are accessible to a wide spectrum of people. Virtually anyone can influence their health and wellbeing in some way.

CHAPTER NINETEEN ALTERNATIVE MEDICINE

How complementary and alternative health practices can help or harm health and wellbeing

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What is alternative or complementary medicine?

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Why is it not considered mainstream?

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Can its efficacy be investigated in scientific ways?

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What is the appeal and how common is its use?

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What are the potential benefits and dangers?

Tucked away between India and China’s autonomous region of Tibet, the democratic kingdom of Bhutan is a nation of fewer than 800,000 people that remains enigmatic, remote, and steeped in ancient customs and beliefs.1 The beautiful and largely mountainous landscape is dotted with impressive Buddhist monasteries, but Bhutan is probably best known for its government focus on Gross National Happiness instead of Gross Domestic Product. Bhutan is a country with a long history of cultural and geographic isolation that aims to protect its pristine environment and cultural treasures while opening up to international interactions in a thoughtful way. For example, Bhutan’s strong commitment to conservation is written into its constitution. It preserves 60% of its country as forest, and protects more

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than 51% of the country overall, resulting in a healthy environment for its native wildlife, and for its people.2 Healthcare and education are free, and, in recent years, the nation has made great strides by ensuring that girls and boys have equal opportunities to complete primary and secondary education. Bhutan, in many respects, is an inspiration and a guiding light. Yet, it also is encumbered by the general challenges of low-income nations. Life expectancy, for instance, at 72.3 and 73.3 years for men and women, respectively, is years below that of more developed countries, and medical services are limited in scope. Moreover, there are relatively few doctors in the country, as Bhutan does not yet have a comprehensive medical school.3 I was privileged to travel in Bhutan in 2005, when almost all people still adhered to the traditional dress code, when ubiquitous large penis paintings joyfully symbolized fertility on the outside walls of buildings, and when cities (even the capital Thimphu) did not have a single traffic light. The latter, by the way, remains the case 15 years later! English is widely spoken by Bhutan’s genuinely friendly people, and the art of storytelling and singing together is alive and well. I rather admired that at evening campfires, when I realized (with some regret) that such traditions have been largely lost in “modern society”. On the way to the eastern part of the country, I took the opportunity to visit Wangdicholing General Hospital in Jakar, a town in the Bumthang district. From my perspective of a physician trained in western medicine, this hospital was quite unlike the ones I was accustomed to. The first striking difference was the presence of a gigantic prayer wheel housed in a narrow shrine in front of the hospital entrance. One was expected to spin it for good blessings as one walked around it in the prescribed clockwise direction. I remember wondering how that would work for someone who could not walk or pass through the little building, but I assumed that there must be another entrance for patients who needed urgent care. Inside the austere facility, a practitioner who specialized in traditional medicine shared that she treated about a third of all patients with herbal medicine and traditional methods. The youngest and the most challenging patients were treated by western medicine in another part of the hospital. Her education consisted of the medical training provided by her father, who was originally educated in Tibet. The practice, she said, had not changed much over the years, as it adhered to Chinese practices and Indian Ayurvedic philosophies.

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Success rates between western and traditional methods were not compared. Instead, the patients could choose to be treated according to preference or, if a problem was determined to be too complex for traditional practice, they were referred to “the other side” of the hospital, as, indeed, also could happen vice versa. Overall, the hospital was very basic but it clearly illuminated that healthcare in Bhutan, just as other aspects of life, is in the process of being brought up to date while also maintaining strong ties to traditions.3,4 Meanwhile, the question for the individual patient simply is “do I go left, or do I go right?”. Traveling offers perspectives and insights that cannot be offered by a book. Just like the fact that reading the menu and tasting the food in a restaurant are very different experiences, so is learning about a place from an armchair as compared to the immersion in another environment or culture. As eighteenth-century English author Samuel Johnson observed: “The use of travelling is to regulate imagination by reality, and instead of thinking how things may be, to see them as they are.”5

The same can be said for science, which gives us the challenge and explicit encouragement to question absolutely everything in a systematic way. As such, it forms the foundation of knowledge and, correspondingly, the basis of western medicine (as outlined in chapter 9). So how does alternative medicine fit into this? The designation “alternative medicine” should give cause for pause, even before we address its merits and flaws or consider its long history of empiric experience. After all, the designation is a contradiction in terms because it links together incompatible words. If its healing properties can be proven by impartial scientific investigation and analysis, it squarely belongs within the realm of medicine, regardless of its historical context, philosophical roots, cultural basis, or geographic origin. If, however, it is not proven to work, or if it is actually proven not to work, then it can not be an alternative to medicine that does work. In that circumstance, it would not deserve the label “medicine”. Another area in which the term “alternative” is suggested to have credibility is in the fallacy of “alternative facts”. Preferences and beliefs notwithstanding, either something is a verifiable fact, or it is not. In the realm of reality, there may be alternative interpretations, but alternative facts do not exist. Sometimes, of course, the term “alternative medicine” is merely used to distinguish between different approaches to healing and, in particular, to set

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them apart from the general framework of conventional (also called allopathic or western) medicine. If being inclusive is the intent, however, the more appropriate term “complementary medicine” can be used.6 In chapter 15, we saw how an independent commission tested and debunked Dr. Mesmer’s therapeutic methods with a variety of carefully designed experiments. The aim was to objectively evaluate the efficacy of his treatment methods, not on whether the effects were real or not. This is an important distinction. Beneficial effects for individual patients were not (and should never be) dismissed, even if they were not caused by, in Mesmer’s case, “animal magnetism”. The placebo effect and a variety of other factors can certainly cause a patient’s improvement, but what needs to be determined is whether any observed efficacy is the direct result of the used method. One complicating factor is that, to date, the various diagnostic methods and therapies of complementary medicine have been less rigorously tested than those in mainstream medicine. This is unfortunate, but there are multiple and diverse reasons for that. These only recently began to receive methodical attention.7 One barrier is the perceived requirement to use the highly valued unbiased research methodology of the randomized controlled trial. This research method is typically applied when, for example, new pharmaceutical drugs are being considered for approval in patient care. In some types of complementary medicine, especially the ones that rely on interventions and treatments other than drugs, such trial-based research is not feasible because the routine use of identical-looking inert pills in one group of the trial and the use of the new drug in the other group is not an option. Thus, patient, practitioner, or both will know whether the patient is in the therapeutic research group or not. In other words, such research is not double-blinded. Of note, however, this dilemma also applies to mainstream disciplines such as psychotherapy, physical therapy, and nursing, so the issue certainly is not unique to complementary medicine. Other objective research methods can be used in a valid, applicable, and quite an appropriate way. Practitioners of complementary medicine are also concerned that the testing of their claims with a lens of rigorous scientific experiments may distort the likelihood of a positive response, because they offer individuallytailored treatments and, at times, they use individual measures of efficacy.6 A counter-argument to this, however, is that mainstream medicine also aims to offer what is called “precision medicine”. This term describes the timely diagnosis and treatments that are tailored to the patient’s medical and personal needs.8 Western medicine still has a way to go in achieving this

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goal, but that is no reason not to validate used methods and to verify claims made in all arenas of medical practice. Although the scientific literature has plenty of examples of manuscripts that leave room for improvement, it must be acknowledged that the supportive evidence for complementary medicine and the standards used for evaluation have frequently been low. They have been plagued by poor study design, flawed methodologies, and suboptimal results analysis or statistical evaluation.6 As an example, in studies that include only a small number of people, the risk of false-positive or false-negative results (and therefore erroneous conclusions) is much higher than with a well-designed large study. In addition, many practitioners in complementary medicine have not received academic training that included research experience, which makes successful competition for funding or even solid study design and data analysis particularly challenging. To boot, there often is a culture of distrust and prejudice, in both directions. In view of the lack of incentives to overcome research barriers in complementary medicine and given the communication divide between allopathic medicine and other, seemingly disparate realms of practice, collaborations on research projects and also in the care for patients are still in the stage of infancy.9 But in light of the widespread use of complementary medicine by patients, the need for careful assessment of the evidence for efficacy has finally been recognized. Efforts to address the validity of this assorted collection of previously neglected medical practice areas are now underway. At the National Institutes of Health, for instance, in the United States, there is a National Center for Complementary and Integrative Health (NCCIH) that evaluates efficacy based on rigorous scientific evidence so that proven approaches can be integrated into patient care.10 Similar efforts to assess efficacy and effectiveness are also taking hold in Australia and elsewhere, because of the clinical and safety needs to diagnose and treat patients with evidence-based medicine, no matter its discipline or origin. Increasingly, but not universally, this view is supported by complementary medicine practitioners.7,10 The terms alternative medicine and complementary medicine lump together a multifarious group of hundreds of healing traditions worldwide. These practices are markedly divergent in philosophical frameworks, used methodologies, origins, and merit, and they have been classified in different ways.6 Some, such as acupuncture and homeopathy, are considered to be

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among the most traditional because they have been practiced for centuries. Others, such as chiropractic techniques and Tai Chi, are primarily categorized as body therapies that aim to improve physical and mental health by manipulation, touch, or movement. Still another set of practices seeks to optimize the body’s nutritional wellness with the use of herbal remedies or dietary changes. And Reiki and other energy practices are considered different yet again, in that they are based on the idea that external energies directly influence health and wellbeing.6,11 It is often assumed that all these practices are wholistic and that they have deep roots, but some are narrowly focused and have been developed only recently. For example, whereas the ancient philosophy of Ayurveda dates back thousands of years, the practice of psychic surgery seems to date back only decades.12 During this quackery, a “surgeon” is reputed to enter the body of a patient by psychic means to remove diseased tissue (that, incidentally, does not match the patient when tested), leaving no wound. And then there are the fringe medicine practices that capitalize on science as it evolves, but use none of it to actually accomplish what they proclaim. One such example is cryonics, a pseudoscientific technique that promises corpse or brain preservation after clinical death. It is based solely on wild speculation and a rather desperate hope for resurrection in the future. Even if the mush-inducing process of freezing and thawing could be optimized to result in an intact defrosted corpse far into the future, one would still need to cure the deceased’s original cause of death, undo the inevitable tissue damage and degradation between the moment of death and the time of freezing, and then, preferably, rejuvenate the person. Imminently doable? I think not!13,14 With such a mixed bag of options to choose from, one could think that people cannot see the forest for the trees, resulting in a diminished appetite for alternative and complementary practices. But make no mistake: the appeal is there, and it is enormous. In the United States in 2012, 34% of adults used some complementary health approach, a percentage consistent with earlier research.15 A large European survey from 2014 revealed that almost 26% of people in the general population had used complementary and alternative medicine in the preceding year. Whereas the use of these approaches was more often complementary to conventional medicine than used as an actual alternative to it, there was a lot of variability between countries in overall use, with a range from 10% in Hungary to about 40% in Germany.16

