Neuroscience and the Problem of Dual Use: Neuroethics in the New Brain Research Projects [1st ed.] 9783030537890, 9783030537906

Table of contents :
Front Matter ....Pages i-xxv
Front Matter ....Pages 1-1
Modern Neuroscience (Malcolm R. Dando)....Pages 3-15
The Chemical and Biological Non-proliferation Regime in 2018 (Malcolm R. Dando)....Pages 17-31
Neuroethics and the Regulation of Misuse (Malcolm R. Dando)....Pages 33-51
Dual-Use Neuroscience? (Malcolm R. Dando)....Pages 53-71
Front Matter ....Pages 73-73
The EU Human Brain Project (Malcolm R. Dando)....Pages 75-93
The US BRAIN Initiative (Malcolm R. Dando)....Pages 95-114
Global Neuroethics in Early 2019 (Malcolm R. Dando)....Pages 115-126
Japan’s Brain/MINDS Project (Malcolm R. Dando)....Pages 127-147
China’s Brain Project (Malcolm R. Dando)....Pages 149-172
Front Matter ....Pages 173-173
Conclusion (Malcolm R. Dando)....Pages 175-193
Back Matter ....Pages 195-210

Citation preview

Advanced Sciences and Technologies for Security Applications

Malcolm R. Dando

Neuroscience and the Problem of Dual Use Neuroethics in the New Brain Research Projects

Advanced Sciences and Technologies for Security Applications Series Editor Anthony J. Masys, Associate Professor, Director of Global Disaster Management, Humanitarian Assistance and Homeland Security, University of South Florida, Tampa, USA Advisory Editors Gisela Bichler, California State University, San Bernardino, CA, USA Thirimachos Bourlai, Lane Department of Computer Science and Electrical Engineering, Multispectral Imagery Lab (MILab), West Virginia University, Morgantown, WV, USA Chris Johnson, University of Glasgow, Glasgow, UK Panagiotis Karampelas, Hellenic Air Force Academy, Attica, Greece Christian Leuprecht, Royal Military College of Canada, Kingston, ON, Canada Edward C. Morse, University of California, Berkeley, CA, USA David Skillicorn, Queen’s University, Kingston, ON, Canada Yoshiki Yamagata, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan

Indexed by SCOPUS The series Advanced Sciences and Technologies for Security Applications comprises interdisciplinary research covering the theory, foundations and domain-specific topics pertaining to security. Publications within the series are peer-reviewed monographs and edited works in the areas of: – biological and chemical threat recognition and detection (e.g., biosensors, aerosols, forensics) – crisis and disaster management – terrorism – cyber security and secure information systems (e.g., encryption, optical and photonic systems) – traditional and non-traditional security – energy, food and resource security – economic security and securitization (including associated infrastructures) – transnational crime – human security and health security – social, political and psychological aspects of security – recognition and identification (e.g., optical imaging, biometrics, authentication and verification) – smart surveillance systems – applications of theoretical frameworks and methodologies (e.g., grounded theory, complexity, network sciences, modelling and simulation) Together, the high-quality contributions to this series provide a cross-disciplinary overview of forefront research endeavours aiming to make the world a safer place. The editors encourage prospective authors to correspond with them in advance of submitting a manuscript. Submission of manuscripts should be made to the Editor-in-Chief or one of the Editors.

More information about this series at http://www.springer.com/series/5540

Malcolm R. Dando

Neuroscience and the Problem of Dual Use Neuroethics in the New Brain Research Projects

123

Malcolm R. Dando Department of Peace Studies University of Bradford Bradford, UK

ISSN 1613-5113 ISSN 2363-9466 (electronic) Advanced Sciences and Technologies for Security Applications ISBN 978-3-030-53789-0 ISBN 978-3-030-53790-6 (eBook) https://doi.org/10.1007/978-3-030-53790-6 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

“… seven national or regional brain research initiatives in the United States, the European Union, China, Australia, Japan, Korea, and Canada have joined together under the umbrella of the International Brain Research Initiative… Collectively, these initiatives represent a potential investment of more than US$7 billion in neuroscience research…” Emerging Issues Task Force, International Neuroethics Society (2019) Neuroethics at 15: The Current and Future Environment for Neuroethics. AJOB Neuroscience, 10(3): 104–110. (Page 106).

“… the area of military neurotechnology continues to pose significant ethical, legal, and social challenges, such as the problem of regulating the dual-use aspect of neurotechnology… the possibility of a neurotechnological arms race, and the human rights questions regarding the legitimacy of what Noll… has termed ‘neuroweapons’ for lethal and nonlethal warfare or policing.” Emerging Issues Task Force, International Neuroethics Society (2019) Neuroethics at 15: The Current and Future Environment for Neuroethics. AJOB Neuroscience, 10(3): 104–110. (Page 108).

Preface: Neuroscience and Chemical and Biological Warfare

In July 2015, Ulf Schmidt of the University of Kent launched his seminal book Secret Science: A Century of Poison Warfare and Human Experiments in the precinct of ancient Canterbury Cathedral.1 The book gave an exhaustive account of the development of chemical weapons’ agents in the UK over the previous century and of the evolution of the ethical stances taken by the scientists involved as what was culturally acceptable changed. The book included the story of the deadly first generation of lethal nerve agents discovered in Germany before the Second World War that subsequently became known to the Allies at the end of the war and then of the second generation discovered after that war in the UK and other countries. In both cases, the original discoveries were made in civil scientific work and only then taken up later for military purposes. A particular focus of the book was the experiments carried out during the Cold War on UK servicemen at Porton Down (where the UK did most of its chemical and biological defence work) without proper informed consent, and of the struggle by those servicemen to obtain official acknowledgement of what happened to them. I was one of the academics invited to be present at the launch of the book as I had worked for some 20 years previously on strengthening the chemical and biological non-proliferation regime which is embodied in the Chemical Weapons Convention (CWC) and the Biological and Toxin Weapons Convention (BTWC). In particular, I had been interested since the turn of the century in the efforts that were being made to raise the awareness and education of practicing life scientists, and other scientists working in related fields, about the problem of what had become termed dual-use—the fact that scientists’ benignly intended civil work might be used later by others for hostile purposes in the development of novel chemical and biological weapons.2

1

Schmidt U (2015) Secret Science: a history of poison warfare and human experiments. Oxford University Press, Oxford. 2 See the study produced for the UK Royal Society: Science Policy Centre (2012) Brain waves module 3: neuroscience, conflict and security. Royal Society, London, February.

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However, I was somewhat unusual amongst the academics present at Canterbury as my first degree was not in the political or social sciences but in Zoology. So, like many students of my generation, I had repeated Otto Lowie’s experiment in which he demonstrated the existence of a chemical neurotransmitter.3 That neurotransmitter was later shown to be acetylcholine—the operations of which within the nervous system is disrupted by the deadly nerve agents like Sarin and VX. Moreover, my doctoral and postdoctoral research was in what would now be called neuroscience.4 I had the uneasy feeling at the book launch that if I had been born earlier in the past century than I had been I could well have been involved in what Ulf had described in his book. I certainly have no recollection of taking part in any serious discussion of the possible misuse of work on nervous systems when I was part of the life science community despite the large-scale use of riot control agents and herbicides in the Vietnam War during that period. On the other hand, I had begun to study the work of systems thinkers during my time as a postdoctoral fellow in the United States and I carried on that work as I moved into social science. I was particularly interested in the work of Sir Geoffrey Vickers and his ideas on appreciative systems and how they influence our behaviour and I helped to edit a collection of papers on his work.5 Vickers publications ranged across many issues concerned with how we manage our way through these turbulent and rapidly changing times. As I was interested in how conflicts might be better managed my contribution to the collection of essays was devoted to a paper he produced in the journal Futures on that subject. I was particularly struck by one passage from his paper which suggested that our behaviour is restricted by three very different kinds of constraints.6 As he put it: The three kinds of constraint which I have described are reflected in three familiar verbs. What we can and cannot do, must and must not do, ought and ought not to do are defined by the constraints imposed on us by circumstances, by other people and by ourselves.

3

There is an excellent article on Otto Lowie and his friend Sir Henry Dale, who jointly received the Nobel Prize for their work in 1936 on Wikipedia. This includes a section on Lowei’s experiment and why it was important. 4 See, for example, Maynard DM, Dando MR (1974) The structure of the stomatogastric neuromuscular system in Callinectes sapidus, Homarus americanus and Palinirus argus (Decapoda Crustacea). Phil Trans Roy Soc B Biol Sci 268:161–220; (for modern work on this system see Nassim C (2018) Lessons from the Lobster: Eve Marder’s work in neuroscience. The MIT Press, Cambridge, Mass.); Clarac F, Dando MR (1973) Tension receptor reflexes in the walking legs of the crab Cancer pagurus. Nature 243(5402):94–95. 5 Blunden M, Dando MR (1994) Rethinking public policy-making: questioning assumptions, challenging beliefs. Essays in Honor of Sir Geoffrey Vickers on his Centenary. Am Behav Sci 38 (1):1–192. These essays were also published as a hardcover book with the same title by Sage in 1995 (ISBN-10: 080397602X). 6 Dando MR (1994) The management of international conflict. Am Behav Sci 38, 133–152. (page 138).

Preface: Neuroscience and Chemical and Biological Warfare

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And he made clear that in his view it was the constraints that we impose on ourselves that are most important as they underlie the trust that others have about us and that we have about others. There is a striking illustration of this in Ulf Schmidt’s account of the UK’s chemical weapons programme.7 In the early 1960s the government had instigated a secret offensive programme to develop novel so-called non-lethal chemical incapacitating agents. The medical staff at Porton Down were showing signs of concern about the experiments they were carrying out on the volunteer servicemen. In 1965 a secret committee met to consider the question of “whether Porton’s medical staff was acting with permission when ‘deliberately dosing healthy men with drugs specifically designed to induce some malfunction either physiological or psychological.’ For most of the experts present this seemed ethically justified, as long as the intention was that Porton would as a result ‘develop therapies’ against such agents.” An official account notes that at this point the Director of Porton’s Medical Division intervened and his notes state that8: I had therefore to disclose after warning those present that this was a highly secret matter that we were in fact looking for an agent which we could use under certain circumstances.

And this account goes on to state “[T]his admission ‘changed the complexion [of the meeting] very considerably.’” Clearly many of those present, who accepted the need for defensive research, were far from sure about whether Porton ought to be involved in the development of novel offensive incapacitating chemical agent capabilities. The experiments continued for a time, but as Schmidt’s account shows many of the medical staff who had been concerned left for various reasons. There are many different ways in which advances in neuroscience and related scientific and technological fields could be misused for hostile purposes,9 and the question of dual use in relation to these fields is complex.10 However, here I focus on the possibility that advances in neuroscience could eventually threaten the integrity of the chemical and biological non-proliferation regime which has been slowly developed over the past 100 years by the international community. Discussions of the impact of scientific and technological changes on the chemical and biological non-proliferation regime amongst State Parties to the CWC and BTWC during this century have mainly concerned the need to improve the

Reference 1, pages 347–355 on ‘Crisis Management’. Ministry of Defence, Historical Survey of the Porton Down Service Volunteer Programme 1939– 1989, Part IV, Human studies with incapacitating agents, 109–141, Ministry of Defence, London, June 2006. 9 DeFranco J et al (2019) Emerging technologies for disruptive effects in non-kinetic engagements. HDIAC J 6(2):48–55. 10 Ienca M et al (2018) From healthcare to warfare and reverse: how should we regulate dual-use neurotechnology? Neuron 97:269–274. 7 8

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awareness of the dual-use problem amongst microbiologists and chemists because currently these fields are widely considered most likely to be misused and if scientists are unaware of the issue they are most unlikely to realise that anything needs to be done about it.11 However, as the UK has pointed out in official papers, neuroscience could also be misused again as advances continue. In 2012 it noted that12: …Many of the benefits and risks of advances in the neurosciences lie in the future. However, in the development phase it is timely to consider issues related to governance of this dual-use technology area, balancing the obligation to take measures to prohibit and prevent misuse with the need to ensure that beneficial development of science is not hampered…

Personally, I doubted that neuroscientists were any better informed about the problem of dual-use than the microbiologists and chemists that had been investigated more thoroughly,13 and I, therefore, agreed strongly with the UK Royal Society study’s recommendation that14: There needs to be fresh effort by the appropriate professional bodies to inculcate the awareness of the dual-use challenge (i.e., knowledge and technologies used for beneficial purposes can also be misuse for harmful purposes) among neuroscientists at an early stage of their training.

It was against this background that I saw the rapid instigation of a series of State-level funding of new brain research projects around the world. I wondered to what extent these major new projects would be accounting for the problem of dual-use and what the implications would be if they did not? Thus, I had three questions in mind in my investigation: 1. How are the major State-level brain projects organised and what is their objective? 2. Is any of the research being carried out within these major projects likely to raise concerns about potential dual-use applications by others in the future? 3. If there are likely to be such concerns about dual use in relation to these projects what policies were being developed and implemented within these major projects, and related projects, to help protect the work from future dual use? Those questions were the basis for this book. It is in three parts. Part I sets the context when I began my research in early 2018 with Chap. 1 giving an account of the rapid changes in capabilities that neuroscientists had recently gained in order to investigate the operations of the Central Nervous System. Chapter 2 then A general point made recently by Ben Okri. See the version of his lecture “At last the cure for populism: we need active citizenship” in The Guardian, 31 January, Journal section, pages 1–2. 12 UK, The convergence of chemistry and biology: implications of developments in neurosciences, BWC/MSP/MX/WP.1. United Nations, Geneva, 12 July 2012. (page 3). 13 Dando MR (2009) Biologists napping while work militarized. Nature 460(7258):950–951. 14 Reference 2, page 60. 11

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provides a brief review of the state of the chemical and biological weapons non-proliferation regime at that time. Chapter 3 reviews what kinds of problems the advances in our understanding of the CNS have produced for society and how neuroethicists had tried to deal with these problems. Within that more general framework of possible misuse the chapter ends by outlining how the debate on dual-use in regard to the CWC and BTWC has developed recently, and Chap. 4 reviews how neuroscience has been subject to dual-use in the past and offers pointers as to what we should be concerned about in the near- to medium-term future. Part II of the book presents a description and an analysis of the brain projects that have been instigated in the European Union (Chap. 5) and the United States (Chap. 6). Then Chap. 7 reviews the situation in regard to dealing with dual use more generally in early 2019 before turning to the brain projects in Japan (Chap. 8), and China (Chap. 9). In these chapters, the organisation, aims, and achievements that might be of concern in the projects are investigated, as are the procedures for dealing with the problem of dual use. Part III of the book has one Chap. 10, which sets out to answer my three questions, and then an assessment is made of the implications of these findings and suggestions are made as to what more could be done to improve the governance of this dual-use technology. The chapters were written in their numerical order from early 1918 through to early 2020. The different sections of Appendix 1 give timelines of relevant events during this period in order to help the reader following the parallel processes being described. My intention throughout was to make this book useful not just to people from the very wide range of disciplinary backgrounds who are now involved in neuroscience, but also to people who, while not directly involved in neuroscience, are interested in dealing with the problem of dual use. In view of this intended readership, I have had to think carefully about how to handle the descriptions of technical issues. Clearly in order to establish whether there were dual-use concerns, it was necessary to examine some of the work of the brain projects, but I have tried to make my descriptions understandable to a general audience and have given detailed references to the original materials so that my interpretations can be checked if the reader wishes to do so. I have also tried to discuss a limited number of the same aspects of brain function in the different chapters in order that the main argument about the drive towards a mechanistic understanding of the brain, and the consequent possibilities of more complex and dangerous dual use, is not obscured by my referring to a wide variety of systems in different chapters. For readers who would like a concise and readable introduction to modern thinking about the brain and the ethical issues that arise from advances in neuroscience more generally I would recommend The Brain in Context: A Pragmatic Guide to Neuroscience by Jonathan Moreno and Jay Schulkin.15

15

Moreno JD, Schulkin J (2020) The brain in context: a pragmatic guide to neuroscience. Columbia University Press, New York.

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In May 2018, I was awarded a Leverhulme Trust Emeritus Fellowship (EM-2018-005\10) at the University of Bradford in the UK for “A study of how the brain research projects are dealing with dual-use.” The award allowed me to carry out the project. I would like to gratefully thank the trust for the award of this grant and the many people who kindly helped me with my investigations.

Contents

Part I

The Context

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Modern Neuroscience . . . . . . . . . . . . . . . . 1.1 Introduction: Healing the Brain . . . . . 1.2 Towards a Mechanistic Neuroscience? 1.3 Sleep Research . . . . . . . . . . . . . . . . . 1.4 A Revolution in Neuroscience . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .