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All these statistics for individual studies and countries depend on what is included in the surveys and is considered to belong within the sphere of alternative or complementary medicine. Massage, yoga, a vegetarian diet, meditation, and vitamin D supplements, for example, may be contained in some lists but omitted in others. Notably, people who incorporate any of these options into their lives may not view them as complementary medicine at all, but rather simply as something that provides recreational pleasure, is part of their lifestyle, reduces stress, or is an over-the-counter supplement pill recommended by their allopathic doctor. Reviewing the numbers worldwide, it is even more daunting to estimate with any accuracy how many people use complementary practices and therapies. Based on a systematic literature search that included European and North American countries, Australia, and South Korea, the average utilization was estimated to be roughly one third of all people.17 Among the 194 member states of the World Health Organization, 170 (88%) have declared the use of these approaches. Because these are the countries that report having developed policies, programs, or regulations for such practices, the actual number of states that apply them is likely to be higher.18 Indeed, there probably is not a single country in the world where some form of traditional medicine is not being practiced, be it publicly or privately. The widespread interest in traditional, complementary, alternative, and fringe medicine practices makes them and their products a lucrative business. Americans, for example, according to data from 2012, spend more than 30 billion U.S. dollars per year on this, on their own dime, beyond what insurance might cover. The number was broken down to some $15 billion for visits to practitioners, some $13 billion on products, and around $3 billion on materials such as books and other self-help items on the topic. This out-of-pocket spending represented 8.4 percent of all ($359 billion) self-paid healthcare.19 In Germany, some types of complementary medicine are covered by insurance, and, as early as the year 2000, these approaches were responsible for approximately one tenth of overall medical treatment expenditures.17 Which raises the question: which ailments are most often targeted and what are the practices that are used to treat them? Complementary and alternative therapies are often employed for back pain and other physical pain, but also for depression, anxiety, sleep disturbances, headache, and intestinal problems. Having said that, people may seek them out for any health concern. The most commonly used healing practices

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include prayer, herbalism, acupuncture, yoga, homeopathy, meditation, and manual treatments such as massage and chiropractic manipulation.17,19, 20,21 Increasingly, physicians are learning about these practices too, and are incorporating them into the care for their patients. These doctors typically prefer the term “integrative medicine”, over any designation that includes the word “alternative”, because the latter is associated with a categorical rejection of allopathic medical care. Cardiologist and researcher Dr. Mimi Guarneri explained: “Because it implies, ‘I’m diagnosed with cancer and I’m going to not do any chemo, radiation, or any conventional medicine, I’m going to do juicing’.”21

The increasingly positive attitude toward health practices that historically were outside of the scope of allopathic medicine has wide-ranging effects. It is influencing patients who are seeking healthcare and prevention of illness, consumers who are seeking self-care, it attracts attention from health professionals within the medical establishment, and it makes fortunes for the industries that are centered around services and products. The reasons that draw people toward these treatments are diverse and complex. They may find their origin in dissatisfaction, in a sense of empowerment, or in both. Much of the appeal is based on perceptions that may or may not be justified. One of the most common perceptions is that complementary medicine methods are more natural and therefore less risky. They seem to offer a wholistic and more personal approach that may not require pharmaceutical drugs. They are also less invasive. And when patients are being offered more time to interact with a practitioner, trust in the relationship is built more easily, which, in turn, facilitates a felt connection between patient and practitioner and more active engagement in therapy decisions by the patient. Apart from the power of perception, there are also practical considerations. A patient may be swayed because the cost of therapies (regardless of efficacy) is lower than in regular healthcare, or because pharmaceutical drugs that were prescribed by their physician had unpleasant side effects, or because prior medical care did not result in relief for a specific complaint. People seek alternatives when they are frustrated, and medical care is no exception. Especially individuals who are more health-conscious and who are interested in improving their health through lifestyle and actions tend to be open-minded about complementary medicine if they think that it will have positive effects on their wellbeing. Not only do they want to have a say in

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their healthcare, but they also are simply not satisfied with medical providers who control most of the process.6,17,20 The positive empowerment of individuals who actively participate in their health and wellbeing notwithstanding, it is quite challenging to assess which of the complementary therapies have value, and if they do, what their best uses and limitations are. This is an area in which the judicious application of scientific rigor has been lacking, and even though that is beginning to change, evidence-based evaluations are not available for every method. Where they are emerging, they may be relatively sparse, so that the body of literature and scientific knowledge is not yet fully developed. In practical terms, it means that in those cases an objective, definitive assessment can be unrealistic, even for the most qualified and open-minded of medical professionals, let alone for the general public! And yet, nobody deserves any less. Just as with any form of information and knowledge there can be an (often imperceptible) undercurrent of manipulation, be that by well-placed compelling ads, by celebrity endorsements, or by the charismatic promotion of a message of safety and effectiveness that, at the same time, fosters distrust in modern medicine.22 The question that must remain front and center is: does it work?23 But by now, it should be obvious that there is no one “it”. These approaches, taken together, are a rather motley crew of diagnostic and therapeutic practices and products that can not be viewed as a single entity. So in terms of the plausible effect of the method itself (and not the effect as experienced by the patient), they have to be evaluated one by one. And not until there are collections of scientifically conducted and statistically well-powered studies that systematically build evidence, will it be clear whether or not acupuncture moves the needle toward health, massage therapy is a stroke of genius, and chiropractic practices are not merely manipulative. It will take considerable effort and that effort will require funding, but we (the doctors, the patients, the believers, the skeptics, the consumers, the abstainers, the practitioners, the clients, the benefactors, the victims, and society at large) should not be lazy and, out of convenience, take what we are told for granted. Humanity has a right to know, whatever the outcome for each particular therapeutic approach. Wouldn’t you like to be able to separate things that have merit from those that are nothing other than hocuspocus? For some complementary and alternative approaches, it remains to be seen whether they work by objective and measurable benchmarks, whereas for others there is enough evidence to make a determination of efficacy,

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safety, and side effects. The NCCIH established one of the most reliable sources of current information about the efficacy of herbs and for health topics overall, including acupuncture, chiropractic manipulation, and homeopathy.10,24,25 Because of such efforts, products from a largely unregulated industry are now subjected to objective analysis and tested for their ingredients. An article in The New York Times in which Dr. Josephine Briggs (who served as Director of the NCCIH from 2008 to 2017) was interviewed, pointed out that “Over the years, laboratories have found that up to 75 percent of the samples of ginkgo biloba failed to show the claimed levels of the active ingredient. Scientists doing a clinical trial have a large incentive to fix that kind of inconsistency.”26

Scientists can not fix the industry, but at least they can highlight false claims. Scientists want and need to test accurately labeled products to obtain the best possible data. The science on ginkgo, by the way, ultimately did not support the claims that it helps to prevent or slow dementia, and there is no conclusive evidence that ginkgo is helpful for any health condition.24 But in other cases, science does support efficacy. In fact, many pharmaceuticals have been derived from plants. Foxglove is one example. It contains digitalis, which is a powerful heart medicine. It has been studied, tested, and validated and is used as a therapeutic drug in conventional medicine. Similar scientific assessments can be made of any herb. Treatment procedures are more complex than individual products (such as pure herbs), and therefore require a somewhat different approach. In any assessment of a practice method, it is useful to first consider whether a postulated mechanism of action is plausible.27 In other words: if something goes against the laws of nature, then any observed effect can not be interpreted as a result of the applied method. One central tenet of homeopathy, for example, is the idea that more extreme dilutions of a medication cause greater effects. That, however, means that many (although not all) homeopathic remedies are so diluted that they do not contain even a single molecule of the original substance that is supposed to treat the ailment for which it is prescribed. According to the NCCIH, on homeopathy, “A number of its key concepts don’t agree with fundamental scientific concepts. For example, it’s not possible to explain in scientific terms how a product containing little or no active ingredient can have any effect. This, in

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turn, creates major challenges to the rigorous clinical investigation of such products.”25

Despite demonstrable efforts, evidence for the efficacy of utterly diluted products is lacking. Importantly, that does not mean that science is not applicable, as has been suggested.9,20,28 Uncertainty about mechanisms of action, or even unequivocal rejection of proposed mechanisms that contradict the laws of physics and human physiology, does not necessarily mean that a treatment can not work. For one, as described in chapter 15, effects may result from placebo and nocebo effects. A treatment may seem to work, at least for a time, but if the placebo effect truly were able to heal a condition, it would not be called a placebo: it would be a cure.29 What happens with the placebo effect in conditions that do not improve by themselves is that the results only last for a while. Effects may last (or seem to last), however, when a condition resolves on its own. Many conditions improve and eventually get better without intervention. Nature and the impressive regenerative capacity of the human body do take care of many ailments, including the common cold. Patients with a cold often request antibiotics, but the upshot is this: it will take seven days with antibiotics, and a week without. For one, antibiotics do not target the viruses that cause a common cold, but it is also a selflimiting disease, that, while quite unpleasant, will just pass in otherwise healthy people. Likewise, a treatment in the “alternative medicine” category may seem to do the trick, but not actually be responsible for any of the healing. Conditions may improve for individual patients not only because of the placebo effect or because they are self-limiting, but simply because many diseases have natural ups and downs. They wax and wane as time goes on. Pain is an example of this. Someone with chronic pain often has good days and bad days, because pain is an elusive symptom that can change in quality, intensity, and even location. It may well be that a massage of the painful area brings relief and supports circulation, and if this kind of supportive care improves wellbeing, then it makes good sense to make use of it, even if it cannot cure the underlying cause of the pain. In a time when healthcare costs are soaring, the benefits of complementary and alternative approaches deserve a closer look. Even the World Health Organization acknowledges that some of these therapies may be underestimated in their usefulness as a health resource, as they have multiple possible applications and the possibility to bridge cultures. They

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can be quite helpful in the context of wholistic healthcare that seeks to address the continuum of health, wellbeing, and prevention. An example is the management of lifestyle-related chronic diseases. Many of such diseases can be prevented, treated, or even reversed.30 Sometimes, however, they can be mitigated but not mended.18 As mentioned above, another area for the application of complementary and alternative approaches is pain management. In the United States, chronic pain affects the wellbeing, productivity, and healthcare expenses of approximately 40% of all adults. Providing pain management with pharmaceutical means comes at a very high price, not only in dollars but also because of the negative impact these drugs can have. This is especially concerning when they are used for an extended period of time. Opioids are (too) often prescribed for the treatment of pain, but they are highly addictive, can be fatal in case of overdose, and gradually require higher doses to reach the same effect. Medication in the class of nonsteroidal anti-inflammatory (NSAID) drugs are frequently used as a more benign alternative, but when these are used long-term, there is an associated risk of stomach ulcers and internal bleeding, interactions with other medications, and other serious health risks. Pain is difficult to treat due to its intermittent and subjective nature.21 Anything that increases a general sense of wellbeing is likely to help a person cope better with pain. Next to chronic diseases and pain, the third example of a recognized application of complementary and alternative approaches is the increase in wellbeing of patients who have a serious illness and undergo difficult treatments. If someone is undergoing cancer treatment, meditation may reduce stress, guided imagery may help with relaxation and pain relief during medical procedures, and ginger may alleviate nausea. As long as a complementary treatment does not interfere with the cancer treatment, does not pose a danger of harm, and improves the quality of life, the American Cancer Society supports consideration of practices like acupuncture, art or music therapy, biofeedback, massage therapy, tai chi, yoga, and spiritual practices to help with pain, nausea, anxiety, depression, stress, strength, and balance.31 In summary, the benefits of such practices are not lost on allopathic medicine. Even harnessing the power of the placebo effect may not be a problem in itself, if it weren’t for the concern that patients who resort to alternative practices and products are often misled to believe that they are receiving a proven therapy that truly does work, and, more importantly, that cures their illness.

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A serious problem with complementary and alternative practices is the general perception that they are harmless. But the label “natural” does not necessarily mean that a product is safe. A practitioner may not even be qualified to assess safety! Additionally, because the term “natural” is not regulated, a product with that label may contain a number of undisclosed chemical components, or it may have dangerous contaminants because good manufacturing processes were not followed. Such products, and even homeopathic products that are not diluted, may contain active substances that can interact with other medications or generate side effects. The perception of product safety and harmlessness may cause patients to omit mentioning these products when they are asked about medication use by their physician or their pharmacist. This not only hampers the possibility of integrated care, but it also presents the risk of side effects, overdoses, and drug interactions, all of which may cause severe health issues and, indeed, result in death. There are still more dangers when these practices are pursued instead of regular healthcare: diagnoses may be missed altogether, or a delay in conventional treatment may cause a disease to advance beyond a stage where it can be cured. This is especially tragic when a cancer spreads because precious time was lost before allopathic treatment was sought.31 So let’s get real: medicine cannot be replaced by something that does not live up to scientific standards. Hugh Laurie, the actor who played the illustrious and outrageous Dr. House, put it this way: “You can chew all the celery you want, but without antibiotics, three quarters of us would not be here.”32

Medicine is complicated, it evolves as knowledge develops, and it can feel impersonal and scary. I get that. I also understand that it may be comforting to believe in a practice that has a long history, during which it mostly stayed the same. There can be entire training programs configured around such practices, giving the practice the aura of credibility, and creating the impression that something valid was studied. An individual practitioner may well have made a genuine effort to learn everything there is to know about a particular practice! Unfortunately, that effort in itself has no bearing whatsoever on the validity of the studied practice. Take astrology: it dates back far further than most alternative and complementary medicine practices, and yet it has been firmly demonstrated that the time and place of birth do not determine fate. One can discuss the concept of free will till the cows come home, but studying the stars will not dictate the course of anyone’s life, unless of course you saw an asteroid headed straight for you and moved out of the way in time.

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Similarly, ancient beliefs in Bhutan are used to explain phenomena that have their basis in something else. According to a UNICEF report from 2016, six out of every ten children in Bhutan in the age range of 13 to 17 have experienced some form of physical violence in their lifetime.33 This very troubling issue is now being addressed and countered in a variety of ways, but when I was in Bhutan in 2005, it was explained to me that a child covered in bruises must have been visited at night by the demons of stones and rocks. Child abuse was something of a taboo and the spirit world was the culturally acceptable explanation. In the end, none of this kind of thinking is helpful. We need to call a spade a spade. As comedian, actor, writer, and director Ricky Gervais once remarked: “Beliefs don’t change the facts. Facts, if you are rational, should change your beliefs.”34

The field of medicine adapts as knowledge is developed further, although it does not always get it right from the start. Sometimes, this is a result of slow adoption by doctors themselves. A point in case: just decades ago, even after the link between smoking and lung cancer became clear through scientific studies, a physician still might have offered a patient a cigarette to establish rapport and to decrease stress during the office visit.35 They even may have smoked together! Back then, there was a much greater emphasis on acute illness than on prevention or the management of chronic diseases. Today, that is different. We live in a world where many medical issues result from the ways in which people live their daily lives, and that fact requires an adaptation of the medical system. Whereas that system originally primarily focused on acute care, now there is not only a desire but a need to include additional approaches that serve a patient population in which chronic conditions are prevalent, and in which prevention is becoming a priority.21 Addressing lifestyle, and bringing about lifestyle changes, will be imperative to improve personal and public health. In addition, by combining evidence-based medicine with honest experiential complementary practices, integrative healthcare may well be a path to a healthier future with greater wellbeing overall. For anyone who considers practices outside of evidence-based medicine, there are several claims that should raise red flags, for instance that a treatment can cure cancer or eliminate diseases that do not have a cure such as multiple sclerosis, Parkinson’s disease, cystic fibrosis, or rheumatoid arthritis. Claims of no side effects, of efficacy (delivered by passionate

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personal attestations), and of scientific breakthroughs with secret ingredients cannot be considered trustworthy in the absence of the necessary studies to back them up. The same goes for the categorical rejection of modern medicine and any treatment that can only be obtained in a single clinic. Likewise, promotion by mass media (internet, radio, TV, books, magazines), however persuasive, cannot take the place of science-based studies in reputable journals that report on effects in humans (and not only in animals).31 A practice that claims to offer a cure must go beyond what feels good. After all, the usual goal is not to feel good and then to be incurably ill four months later because no other action was taken... For all the listed reasons, communication about therapeutic approaches outside of evidence-based medicine is critical, either with a physician or with someone else in the medical healthcare team. It may be uncomfortable to have these discussions, especially in case complementary approaches seem to be rejected unconditionally. But the tide is changing, and many physicians become increasingly interested in learning about complementary medicine in order to best meet the needs of their patients, which is a vital goal of medicine.17,36 Key points: G Complementary and alternative practices have wide appeal but are highly divergent in philosophical frameworks, used methodologies, origins, and merit. G Complementary and alternative methods generally have been less rigorously tested. This is improving because of the recognized clinical and safety needs to diagnose and treat patients with evidence-based medicine, no matter its discipline or origin. G For some complementary and alternative approaches, it remains to be seen whether they work, whereas for others there is enough evidence to make a determination of efficacy, safety, and side effects. G Treatments that have no efficacy in the method may still have positive effects by the placebo effect and may give the impression that they work when a disease is naturally self-limiting or when a condition changes over time.

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G Dangers of complementary and alternative practices include the general perception that they are harmless and natural. Benefits include the fact that supportive care improves wellbeing even if it cannot cure an underlying cause of illness.

CHAPTER TWENTY ARE YOU HAPPY YET?

How happiness contributes to health and longevity

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What is happiness and what influences it?

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Do people with serious illness have to stay upbeat to get well?

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Does money buy happiness?

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Which nations around the world are happiest?

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Does happiness influence health and longevity?

Every year on July first, Stanford University Medical Center is even more of a beehive than on other days. On that day, junior doctors are just beginning their residency or fellowship training to become specialists in their chosen field. In the Molecular Pathology laboratory, which performs diagnostic testing for inherited genetic diseases and an ever-increasing diversity of cancers, the vibe is no different. Several new fellows start their subspecialty training in the leading-edge area of pathology and genetics and navigate their path toward a busy and fulfilling career. As the attending physician and fellowship director, on one such July first I was responsible for patient care and, therefore, for all the patient cases that were to be reviewed and interpreted that day. As I walked through the lab, I could see that the new fellows were busy preparing their caseload for the

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daily sign-out session. Even on their first day, they are expected to present their patients’ history, clinical findings, the performed diagnostic testing, and their initial interpretation of the genetic findings. It is a tall order, so I decided to check in and to see whether they had any questions. After all, we cannot expect new trainees to already know what they came to learn! In the fellows’ area, I saw that the desks were stacked with big piles of case folders. A row of desktop computers and laptops were in the process of mutation database searches and genetic sequence analyses. One of the fellows was glued to the screen and looked determined to put it all together. I said to him, “Are you holding up?”. As he looked up from his work, he beamed a smile that contained a hint of hubris balanced with an enormous amount of enthusiasm and replied, “Holding up? I am thriving!”. I laughed at this unexpected answer and said something along the lines of “OK! Keep up the good work!”. And I knew right then that this “Can Do” mindset would be of tremendous benefit to him throughout the fellowship year, and that we had made an excellent choice by accepting him into our training program (as, indeed, his bright career trajectory has proven). The bottom line? Attitude is altitude. What, exactly, it was that enabled the fellow to give such an energetic answer on this stressful day we will probably never know, but I suspect that it was a combination of his innate thirst for learning, his feeling fortunate to have been accepted into a specialty program that he really wanted to be in, and being highly motivated to make this opportunity a success while having fun along the way. In that moment, he was happy, and he was resilient to the circumstances of starting a new job. After all, what is happiness if not perceived wellbeing? According to positive-psychology researcher Dr. Sonja Lyubomirsky, happiness is “the experience of joy, contentment, or positive well-being, combined with a sense that one’s life is good, meaningful, and worthwhile.”1

Happiness, when comprehensively assessed, is a combination of positive emotions that come and go (as emotions do) and a broader, more grounded feeling of purpose and fulfilment. It is characterized by contentment and by general satisfaction with one’s current situation.2 Regardless of definitions though, most people will recognize happiness when they experience it, however they define it for themselves. In my view, Charles Schulz captured it perfectly when he wrote:

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“Happiness is a warm puppy.”3

Whatever it is that floats your boat, happiness is not just particular to each person, it is also different between cultures. People use language to describe emotions such as happiness, but similar descriptions do not necessarily indicate the same emotional quality or experience. For example, in western individualistic cultures, happiness is generally associated with being upbeat, whereas that is not necessarily the case in eastern collectivist cultures where happiness may have less to do with excitement and more with being harmonious and dignified, and with feeling at peace.4 Happiness is cultural, influenced by religion and philosophy, and it can be both internal and external. It is also a temporary state, not to be confused with an attribute. Whereas it may last longer than pleasure, which is a more momentary and often sensory experience associated with, for example, a delicious taste of food, feelings during sex, or receiving praise for a job well done, it is not a permanent feature or a set trait. It can, and does, change.2 In the United States, almost a third of all people are faced with a mental condition sometime during their lifetime. Until recently, psychologists have primarily focused on helping those people and great strides have been made. But what about the other 70%? Is it not fair to say that, just in the way that absence of disease is not the same as health, the absence of mental illness does not correspond to happiness?5 A pioneer in the field of positive psychology, Dr. Martin Seligman explains that “The goal of understanding well-being and building the enabling conditions of life is by no means identical with the goal of understanding misery and undoing the disabling conditions of life.”6

In other words, the difference between positive psychology and (most of) traditional psychology is that the former advocates a “build what’s strong” approach that can augment the “fix what’s wrong” approach of the latter.7 Positive psychology aims to measure and to build human flourishing. And whereas traditional psychology and psychotherapy target psychopathology, Seligman identifies five pillars that contribute to a fulfilling life: 1) the positive emotion of happiness, 2) an active engagement with life and focused absorption (flow) during some of our activities, 3) authentic connection and positive relationships, 4) the perception of purpose and meaning, and 5) experiencing the satisfaction of accomplishment.5 As should be clear from this list of pillars for a fulfilling life, positive psychology goes well beyond people’s awareness of the feelings of