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The Chemical and Biological Non-proliferation Regime in 2018 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 The Biological and Toxin Weapons Convention . . . 2.3 The Chemical Weapons Convention . . . . . . . . . . . . 2.4 Novichocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Neuroethics and the Regulation of Misuse . . . . . . . . . . 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Neuroethics and Dual Use in 2016 and 2018 . . . . . 3.3 Governance of Dual Use: Zagreb, Croatia . . . . . . . 3.4 Development of a Code of Conduct: Tianjin, China 3.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Dual-Use Neuroscience? . . . . . . . . . . 4.1 Introduction . . . . . . . . . . . . . . . 4.2 Forecasting Technology Change 4.3 Modulation of Neuronal Circuits

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4.3.1 Parkinson’s Disease and Drug Delivery . 4.3.2 Orexin . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.3 Oxytocin . . . . . . . . . . . . . . . . . . . . . . . 4.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Part II

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The Brain Projects

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The EU Human Brain Project . . . 5.1 Introduction . . . . . . . . . . . . . 5.2 The EU Human Brain Project 5.3 Dealing with Dual Use . . . . . 5.4 Conclusion . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . .

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The US BRAIN Initiative . . . . . . . . . . . . . . . . . . . . . . . 6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 Neuroethics Developments in the BRAIN Initiative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 The BRAIN Initiative and Dual Use . . . . . . . . . . . 6.3.1 Structure and Function of Opioid Receptors 6.3.2 BRAIN Research on Circuits: Sleep/Wake . 6.3.3 BRAIN Research on Circuits: Threat, Fear and Anxiety . . . . . . . . . . . . . . . . . . . . . . . . 6.3.4 BRAIN Research on Circuits: Aggression . . 6.4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Global Neuroethics in Early 2019 . . . . . . . . . . . . . . . . . . . . 7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 Objectives of the Brain Projects in 2016 . . . . . . . . . . . 7.3 Neuroethics in the Brain Projects in 2019 . . . . . . . . . . 7.4 Assessment of the Progress in Dealing with Dual Use . 7.5 Strategic Interactions in 2019 . . . . . . . . . . . . . . . . . . . 7.6 A Potential Opening for Scientists? . . . . . . . . . . . . . . . 7.7 Hybrid Warfare and Chemical and Biological Weapons References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Japan’s Brain/MINDS Project . . . . . . . . . . . . . . . . . . . . . . . . 8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Japan’s National Brain Project for Marmoset Neuroscience 8.3 Research on Non-human Primate Models . . . . . . . . . . . . . 8.4 The Dangers of Dual Use . . . . . . . . . . . . . . . . . . . . . . . .

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Contents

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8.5 Research in the Brain/MINDS Project . . . . . . . . . . . . . . . . . . . 134 8.6 Neuroethics and Dual Use in Japan’s Brain Projects . . . . . . . . . 144 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 . . . . . . . . . . . .

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10 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2 The International System and Advances in Neuroscience 10.3 The Role of Neuroscientists . . . . . . . . . . . . . . . . . . . . . . 10.4 Top Down Developments . . . . . . . . . . . . . . . . . . . . . . . 10.5 A Role for Neuroethics . . . . . . . . . . . . . . . . . . . . . . . . . 10.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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9

China’s Brain Project . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2 China’s Brain Project . . . . . . . . . . . . . . . . . . . . . . . . . 9.3 Macaque Neuroscience Today . . . . . . . . . . . . . . . . . . . 9.3.1 Circuits of Neurons . . . . . . . . . . . . . . . . . . . . . 9.3.2 Modulation of Circuits . . . . . . . . . . . . . . . . . . . 9.3.3 Genes, Mechanisms and Behaviour . . . . . . . . . . 9.4 Examples of Chinese Investigations . . . . . . . . . . . . . . . 9.4.1 Genome Editing Technology . . . . . . . . . . . . . . 9.4.2 Research on Consciousness and Self Awareness 9.5 China and Dual Use . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Part III

Possible Futures

Appendix: Timelines of Some Relevant Events and Documents . . . . . . . 195 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

Acronyms

5HT AAVs ABEO ACD AREA BRAIN Brain/MINDS BTWC BWC BZ CAS CBP CD8T CDP CEBSIT CNS COVID-19 CRE CRISPR/Cas CSF CWC dACC DARPA DAT DHS DMN

5-Hydroxytrytamine Adeno-Associated Viruses Advisory Board on Education and Outreach Advisory Committee to the Director Anticipate, Reflect, Engage and Act Brain Research through Advancing Innovative Neurotechnology Brain Mapping by Integrated Neurotechnologies for Disease Studies Biological and Toxin Weapons Convention Biological (and Toxin) Weapons Convention 3-Quinuclidiny Benzilate Chinese Academy of Sciences China Brain Project Cytotoxic T Cell Co-Design Project Center for Excellence in Brain Science and Technology Central Nervous System Virus Cyclisation Recombinase Gene of Bacteriophage P1 Clustered Regularly Interspaced Short Palindromic Repeats/Cas enzyme Cerebrospinal Fluid Chemical Weapons Convention Dorsal Anterior Cingulate Cortex Defense Advanced Research Projects Agency Declaration Assessment Team Department of Homeland Security Default Mode Network

xvii

xviii

DOC DoD DOX DREADDs DSM DTA DURC EDS EEG ELSI EU FAO FET FFM FFP fMRI G20 G7 G and E GA GABA GB GD GPCR GPi H1N1 HA HAC HBP Hcrt IAEA IARPA ICRC ICT IGO IMS INSEN ION IPPC IRB ISIS IT IUPAC LC

Acronyms

Disorders of Consciousness Department of Defense Doxycycline Designer Receptors Exclusively Activated by Designer Drugs Diagnostic and Statistical Manual Diptheria Toxin Dual Use Research of Concern Excessive Daytime Sleep Electroencephalogram Ethical, Legal, Social Implications European Union Food and Agriculture Organisation Future and Emerging Technology Fact-Finding Mission Fabrication, Falsification and Plagiarism Functional Magnetic Resonance Imaging International Forum for governments/central banks of 19 countries and the EU International Organisation for the seven largest economies Gene and Environment Tabun Gamma Amino Butyric Acid Sarin Soman G Protein Coupled Receptor Globus Pallidus internal Influenza Hemagglutinin Holistic Arms Control Human Brain Project Hypocretin (Orexin) International Atomic Energy Agency Intelligence Advanced Research Projects Agency International Committee of the Red Cross Information and Communications Technology Inter-Governmental Organisation Imaging Mass Spectrometry International Nuclear Security Education Network Institute of Neuroscience International Plant Protection Convention Institutional Research Board Islamic State of Iraq and Syria Information Technology International Union of Pure and Applied Chemistry Locus Coeruleus

Acronyms

L-DOPA MCWG MRI MSP MX NATO NDMC NeQN NGO NHP NIH NREM NRRIC NSABB OB OECD OEWG OIE ON-Ramp OPCW OXR OXT OXTR PD PSIM PVT QRP RDoC REM RIKEN RNA ROMER SAB SNpc SNr Tet-off UK UN USSR Vgat Vglut VLPO VMHvl VX

xix

L-Dihydroxyphenylalanine Multi-Council Working Group Magnetic Resonance Imaging Meeting of States Parties Meeting of Experts North Atlantic Treaty Organisation National Defense Medical College Neuroethics Question Non-Governmental Organisation Non-Human Primate National Institutes of Health Non-Rapid Eye Movement Neuroethics and Responsible Research and Innovation Committee National Science Advisory Board for Biosecurity Olfactory Bulb Organisation for Economic Cooperation and Development Open Ended Working Group World Organisation for Animal Health Operational Neurotechnology Risk Assessment and Mitigation Program Organisation for the Prohibition of Chemical Weapons Orexin Receptor Oxytocin Oxytocin Receptor Parkinson’s Disease Political, Security, Intelligence, Military Paraventricular Nucleus of the Thalamus Questionable Research Practice Research Domain Criteria Rapid Eye Movement Japan’s largest comprehensive research institute Ribonucleic Acid Roadmap for Mental Health Research Scientific Advisory Board Substantia Nigra pars compacta Substantia Nigra pars reticulata Promotor system that allows a gene to be turned off United Kingdom United Nations Union of Soviet Socialist Republics Vesicular transporter in a GABA producing neuron Vesicular transporter in a Glutamate producing neuron Ventrolateral Preoptic Area Ventromedial Hypothalamus Nerve Agent

xx

WHO WINS WP

Acronyms

World Health Organisation Warfare, Intelligence and National Security Work Package/Working Paper

List of Figures

Fig. 6.1 Fig. 8.1 Fig. 9.1

The Hijacking process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 The Brain/MINDS organisational chart . . . . . . . . . . . . . . . . . . . . . 137 The design of the China brain project . . . . . . . . . . . . . . . . . . . . . . 152

xxi

List of Tables

Table Table Table Table Table Table Table

1.1 1.2 1.3 1.4 1.5 1.6 1.7

Table 2.1 Table Table Table Table Table

2.2 3.1 3.2 3.3 3.4

Table 3.5 Table 3.6

Table 3.7 Table 4.1 Table 4.2 Table 5.1 Table 5.2 Table 5.3 Table 5.4

Examples of the RDoC dimensions and constructs. . . . . . . RDoC units of analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . Sections of the paper on stratified medicine . . . . . . . . . . . . Characteristics of awake and sleep states . . . . . . . . . . . . . . Making a transgenic mouse . . . . . . . . . . . . . . . . . . . . . . . . Stages in DREADDs Technology. . . . . . . . . . . . . . . . . . . . Using the Tet-off System to Create a Better Mouse Model of Narcolepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Projects suggested by the ABEO for engaging the scientific community. . . . . . . . . . . . . . . . . . . . . . . . . . . Article IX. Consultations, Cooperation and Fact-Finding . . Holistic arms control (HAC) . . . . . . . . . . . . . . . . . . . . . . . Neuroethics concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breakout session topics for the working groups . . . . . . . . . Some conclusions from the Zagreb meeting on governance of dual use . . . . . . . . . . . . . . . . . . . . . . . . . Agenda for the Tianjin meeting on codes of conduct . . . . . Comparison of the elements in the Hague Ethical Guidelines and the draft model code of conduct proposed by China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Core elements in a code proposed by the Russian Federation in 2005 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definitions used in a military forecasting methodology . . . Systems considered for disabling early in the Cold War . . Headlines in the London Guardian and London Observer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Groups of Questions facing the CWC 4th Review Conference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Central nervous system acting chemicals: considerations by the OPCW SAB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Human Brain Project in mid-2018 . . . . . . . . . . . . . . .

. . . . . .

5 5 7 8 10 11

..

13

. . . . .

. . . . .

26 28 34 35 40

.. ..

41 44

..

45

.. .. ..

46 55 56

..

76

..

77

.. ..

78 81

. . . . . .

xxiii

xxiv

List of Tables

Table 5.5 Table 5.6 Table 5.7 Table Table Table Table Table

5.8 6.1 6.2 6.3 6.4

Table 6.5 Table 7.1 Table 7.2 Table Table Table Table

7.3 7.4 7.5 8.1

Table 8.2 Table 8.3 Table 8.4 Table 8.5 Table Table Table Table

9.1 9.2 9.3 9.4

Table 9.5 Table 10.1 Table 10.2 Table 10.3 Table 10.4 Table 10.5 Table 10.6

HBP Partnering Projects . . . . . . . . . . . . . . . . . . . . . . . . . . . HBP subproject 12 work packages . . . . . . . . . . . . . . . . . . . Recommendations for dealing with dual-use neuroscience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . More conclusions from the Zagreb meeting . . . . . . . . . . . . Explicit ethical goals of the BRAIN Initiative . . . . . . . . . . Neuroethics guiding principles . . . . . . . . . . . . . . . . . . . . . . Objectives of the Brain Initiative in 2019. . . . . . . . . . . . . . Some agents and receptors considered for production of a Calmative State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factors driving the VMHvl Cell Firing . . . . . . . . . . . . . . . Neuroethics questions to guide ethical research in the international Brain projects. . . . . . . . . . . . . . . . . . . . Articles on the Brain initiatives in Neuron November 2016 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Articles on global neuroethics in Neuron February 2019 . . Goals of the US biodefense strategy. . . . . . . . . . . . . . . . . . Sub-goal 2.4.2 of the US national biodefense strategy . . . . Major research groups in the Brain/MINDS project in 2016 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Work of the psychiatric disorders group . . . . . . . . . . . . . . . Research groups of the Brain/MINDS-Beyond project . . . . Sections of the Brain/MINDS Beyond innovative research group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Studies listed as ‘Finished Research’ on the Brain/MINDS website . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Description of the China Brain Project, 2016 . . . . . . . . . . . Key points of the China brain project . . . . . . . . . . . . . . . . Social decision-making stages . . . . . . . . . . . . . . . . . . . . . . The rapid evolution of capabilities to manipulate NHP genomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Papers produced for the 2005 discussions on codes of conduct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Problems that we should be able to solve in the next 50 years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Top ten risks of 2020 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The International Brain Projects and Dual Use: Policy Developments in Early 2020 . . . . . . . . . . . . . . . . . . OECD Recommendations for Preventing the Misuse of Neurotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Chairman’s aide memoire on the States Parties’ discussions on science and technology . . . . . . . . . . . . . . . . Roles that scientists can play in strengthening the BTWC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

.. .. . . . . .

82 84

. 87 . 88 . 98 . 99 . 102

. . 103 . . 111 . . 116 . . . .

. . . .

117 119 123 124

. . 135 . . 138 . . 139 . . 140 . . . .

. . . .

142 151 154 157

. . 161 . . 165 . . 177 . . 179 . . 181 . . 182 . . 183 . . 185

List of Tables

Table 10.7 Table 10.8 Table 10.9 Table 10.10

xxv

A social responsibility analytical framework . . A classification of research misconduct . . . . . . A procedural approach to dealing with other stakeholders . . . . . . . . . . . . . . . . . . . . . . . . . . . The possible future of dealing with dual use in the BRAIN Initiative . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . 186 . . . . . . . . . . . 187 . . . . . . . . . . . 188 . . . . . . . . . . . 189

Part I

The Context

Chapter 1

Modern Neuroscience

Abstract This chapter begins the first section of the book by describing how the search for means to help people with mental illnesses has recently turned to concentrate on the neuronal circuits underlying behaviour and how this approach is facilitated by the analysis of similar circuits in other animals where such circuits are also present, and by using powerful new neurotechnologies. The chapter then examines how this approach leads to a mechanistic understanding of the causes of behaviour and how that behaviour could be modified. This issue is investigated using ongoing research into the mechanisms underlying sleep and how recently developed techniques are allowing the circuits of the Central Nervous System (CNS) to be finely dissected. It is concluded that rapid evolution of our knowledge and of our investigatory techniques is inevitable given the resources becoming available for such research and that certain specific conclusions can readily be drawn: 1. That there is an ongoing revolution in the investigative technologies that have become available to neuroscientists in recent years; 2. These technologies will continue to be developed and become more precise and powerful (and it is probable that completely new technologies will be found); 3. The new technologies have been applied to successfully dissect neuronal circuits that underlie complex behaviours and more such circuits will be successfully investigated; 4. More useful animal model systems in a range of species will become available; 5. General properties of circuits will be clarified and allow wider generalisations about how brains operate. It is also clear that at least some of the result of such modern benignly-intended research could be subject to later dual-use applications by those with hostile objectives.

1.1 Introduction: Healing the Brain There is no doubt that brain research is motivated in large part by a desire that scientists have to find ways of helping people with mental illnesses and injuries. At the turn of the century with the human genome being sequenced there were great hopes of rapid progress in this endeavour. As Nancy Andreasen [1] put it in her book Brave New Brain: Conquering Mental Illness in the Era of the Genome “[W]e are at © Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6_1

3

4

1 Modern Neuroscience

present in the midst of a golden age of biomedical research….We are simultaneously mapping the human brain and the human genome.” She suggested that the work in these two fields would meet up in the next decade or two and then: We will understand how the cells in our brain go bad when their molecules go bad, and we will understand how this is expressed at the level of systems such as attention and memory so that human beings develop disease such as schizophrenia and depression.

Thus, she concluded in 2001 “[O]nce mind and molecule meet, prevention is possible. Improvements in treatment are certain.” However, by the middle of the second decade of the century it was clear that these hopes had been dashed. This imaging genetics [2] approach had fallen out of favour in large part because the categories used to define the mental illnesses by clinicians facing the problem of dealing with illnesses were unlikely to be single diseases with unique causes. The clinicians in the United States use the Diagnostic and Statistical Manual (DSM) to classify the diseases they encounter in their practical work. However, in an overview of a new approach being taken by the National Institutes of Mental Health in the United States [3] it was clearly stated that: …There is thus an a priori assumption that the diagnoses refer to real disorders, with ensuing assumptions that they involve a unitary pathophysiology and psychopathology and that the task of a science of disorders is to find the underlying biology of specific disease entities…

Unfortunately, it appears that these three assumptions are false and thus it is not very surprising that the approach had not produced significant advances to help with the treatment of mental illnesses. Moreover, the overview argued that it is surely also unwarranted to assume that “complex higher-order psychological constructs will map simply onto narrower biological mechanisms of psychopathology.” A new approach called the Research Domain Criteria (RDoC) was therefore devised, not to supersede the DMS criteria used by practicing clinicians but as a new framework in which more fruitful research on mental illnesses could be carried out, and it is this framework that is of particular interest here. The RDoC approach steps back from trying to make links from current basic research directly to clinically relevant data but rather to take a step-by-by step approach to building towards that goal. The aim is1 : “…to elaborate a set of psychological constructs linked to behavioural dimensions for which strong evidence exists for circuits that implement these functions, and relate the extremes of functioning along these dimensions to specific symptoms (i.e., impairment) …” (emphasis added).