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happiness: it is not merely positive thinking or “happiology”.6 Regrettably, however, the unjustified extrapolation of positive thinking tends to lead to painful simplifications. My heart goes out to every cancer patient who has been subjected to well-meant but unhelpful platitudes such as, “Just stay positive. Positive thinking will get you back to good health”. If only it were that simple. The social expectation that one can and should remain cheerful in the face of life-threatening illness fosters counterproductive self-blame, a lonely inward-focus, and the suppression of sadness and anger, which are perfectly normal emotions in the face of adversity.8 I do not mean to suggest that a positive outlook is not helpful overall, but it certainly is no panacea. In fact, some people deal with anxiety by using a mechanism called “defensive pessimism”. By considering all the things that could go wrong, such people feel better prepared to address potential stumbling blocks, and, as a result, can work toward avoiding them. It is a coping strategy that illustrates that people have different ways of dealing with life’s challenges, often successfully. Health psychologist Dr. Lisa Aspinwall calls the popular focus on cheerfulness “the tyranny of positive thinking”, also known as “saccharine terrorism”.9 It is likely that, because of the uplifting message of hope, spurious claims about the curative force of positive thinking rapidly gained a foothold in the popular media, and spun off books with attractive but exceedingly simplistic messages. Researchers, in contrast, are much more restrained in their interpretations. Whereas researchers recognize that positive psychology can be a powerful ally in enhancing and maintaining quality of life for anyone, including cancer patients, they are careful not to jump to superficial conclusions.9,10 By learning more about the science of happiness and about the factors that contribute to human flourishing, and by then integrating the insights gained from these studies with “everyday” psychology, the field of psychology overall will be more reflective of human experience and will be well-positioned to help nurture good mental health.5 Let me illustrate the concept of happiness some more by having a closer look at what does (and what does not) make people happy. We can then consider what that implies for communities and on even larger scales. One uniquely compelling analysis on the topic comes from Harvard psychiatrist Dr. Robert Waldinger, who has shed light on lessons learned from the longest study on happiness.11 The Grant Study, then ongoing for 75 years, is one of the most comprehensive long-duration studies on adult development

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in history. Waldinger’s team and their predecessors observed how the lives of 724 men unfolded, from teen-age onward. Now in their nineties, only about 60 of these men are still alive. The study group, which was selected in the 1930s, is unusual in that two originally quite dissimilar groups were enrolled: sophomores from Harvard College and disadvantaged teens from the poorest neighborhoods of Boston. Over the decades that followed, the study included regular questionnaires, personal interviews with the men and their families at home, reviews of medical records, blood draws, and brain scans. The bottom line after all these years of research is this: at the heart of happy and healthy lives are good relationships. It may not be a mindblowing, earth-shattering finding, but it certainly is one of those easily forgotten or ignored things in the toil and moil of life. Fundamentally, relationships are a life-long, ongoing, nurturing endeavor. Especially young people are at risk of not grasping the plain concept that close relationships are more important to a good life than wealth, fame, and superior achievement. And that seems to be a constant over time, because it was the case for the young men who enrolled as subjects in the Grant Study and it still applies to recently surveyed millennials. Overall, the Grant Study revealed three big lessons about relationships: First, social connection is profoundly important. Conversely, loneliness is detrimental to happiness, health, and longevity. Second, what matters most is not just having close relationships, but, more importantly, their quality. One does not need many close relationships (a finding which will be a relief to introverts!), but they need to be good, warm, and supportive. So, despite not being alone, feeling lonely in a relationship such as a hostile marriage is not going to contribute to mental or physical health, and obviously not to happiness. And third, being able to count on another person prevents memory loss. Even continuously quibbling octogenarians who know that they can count on each other in times of need do better overall than people who do not have such a loyal buddy, and people who have that kind of support have better odds that their memory stays sharp into advanced age.11 Clearly, good relationships are important for wellbeing. But what about the relationship with money? Does money buy happiness? Here, the answer is not so straightforward, unless a possibly confusing response of “no-andyes” can be considered to be just that. Let me explain: whereas people are more satisfied with their lives when they have a higher income and more education, an American study

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published in 2010 indicated that the subjective sense of wellbeing increased with income for two-thirds of the population, but did not further increase above an income of about U.S. $75,000. It is useful to know that, at the time of the study, the average and median household income in the United States were $71,500 and $52,000 respectively, with approximately one third of households exceeding the $75,000 mark. The income at which happiness levels off probably needs to be adjusted for subsequent years. The actual number will also depend on people’s location and the associated cost of living, but it gives a rough idea. The conclusion of the study was that, above a certain level of stable income, emotional wellbeing is curbed by other factors, such as life circumstances.12 These could include less available time with family and friends, or less time for leisure activities, because of the work demands and expectations that tend to come with a higher income. Ironically, some of these pressures are also present at the low end of the income spectrum. What about countries other than the United States? Research across the globe confirms that there is an income limit above which happiness does not continue to increase, but that number should be specific to each nation. National levels of wealth do predict the happiness of nations, or, as researchers prefer to call it, explain cross-national differences in subjective wellbeing.13 More income may not buy more happiness beyond a certain point, but there is a distinction between differences and changes in financial situations. Contrasts in national wealth and differences in personal earnings between people within a country are not equivalent to sudden changes in financial circumstances. And one’s financial situation affects life satisfaction and happiness in different ways. The concept of life satisfaction is somewhat distinct from happiness itself, because life satisfaction reflects more of a measure or an evaluation of overall quality of life, whereas happiness is more of a measure or experience of daily emotions. Drastic changes in one’s personal financial situation include getting a hefty raise or winning the lottery. In such scenarios, having more money can certainly be exhilarating and create a burst of happiness, but does it create lasting happiness? Is there a shift in “happiness baseline”? As it turns out, it is the satisfaction with life that becomes and remains higher for those who experience an increase in wealth. An elevation of happiness itself typically does occur as well, but it generally does not last, in part because people adapt to their situation.

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Initially, adaptation to a changed state was attributed to a return to a hypothesized neutral state or to a personal happiness set point, but a subsequent body of research has shown that it is more nuanced than that.14,15,16 First, most people are above “neutral” in their experience of happiness. Which means that most people have a positive rather than a neutral baseline. This pans out in very diverse populations, ranging from the arctic Inuit to the sub-Saharan Maasai. Second, there is not one happiness baseline: the set point is different in separate individuals. Third, happiness is made up of several components and each of these dimensions of wellbeing can be in a different state at a given time. For example, a person may have good life satisfaction because of high achievement and a desirable job, but there may be a caustic work colleague who induces a lot of negative emotions. Or: a retired person may have fewer positive emotions because her physical wellbeing is declining, but there may also be fewer negative emotions because of greater contentment and a loving relationship with her partner, children, and grandchildren. Fourth, even within one person, the happiness baseline is not static but rather depends on life’s conditions, as I will explain in a moment. And fifth, some people adapt more readily than others, so that the happiness baseline is more flexible for some and more stable for others.13 The bottom line is that finding similarities and unifying concepts is useful, but people do not all march to the same tune. The current understanding of the determinants of happiness differentiates several components.15 Some people are happier than others, just based on biology. On average, 30-40% of the individual differences seem to be genetically determined, and 60-70% can be attributed to other factors, including personal actions and thoughts, as well as external circumstances. This is good news, because even though some people will be natural worrywarts instead of Pollyannas, or have curmudgeonly tendencies instead of happy-camper traits, the lion’s share of happiness can be influenced and modified. Happiness is not just a matter of personality traits. One interesting aspect of the biology of happiness is that people seem to have those individual set points for happiness that I mentioned earlier. Daily events can change the extent to which someone feels happy, but the degree of happiness will tend to trend back, over time, to a personal set point for overall happiness. And although it was previously thought that this set point was fixed within one person, more recent studies have demonstrated that this baseline can change, based on circumstances and living environment. For example, if someone lost the love of their life or was unemployed for a time, enduring negative effects on happiness result. And some positive

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experiences, such as migration away from a war zone to a safe and more prosperous country can also lastingly move the baseline, albeit in a positive direction in this case. Another component that helps determine happiness is the satisfaction of valued goals. If key private needs are fulfilled, people are likely to feel satisfied with their lives. That these goals are very personal is illustrated by the fact that both the Amish and multimillionaires might experience similar levels of life satisfaction. Their desires, goals, and perceived needs may be quite different, but as long as these are met within their own framework of reference, they each feel content. A third building block of happiness depends on someone’s mental state. Happiness is influenced by how people perceive their own situation, especially in comparison to others. If someone makes $100,000 per year, for example, happiness appears to depend, in part, on what others in the same neighborhood make, even though everyone may have all their basic needs covered and may be able to live comfortably. If all the neighbors make less money and therefore, relative to them, someone is rich, then that person is likely to feel happier than another person who earns less than all his neighbors. So you see: the comparing mind can thwart an otherwise perfectly good situation! This is the “keeping up with the Joneses” peculiarity. The tendency to compare ourselves and what we have to others and to what they have is already obvious in children. An example is when the challenge presents itself that one child has a highly desirable toy, while another does not. Suddenly, parents find themselves scrambling for diplomacy and arbitration in the midst of massive potential for drama. A fundamental life lesson for children and adults, however, is that more is not better, more is just more. That is, having more stuff does not create more happiness (it actually can decrease it). Nevertheless, money can buy happiness in certain, perhaps unexpected, ways. UC Berkeley sociologist Dr. Christine Carter describes that money can provide access to a greater overall sense of wellbeing because it opens up an advantageous ecology. This is especially the case in the life of children, when money can secure greater wellbeing simply because of the opportunities it can open up in the child’s living environment. A child of a more affluent family may have more comprehensive healthcare, live in a safer neighborhood, go to a better school, have greater access to various social environments that facilitate a feeling of belonging, and perhaps have the privilege of more quality time with one or both parents.17 These factors of emotional and physical wellness enhance children’s likelihood to flourish. Money not only offers opportunity, but also influences

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the larger environment in which children grow up. Their childhood is inexorably intertwined with their community, with society, and with geopolitical realities. Ultimately, their happiness over a lifetime depends on internal and external qualities, and on the opportunities to build a good life, together with the actual outcomes of their efforts. Dr. Ruut Veenhoven of the Erasmus Happiness Economics Research Organisation (EHERO), described happiness as a composite of 1) the livability of the environment (an external factor that depends on chances in life), 2) life-ability or adaptive potential to cope with life’s challenges (an internal factor that also depends on the opportunities one has in life), 3) the usefulness of life (an external but subjective judgment based on life results - but who is or are to judge?), and 4) satisfaction with life (an internal assessment, based on someone’s own appreciation of outcomes).18 Thus, the happiness of children and adults must be considered beyond the boundaries of strictly personal experience. It is also determined by factors that originate in communities and societies and reach all the way up to global influences. In 2012, the United Nations identified the pursuit of happiness as a fundamental human goal and right. With that declaration, May 20 was designated as the annual International Day of Happiness, and U.N. Secretary-General Ban Ki-moon (who served in that role from 2007 to 2016) stated that “Gross National Product has long been the yardstick by which economies and politicians have been measured. Yet it fails to take into account the social and environmental costs of so-called progress. We need a new economic paradigm that recognizes the parity between the three pillars of sustainable development. Social, economic and environmental well-being are indivisible. Together they define gross global happiness.”19

It has been substantiated by research that well-organized nations with greater economic and political freedom and with better gender equality, in which corruption is low, the rule of law prevails, and government organizations function reliably well, achieve a higher level of happiness for their citizens than nations that are lacking in these aspects. And life in richer nations offers greater average happiness, with the caveat that economic growth in itself has a more positive effect on happiness in developing nations, as compared to the impact of such growth in wealthy countries. In addition, whereas GDP per capita is strongly associated with overall wellbeing, the correlation with positive emotions is not as pronounced. Whether people can enjoy their lives and smile frequently, for example, is more dependent on whether they are able to choose how they spend their

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time, rather than on whether a country is rich or poor.13,15,19 Self-determination and having the option to make personal choices contribute to individual and societal wellbeing, possibly because they enable people to pursue, and perhaps approach, their own vision of an ideal way of living. But what about the environment? Do good lives have to cost the earth? For Nic Marks, who specializes in the—for a statistician—unusual niche of happiness, this question became a driving force. By creating the Happy Planet Index, he and his team developed a measure of progress that scores nations based on how successful they are in providing happy and healthy living conditions for their citizens. For each country, they analyzed ecological footprint (resource use and environmental burden), life expectancy, wellbeing, and inequality, to thus arrive at a qualitative and quantitative score of wellbeing.20,21 Some countries (such as the United States, some European nations, and a few Gulf states) were found to score high on wellbeing. The associated environmental cost, however, was very high as well. That this does not have to be the case is demonstrated by, for example, the profile of some Latin American countries such as Costa Rica, where life expectancy and wellbeing are both high. Costa Rica, in fact, surpasses the United States in these two benchmarks, with 79.1 years of life expectancy and a wellbeing score of 7.3 out of 10, compared to 78.8 years and a score of 7 for the United States.21,22,23 In Costa Rica, the quality of healthcare and education is good and the environment has been prioritized. As a result, it was ranked at the top of the Happy Planet Index in 2009, 2012, and 2016. That does not mean that there is no room for improvement, but in terms of sustainable wellbeing and striking the balance between the needs of people and the planet, it certainly is a world leader.20,21 A different measurement of global data on national happiness, independent from the Happy Planet Index, is the World Happiness Report. This United Nations report ranks 156 countries by how happy their citizens perceive themselves to be. The World Happiness Report makes use of the science of wellbeing to analyze a variety of subjective wellbeing measures in a coherent, reliable, and valid way.24 In the seventh annual report, using six key variables (GDP per capita, social support, healthy life expectancy, freedom to make life choices, generosity, and perceptions of corruption), life evaluations for each nation, averaged over the years 2016-2018, showed that Finland, Denmark, Norway, Iceland, and the Netherlands were the happiest countries. Rwanda,

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Tanzania, Afghanistan, the Central African Republic, and South Sudan were at the bottom of that list of 156 countries. Just for comparison, on this specific analysis, Costa Rica was in place 12 and the United States ranked 19th. Any kind of evaluation of happiness should bring up the question of causality. Because how does happiness arise? As discussed, it is not something that solely depends on internal factors. Living conditions influence wellbeing, and, at the very least, modify the chances for happiness to come about. It is compelling to think of happiness and circumstances as mutual amplifiers, with the arrow of causality traveling in both directions.15 This kind of empowerment makes sense for the link with health, as well. Happiness influences health and vice versa: the degree to which someone is healthy will influence subjective wellbeing. In the same vein, social connections generate happiness and benefit health, whereas social isolation diminishes wellbeing and predisposes to illness. Also, someone who is happy is much more likely to have and sustain good social interactions than someone who is unhappy or depressed. The causality of happiness is, it seems therefore, at least in part a two-way-street. The notion that health and happiness should be intertwined seems intuitively right. Today, however, there also is evidence to back that up. Happiness contributes to health and to longevity, although unhappy people do not necessarily live shorter lives.15,25,26,27,28 One differentiating determinant may well be behavior. People who are happier tend to have better health habits. For example, they are more likely to have an active lifestyle and to be nonsmokers.26 Beyond health habits, several body systems such as the cardiovascular, hormonal, and immune systems are in better shape in people who feel happy and well, although here, too, the arrow of causality is likely bidirectional. And happiness has been associated with a reduced risk of systemic inflammation and of some serious diseases such as stroke and high blood pressure, which seems a logical consequence of the proper functioning of various body systems. But happiness certainly is no guarantee for good health, because unfortunately there are no guarantees in life, only likelihoods. And everybody knows (a story about) someone (somewhere) (maybe) who had the audacity to always smoke and drink and be a cantankerous pain in the butt, and who nevertheless (just to spite everyone around him) lived to 100 on a diet of Twinkies and Spam (okay, maybe that is pushing it, but I am trying to make

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a point...). These outlier stories may offer hope to anyone who is not ready to accept the conditions that increase the odds for a long and happy life, but these tales do not make a body of evidence. That, fortunately for the rest of us, points in a very different direction. Dr. Ong, who is a Professor of Human Development at Cornell University, summed up the next steps toward an increased understanding of happiness: “In short, comprehensive understanding of happiness and health will require that we move beyond simply asking whether happiness is good for health to a serious consideration of measuring happiness in context.”28

Such context is important because it can more accurately probe individual risks and strong points. It may include a wide range of personal and environmental factors, ranging from genetics and cell biology to someone’s history and culture. This is an exploration that is as exciting as it is promising, and it is crucial for better insight into how human emotions impact the health of groups of people, and influence it on the level of the individual. Happiness, with its elements of life satisfaction (evaluation), recent feelings (hedonic aspects), and purpose (eudaimonia), is a key element of the human quest.25 And its importance is recognized by scientists and nonscientists alike. As the 14th Dalai Lama said: “Our survival is based on hope—hope for something good: happiness. Because of that, I always conclude that the purpose of life is happiness. With hope and a happy feeling, our body feels well. Therefore, hope and happiness are positive factors for our health.”29

I subscribe to the possibility of increased wellbeing for all. Happiness depends in part on how you interpret your circumstances and on how you perceive yourself compared to others. Happiness is, to some extent, a matter of the mind: a mind that can play tricks on you, but that also can wake up to the fact that you are worthy. That realization, by leaps and bounds, surpasses the bleak prospect of simply holding up, and instead fosters a healthy living environment in which health, happiness, and people can genuinely thrive.

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Key points: G Happiness, a component of wellbeing, is personal and influenced by culture. G Happiness is multi-faceted and depends on factors such as relationships, engagement, and accomplishment. It is influenced by genetics, the satisfaction of key needs, and one’s mental state. G The broad categories of happiness are life satisfaction (evaluation), recent positive and negative feelings (hedonic aspects), and purpose (eudaimonia). G Positive psychology is a field that studies happiness in a scientific way. It aims to measure and enable human flourishing. G Money does influence happiness, up to a point. And living conditions influence personal happiness as well as national happiness. G Happiness contributes to health and longevity.

CONCLUSION A TIME OF HOPE

~Vires acquirit eundo~ [We gather strength as we go]

CONCLUSION

On the path to health and wellbeing, we need to understand where we came from, take a good look at where we find ourselves at present, envision a compelling future, and take some time for introspection: which aspects of your health and wellbeing can use a boost? With this book, I hope to have demystified the process of vetting medical information through science, the only proven method that systematically and reproducibly sifts through heaps of data and eventually can determine what stands the test of time. The checks and balances in the scientific process are of vital importance to reaching accurate conclusions about medical treatments. This process should be the touchstone for every single person who provides and who receives healthcare. Life simply is too precious to be bamboozled by empty promises. You are too precious. I am convinced that some positive change is possible for everyone. The first step toward that, however, is finding reliable information. Once we have that, we can make informed decisions that sustain our health and nourish wellness. Time and again, we must avoid falling into the distracting trap of deception. We need to take charge of where we focus our efforts, and wisely act upon our intentions whenever we are ready. And ready we should be, at least for doing something, knowing that a critically important part of any change is to stop being our own worst enemy. Making good choices is simple, but implementing them is not easy. Whereas all this is important for each of us individually, it also applies to the communities in which we live, including the delivery of healthcare within those communities. I see healthcare as a fundamental right, but the current setup has become unsustainable. Healthcare delivery has suffered from the pressures stemming from a broken system that has fallen victim to the politics and skewed dynamics of care and reimbursement. This is especially obvious in the U.S., but other countries are trending toward the same erosion of care. Healthcare also has become unsustainable because of the rapid rise in serious risk factors for disease. The world is facing increasing health

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disparities, an obesity epidemic, and an escalation of chronic diseases, most of which are related to lifestyle. The COVID-19 pandemic, caused by an acute infectious disease, has underscored the influence on patient outcomes of underlying chronic medical conditions such as diabetes and heart disease. Such disorders amplify the most serious symptoms of COVID-19 and contribute to the need for hospitalizations and the alarming number of fatalities worldwide. Poor health is a bad starting point. Good health at baseline, in contrast, significantly protects against a severe disease course. And that not only applies to COVID-19; it applies to any new health challenge one might face. The search for new medical cures and treatments continues, and while we do not have all the answers, science is giving us many. Decades of studies are showing us that there is reason for hope because there is something we can do: we know how to improve overall health, and can take measures that decrease the risk of widespread chronic diseases and even common cancers. If individual people and societies are to improve overall health, then health care must return to the founding principles of medicine. This return is not a step back to the “olden days”, but rather a step up from a complacent approach to care that settles for management of largely preventable chronic diseases. Healthcare needs to offer the tools of disease prevention and should provide effective treatment of the root causes of disease. It can do so by utilizing the proven steps that lead to better general health and that, in many cases, can lead to disease reversal. This kind of care does not merely manage symptoms but addresses the very sources of many illnesses that are prevalent today. And it is a veritable leap from the band aid that obscures the wound, to an actual restoration of health. The prevention, treatment, and reversal of chronic conditions through lifestyle changes is not only effective and scientifically validated, but it is also within range. It is affordable, accessible, and sustainable. Sensible adoption of this concept nourishes the health of individuals and of the entire healthcare system, which could become more equitable and inclusive, and viable once more. The tools for this kind of medicine have been highlighted throughout the book. A whole food, plant predominant eating pattern, regular moderate physical activity, the avoidance of harmful substances, positive relationships, stress management and good sleep are separate but interconnected pieces that foster health and that each can be targeted for improvement. In

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medicine, these principles can be applied to patient care through guidance and through prescription of lifestyle changes. As such, they can be used as the primary treatment for conditions in which lifestyle plays a major role. In all this, a patient is not a passive recipient of care, but rather at the wheel in deciding which health challenges she or he is ready to take on. It is a collaborative effort between patients and supportive healthcare providers. Every change presents inevitable barriers, but the benefits are greater. And although intensive lifestyle changes will lead to the largest amount of positive change, even baby-steps are steps forward, taken one step at a time. This is an exciting time to be alive, with unprecedented scientific breakthroughs for diagnosis and treatment, and groundbreaking insights into how things work. Our life depends on science in so many ways, even as our perceptions of what leads to wellness are colored by cultural influences, subtle messaging, and, at times, egregious manipulation. I hope to have inspired you to see that better health and wellbeing are within reach. You now have the knowledge to steer clear of smoke and mirrors. You are empowered to be an advocate for health, wellbeing, and fulfilment. You have every right and reason to reflect on what is most important to you, so that you may receive—or provide—healthcare that truly heals. I have shared my vision for a sustainable way forward, and offer these parting words: Have courage. You matter. Be well and do well. Live your life.

BIBLIOGRAPHY

A note on the Bibliography The Bibliography presented in this section is organized by appearance in each chapter. The purpose of these references is to help you find a relevant source for a statement in the book and/or to provide a connection for finding additional information about a topic that was addressed. The references cited are therefore representative of the body of literature that I consulted, but in no way meant to be exhaustive, given that I reviewed and considered numerous sources before and during the writing of this book. I analyzed and interpreted these sources to the best of my ability. For the benefit of further exploration, I included what I consider to be the most helpful references that illustrate the concepts described and the specific points made in the book.

Introduction 1.

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Chapter One: A fountain of information 1. 2.

Handley, R., and Neff, P. 1987. Anxiety & panic attacks – their cause and cure. New York, N.Y.: Random House Publishing Group, a division of Random House. Singh Ospina N., Phillips K.A., Rodriguez-Gutierrez R., CastanedaGuarderas A., Gionfriddo M.R., Branda M.E., Montori V.M. 2019. “Eliciting the patient’s agenda- secondary analysis of recorded clinical encounters”. J Gen Intern Med. No. 34: 36-40. https://doi.org/10.1007/s11606-018-4540-5.