As will become clear in Chap. 6 the United States BRAIN Project was making the same point about the importance of research on the circuits of the brain that underlay behaviour at about the same time [4]. The Working Group on research priorities stating that “[I]n considering these goals and the current state of neuroscience, the working group identified the analysis of circuits of interacting neurons as being particularly rich in opportunity, with potential for revolutionary advances.” 1 Reference

[3, p. 287].

1.1 Introduction: Healing the Brain Table 1.1 Examples of the RDoC dimensions and constructsa

5

Dimensions

Constructs

Negative valence systems

Acute Threat (“Fear”) Potential Threat (“Anxiety”)

Social processes

Affiliation and Attachment

Arousal and regulatory systems

Arousal Biological Rhythms Sleep-Wakefulnes

a From

Table 1.2 RDoC units of analysisa

Reference [3]

Genes Molecules Cells Circuits Physiology Behaviors Self-Reports Paradigms a From

Reference [3]

(emphasis added). It is clear that the RDoC approach was not intended to replace the DMS approach at that time2 but “rather to describe an approach to formulating and evaluating explanatory hypotheses for clinical phenomena that psychopathologists estimate are ripe for biopsychological explanation.” The RDoC approach was developed through a series of workshops with scientists and is summarised in a two-dimensional matrix which has six rows of domains (negative valence systems, positive valence systems, cognitive systems, systems for social processes and arousal/modulatory systems) which each have a small number of specific defined constructs. Some examples of these domains and constructs are shown in Table 1.1. Then the columns of the matrix show the units of analysis within which the constructs can be examined. These units of analysis are listed in Table 1.2. So, the RDoC approach, for example, suggested that the genes, cells, circuits or behaviour related to fear could be the subject of specific research and research funding. However, as the National Institute of Mental Health’s website made very obvious, the central concern was with circuits. It notes that [5]: “The current set of constructs is focused on (and constrained by) circuit definitions in order to (1) avoid over-specification and proliferation of constructs, and (2) provide an organizing point that facilitates the integration both of genetic, molecular, and cellular levels of analysis regarding sub-components of circuits …” (emphasis added).

2 Reference

[3, p. 288].

6

1 Modern Neuroscience

While great advances in our understanding of the operations of the Central Nervous System (CNS) have been made through the use of brain imaging, it is obvious that to investigate the brain in the detail required to dissect the neuronal circuits experimental work on animal models is required. In an interesting analysis of the relevance of animal models for psychiatric research Anderzhanova and colleagues concluded that in the RDoC system [6]: …The general regulation and arousal, positive valence, negative valence, and social interaction behavioural domains… show basic construct, network, and phenomenological homologies between human and experimental animals…

But they were less sure of the cognitive behavioural domain, suggesting that that part of the system needed further clarification. In this analysis the authors drew first on MacLean’s early suggestion of the evolutionary development of the “Triune Brain” in vertebrates and particularly on Panksepp’s view that mammalian systems have conserved networks within the CNS. As they pointed out3 : …According to Panksepp’s theory, core emotional affects and defensive behaviours are represented by the diencephalic action systems of ‘Panic’, ‘Fear’, ‘Rage’, ‘Lust’, ‘Seeking’, ‘Care’, and ‘Play’. Genetically determined neuronal networks are considered as neurobiological substrates of these behaviours and appear to be conserved throughout mammalian evolution…

Therefore, they argue that although these networks are modifiable from higher centres within the CNS they are of fundamental importance and can be studied in other mammals. Indeed, as they go on to enumerate, considerable work had already been carried out on the circuits underlying these behaviours and they provided an illustration which links Panksepp’s action systems with the relevant domains and constructs of the RDoC matrix. Similar developments were taking place in Europe in an approach termed ‘Stratified Medicine’. As a group of the experts involved in this Roadmap for Mental Health Research (ROMER) strategy noted, recent neurobiological techniques had allowed considerable advances in our understanding of the brain and thus [7]: …Stratified medicine for mental disorders aims to identify somatic, cognitive, affective, motor and social behaviour domains defined by associated potentially common, aetiological neural mechanisms. This is in contrast to existing diagnostic criteria which are usually based on patient report, observation and duration of symptoms…

Unsurprisingly, the list of topics under investigation was similar to the developed under the RDoC strategy (Table 1.3). Commenting on the RDoC approach4 and by implication also their approach these experts pointed out that “[S]uch a convergent approach harnesses the closer correspondence from genotype to brain function than clinical diagnosis. It allows the investigation of the genetic vulnerability and neurobiological underpinning of 3 Reference 4 Reference

[6, p. 48]. [7, p. 28].

1.1 Introduction: Healing the Brain Table 1.3 Sections of the paper on stratified medicinea

7

Arousal and stress regulatory systems Cognitive systems Positive and negative valence Systems for social processes Pharmacological treatments Psychiatric somatic comorbidity a From

reference [10]

psychological traits and their value for predicting the development of mental disorders.” The additional category “Pharmacological treatments” in the ROMER system (Table 1.3) should be noted, as should the addition of “[M]oreover it has the potential to provide novel drug targets, particularly when coupled with a symptom cluster approach to psychopathology” to this comment on the RDoC approach. The question then is just how detailed are mechanisms being revealed by these new approaches using very recently developed techniques and what kinds of novel drugs and other chemical agents might be discovered?

1.2 Towards a Mechanistic Neuroscience? The question to begin with then is what has been going on in neuroscience during this century? In an introduction to a set of papers on the neurobiology of sleep in 2017 Thomas Kilduff and Yang Dan summarised as follows [8]: “Over the past decade, the advent of viral tools for neuroanatomical tracing and cellular targeting, the ability to manipulate neurons using optogenetic and chemogenetic tools, the expanded range of transgenic mouse strains expressing Cre recombinase, and a renaissance of comparative studies… has had a major impact on system neuroscience generally and sleep research, in particular…” (emphasis added).

Systems neuroscience can be defined [9] as “an umbrella term, encompassing a number of areas of study concerned with how nerve cells behave when connected together to form neural pathways and networks.” Thus, it is clear that there have been significant advances in our understanding of and capabilities for further investigation of the neuronal circuits that underlie our behaviour [10]. We can obtain a sense of what has been happening through a more detailed look at an example of current research: the topic of which—sleep—is well known to us all.

1.3 Sleep Research In the influenza virus epidemic of the early decades of the last century many people were affected by encephalitis and subsequent post-mortems showed that if anterior

8

1 Modern Neuroscience

Table 1.4 Characteristics of awake and sleep states States

Characteristics EEG

Sensations

Thoughts

Movements

Fast, low voltage

Normal, externally generated

Normal, logically organized

Normal and voluntary

NREM

Slow, high voltage

Usually absent

If present logical, but repetitive

Infrequent, involuntary

REM sleep

Fast, low voltage looks like normal awake EEG

Internally generated vivid, dreams often present

Illogical

Most muscles paralysed, but rapid eye movements occur

AWAKE

SLEEP

parts of the hypothalamus were damaged people had insomnia, but damage to posterior parts of the hypothalamus was linked to increased sleep. This suggested that there was an active mechanism in lower parts of the brain that then influenced the state of the higher centres. During the middle years of the last century new research, for example the recording of electrical activity from the higher cerebral cortex regions of the brain during sleep began to reveal a complex state of affairs. When we sleep we cycle through stages of different kinds of sleep. We begin by sinking through what were seen as four stages of what is called Non-Rapid Eye Movement (NREM) sleep (more recently the last two deeper stages have been seen as linked together as just one third stage). As noted in Table 1.4 the EEG (electroencephalogram) recordings from our brain consists of large slower waves of activity which are very different from the fast, low voltage normal awake activity. Our muscular activity during such slow wave sleep is irregular and involuntary. After a period of the deepest sleep something quite different happens, the EEG recordings become similar to normal awake activity, internally generated sensations are illogical, and dreams occur most often in this new state. Additionally, most muscles are paralysed except for the respiratory muscles, and the eye muscles which exhibit bouts of rapid activity and cause eye movement. There is also a disruption of normal thermoregulation. This state is called Rapid Eye Movement (REM) sleep in contrast to the NREM slower wave sleep. After the period of REM sleep the series of slower wave sleep states begin again and the cycle repeats. In a normal period of sleep of about 8 h the cycle would repeat about four times and REM sleep would normally take up about 2 h of the time and NREM about 6 h of the time. In addition to making us less sleepy sleep probably has a range of other functions such as memory consolidation. These functions have not all been clarified, but the conservation of NREM and REM sleep throughout mammalian (and avian) species strongly suggests that it has important functions. Moreover, there are many sleep problems, such as insomnia and narcolepsy, that cause difficulties for numerous people and that could, perhaps, be treated if the mechanisms that produce the sleep and awake states were better understood. Clearly sleeping mammals are vulnerable to predation and therefore the switch from sleep to the awake state happens quickly.

1.3 Sleep Research

9

Investigations during the latter half of the last century gradually led to the development of a widely-accepted model of the mechanism which was based on the idea of an electrical flip-flop switch which could rapidly move from one state to the other [11]. As one major review noted [12]: …Wakefulness promoting systems cause low-voltage, fast activity in the electroencephalogram (EEG). Multiple interacting neurotransmitter systems in the brain stem, hypothalamus, and the basal forebrain converge onto common effector systems in the thalamus and cortex…

and then as it continued: …Sleep results from the inhibition of wake-promoting systems by homeostatic sleep factors such as adenosine and nitric oxide and GABAergic neurones in the preoptic area of the hypothalamus…

The networks on each side of the switch were known to be complex, but undoubtedly the dominant neurons involved in wake promotion were thought to be monoaminergic (producing noradrenaline, serotonin, and histamine) and cholinergic producing acetyl choline. The general idea5 was that “because the neurons on each side of the circuit inhibit those on the other side, if either side obtains a small advantage over the other, it turns the neurons off on the other side, thus causing a rapid collapse in activity and a switch in state.” A similar kind of mutual inhibitory mechanism was envisaged for the switch between Non-REM and REM sleep states. Writing in 2017, Clifford Saper and Patrick Fuller, who had been influential in developing the flip-flop model, suggested that over the previous decade serious deficiencies had been revealed in this model. In their opinion [13]: Although earlier models of brain circuitry controlling wake-sleep focused on monoaminergic and cholinergic arousal systems, recent evidence indicates that these play mainly a modulatory role, and that the backbone of the wake-sleep regulatory system depends upon fast neurotransmitters, such as glutamate and GABA…

So rather than slower acting modulatory set of neurons being principally involved a radically different fast-acting neurotransmitter basis is seen to be the dominant factor in the mechanism underlying the sleep-wake cycle. How then did this radical change come about? A critical factor has been the advance of the technical capabilities available to neuroscientists. In this case the ability to dissect the operation of glutamate and GABA neurons was an important factor. Neurons producing glutamate are the major excitatory neurons of the brain and those producing gamma aminobutyric acid (GABA) are the major inhibitory neurons of the brain. These two amino acids are used in protein synthesis and are therefore widely distributed in cells but6 “the ability to load these amino acid transmitters into synaptic vesicles is now recognised as nearly synonymous with using them for synaptic transmission.” The synapse is the junction between two neurons and the synaptic vesicles hold the neurotransmitter in the presynaptic neuron. When this neuron is activated the neurotransmitter is released to 5 Reference 6 Reference

[11, p. 9–10]. [13, p. 186].

10

1 Modern Neuroscience

Table 1.5 Making a transgenic mousea Step 1 Make the gene construct required Step 2 Inject this gene into the male pronucleus of a recently fertilised mouse egg Step 3 Place the embryo into a female mouse that has been tricked into a physiological state of pregnancy. Repeat steps 2 and 3 to generate many offspring Step 4 Test these (first generation) mice to check that the transgene is expressed in the appropriate tissues Step 5 Mate these transgenic mice with wildtype mice to further investigate the gene and its expression From reference [10]

affect the activity of the postsynaptic neuron. Thus, the presence of a specific GABA vesicular transporter (Vgat) shows that the neuron has a GABA inhibitory function and similarly the presence of a specific glutamate vesicular transporter (Vglut) indicates that the neuron has a glutamate excitatory function. The problem for the scientists was that these glutamate and GABA producing neurons were intermingled and there were also neurons producing acetyl choline in the area of the brain that was of interest. So, it was difficult to activate one set of these neurons alone and thus to examine their function. However, new methods have begun to make that possible. Probably the most important innovation was to develop the capability to genetically modify mice. This can be done in a series of steps as set out in Table 1.5. Obviously, this simple strategy has been developed in many ways. For example, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) technology can also be used in such studies. As a recent review of the use of this technology outlined the general strategy [14]: …The selective targeting of DREADDs to a cell population can be achieved by using a cell type-specific promotor to drive DREAD expression, and the expression of this promotor can be further controlled using a recombinase-based system …

And as the review points out, there are now a wide range of transgenic mouse lines in which Cre expression is restricted to only one particular cell type. Cre recombinase is an enzyme originally found in a bacteriophage. It is widely used to produce various genetic modifications of mice [15]. The use of DREADDs technology in one significant study aimed at elucidating the role of glutamate producing neurons is summarised in Table 1.6 [16]. The authors noted that when the glutamate neurons were activated7 : 7 Reference

[16, p. 1358].

1.3 Sleep Research

11

Table 1.6 Stages in DREADDs Technologya Aim To emplace an engineered membrane-bound receptor in designated neurons so that they can be stimulated through the binding of a chemical that would not otherwise affect the cells Step 1 To study glutamergic neurons use mice expressing Cre recombinase exclusively in neurons producing the vesicular glutamate transporter-2 (there are three different types) Step 2 To chemogenetically activate glutamate neurons bilaterally microinject an AAV coding for the Cre-dependent hM3 DREADD receptor. This puts the receptor in place in the required neurons Step 3 Put instruments on the mice to measure EEG recordings Step 4 Three weeks later administer clozapine-N-oxide (CNO) or saline and record the EEG and the resulting behaviour. The CNO specifically activates the designed receptor and thus stimulates only glutamate neurons. The saline treated animals are controls to ensure that the CNO is the cause of any activity change in those treated with CNO Step 5 Analyse the resulting behaviour to see if there is an increase in the awake state of the injected animals a From

reference [16]

…Across the 6 h after injection at 8:00am CNO increased the average amount of wake >3fold compared with saline…. In parallel, CNO reduced the average amounts of both NREM and REM sleep…. The EEG power spectra during CNO-induced wake was very similar to that seen during spontaneous wake during the dark period…

So, this manipulation in increasing glutamate output by these neurons significantly increased the awake state. In summary, Saper and Fuller concluded that8 : …the landscape for cell groups that regulate wake-sleep has expanded dramatically over the last few years as investigators have taken advantage of the newer methods that allow the manipulation of cell groups that use fast transmitters such as GABA and glutamate…

So, the advances in technological capabilities have had a dramatic effect in illuminating the role of the fast transmitter systems, but of course that does not mean that the modulatory systems are insignificant in the effects they underpin. A particularly interesting example is the orexin (also known as hypocretin) neuropeptides that were only discovered in the late 1990s [17]. Neurons expressing orexins are located in the hypothalamus but have axons distributed throughout the brain and spinal cord. There are two orexin neuropeptides orexin A and orexin B and two receptors OXR1 and ORX2. ORX1 has a much higher affinity for orexin A than for orexin B, but ORX2 binds each peptide equally. These peptides have an excitatory effect on the neurons innervated. In mice there are about 3,000 to 4,000 8 Reference

[13, page 190].

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orexin neurons and in human beings there are some 50–80,000 orexin neurons. In humans, loss of these neurons is associated with the debilitating disease of type 1 narcolepsy which involves both narcolepsy and catalepsy. These symptoms [18] are caused first by dysregulation of NREM sleep onset “the inability to maintain a consolidated awake period, characterized by abrupt transitions from wakefulness to NREM sleep” and second by dysregulation of REM sleep onset “the pathological intrusion of REM sleep or REM atonia into wakefulness or at sleep onset.” This then causing the cataplexy, hallucinations and sleep paralysis. Almost all human narcolepsy is caused by the loss of these orexin neurons and this may be the result of an autoimmune process. However, it has been possible to develop transgenic mice that lack orexin neurons and these mice exhibit much the same symptoms. It is now possible for the orexin neurons’ activity to be studied in detail and it has been found that they are highly active in the awake state, have reduced activity during NREM sleep and are almost silent during REM sleep. Optogenetic excitation of orexin neurons increases the probability of awakening sleeping animals. The orexin neurons are also inhibited by sleep promoting neurons and activated by wake promoting neurons. This, together with the effects of their loss, leading to their function being seen as stabilising the awake state. During the transition from sleep to wakefulness orexin neurons fired before the change in EEG and they also responded quickly to sound stimuli during sleep suggesting that their functions are more complex than just stabilisation of sleep. It has been possible to dissect out much of how the orexins contribute to the regulation of sleep. For example, it has been found that9 : Collectively, mouse reverse genetic studies suggest that normal regulation of wakefulness and NREM sleep transitions depends critically on OX2R activation, whereas the profound dysregulation of REM sleep control unique to narcolepsy emerges from a loss of signalling through both OX1R and OX2R-dependent pathways.