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Chapter Two: In the know 1. 2. 3. 4.

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Chapter Three: Know way 1. 2. 3. 4. 5. 6.

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This website is in Dutch, but has an example image of an alcove bed. It also explains how these beds were used. Marnegebied. 2003. “De bedstee”. Accessed June 4, 2021. https://www.marnegebied.nl/de_bedstee.html This website is in Dutch, IsGeschiedenis. ‘n.d.’, “De geschiedenis van het slaapcomfort”. Accessed June 4, 2021. https://isgeschiedenis.nl/reportage/de-geschiedenis-van-hetslaapcomfort. It can be used together with Worsley, L. 2011. “History of the home”. Accessed June 4, 2021. https://www.bbc.co.uk/history/british/middle_ages/history_of_hom e.shtml, which offers relevant information in English. Withers, M., Kharazmi, N., Lim, E. 2018. “Traditional beliefs and practices in pregnancy, childbirth and postpartum: A review of the evidence from Asian countries”. Midwifery, No. 56: 158-170. https://doi.org/10.1016/j.midw.2017.10.019. Hsu Oh, L. 2017. “I tried the Chinese practice of ‘sitting the month’ after childbirth.” The Washington Post, January 8, 2017. https://www.washingtonpost.com/national/health-science/i-triedthe-chinese-practice-of-sitting-the-month-afterchildbirth/2017/01/06/54517ee0-ad0b-11e6-a31b4b6397e625d0_story.html?utm_term=.a43784ffaa19 World Health Organization. 2019. “Maternal mortality fact sheet”. Accessed June 4, 2021. https://www.who.int/news-room/fact-sheets/ detail/maternal-mortality Teh, V. 2017. “Should you avoid bathing or leaving the house after childbirth, as Chinese tradition dictates?” South China Morning Post, May 27, 2017. https://www.scmp.com/lifestyle/health-beauty/ article/2095710/should-you-avoid-bathing-or-leaving-house-afterchildbirth Liu, Y.Q., Maloni, J.A., Petrini, M.A. 2014. “Effect of postpartum practices of doing the month on Chinese women’s physical and psychological health”. Biol Res Nurs, No. 16: 55-63. https://doi.org/10.1177/1099800412465107. Doyle, D. 2005. “Ritual male circumcision: a brief history”. J R Coll Physicians Edinb, No. 35: 279-285. World Health Organization. 2010. “Neonatal and child male circumcision: a global review”. Accessed May 8, 2019. https://www.who.int/hiv/pub/malecircumcision/neonatal_child_MC _UNAIDS.pdf Aggleton, P. 2007. “‘Just a snip’?: a social history of male circumcision”. Reprod Health Matters, No. 15: 15-21.

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Chapter Four: Under the influence 1.

2.

3. 4. 5.

6.

7.

8. 9.

Online explanation (in German) of the origin of the German phrase “dreimal schwarzer Kater”. Loch, Sebastian. 2020. “Top 5 Katzensprichworte”. Accessed June 5, 2021. https://www.majaempfiehlt.de/sprichworte Schulz, H., and Basler, O. 1995. Deutsches Fremdwörterbuch: aPräfix - Antike. Berlin: De Gruyter. See “Abrakadabra”, p.26. https://books.google.ch/books?id=DA1-fknhY1cC&pg=RA1PA27&lpg=RA1-PA27&dq=Deutsches+Fremdwörterbuch+Antike +Abrakadabra&source=bl&ots=_fSv5i1DtR&sig=ACfU3U1buch0 Hebn4pWdqX3Rn2zst1mTEQ&hl=en&sa=X&ved=2ahUKEwjcm qm1z4viAhVKwqYKHR7rADMQ6AEwAXoECAgQAQ#v=onep age&q=Deutsches%20Fremdwörterbuch%20Antike%20Abrakadab ra Wikipedia. 2021. “Thirteenth floor”. Accessed June 5, 2021. https://en.wikipedia.org/wiki/Thirteenth_floor Perkins, B. 2002. “Bottom line conjures up realty’s fear of 13.” Accessed November 16, 2018. http://realtytimes.com/rtpages/20020913_13thfloor.htm Li, S. 2015. “Skipping the 13th floor.” The Atlantic, February 13, 2015. https://www.theatlantic.com/technology/archive/2015/02/skippingthe-13th-floor/385448/ Valtin, H. 2002. “‘Drink at least eight glasses of water a day.’ Really? Is there scientific evidence for ‘8 x 8’?” Am J Physiol Regul Integr Comp Physiol, No. 283: R993-1004. https://doi.org/10.1152/ajpregu.00365.2002. Dartmouth Geisel School of Medicine, DMS news. 2002. “‘Drink at least 8 glasses of water a day’ - Really?” Accessed June 5, 2021. https://geiselmed.dartmouth.edu/news/2002_h2/08aug2002_water.s html Hydro Coach. ‘n.d.’ “Drink reminder app.” Accessed June 5, 2021. https://hydrocoach.com Townson, S. 2016. “Why people fall for pseudoscience (and how academics can fight back)” The Guardian, January 26, 2016.

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Chapter Five: Rising to the bait 1. 2.

3.

4. 5.

6. 7. 8.

9.

Project Implicit. 2011. “About us”. Accessed June 6, 2021. https://implicit.harvard.edu/implicit/aboutus.html Guy, G.P., Berkowitz, Z., Everett Jones, S., Watson, M., Richardson, L.C. 2017. “Prevalence of indoor tanning and association with sunburn among youth in the United States”. JAMA Dermatol, No. 153: 387-390. http://dx.doi.org/10.1001/jamadermatol.2016.6273. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. 2017. “Skin Cancer Prevention Progress Report 2017”. Accessed June 6, 2021. https://www.cdc.gov/cancer/skin/pdf/SkinCancerPreventionProgres sReport_2017.pdf World Health Organization. 2017. “Artificial tanning devices: public health interventions to manage sunbeds.” Accessed June 6, 2021. https://www.who.int/uv/publications/artificial-tanning-devices/en/ Holman, D.M., Fox, K.A., Glenn, J.D., Guy, G.P., Watson, M., Baker, K., Cokkinides, V., Gottlieb, M., Lazovich, D., Perna, F.M., Sampson, B.P., Seidenberg, A.B., Sinclair, C., Geller, A.C. 2013. “Strategies to reduce indoor tanning: current research gaps and future opportunities for prevention”. Am J Prev Med, No. 44: 672681. http://dx.doi.org/10.1016/j.amepre.2013.02.014. Olson, J.A., Amlani, A.A., Raz, A., Rensink, R.A. 2015. “Influencing choice without awareness”. Conscious Cogn, No. 37: 225-236. http://dx.doi.org/10.1016/j.concog.2015.01.004. Christin, A. 2018. “Counting clicks: Quantification and variation in web journalism in the United States and France”. AJS, No. 123: 1382–1415. https://doi.org/10.1086/696137. De Witte, M. 2018. “What this Stanford scholar learned about clickbait will surprise you”. Stanford News, March 21, 2018. https://news.stanford.edu/2018/03/21/this-stanford-scholar-learnedclickbait-will-surprise/ Dachis, A. 2011. “How advertising manipulates your choices and spending habits (and what to do about it).” Lifehacker, July 25, 2011. https://lifehacker.com/how-advertising-manipulates-your-choicesand-spending-h-30812671

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Chapter Six: So what, who cares? 1. 2. 3. 4.

5. 6. 7. 8. 9.

Ellis, M. 2019. “The 8 best fact-checking sites for finding unbiased truth.” MakeUseOf, December 8, 2019. https://www.makeuseof.com/tag/true-5-factchecking-websites/ Snopes. 2008. “How are baby carrots made”. Accessed June 7, 2021. https://www.snopes.com/fact-check/baby-carrots/ United States Department of Agriculture. Guidance. 2018. “The use of chlorine materials in organic production and handling.” United States Department of Agriculture, September 5, 2018. Baker, S.A., and Rojek, C. 2019. “The scandal that should force us to reconsider wellness advice from influencers.” The Conversation, May 21, 2019. https://theconversation.com/the-scandal-that-should-force-us-toreconsider-wellness-advice-from-influencers-117041 Donelly, B. and Toscano, N. 2017. The woman who fooled the world – Belle Gibson’s cancer con. Melbourne: Scribe Publications. Suggett, P. 2019. “Is advertising harmful to society?” The Balance, updated June 25, 2019. https://www.thebalancecareers.com/isadvertising-harmful-to-society-38971 Ventola, C.L. 2011. “Direct-to-consumer pharmaceutical advertising: therapeutic or toxic?” P&T, No. 36: 669-684. Schwartz, L.M., Woloshin, S. 2019. “Medical marketing in the United States, 1997-2016”. JAMA, No. 321: 80-96. http://dx.doi.org/10.1001/jama.2018.19320. Greene, J.A., Watkins, E.S. 2015. “The vernacular of risk— rethinking direct-to-consumer advertising of pharmaceuticals”. N Engl J Med, No. 373: 1087-1089. http://dx.doi.org/10.1056/NEJMp1507924.

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Chapter Seven: Public relations 1. 2. 3.

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Chapter Eight: Healers in the making 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

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Chapter Nine: Science, not fiction 1. 2.

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Chapter Ten: Windows of opportunity 1.

2.

3.

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Chapter Eleven: What is health? 1.

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Chapter Twelve: The instruction manual 1. 2. 3. 4. 5.

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Chapter Thirteen: Keeping it together 1. 2. 3. 4.

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Chapter Fourteen: The matter of the mind 1. 2. 3. 4. 5. 6. 7.