With partial funding from Japan’s brain project, Brain Mapping by Integrated Neurotechnologies for Disease Studies (BRAIN/Minds), Daisuke Ono and Akihiro Yamanaka provided an overview of the many technologies that are being applied to study the orexin system [19]. One problem they noted was in creating a valid mouse model of human narcolepsy because simply removing the orexin gene from the mice does not necessarily map across to the destruction of the orexin neurons in later life in the human disease as compensatory mechanisms may take place on the growing mouse. In an effort to produce a better model Tabuchi [20] and colleagues: “used the Tet-off system in which the expression of diphtheria toxin A (DTA) in orexin neurons was controlled by the presence of doxycycline (DOX).” The Tet-off system is used in mice to temporarily control transgene expression [21]. The experimental system used by Tabuchi and his colleagues is outlined in Table 1.7. 9 Reference

[18], p. 59].

1.3 Sleep Research

13

Table 1.7 Using the Tet-off System to Create a Better Mouse Model of Narcolepsya Aim To add an inducible promotor system to orexin neurons so as to allow the orexin neurons to be killed by diphtheria toxin when the promotor is allowed to operate Step 1 Generate bigenic (orexin-tTA;TetO DTA) mice by breeding tetracycline operator (TetO) -DTA mice, which express diphtheria toxin A fragment (DTA) in the presence of tetracycline transactivator (tTA) with orexin-tTA mice, which express tTA in orexin neurons under the control of the prepro-orexin promotor Step 2 Add doxycycline(DOX) to the diet of the mice so that tTA cannot induce the expression of diphtheria toxin A fragment (DTA). Thus, the animals can grow naturally until the DOX is removed from their diet Step 3 At a set time remove the DOX from the diet of the mice. Now DTA is expressed exclusively in the orexin neurons and these are gradually killed Step 4 Monitor the behavioural and physiological consequences of the removal of DOX from the diet and the death of the orexin neurons a From

reference [20]

The net result of removal of the DOX from the diet of the mice was that10 “orexin neurodegeneration was rapid, with 80% cell loss within 7 d[ays], and resulted in disrupted sleep architecture. Cataplexy, the pathogonomic symptom of narcolepsy occurred by 14 d[ays] when about 5% of the orexin neurons remained.” This then represents a model that is a more useful tool to investigate narcolepsy. Moreover, it is also possible in such models to investigate various means of treating narcolepsy [22]. If the definition of sleep is widened to include criteria such as [23] “loss of locomotion, maintaining distinct postures, enhanced arousal thresholds to environmental stimuli, rapid reversibility” and so on it can be argued that sleep can be found and studied throughout the animal kingdom. This then opens up the possibility of investigating an even wider range of avenues for understanding the functions and mechanisms of sleep and sleep-like states. Questions such as11 “Is there a universal molecular pathway that encodes ‘sleepiness’?”, “Why is sleep essential?” and “How did REM and NREM sleep stages evolve, and how are they beneficial?” to be investigation by modern methods in more easily manipulated model organisms such as zebra fish, fruit flies and roundworms.

10 Reference 11 Reference

[20] p. 6495]. [23, p. 9]

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1.4 A Revolution in Neuroscience From this brief account it would seem that certain conclusions can readily be drawn: 1. That there is an ongoing revolution in the investigative technologies that have become available to neuroscientists in recent years; 2. These technologies will continue to be developed and become more precise and powerful (and it is probable that completely new technologies will be found); 3. The new technologies have been applied to successfully dissect neuronal circuits that underlie complex behaviours and more such circuits will be successfully investigated; 4. More useful animal model systems in a range of species will become available; 5. General properties of circuits will be clarified and allow wider generalisations about how brains operate. Indeed, it may not be over-optimistic to suggest that Andreasen’s conjecture about the meeting of the map of the brain and the map of the genome producing new means of prevention and treatment of mental illnesses is much nearer now than we imagine. If that is correct then it is all to the good, but what if these new capabilities are misused for hostile purposes? It is as well to remember that not too long ago in a secret UK committee the Chairman emphasised to his colleagues that [24] “the Committee was looking for agents which would produce not cure psychoses” and that “we might succeed by modifying curative agents.” Before turning to the question of how neuroethicists have tried to deal with the potential for the misuse of our rapidly increasing understanding of the brain we need to look first, in the next chapter, at how the international community attempted to deal the problem of chemical and biological weapons over the last century.

References 1. Andreasen NC (2001) Brave new brain: conquering mental illness in the era of the genome. Oxford University Press, Oxford (page 7) 2. Patrick CJ, Hajcak G (2016) Reshaping clinical science: introduction to the special issue on psychophysiology and the NIMH research domain criteria (RDoC) initiative. Psychophysiology 53:281–285 (page 281) 3. Kozak M, Cuthbert BN (2016) The NIMH research domain criteria initiative: background, issues, and pragmatics. Psychophysiology 53:286–297 (page 287) 4. Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Working Group Report to the Advisory Committee to the Director, NIH (2014) BRAIN 2025: A Scientific Vision. National Institutes of Health, June 5th, 2014 (page 5) 5. See the Discussion at https://www.nimh.nih.gov/research-priorities/rdoc/discussion.shtml. Assessed 31 Jan 2018 6. Anderzhanova E et al (2017) Animal models in psychiatric research: the RDoC system as a new framework for endophenotype-orientated translational neuroscience. Neurobiol Stress 7:47–56 (page 47) 7. Schumann G et al (2014) Stratified medicine for mental disorders. Europ Neuropsychopharmacology 24:5–50 (page 7)

References

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8. Kilduff TS, Yang D (2017) Editorial overview: Neurobiology of sleep 2017. Curr Opin Neurobiol 44:A1–A3 (page A1) 9. Definition available on Wikipedia at https://en.wikipedia.org/wiki/Systems_neuroscience. Accessed 08 Fed 2018 10. Carter M, Shieh J (2015) Guide to research techniques in neuroscience, 2nd edn. Academic Press, London 11. Saper CB et al (2010) Sleep state switching. Neuron 68(6):1023–1042 12. Brown RE et al (2012) Control of sleep and wakefulness. Physiol Rev 92(3):1087–1187 (page 1087) 13. Saper CB, Fuller PM (2017) Wake-Sleep circuitry: an overview. Curr Opin Neurobiol 44:186– 192 (page 186) 14. Whissell PD, Tohyama S, Martin LJ (2016) The Use of DREADDs to deconstruct behavior. Front Genet 7:70. https://doi.org/10.3389/fgene.2016.00070 (page 2) 15. Carter M, Shieh J (2015) Guide to research techniques in neuroscience. (Second Edition) Academic Press, London (pages 263–264 and 282–283) 16. Kroeger D et al (2017) Cholinergic, Glutamatergic, and GABAergic Neurons of the Pedunculopontine tegmental nucleus have distinct effects on sleep/wake behavior in mice. J Neurosci 37(5):1352–1366 17. Dando MR (2015) Neuroscience and the future of chemical-biological weapons. Palgrave Macmillan, Basingstoke (pages 113–118) 18. Mieda M (2017) The role of orexins in sleep/wake regulation. Neurosci Res 118:56–65 (page 57) 19. Ono D, Yamanaka A (2017) Hypothalamic regulation of the sleep/wake cycle. Neurosci Res 118:74–81 20. Tabuchi S (2014) Conditional ablation of Orexin/Hypocretin Neurons: a new mouse model for the study of narcolepsy and Orexin system function. J Neurosci 34(19):6495–6509 (page 6406) 21. Carter M, Shieh J (2015) Guide to research techniques in neuroscience. Academic Press, London (pages 264–265) 22. Liu M et al (2017) Rewiring brain circuits to block cataplexy in murine models of narcolepsy. Curr Opin Neurobiol 44:110–115 23. Miyazaki S, Liu C-Y, Hayashi Y (2017) Sleep in vertebrate and invertebrate animals, and insight into the function and evolution of sleep. Neurosci Res 118:3–12 (page 4) 24. Chemistry Committee (1959) Minutes of the Thirty-Second Meeting of the Committee held in room 270, The Adelphi, John Adam Street, London W.C. 2, on Thursday, 5th March at 2p.m. Advisory Committee on Scientific Research and Technical Development. National Archives, London

Chapter 2

The Chemical and Biological Non-proliferation Regime in 2018

Abstract This chapter starts by noting Professor Meselson’s warning in 2000 that as all previous revolutions in science and technology had been used in major ways for hostile purposes the same could happen to new advances in the life sciences unless rigorous steps were taken to prevent that happening. The chapter then looks at the strengths and weaknesses of the chemical and biological non-proliferation regime in early 2018. The Biological and Toxin Weapons Convention (BTWC) after its unsatisfactory 8th Five Year Review conference in 2016 seemed set only for modest incremental strengthening through to the 9th Review Conference in 2021, but there was a possibility that the rapid advances in genome editing would produce a stronger reaction and attempts to deal with the problem of dual use. The Chemical Weapons Convention (CWC), although being a much stronger Convention than the BTWC and the OPCW having successfully destroyed most of the chemical weapons stocks built up during the last century, now faced a similar problem of preventing the re-emergence of chemical weapons at a time of rapid scientific and technological change within an unstable international security system in which chemical weapons had again been used in warfare and for assassinations. Efforts to deal with the potential loophole in Article II.9(d) of the Convention, that might be seen to allow the development and use of so-called non-lethal chemical agents that attack the Central Nervous System, are reviewed and efforts to improve the education and awareness of chemists about such problems is noted. The chapter ends by suggesting that neuroscientists should understand that there is a long history of the potential misuse of scientific advances being ignored and that developments in our capabilities in genome editing and increases in our understanding of the operations of the Central Nervous System are example of advances that could potentially also be misused

2.1 Introduction At the turn of the century in 2000 Matthew Meselson, Professor of Molecular Biology at Harvard University, suggested that as all previous scientific and technological revolutions had been applied in major ways to hostile purposes it was probable that © Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6_2

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the same would happen to the revolution in civil biotechnology unless we found ways to prevent that happening. He also thought that this would be a long drawn out struggle, stating that [1]: …During the century ahead, as our ability to modify fundamental life processes continues its rapid advance, we will be able not only to devise additional ways to destroy life but will also become able to manipulate it – including the processes of cognition, development, reproduction and inheritance…. Therein could lie unprecedented opportunities for violence, coercion, repression, or subjugation…

And he pointed out that dangerous capabilities could be available to a much wider range of actors than were available in relation to nuclear weapons: …Unlike the technologies of conventional or even nuclear weapons, biotechnology has the potential to place mass destructive capabilities in a multitude of hands and, in coming decades, to reach deeply into what we are and how we regard ourselves. It should be evident that any intensive exploitation of biotechnology for hostile purposes could take humanity down a particularly undesirable path.

Clearly, when he referred to reaching “deeply into what we are and how we regard ourselves” he must have had advances in neuroscience at least partly in mind. As I began work on this book in January 2018 it appeared that we could be a little more optimistic about the course of that struggle. The 2017 edition of the National Security Strategy of the United States of America evidenced clear concerns about defence against chemical and biological weapons of mass destruction [2] stating that “[T]he danger from hostile state and non-state actors who are trying to acquire nuclear, chemical, radiological, and biological weapons is increasing.” Part of that concern was obviously caused by the recent use of chemical weapons in the Syrian conflict as the text continues “[T]he Syrian regime’s use of chemical weapons against its own citizens undermines international norms against these heinous weapons, which may encourage more actors to pursue and use them. ISIS has used chemical weapons in Iraq and Syria.” The undermining of the norm against the use of such weapons and the international community’s difficulties in agreeing what should be done to stop the parties in the Syrian conflict using these weapons was a widely shared concern. However, there was another aspect of the problem that was not so widely understood: that revolutionary advances within the life and associated in sciences and technologies being pursued for beneficial civil purposes could make it easier for less and less skilled people to develop and use such weapons [3], and that the international community was also finding it difficult to decide what should be done to minimise this potentially very dangerous dual use of the scientific and technological developments. Yet there were also encouraging developments. This chapter is in two parts, looking first at the situation in regard to the Biological and Toxin Weapons Convention (BTWC) one year after its rather unsuccessful Eighth Five–Year Review Conference in late 2016 and then at the Chemical Weapons Convention (CWC) almost a year before its Fourth Five-Year Review Conference in late 2018 (see Appendix 1.1 and 1.2).

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2.2 The Biological and Toxin Weapons Convention The BTWC is the weakest of the three international arms control agreements that deal with the nuclear, chemical and biological weapons of mass destruction. It was negotiated in the 1970s and embodies an all-encompassing prohibition that adds a series of critical restrictions to the ban on the use of biological weapons agreed in the I925 Geneva Protocol. Its first Article states that: Each State Party to this Convention undertakes never in any circumstances to develop, produce, stockpile or otherwise acquire or retain: 1. Microbial or other biological agents, or toxins whatever their origin or method of production, of types or in quantities that have no justification for prophylactic, protective or other peaceful purposes; 2. Weapons, equipment or means of delivery designed to use such agents or toxins for hostile purposes or in armed conflict. Unfortunately, the implementation of the Convention is far from adequate and its well-known deficiencies in the lack of an adequate verification system and of a large international organisation have proved difficult to correct despite decades of discussions amongst States Parties [4]. On February 9th 2016 James R. Clapper, Director of National Intelligence, gave a statement for the record on the Worldwide Threat Assessment of the US Intelligence Community to the Senate Armed Services Committee. Included in the assessment, under “Weapons of Mass Destruction and Proliferation,” there was a section on the new dangers of genome editing [5]. This stated: “Given the broad distribution, low cost, and accelerated development of this dual-use technology, its deliberate or unintended misuse might lead to far-reaching economic and national security implications.” Since the beginning of the century there had been discussion of experiments with dual-use implications, such as those with the mousepox virus and highly pathogenic influenza, amongst the security community and at the level of national academies [6], but this had had little effect on the work of most life scientists. Many remained ignorant of the dangers of the hostile misuse of their benignly-intended work. In the United States where most effort had been made to find a way to deal with this problem the National Academies commissioned a study to review the situation in 2017. This study concluded that [7]: Despite decades of effort, there is little national or international consensus with regard to appropriate policies for addressing issues associated with the conduct and dissemination of life science research that might qualify as DURC. The absence of an international commitment to addressing such issues; the lack of agreement regarding a framework for assessing risk, uncertainty, and benefit; and the difficulties the U.S. government has faced in developing policies that effectively manage DURC illustrate the challenges of resolving these issues concerning information dissemination raised by DURC.

Clearly, benignly-intended civil research could be misused in a variety of ways and with various levels of difficulty now or in the future. Dual Use Research of

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Concern (DURC) is defined in the United States as “[R]esearch that, based on current understanding can be reasonably anticipated to provide knowledge, products, or technologies that could be directly misapplied by others to pose a threat to public health and safety, agricultural crops and other plants, animals, the environment, or materiel.” It is therefore an important subset of dual-use research that might be subject to misuse in the near term. The assessment by the US Intelligence community suggested that CRISPR/Cas genome editing technology is so specific and easily carried out that life scientists soon might have to take a much more serious interest in biosecurity and the problem of dual use. Also, in early 2016, intensive preparations for the 8th Five Year Review Conference of the Biological and Toxin Weapons Convention (BTWC) were underway and, unusually, these included two meetings of the Preparatory Committee prior to what was widely regarded as the best prepared of all BTWC Review Conferences in November of that year. Unfortunately, longstanding differences between States Parties emerged again during the Review Conference, and although the dangers of advances in genome editing had been well demonstrated to States Parties, little could actually be agreed apart from meeting again in late 2017. The final document stated [8]: “At its final plenary meeting, on 25 November 2016, the Conference decided that States Parties will hold annual meetings. The first such meeting, to be held in Geneva in 2017 starting on 4 December 2017, and having a duration of up to five days, will seek to make progress on issues of substance and process for the period before the next Review Conference, with a view to reaching consensus on an intersessional process.” (emphasis added)

It would appear then that the dual-use dangers of advances in the life sciences had not had a significant impact on the operations of the BTWC and so the low level of its impact on life scientists could be expected to continue. Indeed, given the difficult state of relations between the Russian Federation and the West there seemed little prospect of this situation changing at the December 2017 meeting. That pessimistic expectation was called into question when a large meeting of States Parties to the BTWC was held in Sochi in August 2017 and the three Depositary States for the Convention—the Russian Federation, the United States and the United Kingdom—produced a joint Working Paper [9] suggesting elements of a possible outcome for the December meeting. Crucially, this paper stated: “As proposed by [8th ] Review Conference President Molnár, four OEWGs [Open Ended Working Groups – meetings of experts] would be established on the following topics: Science and Technology; National Implementation; International Cooperation; and Preparedness, Response and Assistance. OEWGs would prepare factual reports, including possible recommendations, for consideration by States Parties at the annual meeting; in the absence of consensus on recommendations, all views would be reflected.” (emphasis added)

In regard to Science and Technology the paper suggested that the topics for consideration should be: Potential benefits and risks of new science and technology developments; Biological risk assessment and management; Voluntary model code of conduct for biological scientists and

2.2 The Biological and Toxin Weapons Convention

21

all relevant personnel, and biosecurity education, by drawing on the work already done on this issue in the context of the Convention, adaptable to national requirements; Science and technology-related developments relevant to the Convention and to the activities of multilateral organizations; Any other science and technology developments of relevance to the Convention;

And further that: “In 2018, the OEWG will address the specific topic of gene editing, taking into consideration, as appropriate, the issues identified above.” (emphasis added)

This important intervention by the three Depositary States of the Convention opened up the possibility of annual Meetings of Experts in the Science and Technology OEWG making recommendations across a range of issues related to genome editing in 2018 and then to other issues of concern in 2019 and 2020. Yet that would depend on what happened at the meeting in December 2017. It was obvious from the start of the meeting that there was considerable interest in the outcome of the meeting amongst States Parties. The initial General Debate ran over into the second day with an unusually large number of statements (69) from States Parties. This was followed by 9 statements by Inter-Governmental Organisations (IGOs) and 13 statements by Non-Governmental Organisations (NGOs) before the meeting went into closed session. Of particular interest was the number of statements that supported the vision set out in the Depositaries’ Working Paper. A number of other Working Papers, such as that of Switzerland, [10] also concentrated on the possible format and content of the OEWG on science and technology. However, given past difficulties, there was no certainty among observers at the meeting in the UN in Geneva that there would be an agreed outcome. One positive note was struck in the open plenary at the end of the first session of closed discussion when it was reported that [11]: Before the meeting was adjourned, Russia took the floor. Mikhail Ulyanov, Director of the Non-Proliferation and Arms Control Department of the Foreign Ministry, noted there were only two days remaining and that if the MSP [Meeting of States Parties] could not reach consensus there would be ‘no tangible work done’ to strengthen the BWC regime in the coming three years. He suggested that willingness to seek compromise was especially crucial at this time, otherwise in 48 h delegates would leave ‘with a sense we have failed in our duty to agree’, concluding ‘I would very much like to avoid that.’

What then was the outcome of the meeting and what might be the implications for the worldwide life science community? The meeting, under the chairmanship of Ambassador Singh Gill of India, reached a consensus report [12] that reflected many of the elements set out in the Working Paper by the Depositary States. There would be a Meeting of the States Parties each year to receive the reports of Meetings of Experts (MXs) held at least three months previously and to manage the intersessional process through to the Ninth Review Conference in 2021. The Meetings of Experts would consider five set topics back-to-back each year as follows: MX1: Cooperation and assistance, with a particular focus on strengthening cooperation and assistance under Article X; MX2: Review of developments

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in the field of science and technology related to the Convention; MX3: Strengthening national implementation; MX4: Assistance, Response and Preparedness; MX5: Institutional Strengthening of the Convention. The report of the 2017 Meeting of States Parties stated that “Each Meeting of Experts will prepare for consideration of the annual Meeting of States Parties a factual report reflecting its deliberations, including possible outcomes.” The topics considered by MX2 on developments in science and technology would be: Review of science and technology developments relevant to the Convention, including for the enhanced implementation of all articles of the Convention as well as the identification of potential benefits and risks of new science and technology developments relevant to the Convention, with a particular attention to positive implications; Biological risk assessment and management; Development of a voluntary model code of conduct for biological scientists and all relevant personnel, and biosecurity education, by drawing on the work already done on this issue in the context of the Convention, adaptable to national requirements; In 2018, the MX2 will address the specific topic of genome editing, taking into consideration, as appropriate, the issues identified above; Any other science and technology developments of relevance to the Convention and also to the activities of relevant multilateral organizations such as the WHO, OIE, FAO, IPPC and OPCW.” (emphasis added).

In 2018 therefore, the States Parties to the Biological and Toxin Weapons Convention were set to examine the topic of genome editing through the lens of the sub-topics set out in this mandate. It was hard to imagine that the outcome of their deliberations would be that the dual-use implications of genome editing are insignificant and that no action need be taken to further ensure that this technology is only used for peaceful purposes. Maybe the game had changed, and States would soon require that life scientists take much more care about the dual-use implications of their work. These deliberations should, of course, be of interest to neuroscientists as CRISPR/Cas systems were being extensively used in neuroscience research [13]. Whether that happened would have to wait until the outcomes of the meetings in 2018, beginning with the Meeting of Experts in Geneva during the summer, were known. If nothing effective was done about the new capabilities in genome editing, then we could be entering extremely dangerous times, but at least it appeared that the problem was widely recognized. A further encouraging sign was that after some six years of controversy the United States government had agreed a new policy for dealing with so-called ‘gain-of-function’ experiments with dangerous viruses and that despite some concerns the new policy was broadly welcomed by critical observers [14]. This suggested that really difficult and controversial dual-use research could be contained in acceptable ways.

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2.3 The Chemical Weapons Convention The Chemical Weapons Convention was negotiated in the 1990 s at the end of the East-West Cold War and also has a sweeping set of restrictions in its first Article. This states that: 1. Each State Party to this Convention undertakes never under any circumstances: (a) To develop, produce, otherwise acquire, stockpile or retain chemical weapons or transfer, directly or indirectly, chemical weapons to anyone; (b) To use chemical weapons… However, the CWC is a much more comprehensive agreement than the BTWC in its implementation, involving the establishment of a large international organization, the Organisation for the Prohibition of Chemical Weapons (OPCW) located in The Hague. The OPCW was awarded the Nobel Peace Prize in 2013 having effectively overseen the destruction of much of the huge deadly chemical weapons stocks accumulated by States during the last century. Following this successful disarmament phase of operations, the OPCW was then having to re-orientate its structure and function in order to focus on the different task of preventing the reemergence of chemical weapons during this century. In that regard, there was concern over the deviations from the norm of non-use of chemical weapons that had been seen in Syria, but also about the potential misuse of scientific advances that give us ever more detailed understanding about how chemical agents can affect the functions of living organisms. This issue had come more and more into focus in discussions amongst State Parties to the CWC because the Convention text allows as a peaceful purpose under Article II.9 (d) “[L]aw enforcement including domestic riot control purposes.” Standard riot control agents are certainly allowed under the Convention if the types and quantities are suitable for domestic riot control purposes, but some may have viewed this article as also allowing the use of a larger category of so-called non-lethal law enforcement agents. The use of derivatives of the opiate fentanyl to break the 2002 Moscow theatre siege illustrated the dangers of this approach because although many of the hostages were rescued over 100 died as a result of the use of these toxic agents [15]. There had long been concerns over the potential bypassing of the Convention’s prohibitions in the search for such agents. At the First Five-Year Review Conference of the CWC the International Committee of the Red Cross attempted to raise the issue, but it was only discussed at an Open Forum on the Chemical Weapons Convention hosted by the Technical Secretariat and supported by a number of NonGovernmental Organisations. The Open Forum included a panel discussion of “The Chemical Weapons Ban and the Use of Incapacitants in Warfare and Law Enforcement” [16]. The International Committee of the Red Cross continued to raise concerns about the use of such chemical agents, for example organizing an experts workshop on Incapacitating Chemical Agents: Implications for International Law in 2010 [17]. In its 2012 Brain Waves Module 3 on Neuroscience, conflict and security the UK Royal Society [18] paid considerable attention to incapacitating chemical agents

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which it defined as “substances intended to cause prolonged but transient disability and include centrally acting agents producing loss of consciousness, sedation, hallucination, incoherence, paralysis, disorientation and other such effects” and it emphasized the difference between such agents and peripherally acting riot control agents. The Royal Society report also noted that contemporary interest in such agents has focused on chemicals that produce rapid action and have short effects, but even within this restricted category of agents that aim to produce temporary unconsciousness the report pointed out the difficulties of safe use in an operational context. As the report stated, “the feasibility of developing an incapacitating chemical agent and delivery system combination that is safe (i.e. has a low risk of lethality) is questionable.” Clearly it is difficult to control the concentration of the chemical in different parts of the contaminated area and different people will have diverse reactions to any particular dose. Additionally, all drugs are likely to affect more than one type of receptor in the circuits of the nervous system and thus to have side effects other than those intended. It is important to understand that, as the Scientific Advisory Board of the OPCW pointed out in 2012, “[T]he types of chemicals and pharmaceuticals known to have been considered as incapacitants from open-literature sources were discussed. Most are centrally acting compounds that target specific neuronal pathways in the brain. All of them emerged from drug development programmes undertaken from the 1960s to the 1980s.” So, all of the agents known to have been considered as incapacitants at that time were derived from dual-use applications of benignly-intended civil research [19]. Therefore there remained the danger that benignly-intended civil research might produce results that suggested much more specific incapacitation could be obtained and that pursuit of these agents, even to check them for defensive purposes, could lead to an action/reaction arms race in what has been called a “degradation market” [20]. Given these circumstances it is hardly surprising that some States Parties attempted to have the problem resolved with agreement on limiting the potential loophole for “law enforcement chemical agents” to be developed and used. Switzerland took the lead in these efforts to clarify the situation, but nothing could be agreed even at the Third Five-Year Review Conference in 2013. Then in November 2014 at the regular Conference of States Parties Australia presented a paper titled Weaponisation of Central Nervous System Acting Chemicals for Law Enforcement Purposes [21]. This noted the discussion of the issue that had taken place at the previous Review Conference and acknowledged the leadership role that Switzerland had taken “in raising attention to this important issue” and thanked the 13 States Parties that had made their positions clear on the issue of ICAs. These States included the UK and the United States. Australia identified fentanyls as the best known of such CNS acting chemicals, but added that “other anaesthetics, sedatives or analgesics that also could be considered including dexmedetomidine and clonidine.” Australia stated its position clearly as follows: The weaponisation of CNS acting chemicals for law enforcement purposes is of concern to Australia due both to the health and safety risks and the possibility of their deliberate misuse, both of which have the potential to undermine the global norm against the use of toxic chemicals for purposes prohibited by the Convention.

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The paper ended by confirming that Australia had no interest in developing such chemical agents, calling on other States Parties to make their positions known and for consultations amongst members of the Executive Council of the OPCW with a view to “commencing discussions as to whether weaponisation of CNS acting chemicals should be permitted for law enforcement purposes.” In the following year at the November 2015 Conference of States Parties Australia was joined by a total of 20 States Parties in the presentation of a further paper titled Aerosolisation of Central Nervous System-Acting Chemicals for Law Enforcement Purposes [22]. This paper began by recalling statements at previous Executive Council and Conference meetings asking for the OPCW to “recognise new developments in the use of chemistry and increase the Organisation’s focus on preventing the re-emergence of chemical weapons, including new types of potential chemical weapons.” The paper then elaborated on the points made in the 2014 paper and ended by recommending that discussions should focus on “developing concrete recommendations for how to address CNS-acting chemicals in a way that would significantly advance one of the OPCW’s priorities—preventing the re-emergence of chemical weapons.” Similar papers in 2016 [23] and 2017 [24] gathered support from 36 and 39 States Parties respectively. So, there was support for agreeing to deal effectively with this issue, but the number of States Parties in support seemed to have stalled, and key States such as China, India and Russia had not added their names to these papers. The outcome the discussions of incapacitating chemical weapons at the next Review Conference later that year therefore remained in doubt, particularly given the wide range of other issues that would undoubtedly be on the agenda [25]. Again, however, there were signs of potential progress in dealing with the problem of dual use. The Director General of the OPCW had instructed its Advisory Board [AB] on Education and Outreach [E&O] in early 2017 to provide a report: (a) to identify best practices and the latest advances in E&O theory and practice relevant to the OPCW’s E&O activities; (b) to relate the relevant E&O theory and practice to the OPCW’s mandate and main areas of work, as the Organisation moves its focus to preventing the re-emergence of chemical weapons; and (c) to develop on this basis a portfolio of specific E&O activities and projects that the Organisation, States Parties, and the ABEO and its individual members should pursue as a matter of priority from 2018 onward. The Advisory Board reported in February 2018 and argued that [26]: …the OPCW should reach out to new stakeholder communities to raise awareness about their possible contributions to the ‘prevention of the re-emergence of chemical weapons’ and promote professional, scientific, and business cultures that aim to reduce the risks of inadvertently undermining the norm against chemical weapons… (original emphasis)

Moreover, one of the stakeholder communities it identified as important was the scientific community, and in regard to education and awareness-raising it argued in regard to best practice that there had been extensive research and that:

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Table 2.1 Projects suggested by the ABEO for engaging the scientific communitya “Actions to reach the scientific community could include: (a) continuation or even an incremental increase of the OPCW’s participation in international scientific meetings by means of lectures, posters, or any other relevant activity (b) engagement of other international scientific associations in addition to IUPAC and ICCA, for example in fields such as biochemistry (c) engagement of scientific associations at the regional level; (d) increased efforts to raise awareness through publishing in relevant scientific journals, including: (i) technical articles about the scientific work carried out by the OPCW; and (ii) awareness-raising about chemical safety and security policies; (e) greater awareness-raising about the Research Projects Support Programme at scientific meetings and through chemistry and related sciences journals; and (f) identification of scientific leaders within each region who could become ‘OPCW Ambassadors’.” a From

Reference [26] (Annex 2)

One of the most important implications of this research is that ‘active learning’ methods, as opposed to traditional, lecture-based instruction in which students are passive recipients, produce better and longer lasting results. The results hold for factual information and for more fundamental concepts. The methods can be applied in many settings, including the classroom, the laboratory, or the field.

This conclusion clearly drew on the longer experience that had been accumulated on educational initiatives related to the BTWC [27, 28] and indicated that there was a good chance of the OPCW putting major investments into a longer-term educational strategy that might well begin to involve neuroscientists. Indeed, in an annex to their report the Board set out ambitious proposals for putting their ideas into action (Table 2.1).

2.4 Novichocks Then in the afternoon of March 4th 2018 the former Russian spy Sergei Skripal and his daughter Yulia were found slumped on a bench in the center of Salisbury in the UK. By the beginning of the following week [29] the UK Government had concluded that the Skripals “had been targeted by ‘a military-grade nerve agent of a type developed by Russia’”. The agent being described as from a group known as Novichoks. These agents were discussed by a scientist [30] in a long article on the “Development, Historical Use and Properties of Chemical Warfare Agents” published in 2016. In the section on nerve agents he described how the original nerve agents such as Tabun (GA), Sarin (GB) and Soman (GD) were developed from civil research on pesticides in Germany before the Second World War and how several nations

2.4 Novichocks

27

continued to study such agents after the war. This work produced a number of possible new agents, but again it was civil work on pesticides led to the development by the USA, UK and Canada of the new series of V agents such as VX which were “characterized by low volatility, high percutaneous toxicity and high systemic toxicity.” The account noted that a close analogue of VX was also developed by Russia. Finally, the author identified two other series of nerve agents the first named GV in some countries combined properties of both G and V agents. The second, according to this account were named Novichoks and were developed in Russia in the 1970 s with the aim of finding ways to compromise defensive measures. The author noted that: …Information on these compounds has been sparse in the public domain, mostly originating from a dissident military chemist, Vil Mirzayanov. No independent confirmation of the structures or properties of such compounds has been published.

Mirzayanov published an account of these compounds in a collection of essays in 1995 [31]. He argued that the main reason that the Soviet Union continued work on these new agents was that the USA had produced a binary agent that only became a toxic when precursors mixed just before delivery. It was considered necessary to have an equivalent even though the Chemical Weapons Convention negotiations were reaching a successful conclusion. He also suggested that as the precursors could be used for civil purposes it would be difficult for a programme for the production of these agents to be detected. By March 12 a week following the attack the UK Government decided that there were just two possible explanations of what had happened:1 Either this was a direct act by the Russian state against our country. Or the Russian government lost control of this potentially catastrophically damaging nerve agent and allowed it to get into the hands of others.

The Russian Government were given a short time to explain what had happened or the UK said it would act. The Russians pointed out that the UK could have taken their questions to the OPCW where the Russians would have ten days to reply under Article IX (see Table 2.2) once the procedure was initiated. Inevitably perhaps a tit-for-tat round of expulsions from Russia and Western States got underway and tensions between these parties rose quickly. Clearly, there was a danger that the BTWC and CWC meetings would be affected by this degenerating atmosphere and that the chance to strengthen the CBW Non-proliferation regime in 2018 would be severely limited. Indeed, the regime seemed quite fragile and this feeling was not eased by the appointment of the hardline anti-multilateralist John Bolton as National Security Advisor to President Trump [32]. Such concerns were also not eased after what appeared to be renewed use of chemical weapons in Syria was followed by a military response by the United States, Britain and France [33]. Then a frontpage lead of The Guardian on Friday May 4th 2018 concerned an effort by the UK to gain support for a new strategy to combat Russia [34]. The article stated that “[B]ritish diplomats plan to use four major 1 Reference

[29, p. 1].