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INDEX

8x8 rule, 45 a posteriori knowledge, 23 a priori knowledge, 22 AAAS, 81 academic institutions, 117 accepting, 54 access to healthcare, 16 accuracy, 123 acupuncture, 237 acute inflammation, 222 acute stress, 171 acute stress response, 170 adaptability, 132, 134 adaptation, 162 addiction, 138, 188 adolescence, 55 advanced age, 163 adversity, 132, 252 advertising, 58, 59, 62, 67, 69, 70, 212, 213, 217 affirmation, 51 ageing, 163, 188, 221, 224 age-related disorders, 163 Aggleton, 40, 41 AIDS, 121, 122 alcohol, 67 alcove bed, 36 allopathic medicine, 237, 240 Alon, 112 alternative cancer treatment, 66 alternative facts, 88, 235 alternative medicine, 71, 235, 238, 243 altitude sickness, 150 Amazon, 15 American Association for the Advancement of Science, 81 American Cancer Society, 244 American Heart Association, 212

anatomy, 90, 91, 93 Angelou, 139 antibiotics, 188 anticipation, 181 anticipation effect, 186 anxiety, 11, 170, 202 Aristotle, 22, 89, 105 Asian cultures, 37 Aspinwall, 252 astrology, 245 Augustin, 29 automatic preferences, 55 autonomic nervous system, 170, 174 autonomy, 134 autopsy, 95 autosomal recessive, 142 Avicenna, 91 Ayurveda, 238 Bacon, 25 Baillargeon, 34 Baker, 66 balance fallacy, 73 Baron, 16 barriers, 116 barriers to weight loss, 215 Baumeister, 203, 204 behavior, 164 beliefs, 82, 85, 92 bench to bedside, 78 Bhutan, 233, 234, 246 bias, 69, 104, 118, 119, 123, 182 biology of happiness, 255 biomarkers, 224 biomedical healthcare, 172 biopsychosocial, 172 blood glucose, 161 blood sugar, 161 Blüher, 214 BMI, 214

308 body and mind, 166, 167, 169, 171, 177, 178 body mass index, 214 brain, 51, 168, 173 brain development, 34 breakfast, 211 breakthrough, 72, 94 breast cancer, 77 Briggs, 242 Buddhist, 57 burnout, 200, 201 busyness, 198 caffeine, 210 calorie consumption, 210, 215 Cambodia, 17 Canada, 176 cancer, 71, 72, 76, 107, 109, 125, 152 cancer treatment, 66 carbon dating, 103 carcinogenic, 56 cardiovascular disease, 196, 229, 230 Carney, 162 Carter, 256 case study, 107 causes of chronic inflammation, 224 CDC, 15, 187 cell division, 145 Centers for Disease Control and Prevention, 15 central nervous system, 168, 175 CF, 77 CFTR gene, 77 Chambliss, 168 character, 81 chemistry, 93 chemotherapy, 77 chi, 37 Chigwedere, 122 Child abuse, 246 childbirth, 36, 38 Chile, 150 China, 36, 37 chiropractic, 238 chlorine, 65

Index choice, 11, 57, 61, 62, 70 cholesterol, 230 Christian, 33 Christin, 58, 59 chronic condition, 15, 66, 246 chronic disease, 6, 125, 131, 151, 152, 160, 220, 222, 224, 265 chronic inflammation, 222, 223, 224 chronic pain, 243 chronic stress, 195, 202, 205 circadian rhythm, 155, 156 circumcision, 39, 40, 41, 42 Clackamas Volunteers in Medicine, 17 clickbait, 50 climate change, 159 clinical research, 100 clinical trial, 41, 181, 182, 186 cochlear implant, 143 cognitive bias, 46, 47 cognitive flooding, 12 cognitive misers, 82 collaboration, 111 collective knowledge, 21 collectivist cultures, 251 Collins, 111 color schemes, 60 common belief system, 33 communication, 70, 182 competence, 80 competition, 118 complementary medicine, 236, 237, 239 complete health, 130 confidence interval, 123 confinement, 38 confirmation bias, 46 congenital, 145 connection, 240 consumers, 60 continuing medical education, 14 contraindications, 69 control group, 182 controls, 123, 182 controversy, 41, 73 convenience foods, 212

On the Path to Health, Wellbeing, and Fulfilment: To Your Health conventional approach, 66 Cooper, 119 core beliefs, 82 coronary artery disease, 152 cortisol, 171, 175 cost of healthcare, 191 Costa Rica, 258 Couric, 116 COVID-19, 229, 265 craniosacral manipulation, 71 Crislip, 122 critical thinking, 34 cryonics, 238 cultural beliefs, 6 cultural framework, 33 culturally sensitive patient care, 17 culture, 59, 85, 132, 251 curriculum, 15 cystic fibrosis, 77 Czechoslovakia, 26 Darwin, 47, 120 death, 71 decision-making, 203 defense mechanisms, 202 defensive pessimism, 252 definition of health, 130, 131, 133, 136 definition of knowledge, 21 dehydration, 45 denial, 54 deoxyribonucleic acid, 143 depression, 174, 202 Descartes, 167 determinants of happiness, 255 determinants of health, 135, 139 development, 162 diabetes, 160, 161, 213 diagnostic laboratory, 110 diagnostic microbiology, 17 Diagnostic Microbiology Development Program, 17 diet, 216, 230 diet culture, 208 diet industry, 217 dietary supplements, 70, 189, 190, 191

309

dieting, 217 digestive system, 175, 177 digestive tract, 209 direct-to-consumer, 68 discovery, 80 disease management, 188 disease reversal, 188, 265 disruptive technology, 152 dissection, 90, 91, 93 distress, 195 diversity, 119 DNA, 103, 111, 115, 143, 148 doctrine, 92 Dor Yeshorim, 84 double-blind, 182 drinking, 45 drug, 68 drug interactions, 188 drug pipeline, 186 DTC, 68, 69, 70 Dunning-Kruger effect, 47 Easter bunny, 33 economic development, 199 education, 15, 46 educational advertising, 67 efficacy, 186, 190, 236, 237, 241 ego depletion, 204 Einstein, 104 Ekstein, 84 Elisabeth of Bohemia, 167 Emerson, 25 emotional eating, 208 emotional states, 166 emotions, 60, 252 empathy, 61 endocrine system, 160, 171 endorphins, 210 energy, 228 energy-efficiency, 159 environment, 131, 134, 146, 155, 156 epidemiology, 97 epigenetics, 147, 148 epilepsy, 162 epistemologist, 21 equality, 119

310 equity, 159 Erasistratos, 90 erroneous credulity, 49 erroneous incredulity, 49 Esselstyn, 112 Esteller, 147 ethical, 124, 184 ethical standards, 108 ethnic groups, 40 eudaimonia, 260 European average height, 35 European Union, 187 eustress, 194 evidence, 4, 5, 105, 237, 241, 260 evidence-based, 98 evidence-based evaluation, 241 evidence-based medicine, 69, 105, 106, 109, 124, 237, 246 experience, 93 experimentation, 98 experiments, 91 expert, 11, 18, 28, 93 explicit knowledge, 23 exposome, 151 extremes, 162 fact finding, 65 fact-checked, 51 factual knowledge, 35 false belief, 34, 35, 46 false claims, 65, 242 fast food, 212 FBN1, 102 FDA, 56, 182, 190, 191 feedback loop, 156, 160, 161 fever, 159 field of medicine, 13 fight-or-flight, 170 Fischer, 4 fitness, 228 fixed beliefs, 33 Fleming, 110, 111 fluid intake, 45 Food and Drug Administration, 56, 182 food consumption, 211 food production, 210

Index forcing, 58 Fraga, 147 frame of reference, 33 France, 58 Francke, 101 Franklin, 183, 220 fraud, 65, 66 free will, 57 fulfilling life, 251 fulfilment, 250 funding, 117, 118, 178 Galen, 91, 120 Gassendi, 167 gatekeeper, 69 gender difference, 157, 158 gene expression, 144, 147 genes, 172 genetic counseling, 78 genetic predisposition, 150 genetic risk, 151 genetic testing, 77, 84, 142 genetics, 5, 142, 152, 225, 249 genome, 143, 144, 151, 152, 185 genomic, 76 genomic testing, 76 genotype, 147 germ-theory, 97 Gervais, 246 Gibson, 65, 66 GJB2, 142 global research funding, 117 globalization, 210 gold standard, 13 grant proposal, 117, 118 Grant Study, 252, 253 Greally, 148, 149 Greece, 89 Greger, 105 grieving process, 137 Grimes, 72, 105 gross global happiness, 257 growth, 145 Guarneri, 240 Guillotin, 183 gut-brain communication, 175, 176 Hanson, 49

On the Path to Health, Wellbeing, and Fulfilment: To Your Health happiness, 2, 250, 251, 254, 257 happiness baseline, 255 Happy Planet Index, 258 Harvard T.H. Chan School of Public Health, 37 Harvard University, 88 Harvey, 94 Hawking, 79, 104 Hawley, 124 healing, 177 healing practices, 239 healing traditions, 237 health, 5, 130, 136, 165, 221, 226 health advances, 125 health and wellbeing, 11, 136, 189, 191, 266 health as a resource, 134 health behavior, 189 health checks, 227 health communication, 18 health experts, 19 health food, 190 health habits, 259 health improvement, 138 health information, 66 health literacy, 16 health outcomes, 16 health risks, 57 health rumors, 62 healthcare, 62, 166, 240, 264 healthcare costs, 192, 230, 243 healthcare crisis, 201 healthcare facilities, 18 healthcare information, 69 healthcare professionals, 12 healthcare provider, 12, 18, 39, 133 healthcare spending, 191 healthcare system, 16 healthcare team, 76 healthspan, 220, 221, 222 healthy, 129 healthy habits, 228 healthy lifestyle, 216 healthy lifestyle behaviors, 151 hearing loss, 142 heart disease, 151, 152, 174, 229

311

heat loss, 157 Heaviside, 3 height, 35 Henikoff, 148, 149 herbs, 242 Herophilos, 90 health-centered science, 138 historic beliefs, 37 historic knowledge, 33 history of knowledge, 88 history of science, 89 HIV, 41, 121, 122 Hof, 162 home-cooked meals, 211 homeopathy, 237, 242 homeostasis, 155, 159, 161, 162, 163, 170 homeostatic range, 156 hormones, 157 HPV, 71 Hudson River, 116 human genome project, 111 human immunodeficiency virus, 41 Human Papillomavirus, 71 Hunter, 95 Huxley, 121 hygiene, 38, 39, 40, 95, 227 hypothalamus, 156, 160, 171 hypothesis, 110, 124 IBS, 176, 177 ideas, 115, 116 identity, 40, 42 illusory truth effect, 50 Iman, 202 immune response, 173 immune system, 160, 223 impact factor, 106 impermanence, 28, 132 implicit, 55 improving personal health, 227 income, 15, 16, 254 individualism, 133 individualistic cultures, 251 indoor tanning, 55, 57 inequities, 16 infection control, 96, 97

312 infections, 38 inflammation, 172, 174, 223 influencers, 66 information, 2, 11, 87, 88, 142 information overload, 14, 15, 87 information sharing, 50 informed consent, 77, 182 informed decision, 85 injury, 71 innovation, 117 instrument, 110, 122, 123 insulin resistance, 161 insurance, 239 integrative healthcare, 246 integrative medicine, 240 interactive, 139 interconnectedness, 134, 177 interdisciplinary, 178 interdisciplinary care, 171 International Day of Happiness, 257 irritable bowel syndrome, 176 Italy, 93 Japan, 200 jargon, 16, 70, 120 Jews, 40 Johnson, 235 journal articles, 13 journalism, 58, 73 Kaeberlein, 221 Kaptchuk, 184 karoshi, 200 Ki-moon, 257 knowledge, 6, 21, 62, 87, 88, 142 Koch, 98 Kolletschka, 96 Kuwait, 214 laboratory medicine, 76 laboratory testing, 123 Laennec, 96 Lamott, 18 Lander, 152 language barrier, 17 Laurie, 245 Lavoisier, 183 Le Bon, 51 Levitin, 14

Index Li, 44 life expectancy, 15, 131, 214, 216, 221, 222, 258 life satisfaction, 254, 256 life-long learning, 27 lifespan, 2, 131, 151, 187, 220, 221 lifestyle, 2, 5, 39, 60, 66, 69, 112, 139, 151, 152, 189, 213, 239 lifestyle behaviors, 174 lifestyle changes, 161, 188, 213, 217, 230, 246, 265, 266 lifestyle medicine, 5, 75, 105 Lind, 95 Lister, 98 logic, 4 logical thinking, 89 longevity, 135, 220, 253, 259 Louis XVI, 183 macroscopic, 76 magnetism, 183, 184 male circumcision, 39 Malpighi, 94 manipulation, 57, 69, 241 manual therapist, 71 Marfan syndrome, 102 marketing, 60, 61, 67, 68, 190 marketing strategies, 57 Marks, 258 Massachusetts Institute of Technology, 119 maternal deaths, 38 maternal mortality, 38, 96 Mbeki, 122 McGonigal, 196, 204 McLaughlin, 17 measles, 3 media, 59, 60 medical care, 66 medical education, 93 medical information, 13 medical instrument, 96 medical knowledge, 91, 92 medical marketing, 68 medical practice areas, 237 medical school, 29, 100, 101 medical treatment, 181