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Table 2.2 Article IX. Consultations, Cooperation and Fact-Findinga “1. States Parties shall consult and cooperate, directly among themselves, or through the Organization or other appropriate international procedures, including procedures within the framework of the United Nations and in accordance with its Charter, on any matter which may be raised relating to the object and purpose, or the implementation of the provisions, of this Convention 2. Without prejudice to the right of any State Party to request a challenge inspection, States Parties should, whenever possible, first make every effort to clarify and resolve, through exchange of information and consultations among themselves, any matter which may cause doubt about compliance with this Convention, or which gives rise to concerns about a related matter which may be considered ambiguous. A State Party which receives a request from another State Party for clarification of any matter which the requesting State Party believes causes such a doubt or concern shall provide the requesting State Party as soon as possible, but in any case not later than 10 days after the request, with information sufficient to answer the doubt or concern raised along with an explanation of how the information provided resolves the matter. Nothing in this Convention shall affect the right of any two or more States Parties to arrange by mutual consent for inspections or any other procedures among themselves to clarify and resolve any matter which may cause doubt about compliance or gives rise to a concern about a related matter which may be considered ambiguous. Such arrangements shall not affect the rights and obligations of any State Party under other provisions of this Convention” a From

the text of the Chemical Weapons Convention

summits this year—held by the G7, the G20, NATO and the European Union—to try to deepen the alliance against Russia built by the Foreign Office after the poisoning of the former Russian double agent Sergei Skripal and his daughter Yulia in Salisbury,” and that one area most likely to be pursued would be “finding a mechanism to enforce accountability for the use of chemical weapons.” The article ended by noting that some old hands in the Foreign Office thought that demonizing Russia was a disastrous strategy and that Sir Anthony Brenton, the British Ambassador to Russia from 2004 to 2008, insisted that “a fruitful common agenda with Moscow on issues such as nuclear disarmament, terrorism and cyberwarfare is still possible.” The various ad hoc mechanisms set up to deal with the problem of compliance in Syria—such as the DAT (Declaration Assessment Team) and FFM (Fact-Finding Mission)—were attempts to apply the provisions of the Chemical Weapons Convention in highly charge political circumstances rather than to use the agreed tools of the Convention such as challenge inspections and investigations of alleged use of chemical weapons under Article IX. However, there is a penalty to pay for the use of ad hoc solutions because, whereas the rules of the Convention have been painstakingly negotiated, the rules of engagement for ad hoc mechanisms are open to interpretation and the standards used in the assessment of the results are not agreed. Thus, the problems that had arisen were perhaps to be expected and the 4th CWC Review Conference now faced the problem of how to deal with the fallout. This was the topic of an article in Arms Control Today [35]. In the authors’ view “[I]t is important to find ways to manage the Syrian chemical weapons issue so as to avoid lasting damage to the CWC regime and its institutions.” They suggested

2.4 Novichocks

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three different strategies to respond to this issue—which could derail the Conference and seriously deepen the political divisions between States Parties. One approach would be to force a vote that would explicitly condemn Syria for the use of chemical weapons, but they suggested that there was no certainty that the vote would be carried, and it would certainly be likely to make divisions worse. A second option could be to let the issue recede quietly away on the back burner until the international political situation improved. This might allow the other issues at the conference to be approached in a co-operative manner and lead to the “success” of the Review Conference, but at the risk of seriously weakening the norm against use of chemical weapons. However, the authors suggested that there was a third option in which subjects for which consensus can be achieved—such as unequivocal condemnation of any use of chemical weapons, continued work of the DAT and FFM and improving the OPCW forensic capabilities—were divided from issues where consensus was unlikely—such as “attribution of culpability and clearly articulated decisions on what the OPCW should do about it.” This somewhat more sophisticated strategy might achieve agreement on some of the many measures needed to strengthen the Convention while still strongly upholding the prohibition against chemical weapons. In the early Spring of 2018 whether this approach would be taken at the Review Conference remained to be seen.

2.5 Conclusion Revolutionary advances are taking place in the life and associated sciences and these will bring great benefits, but like previous scientific and technological revolutions the results of the benignly-intended work of civil scientists could open up avenues for hostile misuse in dual-use applications. In the UK Royal Society’s 2011 Brain Waves Module 1 [36] titled Neuroscience, society and policy Andrew Stirling provided a chapter on “Governance of Neuroscience: challenges and responses” in which he reflected on the lessons we have learnt from our attempts to deal with previous radical changes in our scientific and technological capabilities. He suggested that there were seven syndromes that we should be careful to look out for in attempting to deal with these revolutions and these included one that he titled “See no evil.” As he noted: …Although readily foreseeable in the same terms as benign uses, malign applications are typically understated in regulatory assessment, sometimes for legal reasons. Yet easily anticipated effects may be of a magnitude that seriously jeopardises overall benefits. This is exemplified by the paradox that military aims are at the same time so prominent and so under-scrutinised in global research…

And as he continued: …However, this ‘see no evil’ syndrome has long been acute with ‘dual use’ technologies in the nuclear, biological, and chemical sector …. Misuse even of ostensibly non-military applications of neuroscience may hold profound security implications…

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Here then were two examples in which the “See no evil” syndrome should be avoided, and civil society should endeavor to bring political attention to dealing with genome editing and incapacitating chemical agents in coming years in order to strengthening the chemical and biological non-proliferation regime before the science and technology developments that could be misused overwhelm our capacity to constrain them. Both examples should clearly have been of concern to neuroscientists if they wanted to protect their work from dual-use applications. What then did they have to say about such issues in 2018?

References 1. Meselson M (2000) Averting the hostile exploitation of biotechnology. Chem Biolog Weapons Convent Bull 48:16–19 (page 16) 2. United States (2017) National security strategy of the United States of America. Washington D.C., December, The White House (page 8) 3. Dando MR (2015) Neuroscience and the future of chemical-biological weapons. Palgrave Macmillan, Basingstoke 4. Dando MR (2015) Neuroscience and the future of chemical-biological weapons. Palgrave Macmillan, Basingstoke. (See Chapter 3: The CBW Non-Proliferation Regime, pages 39–49) 5. Clapper JR (2016) Statement for the record: worldwide threat assessment of the US intelligence community. Senate Armed Services Committee, US Congress, Washington D.C., 9 February (page 9) 6. InterAcademy Partnership (2016) Doing Global Science: A Guide to Responsible Conduct in the Global Research Enterprise. Princeton University Press, Princeton (See Chapter 3: Preventing the Misuse of Research and Technology) 7. Committee on Dual Use Research of Concern: Options for Future Management (2017) Dual use research of concern in the life sciences: current issues and controversies. Washington D.C, The National Academies (page 8) 8. United Nations (2017) Final Document of the Eighth Review Conference. BWC/CONF.VIII/4. United Nations, Geneva, 11 January (page 21) 9. Russian Federation, United Kingdom and United States (2017) Elements of a Possible Intersessional Process. BWC/MSP/2017/WP.10, United Nations, Geneva, 30 November (page 2) 10. Switzerland (2017) Need to Establish a BWC Science and Technology Review Process. BWC/MSP/2017/WP.2, United Nations, Geneva, 17 November 11. Bioweapons Prevention Project (2017) The BWC Financial Situation and the Start of Private Meetings. MSP report 4, Thursday 7th December. Available at http://www.bwpp.org/reports. html (page 2) 12. United Nations (2017) Report of the Meeting of States Parties. BWC/MSP/2017/5. December (pages 5–6) 13. Heidenreich M, Zhang F (2016) Applications of CRISPR/Cas systems in neuroscience. Nat Rev Neurosci 17(1):36–44 14. Koblentz G, Klotz L (2018) New pathogen research rules: Gain of function: loss of clarity. Bulletin of the Atomic Scientists, 28th February. Available at: https://thebulletin.org/new-pat hogen-research-rules-gain-of-function-loss-clarity11540 15. Riches JR et al (2012) Analysis of clothing and urine from Moscow theatre siege casulaties reveals Carfentanil and Remifentanil use. J Anal Toxicol 36:647–656 16. Kelle A et al (2006) Controlling biochemical weapons: adapting multilateral arms control for the 21st century. Palgrave Macmillan, Basingstoke (See Chapter 2: Science and Technology and the CW Prohibition Regime at page 33)

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17. Kelle A et al (2012) Preventing a biochemical arms race. Stanford University Press, Stanford (See Chapter 9: Conclusions at page 195) 18. Royal Society (2012) Brain Waves Module 3: Neuroscience, conflict and security. Royal Society, London. February (See Chapter 5: Performance degradation or weaponization, page 44) 19. OPCW, Report of the Scientific Advisory Board on Developments in Science and Technology for the Third Special Session of the Conference of the States Parties to Review the Operation of the Chemical Weapons Convention, RC-3/DG-1, OPCW, The Hague, 29 October 2012, 1–31 (page 4) 20. Dando MR (2015) Neuroscience and the future of chemical-biological weapons. Palgrave Macmillan, Basingstoke (See Chapter 6: Novel Neuroweapons, pages 83–86) 21. Australia (2014) Weaponisation of Central Nervous System Acting Chemicals for Law Enforcement Purposes. C-19/NAT.1, OPCW, The Hague, 14th November (page 1) 22. Australia et al (2015) Aerosolisation of central nervous system-acting chemicals for law enforcement purposes. C-20/NAT.2, OPCW, The Hague, 24th November (page 1) 23. C-21/NAT.3/Rev.3, 2 December, 2016 24. C-22/NAT.5, 28 November, 2017 25. Crowley M et al (eds) (2018) Preventing chemical weapons: arms control and disarmament as the sciences converge. Royal Society of Chemistry, London 26. Advisory Board on Education and Outreach (2018) Report on the Role of Education and Outreach in Preventing the Re-Emergence of Chemical Weapons. ABEO-5/1, OPCW, The Hague, 12 February (pages 1, 2 and 7) 27. Novossiolova T et al (2013) Effective and sustainable Biosecurity education for those in the life sciences: the benefits of active learning. Briefing Paper No. 7 (Third Series). University of Bradford, June 28. Ukraine and the UK (2016) Awareness-raising, education, outreach: an example of best practice. BWC/Conf.VIII/WP.10, United Nations, Geneva, 19 October 29. Asthana A et al (2018) May points the finger at Russia over ‘reckless’ poisoning of spy. The Guardian, London, 13th March (page 1) 30. Black R (2016) Development, historical use and properties of chemical warfare agents. pp 1–28, Worek F et al (Eds), Chemical warfare toxicology, Vol 1: Fundamental Aspects. Royal Society of Chemistry, London (pages 18–19) 31. Dismantling the Soviet/Russian Chemical Weapons Complex: An Insider’s View. pp 21–34 in Smithson AE et al (Eds), Chemical weapons disarmament in russia: problems and prospects. Report No. 17, The Henry L. Stimson Center, Washington, D.C., October 32. Borger J, Siddiqul S (2018) Bolton ‘is one of the US’s most dangerous and extreme voices’. The Guardian, London, 24th March (page 31) 33. Jenkins S (2018) Look at Syria. It’s how world wars begin. The Guardian, London, 13 April (page 5) 34. Wintour P (2018) Revealed: Britain’s new drive to strengthen anti-Russia alliance. The Guardian, London, Friday May 4th (page 1 and 28) 35. Hart J, Trapp R (2018) Collateral Damage? The Chemical Weapons Convention in the Wake of the Syrian Civil War. Arms Control Today. Available at https://www.armscontrol.org/act/ 2018-04/features/collateral-damage-chemical-weapons-convention-wake-syrian-civil-war. Accessed 6.4.2018 36. Royal Society (2011) Brain Waves Module 1: Neuroscience, society and policy. Royal Society, London, January (page 92)

Chapter 3

Neuroethics and the Regulation of Misuse

Abstract Among scholars studying arms control and disarmament the view has developed that international agreements on these issues cannot be maintained and developed by States acting alone and that a broad range of other mechanisms, including awareness and action by practicing scientists, is also required. It is noted at the start of this chapter that although neuroethics is a very new discipline its basis within the bioethics tradition that evolved after the Second World War gives it a broad perspective. However, careful examination of the relevant literature shows that only very recently have neuroethicists begun to focus in detail on the problem of dual use in regard to chemical and biological weapons, and to link up with the ongoing studies of dual use and the chemical and biological non-proliferation regime. Two international conferences in mid-2018 allowed an assessment of international progress in developing a regulatory system for such dual use both nationally and internationally. The first conference was organised in co-operation with the InterAcademy Panel and surveyed what was currently known of the regulatory systems around the world and demonstrated the partial and fragmentary nature of these systems rather than a wellstructured and comprehensive system. The second conference was organised by the BTWC Implementation Support Unit and the Chinese Government and focused on China’s proposal for the agreement by BTWC States Parties on a Biosecurity Code of Ethics, similar to the Hague Ethical Guidelines recently developed for chemists, that could then be used to inform various national codes of conduct. The chapter ends by noting the UN Secretary General’s warning in early 2018 that unless effective action is taken the use of “chemical weapons and potentially biological weapons” could tragically become normalised, and in this context concerns about where such a process could end up are noted.

3.1 Introduction Within the community of scholars studying the chemical and biological arms control and disarmament regime there has been a growing consensus in recent decades that international regimes have to be supported by a wide range of other mechanisms in © Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6_3

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Table 3.1 Holistic arms control (HAC)a Stage one: constitutes an examination of the nature of the weapons and technology to be controlled and explores the current and potential future scenarios of application, together with the attendant national and human security concerns of inappropriate use. During this stage the potential relevance of advances in science and technology is assessed. Stage two: constitutes an analysis of the full range of potentially applicable international law, (arms control, disarmament and other) instruments and attendant control regimes; highlighting strengths, weaknesses and ambiguities in these mechanisms. The potential roles of relevant civil society actors are also explored. Stage three: following an analysis of information derived from stages one and two, a comprehensive strategy is developed to strengthen existing mechanisms and/or introduce new mechanisms to facilitate effective regulation or prohibition of the weapon or weapons-related technology of concern. a From

Ref. [3]

order to ensure their successful maintenance and development. This view originated in the idea of a web of deterrence [1] as the Cold War came to a close, and then expanded into the idea of a web of prevention [2] which went well beyond militarilyorientated measures to include such elements as “biosafety measures, disease surveillance measures, and counterterrorism tools.” Most recently this approach has been formulated as Holistic Arms Control (HAC) [3] in which there is a systematic analytic method used to determine the current state of the relevant arms control regime and what needs to be done to strengthen it across the board (Table 3.1). In this approach, for example, it would be necessary to examine the application of international humanitarian law and international human rights law in addition to arms control and disarmament law [4]. It would also, as we have seen in the previous chapter and as is emphasised at the level of National Scientific Academies [5], now be seen to include the question of responsible research by scientists in regard to the problem of dual use and the ethical understanding that such scientists have about their responsibilities under the Chemical Weapons Convention and the Biological and Toxin Weapons Convention. As Professor Steven Rose pointed out in the first module [6] of the UK Royal Society’s Brain Waves study on Neuroscience, Society and Policy even if you are not concerned about the philosophical implications of our growing mechanistic understanding of the brain there are risks that need to be considered as well as benefits as our scientific knowledge merges ever more easily into potential technological applications. Moreover, as he stressed, it is better if these risks are considered before the applications take place rather than when they are actually in operation. Given that Neuroethics arose over the last couple of decades, but against a background of decades of development of Bioethics it is not surprising that it had a broad perspective from the outset. For example, the 2017 edited book on Neuroethics: Anticipating the Future has 31 chapters [7] with major groups of chapters on “Neurotechnology: Today and tomorrow”, “Neuroethics at the frontline of healthcare” and “Social, legal, and regulatory frameworks: Lessons of the past guide policy for the future.” Some

3.1 Introduction Table 3.2 Neuroethics concernsa

35 Neurotechnology chapters topics Neuroimaging Incidental findings Healthcare chapters topics Neurodegenerative diseases Brain death Social issues chapters topics Cognitive enhancement Addiction National security a From

Ref. [7]

illustrative examples of the range of subjects where considerable work has obviously taken place are shown in Table 3.2. Clearly issues concerned with security are now seen as part of the scope of neuroethical investigations. However, dual use is only part of this area of concern and dual use in relation to chemical and biological weapons only part of such dual-use issues. As was clear from Jonathan Moreno’s 2006 study of Mind Wars: Brain Research and National Defense [8], even then there was interest in improving soldiers’ physical and psychological performance, the influence of drugs on the brain and brain machine interfaces as well as concern about novel chemical and biological weapons. And all of these potential application areas of advances in neuroscience raised ethical questions. However, when we surveyed the literature in 2013 we were surprised at how little work had been done by neuroethicists on the problem of dual use in relation to the potential for novel agents to be developed based on the ongoing advances in neuroscience. Indeed, Valentina Bartolucci and I concluded [9] that “[W]orryingly, from a preliminary review of the literature on neuroethics, it clearly emerges that, while publications abound on issues such as lie detection, informed consent for certain patients and around the implications of neuroimaging, the problem of dual use is very marginally addressed.” This despite the calls by Moreno and others [10] for more ethical attention to be given to helping scientists deal with this potential problem in the applications of their benignly-intended civil science. What then was the situation in early 2018 following on from the initiation of the State-level funding of the major brain research projects?

3.2 Neuroethics and Dual Use in 2016 and 2018 In November 2016 the key neuroscience journal Neuron published a special issue on “Global Neuroscience.” In the introduction the editor, Kanja Brose, spelt out the reason for the special issue being published [11]:

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3 Neuroethics and the Regulation of Misuse … this issue of Neuron contains a collection of essays and opinions on the future of global neuroscience. Over the last 5 years, owing in large part to significant technological innovation across the field, we’ve seen an explosion of growth in neuroscience. And these new neuroscience technologies and scientific advances are capturing the imagination not just of the scientific community but also the public at large. Countries around the world are investing in neuroscience and neurotechnologies through initiatives like the U.S.

Amongst the essays in the special issue was one authored by Henry Greely and two colleagues titled “Neuroethics in the Age of Brain Projects.” This gave an account of how ethics was being dealt with in the new brain projects and particularly in the US BRAIN project and the EU Human Brain Project (HBP). The structures and systems described will be discussed in detail in the appropriate later chapters. What is of interest here are the overall conclusions about what was being done. According to this well-informed account [12]: The brain projects, especially the BRAIN initiative but also to some extent the HBP, understandably have focussed on the ethics of the research they are supporting or, sometimes, their near term consequences…

They went on to explain that the projects had not tried to delve into the neuroscience of ethics and state that “more importantly, they have so far done little to investigate the likely effects of neuroscience advances on society.” This point is later strongly reinforced as follows: …scholars have worried about the ethical, legal, and social consequences of neurosciencebased cognitive enhancement, memory manipulation, mind reading, marketing and disease prediction. None of these seem likely to be addressed any time soon by the ethics components of the brain projects. (emphasis added).

The authors end by taking some comfort in the fact that these kinds of societalconsequence issues were being pursued elsewhere in the research community, but they also suggest that as advances in neuroscience continue there will need to be a growth in neuroethics—presumably in the brain projects as well as elsewhere. What can be said for certain is that there is no specific consideration of the problem of dual use within this essay on neuroethics in the age of brain projects and, if the emphasised part of the quotation above is correct, that is likely remain the situation for some time to come. Another of the articles [13] in this collection gave a somewhat more optimistic outlook suggesting that some lessons have been taken from the experience over the last decade of attempting to deal with the human genome project and nanotechnology. Moreover, this article did make explicit mention of the problem of dual use. However, another well-informed essay in the same year by Sara Goering and Rafael Yuste did not mince words about the scale of the advances in neuroscience we will have to respond to [14]: …these methods will provide access to core mechanisms that underlie human identity, memories, emotions, personality and, more generally, our minds. As such, they could have profound consequences for human identity and society.

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Referring to the new brain projects the authors also pointed out that: …As a consequence of these projects, more than two hundred laboratories around the world are now funded to systematically develop new methods for recording and manipulating the activity of neural circuits, including awake behaving animals or human subjects…

They conclude that the use of these new methods will reveal a “trove of neural activity” and argue that there is a need for a new set of guidelines to help “integrate the development and use of these technologies with our core societal and human values.” In particular they suggest that a report of the significance of the Belmont Report that guided medical ethics after the Second World War is required by the scale of the problems we will face. The guidelines would they thought best be produced by the joint efforts of scientists, medical practitioners, legal experts and citizens, and supported by robust funding of neuroethics in order to further develop this resource. Of course, these kinds of considerations did not come out of a clear blue sky but were preceded by a growing number of papers on the links between neuroscience research and the military, including the potential development of novel chemical weapons attacking the Central Nervous System [15], and of the potential social and ethical consequences of such developments. [16] By early 2018 attempts were being made to suggest how these different ideas might be put together in a system designed to protect advances in neuroscience from dual-use applications. For example, it was suggested that [17]: ...The neurosecurity framework should include, at least three main levels of safeguard: calibrated regulatory interventions, codes of ethical conduct, and awareness-raising activities…

So, some activities of neuroscientists, in this formulation, would need regulatory oversight, but most activities would best be protected by ethical codes of conduct accepted by the neuroscientific community and the whole system underpinned by awareness-raising of the problem amongst neuroscientists. It may be necessary to add a fourth level of safeguard in very unusual circumstances where, as Relman [18] asked in the debate on dual-use applications of biology in general, “whether there are experiments that should not be undertaken because of the disproportionately high risk.” Within the neuroethics community these ideas had perhaps been most rigorously pursued by James Giordano and his colleagues [19, 20]. In 2017 Giordano summarised the state of his groups work in this field [21]. In a striking phrase he referred to the situation in regard to advances in neuroscience as a “neuroS/T speedway” which he thought: …Reflective of the racing comparison, it is a highly competitive environment, which while offering definable benefits … is not without risk, if not frank dangers as neuroS/T is ever more broadly engaged in the social milieu…

In dealing with the social implications of advancing neuroscience the group naturally sees neuroethics as central, but not just in a precautionary role. In their view it will be necessary to attempt to assess what is likely to happen and proactively assess the

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benefits and risks and what could be done to prevent or constrain the risks. In that regard Giordano states that: …Prior work by our group has shown that modelling neuroS/T progress and effects beyond a 10 year future horizon becomes difficult….it is particularly problematic for any consideration and guidance of dual-use neuroS/T, especially given ‘world stage’ scenarios, inclusive of economic and political, as well as military applications and capabilities…

Indeed, they suggest that force planning techniques may be needed to prepare for any horizons beyond 10 years from now. They recognise a further complication because the ethical issues will require international agreement and maybe some changes in our standard perspectives. As Giordano notes: …We have argued that to be internationally relevant, neuroethical deliberation and engagement may require consideration of the viability and utility of extant ethical concepts, revision of certain current principles and formulation of others anew…

In this regard he may well have had in mind differing attitudes in China and the West (see Chaps. 8 and 9) to the use of non-human primates in neuroscience research [22]. By mid-2018 then it was not unreasonable to think that neuroethicists were beginning to converge on the same set of responses to the threat of dual-use applications of neuroscience as had been evolving over the last three decades in relation to the BTWC and CWC. Two international conference held in June 2018 allowed an assessment to be made of the progress being made in regard to dual-use research and codes of conduct, primarily in relation to the traditional issues of chemical and biological weapons but by implication to the problems beginning to be encountered in regard to advances in neuroscience.

3.3 Governance of Dual Use: Zagreb, Croatia The first of these two conferences held in Zagreb was titled Governance of Dual Use Research in the Life Sciences: Advancing Global Consensus on Research Oversight [23]. It clearly had the aim of assessing where the governance of dual use research had reached internationally and was organised by the Inter Academy Panel, the US National Academies and the Croatian Society for Biosafety and Biosecurity. Before examining the results of that meeting it is useful to note some more of the results of a 2017 study by the US National Academies of the narrower issue of dual use research of concern within the United States [24]. That study, as we saw in the last chapter, was titled Dual Use Research of Concern in the Life Scie]nces: Current Issues and Controversies and the committee that produced the report was charged quite specifically “with reviewing policies associated with the dual use research of concern (DURC)”. Amongst its findings on policy issues was that: 1. The dissemination of life science information that may raise biosafety and biosecurity concerns is governed by fragmented policies and regulations.

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and that: 7. The current policy focus and definition of DURC does not capture biosecurity concerns in all relevant areas of life sciences research, especially those that are emerging (e.g., synthetic and systems biology, computational modelling, genome editing, gene drives, neuroscience, and the isolation of new micro-organisms and toxins)… (emphasis added)

And further that: 9. Currently no international organisation is giving systematic attention to developing policy or guidance regarding the dissemination of scientific information of concern…

So even in regard to the narrower issue of DURC policy development in the US (and beyond) the system in place could hardly be described as fit for purpose. In regard to the education and training of scientists the committee reported that: 17. Despite the attention given to periodic controversies over DURC, the available evidence suggests that most life scientists have little awareness of the issues related to biosecurity. Those training to become life scientists are rarely introduced to the topic in a systematic way…

The papers commissioned by the committee in order to prepare their report further reinforced this important point. In his background paper Tim Sterns, a biologist working in at Stanford University, but with extensive experience of security concerns, noted that [25]: …From interactions with my colleagues, I believe that very few of the more than 50 faculty in the department are aware of the NSABB and the efforts to manage DURC, other than incidental knowledge from news stories in the science journals…

and he added: Another element of this lack of engagement with respect to biology research and its uses is that there is little knowledge among researchers about the history of the development of biological warfare agents…. Faculty, postdoctoral fellows, and graduate students are largely ignorant of this history…

Little wonder then that the committee concluded in part that: Despite decades of effort, there is little national or international consensus with regard to appropriate policies for addressing issues associated with the conduct and dissemination of life science research that might qualify as DURC…

The report therefore made clear that even in regard to the narrow issue of dual use research of concern there had been little progress in achieving a broad consensus on how such research should be governed. The meeting in Zagreb, with its focus on both DURC and the much broader issue of other less immediately concerning, but still potentially dangerous, dual use research, thus had a quite daunting task. The meeting organisers had brought some 70 experts from around the world for the meeting and the agenda made it clear that the aim was not only to consider dual use in

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Table 3.3 Breakout session topics for the working groupsa

Session 1: Taking stock: where are we now? Session 2: Lessons learned, gaps and opportunities. Session 3: Looking ahead: where do we want to go and how do we get there? a From

Ref. [23]

the broadest possible sense, but also to assess the full range of potential governance measures from international laws through national policies and professional codes of conduct to institutional arrangements and the education of life scientists. A variety of relevant presentations led into the discussions, but most of the work was done in Working Groups (Breakout Sessions) and sub-groups within the Working Groups. Reports from these Working Groups on a series of specific questions (Table 3.3) were then discussed by the whole meeting. The organisers had prepared an extensive table listing all of the information they were able to find about the types of dual use governance activities undertaken by different actors (governments, international bodies, funders, scientists, institutions, journals and so on) and the first task of the all of the participants, split into three Working Groups, was to review this information and add more information to the table if that was possible and then to assess this landscape or ecosystem of layered governance. My own impression of this “Taking Stock” exercise was, I think, shared by many others at the meeting. Rather than a systematic layered set of governance measures broadly applied around the world, my impression was that we were looking at a fragmented set of jigsaw pieces in which various layers of the possible governance system were in place to various extents in different national and regional settings. Following on from that session the participants were divided into three different groups according to their research interests and asked to consider the issues set out for Breakout Sessions 2 and 3 as described in Table 3.3 in relation to three different layers of governance: Governance at the National Level; Governance at the Regional and International Level; and Promoting and Sustaining Governance. I participated in the third of these groups which was asked specifically to think about “Norms, Codes, Education and Training, Outreach.” The official report of the meeting was published in November 2018 [26] and came to some clear conclusions on the need for a layered system of governance, including engaged scientists, as set out in Table 3.4. As in most such meetings the discussions stimulated new thinking about what might be useful in dealing with the issues that were uppermost in each participant’s mind at the time. For me, as I was thinking at that time about assessing how well the brain research projects were dealing with the problem of dual use three particular points stood out. First, it was suggested that we might view the governance system in operation to deal with dual use as a kind of ecosystem (of regulation). That then led on to the thought that the generation of new emerging technologies might render

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Table 3.4 Some conclusions from the Zagreb meeting on governance of dual usea Governance across the research life cycle Governance activities occur at every stage of the research life cycle, from conception and initial planning, to funding, to conduct of research, dissemination of results, and translation and product development, and such activities operate at many levels, from the institutional, to the national, regional, and international… Building success and sustainability in dual use governance …The issue of engagement was raised repeatedly over the course of the workshop, with participants suggesting that engagement allowed norms and ideas to be planted and adapted as science changes. Discussion, development, and promulgation of biosecurity codes of ethics and codes of conduct have been one of the most commonly undertaken global governance activities, with a number of examples from different sectors of the scientific community and from multiple countries discussed during the workshop… Advancing research governance While creating the strong, flexible, and anticipatory systems of governance to address life sciences research with dual use potential is an ongoing challenge, the Proceedings highlights the global nature of efforts to address these issues and provides a basis for further efforts to advance the research governance ecosystem. a From

Ref. [26]

the current ecosystem of regulation unfit for dealing with a radically new situation and require radical adaptation if it was to survive. An obvious example here was the recent discovery of the CRISPR/Cas genome editing system and the implications of the rapid spread of this powerful and not too difficult technology. I was led to ask myself whether we are facing a future where we must expect more examples (“gamechangers”) of such rapid developments in our capabilities and what that might mean for the governance system. A second set of ideas was more specific and related to precisely what the threat was that we were trying to contain. So, if we leave aside the very small number of experiments that either should not be done or are of such clear dual-use of concern now that they are obviously a special case requiring direct immediate attention what are we worried about? Is it sufficient to say to scientists that there have been past offensive biological and chemical weapons programmes based on advances in civil sciences, so we need to be careful about the research we do and the results that we publish? Or is that just too general to motivate concern? Might we be better, I thought, to try to give some specific examples of what could be of concern in the longer run if research is misused - such as the colleague who appears to be going off the rails (the insider threat), or the company that appears to be breaking the rules on export controls, or the terrorist group that might perceive an easy option to cause chaos, or a state considering enhancing its law enforcement capabilities? And might we suggest that single experiments are rarely done in isolation from other experiments in the same field and that these series of experiments might cumulatively become of concern, either together or in combination with work in other fields? The third line of thought ran on from this and led me to ask if there was anything we could suggest that might help scientists think about the implications of their

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ordinary day-to-day work that did not raise immediate issues as dual use research of concern? As Sam Weiss Evans argued in his commissioned paper [27] for the 2017 US National Academies report such an approach would be more in line with our current understanding of the nature of scientific work and the much wider range of dual-use concerns we should consider in addition to DURC. It is, as he points out, in line with the second recommendation of the original 2006 Lemon-Relman report on Globalization, Biosecurity, and the Future of the Life Sciences which noted that there was a need to take a broader perspective of the threat spectrum [28]: 2a. Recognize the limitations inherent in any agent-specific threat list and consider instead the intrinsic properties of pathogens and toxins that render them a threat and how such properties have been or could be manipulated by evolving technologies. 2b. Adopt a broadened awareness of threats beyond the classical ‘threat agents’ and other pathogenic organisms and toxins, so as to include, for example, approaches for disrupting host homeostatic and defense systems and for creating synthetic organisms.

These considerations brought up the idea that we might be able to construct a simple rule similar to the three “Rs” that have helped scientists to radically reduce the use of animals in research. Thinking about “Replace, Reduce and Refine” has had a significant effect on how research on animals is carried out. Could we develop a means of helping scientists to deal with the more general issue of dual use beyond dual use research of concern through a similar set of guidelines? Of course, such a set of guidelines would not solve all of the problems a life scientist could encounter, I doubt that any set of such guidelines would cover all the possible problems and pitfalls, but they might contribute to Sam Weiss Evans’ suggestion about engaging scientists in thinking about the broader implications of their ideas. Moreover, it is important to stress that the scientist does not bear the whole of the responsibility for preventing misuse of her work. The multi-layered system of governance may not catch a dual-use problem at one stage, but at another layer it could still be caught if the system is sufficiently robust and integrated. The important point is to develop the best means we can at each stage without unnecessarily hindering the benignly-intended civil work from going ahead. For example, such a set of guidelines might raise the awareness of a potential problem for the scientist, but that is more likely to happen if she has a professional code of conduct which requires a course of education about the problem of dual use and what might be done to mitigate it. This line of thinking has perhaps been most thoroughly explored by Frida Kuhlau and her colleagues within the concept of Ethical Competence which [29]: …involves three core capabilities: 1) awareness, to initially recognise an ethically challenging situation; 2) reflection, to ethically reflect on it; and 3) action, to adapt one’s behaviour to it. (original emphases)

We will return to these ideas and their application in regard to the brain projects in later specific chapters.

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3.4 Development of a Code of Conduct: Tianjin, China At the Meeting of States Parties to the BTWC in December 2017, Ambassador Fu Cong of China noted in his Statement that [30]: At the 8th Rev Con, China made 2 proposals under the framework of the Convention, namely ‘Model Code of Conduct for Bio-scientists’ and ‘Non-Proliferation Export Control and International Cooperation Regime’. They were welcomed and supported by many countries. In our view the code of conduct will enhance bio-security awareness of research personnel and prevent the misuse and misapplication of bio-science and technology, in order to address the challenges brought by rapid development of bio-science and technology…. We look forward to promote these two initiatives with all parties during the ISP [Intersessional Process] towards an enhanced effectiveness of the Convention.

China was successful in its efforts and thus the issue of codes of conduct became part of the agenda for the Meeting of Experts in August 2018 with, as we have seen in the last chapter, the relevant part of the report of the 2017 Meeting of States Parties [31] reading that “[D]evelopment of a voluntary model code of conduct for biological scientists and all relevant personnel, and biosecurity education, by drawing on the work already done on this issue in the context of the Convention, adaptable to national requirements.” Thus, this would be covered as part of the MX2 section on science and technology. The invitation [32] to the workshop in Tianjin, which was organized by China and the BTWC Implementation Support Unit in Geneva, stated that the meeting would “serve as a platform for comprehensive and cross-regional dialogue on the development of a model code of conduct for biological scientists,” and that it would “review existing initiatives regarding codes of conduct and will explore how to develop a model code of conduct in the framework of the BWC, including the implementation and promotion of such a model code of conduct.” At the meeting itself the introduction made clear that the aim was to help provide an input to the August Meeting of Experts and through that to the later Meeting States Parties in December. As Ambassador Fu Cong stated in 2017, China had been interested in developing a code of conduct as a means of strengthening the Convention for a number of years. At the 8th Review Conference in 2016 China and Pakistan presented a Working Paper [33] which proposed the development of a model code of conduct. They argued that Such a model code of conduct would encourage biological researchers to timely evaluate bio-research risk, consciously avoid and properly tackle possible research impact, preventing misuse of bio-technology.