On the Path to Health, Wellbeing, and Fulfilment: To Your Health medical vocabulary, 17 medication, 68, 69, 71, 138 medicine, 89, 138, 181 memory, 51, 166, 253 mental activity, 168 mental health, 132, 165, 166, 174, 228, 252 mental properties, 166 mental states, 169 Mesmer, 183, 236 meta-analyses, 110 metabolic activity, 157 metabolism, 215 method, 110, 241 metric, 59, 66 microaggression, 119 microbiology, 97 microbiome, 175, 209, 210 microscope, 94, 95 microscopic, 76 Miller, 184 mind and brain, 168 mind-body, 172, 173 mind-body approaches, 172 mind-body problem, 167 mind-brain identity theory, 167 minimal residual disease, 77 misinformation, 3, 4, 62, 72, 73 misleading, 57 MIT, 119 molecular genetics, 75 molecular level, 76 Molecular Pathology, 249 money, 253 mood, 176, 177 Morgagni, 95 multifactorial, 150 Muslims, 40 mutations, 77, 78, 102 National Center for Chronic Disease Prevention and Health Promotion, 224 National Center for Complementary and Integrative Health, 237 National Institutes of Health, 117, 237

313

natural, 70, 240, 245 nature, 103 nature versus nurture, 146, 147 NCCIH, 237, 242 negative information, 48 negative results, 118 negatively-biased credulity, 49, 50 negativity bias, 49 Netherlands, 27, 35 networks, 103 neural networks, 162 neuroscientific model, 203 newborn screening, 78 news, 58 NIH, 117 nocebo effect, 181 non-communicable diseases, 131 nonscientists, 85, 105, 106 normal range, 156 Nuland, 91 nutrients, 191, 212 nutrition, 105, 227 obesity, 15, 214, 215 obesity epidemic, 216, 231 obesity rate, 214 obstetrics, 96 occupational health, 95 Oh, 37 Oldford, 61 Ong, 260 online sharing, 62 on-off switches, 144 open access, 120 opinion, 73 opportunity, 115, 116, 119, 124 organic, 65 Ornish, 112 Ottawa Charter for Health Promotion, 133 outreach, 83 overmedication, 69 overweight, 214, 215 Pagan, 33 pain, 166, 243 pain management, 244 Pap-smear, 72

314 Paracelsus, 92 Parkinson’s law, 199 Pasteur, 97 patents, 117 pathologist, 5, 76, 96 pathology, 75, 95, 249 patient care, 106 patient encounter, 12 patient-centered care, 13 patient-doctor interactions, 12 patient-physician relationship, 13 peer pressure, 55, 58 peer-reviewed literature, 106, 108, 115 Penders, 83 penicillin, 111 Persia, 91 personal approach, 240 personal development, 229 personal knowledge, 20, 27, 33 personalized medicine, 178 persuasion, 59, 61, 67 Pew Research Center, 81 pharmaceutical industry, 186 pharmaceuticals, 68 phenotype, 147 philosophy, 21 phobia, 44 physical activity, 215, 227 physical examination, 90 physical health, 165, 166 physical properties, 166 physical states, 169 physician burnout, 201 physicians, 12 physician-scientist, 101, 122 physiology, 91, 157 placebo, 123, 182 placebo controls, 184 placebo effect, 181, 185, 243 placebo treatments, 185 placebome, 185 Plato, 89 plausible, 44 pleasure, 251 policy, 82

Index political, 88 political views, 47 politicians, 82 politics, 84 Pollan, 227 popular science, 121 portion size, 212 positive psychology, 251, 252 positive thinking, 252 postdoctoral fellow, 101 postpartum, 37, 38 postpartum confinement, 37, 39 postpartum depression, 38 post-traumatic stress disorder, 174 practice guidelines, 14, 105 practice of medicine, 94, 201 practice standards, 39 pragmatism, 133 precision, 123 precision medicine, 125, 178, 236 prejudice, 54 prescription, 189 prescription drug, 187 prescription medication, 189 prevention, 2, 3, 6, 37, 40, 67, 72, 95, 98, 139, 171, 189, 219, 225, 229, 240, 246 primary care, 166 primary prevention, 225 principles of healthy living, 226 privacy, 60 procedural knowledge, 29 process of learning, 88 processed foods, 216 product placement, 59 profiling, 60 prognosis, 77 Program in Placebo Studies and the Therapeutic Encounter, 184 Project Implicit, 55 pseudoscience, 45 pseudoscientific, 46, 48, 105, 217, 238 psychic surgery, 238 psychology, 48, 203, 251 psychosomatic, 171

On the Path to Health, Wellbeing, and Fulfilment: To Your Health psychosomatic medicine, 171 PTSD, 174 public health, 56, 67, 72, 231, 246 public opinion, 82 public perception, 80, 82 public relations, 79 public speaking, 169, 170 public understanding, 104, 119 PubMed, 105 purpose, 131, 250 quality assessment, 124 quality of life, 77, 136, 143, 174, 187, 214, 220, 225, 244, 254 race, 16, 187 Ramsay, 118 randomized controlled trial, 172, 182, 236 Rangnekar, 44 raw data, 87 receptors, 156 red flags, 246 referencing, 60 regeneration, 163 Reiki, 238 relationship with food, 207, 208, 209, 210, 217 relationships, 253 religion, 40, 82 repetition, 50, 59 research, 3, 79, 102, 104, 108, 169 research and development, 186 research barriers, 237 research laboratory, 77, 100 research methods, 236 research project, 101, 117 resilience, 132, 134, 139, 226, 227 restoration of health, 265 reversal, 6 review process, 106 reviewer, 107, 123 ribonucleic acid, 143 risk, 150 risk factor, 15, 152, 161, 174, 196, 216 rite of passage, 40 ritual, 42

315

ritual mutilation, 40 RNA, 143 Rojek, 66 Roosevelt, 19 Rosenthal, 191 rural health, 132 safety, 242 Sapolsky, 197 Schulz, 64, 250 science, 3, 4, 78, 79, 102, 103, 104, 112, 117, 166, 235, 242, 264 science and technology, 82 science communication, 80 science of happiness, 252 science of wellbeing, 258 scientific approach, 93, 98 scientific breakthroughs, 266 scientific discoveries, 3 scientific evidence, 177, 237 scientific experiments, 123 scientific inquiry, 92 scientific institutions, 80, 81 scientific journals, 108 scientific knowledge, 241 scientific literature, 45, 71, 106, 109, 110, 120, 121 scientific method, 66, 81, 98 scientific process, 113 scientific proof, 45 scientific publication, 98 scientific research, 103 Scientific Revolution, 94 scientific tools, 95 scientific uncertainty, 121, 122 scientific understanding, 82 scientists, 46, 77, 79, 84, 85, 104 scooped, 115 Scott, 34 screening, 85, 228 secondary prevention, 225 sedentary, 212 Seinfeld, 169 selection bias, 46 selective representation, 89 self-care, 139, 240 self-correcting, 110

316 self-experimentation, 95 self-help, 15 self-limiting disease, 243 self-regulation, 203, 204 Seligman, 251 Semmelweis, 96, 97 sequencing, 185 sex, 16 sexual activity, 72 Shakespeare, 203 shame, 68, 209, 216 side effects, 69, 70, 188, 191, 230, 242 signaling pathways, 175 Siskel, 32 sitting, 212 sitting the month, 37, 38 Skiles, 116 skin cancer, 56 skipping breakfast, 211 sleep, 155, 227 sleeping, 36 smoking, 15, 246 snack, 208 Snopes, 65 Snow, 97 social connection, 253 social determinants of health, 16 social media, 18, 44 social norms, 40 social support, 197 society and science, 82 socio-economic groups, 211 socio-economic status, 15 Socrates, 89 spending, 239 spirituality, 132 standard deviation, 123 standard of care, 105 Stanford, 77 Stanford University Medical Center, 17, 249 staple foods, 211 statin therapy, 230 status symbol, 199 sterilization, 98

Index stethoscope, 96 stigmatization, 216 stress, 39, 170, 174, 175, 194, 204 stress level, 198, 199 stress management, 227 stress reduction, 205 stress response, 197, 198 stress-induced hormones, 195 study design, 107, 123 subconscious, 59 subconscious bias, 54 Sullenberger, 116 sunk cost fallacy, 47 superstition, 43, 44 supplements, 38, 70, 71, 188, 189, 210 supportive care, 243 systematic reviews, 105, 109, 110 tacit, 24 tacit knowledge, 29 Tai Chi, 238 tanning, 56 Tay-Sachs disease, 84 team effort, 94 technological advances, 125 technology, 115 technology use, 13 TED, 83 temperature, 156, 158 temperature control center, 160 temperature perception, 157 tertiary prevention, 225 the doctor’s doctor, 142 therapy decisions, 240 Tibet, 150 Tierney, 203, 204 time constraints, 212 time poverty, 199 tobacco, 57, 67 tolerant, 54 Townson, 46 toxic, 227 toxic effects, 70 toxicology, 69 tradition, 34, 35 traditional beliefs, 39

On the Path to Health, Wellbeing, and Fulfilment: To Your Health traditional medicine, 234, 239 traditions, 234 traffic systems, 155 transcription, 144 transcription factors, 144 translation, 144 traveling, 235 treat, 208 treatment, 69, 171 trial, 95, 123, 183 triskaidekaphobia, 44 trust, 13, 34, 80, 240 truth, 21, 67 treatment procedures, 242 Twain, 210 twins, 146, 147 types of knowledge, 22 Tyson, 79 uncertainty, 4 underweight, 214 United Nations, 257, 258 United States, 58 Universe, 103, 104 urbanization, 212 UV light, 56 vacation time, 199, 200 vaccination, 71, 72 vaccine, 98, 228 vaccine safety, 72 validation, 64 validity, 11, 35, 41, 67, 108, 123, 237, 245 Valtin, 45 van Leeuwenhoek, 94 van Spijk, 135 variability, 122 Veenhoven, 257 Venter, 111

317

Vesalius, 93 Vietnam, 57 violation-of-expectation test, 34 violence, 246 Vioxx, 190 vitamin D, 57 vitamins, 189 vivisection, 90 Waldinger, 252, 253 Walkerton, 176 Walsh, 95 Wangdicholing General Hospital, 234 weight loss, 215 Weinberger, 88 wellbeing, 5, 130, 136, 137, 166, 240, 254 wellbeing score, 258 wellness, 137, 202 western cultures, 89 western medicine, 234 WHO, 38, 40, 41, 56, 72, 130, 200 whole foods, 191 whole-food plant-based eating, 217 wholeness, 133 wholistic, 238, 244 wholistic approach, 240 willpower, 203, 204, 205 Winfrey, 32 wisdom, 4, 22, 67, 88, 177 workplace stress, 200 World Happiness Report, 258 World Health Organization, 16, 38, 239, 243 world views, 82 World War II, 25 yo-yo effect, 217 Zehnder, 77