The paper pointed out that China had made a proposal previously at the 2015 Meeting of States Parties and that the proposal had gained wide support. A draft model code of conduct was therefore provided in an annex to the paper in order to form the basis for further discussion. Although it was not possible to move forward with this proposal at the Review Conference, China was obviously attempting to move forward again with the code of conduct in 2018 and the meeting in Tianjin was an integral part of that process.

44 Table 3.5 Agenda for the Tianjin meeting on codes of conducta

3 Neuroethics and the Regulation of Misuse DAY 1 Introduction Session 1: Assessment of the global biosecurity situation Session 2: Assessment of developments in the field of science and technology related to the BWC Session 3: Development of a model code of conduct in the framework of the BWC Session 4: Sharing of experience about codes of conduct DAY 2 Session 5: Implementation and promulgation of a code of conduct Session 6: Current situation and reinforcing measures of multilateral non-proliferation mechanisms. Session 7: Recommendations for the way forward (Group Discussions) Session 8: Summary and Conclusions a From

Ref. [34]

Participants at the meeting were from some 15 different countries in addition to those from China and were a diverse set of people including experts from academia and international organisations, and officials from States Parties. The agenda for the meeting is outlined in Table 3.5. This busy schedule contained 17 individual presentations in Sessions 1 to 6, and as codes of conduct had been the subject of numerous previous discussions in Geneva meetings of the BTWC since 2005 the organisers supplied hard copies of a select number of the key papers from these previous meetings in the workshop handbook [34]. Three other general points are worth making clear before reviewing my perception of the discussions at the meeting. First, as the Netherlands pointed out in a Working Paper [35] at the 2008 Meeting of Experts, there are at least three different types of codes of conduct and it can be very confusing if people are not clear about which type of code—Aspirational, Advisory or Enforceable—that is under discussion. These differences can be briefly summarized as follows: Aspirational Codes (such as the Hippocratic Oath for medical doctors) set ideal standards; Advisory Codes (such as those of many professional organisations) set guidelines for practitioners; and Enforceable Codes are legal requirements that must be followed at work. Clearly, the specificity of these codes increases as they move from aspirational ideals to professional guidelines and on to legal requirements—and the sanctions for not observing the codes also increases in line with the specificity of the requirements. Secondly, of course, a code of conduct for life scientists would not be functioning alone as a barrier to misuse if it was agreed and implemented. Clearly a code of conduct would be only be effective if it was a part of a complex multilayered governance system designed to protect benignly-intended research from potential hostile dual-use. Third there was obviously a great deal that could be gained from studying the previous discussions of possible governance systems and of codes of conduct within

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such systems at BTWC meetings over the last decade and a half, and from the experiences gained from the development and implementation of codes of conduct in closely related governance systems such as the Chemical Weapons Convention and in other less closely related systems. Three presentations in Session 5 of the Tianjin meeting were particularly interesting in this regard. Two presentations discussed the experiences of the OPCW and the International Union of Pure and Applied Chemistry (IUPAC) in the development of the Hague Ethical Guidelines for chemists and the third presentation was from a member of the World Organisation for Animal Health and drew of that organisation’s experience of using various codes of conduct in its regulatory system for animal health. This presentation showed how the principles of an internationally agreed (Aspirational) code of conduct could be used to develop national codes of ethics and then transposed into guidelines for institutional (Advisory) codes of conduct, and for local ethics committees dealing with dual-use problems in research and publication in Enforceable Codes of Conduct. It thus, to my mind, supported the idea of developing an international code of conduct [36]. The Hague Ethical Guidelines [37] were developed carefully in order to help the overall objective that “[A]chievements in the field of chemistry should be used to benefit humankind and protect the environment.” The guidelines clearly are an Aspirational Code and contain 8 short elements as set out in Table 3.6a. In comparison the code proposed by China at the 8th Review Conference in its Working Paper 30 has 9 elements as shown in Table 3.6b. The descriptions of the elements of the Chinese code are slightly longer than in the Hague Guidelines, but it is clear again that this is an Aspirational Code and that there are a number of similarities that can be found by comparing the details within the elements of the two codes. For example, the Table 3.6 Comparison of the elements in the Hague Ethical Guidelines and the draft model code of conduct proposed by Chinaa

3.7a The Hague Ethical Guidelines 1. 2. 3. 4. 5. 6. 7. 8.

Sustainability Education Awareness and engagement Ethics Safety and security Accountability Oversight Exchange of information

3.7b The proposed code of conduct 1. 2. 3. 4. 5. 6. 7. 8. 9.

Ethical benchmark Legal restraint Research integrity Respect for the objects of research The scientific research process Constraint on the spread of research outcomes Popularising science and technology Organization’s role International exchanges

a From

Refs. [33, 37]

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safety and security points in element 5 of the guidelines can be found in the research process element 5 of the proposed code. There are, however, clear differences in that, for example, element 4 of the proposed code on respect for the “human and non-human organisms” is not found in the guidelines and this no doubt reflects the greater use of people and animals in biological research than in chemistry. From my point of view there was one very important difference between the two codes in that elements 2 and 3 of the Hague Guidelines on Education and Awareness and Engagement were not set out as elements of the proposed code of conduct. This was somewhat surprising for me as 10 years previously the Netherlands proposed code [38] had as its first element “Raising Awareness” which required, in part, that scientists should: Devote specific attention in the education and further training of professionals in the life sciences to the risks of misuse of biological, biomedical, biotechnological and other life sciences research and the constraints imposed by the BTWC and other regulations in that context.

I had long felt that this and other recommendations for increased education about biosecurity should have been made mandatory and that as they were not mandatory they were largely ignored because the reason for them was not understood by scientists. Yet there is evidence that they would support mandatory education once they understood the need [39]. In my opinion, what needed to be set out in even an Aspirational Code was some detail on what education was needed and why. I liked the requirements set out in paragraph 2 of the Russian paper [40] on Basic Principles (Core Elements) of the Codes of Conduct of Scientists Majoring in Biosciences presented in the 2005 Meeting of States Parties to the BTWC (see Table 3.7). To be Table 3.7 Core elements in a code proposed by the Russian Federation in 2005a Scientists should: (i) Be well informed of, and apply in their practice, international and national regulatory legal instruments on the prohibition of biological and toxin weapons; (ii) Be involved in raising biologists’ awareness of international and national obligations related to the prohibition of biological weapons, including criminal liability for their violation; (iii) Assist in improving and strengthening international legally binding arrangements banning biological weapons and their proliferation; (iv) Participate, within their competence, in the development of national regulatory legal acts aimed at using scientific and practical results of biological research solely for peaceful purposes; (v) Contribute to the reduction of new risks and threats which may affect the enforcement of the BTWC; (vi) Avoid referring to the results of the work, which may be used in violation of the BTWC provisions, in their scientific papers and statements to the mass media; (vii) Take measures to ensure that transfers of biological agents, toxins, equipment and technologies to any natural or legal person are performed in compliance with the BTWC requirements and national legislation enforcing such measures. a From

Ref. [40]

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able to meet these requirements I thought scientists would need careful educational material to be developed and implemented, and I still think that until such requirements are made mandatory scientists will not understand why there needs to be codes of conduct and other methods of regulation of biosecurity and little progress will be made. It was to such more practical questions that attention turned in Sessions 6 and 7 of the meeting in Tianjin. Participants were divided into four heterogeneous groups and asked to consider the following six key questions: 1. 2. 3. 4. 5. 6.

Who should be the target audience for the code? What should be the basic principles (core elements) of the code? What type of code should it be? How should the code be promoted? What measures should be taken to sustain the code? How should the impact of the code be evaluated?

The groups were then asked to report orally in sequence and then these reports were summarized and discussed in the final session. The aim was to give as clear feedback as possible to the organisers as to how the code of conduct proposed by China might be developed and presented in 2018 at the August Meeting of Experts and thereafter at the December Meeting of States Parties. According to the notes that I made of the four rapporteurs’ reports there was both a very positive view of the code and under discussion and a great deal of agreement in the answers to the key questions. These answers might be summarized as follows: 1. The target audience for the code was individual life scientists both those engaged practically in research and those involved in funding, managing and publication roles associated with research. 2. There was general approval of the elements within the code proposed by China, but with agreement that education and awareness-raising should be added as a separate element. 3. The code was seen by all groups as an Aspirational Code that could set an internationally agreed standard to be adjusted to fit varying national and professional circumstances in Advisory Codes and Enforceable Codes. 4. Various routes were put forward that could be used to promote the code, in particular getting agreement at the BTWC meetings in 2018. Working through the InterAcademy Panel and National Academies was seen as a useful follow up to actions taken by States Parties as a result of the BTWC meetings. 5. The important point made here was that sustainability required that scientists bought into the code and had a sense of ownership of it. To reach that goal the implementation of the code had to be part of a broader national biosecurity strategy also involving other measures such as education and oversight where necessary.

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6. Evaluation was seen as a difficult problem by all of the groups, but one idea suggested by all groups was for States Parties to add a section on the implementation of the code in their annual Confidence Building Measures return to the ISU. Every participant probably had slightly differing views from their rapporteur. For myself I would like to have seen the code proposed by China developed to look a little more like the Hague Ethical Guidelines by cutting down some of the descriptions of the elements of the code. I particularly would like to have seen education as being required to be mandatory and going beyond the Hague guidelines statement that “society should cooperate to equip anybody working in chemistry and others with the necessary knowledge and tools to take responsibility for the benefit of humankind.” I would favour a clear statement of the specific issues that should be covered in University courses in order that scientists could understand what was needed. Finally, I would like to have seen a requirement for evaluation of the code and its impact written into the code as I agree with those who point out the lack of effective evaluation of the various means that have been suggested, and implemented, in order to improve biosecurity [41].

3.5 Conclusion By the middle of 2018 it was certainly correct to say that there was evidence of successful initiatives being developed and implemented in various aspects of biosecurity and dual use, and that there were attempts being made to pull all of the relevant information together and to provide an integrated overview of these developments. The meetings in Zagreb and Tianjin were obvious examples of these attempts to draw together the work that has been done over the last couple of decades. Yet it cannot be denied that the well worked out examples were best seen as isolated fragments of an incomplete jigsaw rather than indications of the beginnings of a complex layered system of regulation from the international through to the national, professional institutional and individual levels. At the same time the UN Secretary General was warning of the approach of a new cold war, stating that [42]: We are on the brink of a new cold war. Unlike the first, which emerged from a world wearied from devastating global conflict, the second has come during an era of converging global challenges, a more complex international system and diminishing respect for international norms and institutions…

And in regard to chemical and biological weapons he added that: Ensuring respect for norms against chemical and biological weapons concerns the interests of all humanity. Unfortunately, political differences have frustrated efforts to achieve accountability for the violations of the norm against chemical weapons and to strengthen our shared institutions. Unless these trends are checked, we risk falling back to a moral dark

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age where the use of chemical and, and potentially biological, weapons becomes tragically normalized…

Such fears were not reduced by the threats made by the Russian Federation representatives after the Conference of the States Parties to the Chemical Weapons Convention decided at its Fourth Special Session on June 26th and 27th that the Secretariat would put into place arrangement to identify the perpetrators of the use of chemical weapons in Syria [43]. According to Deputy Foreign Minister Sergei Ryabkov [44]: …we do not consider the work of this so-called attributive mechanism to be legitimate…. We doubt the possibility of preserving the CWC and the OPCW in their present form, which has existed to date…

At the same time, evidence continued to accumulate of the growing impact of advances in our understanding of the nervous system on society at large [45] and of the development of new weapons systems to counter chemical and biological weapons [46]. In such circumstances it is perhaps not surprising that neuroethicists were beginning to contemplate some distinctly unpleasant possibilities later in this century. As Armin Krishnan [47] noted in his book titled Military Neuroscience and the Coming Age of Neurowarfare: …The main argument presented here is that possible future breakthroughs in neuroscience have the potential to fundamentally alter human society, human consciousness, warfare and security. This could make the human mind a distinctive new domain of warfare… (original emphasis)

He goes on to argue that this requires a radical transformation in international regulation of future neuroweapons. Krishnan has a wider focus than just new chemical and biological weapons and a longer time frame than this study. So, the focus here is on whether the potential disaster of neurowarfare can be limited in one particular field of his broader concerns. It is to these more immediate dangers that we turn in the next chapter.

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5. Interacademy Partnership (2016) Doing global science: a guide to responsible conduct in the global research enterprise. Princeton University Press, Princeton (See Chap. 3, Preventing the Misuse of Research and Technology) 6. Rose S (2011) 3.2 risks. In: Brain waves module 1: neuroscience, society and policy. Royal Society, London (pages 69–76) 7. Illes J (2017) Neuroethics: anticipating the future. Oxford University Press, Oxford 8. Moreno JD (2006) Mind wars: brain research and national defense. The Dana Foundation, New York 9. Bartolucci V, Dando NR (2013) What does neuroethics have to say about the problem of dual use? In: Rappert B, Selgelid M (eds) On the dual uses of science and ethics: principles, practices and problems. Australian University Press, Canberra (page 43) 10. Dando MR (2009) Biologists caught napping while work militarized. Nature 460:950–951. See also the accompanying editorial titled, A question of control: scientists must address the ethics of using neuroactive compounds to quash domestic crises. Nature 460:933 11. Brose K (2016) Global neuroscience. Neuron 92(3):557–558 (page 557) 12. Greely HT, et al (2016) Neuorethics in the age of brain projects. Neuron 92(3):637–641 (page 640) 13. Garden H et al (2016) Neurotechnology and society: strengthening responsible innovation in brain science. Neuron 92(3):642–646 14. Goering S, Yuste R (2016) On the necessity of ethical guidelines for novel neurotechnologies. Cell 167:882–885 (page 882) 15. Tracey I, Flower R (2014) The warrior in the machine: neuroscience goes to war. Nat Rev Neurosci 15:825–834 16. Rose N (2014) The human brain project: social and ethical challenges. Neuron 82:1212–1215 17. Lenca M, et al (2018) From healthcare to warfare and reverse: how should we regulate dual-use neurotechnology. Neuron 97:269–274 (page 272) 18. Relman DA (2014) “Inconvenient truths” in the pursuit of scientific knowledge and public health. J Infect Dis 209:170–172 19. Giordano J (ed) (2012) Neurotechnology: premises, potential, and problems. CRC Press, Boca Raton 20. Giordano J (ed) (2015) Neurotechnology in national security and defense: practical considerations, neuroethical concerns. CRC Press, Boca Raton 21. Giordano J (2017) Toward an operational neuroethical risk analysis and mitigation paradigm for emerging neuroscience and technology (neuroS/T). Exp Neurol 287:492–495 (pages 492, 294) 22. Palchik G et al (2018) Monkey business? Development, influence, and ethics of potentially dual-use brain science on the world stage. Neuroethics 11:111–114 23. Inter Academy Panel, US National Academies, Croatian Society for Biosafety and Biosecurity (2018) Governance of dual use research in the life sciences: advancing global consensus on research oversight. National Academies Press, Washington, DC 24. Committee on Dual Use Research of Concern: Options for Future Management (2017) Dual use research of concern in the life sciences: current issues and controversies. National Academies Press, Washington, DC (pages 2, 4, 7, 8) 25. Sterns T (2017) Moving beyond dual use research of concern regulation to an integrated responsible research environment. Commissioned paper available at https://www.nap.edu/catalog/ 24761. Under the Resource tab (page 5) 26. US National Academies (2018) Governance of dual use research in the life sciences: advancing global consensus on research oversight: proceedings of a workshop highlights. National Academies, Washington, DC (pages 1, 3) 27. Weiss Evans S (2017) The construction of new security concerns in the life sciences. Commissioned paper available at https://www.nap.edu/catalog/24761. Under the Resource tab (pages 6–7) 28. Committee on Advances in Technology and the Prevention of their Application to Next Generation Biowarfare Threats (2006) Globalization, biosecurity, and the future of the life sciences. National Academies Press, Washington, DC (page 6)

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29. Kahlau F, et al (2012) Ethical competence in dual use life science research. Appl Biosaf 17(3):120–127 (page 121) 30. The Ambassador’s Statement can be found with other such Statements on the United Nations website in Geneva under the Biological Weapons Convention and then the section on Meetings and Official Documents 31. Meeting of the states parties to the convention on the prohibition of the development, production and stockpiling of bacteriological (biological) and toxin weapons and on their destruction (2017) Report of the meeting of states parties. United Nations, Geneva, 19 December (page 6) 32. Department of Arms Control and Disarmament, Ministry of Foreign Affairs, People’s Republic of China (2018) Invitation letter: BWC Workshop in Tianjin, China, 25 – 27 June. Beijing, 28 May 33. China and Pakistan (2016) Proposal for the development of a model code of conduct for biological scientists under the Biological Weapons Convention. BWC/CONF.VIII/WP.30. United Nations, Geneva, 15th November (page 1 of the unofficial translation) 34. Foreign Ministry of China and the United Nations Office for Disarmament Affairs (2018) Building a global community of shared future for biosecurity: development of a code of conduct for biological scientists: conference handbook. Tianjin, 25–27, June 35. The Netherlands (2008) Development of a code of conduct on biosecurity. BWC/MSP/2008/MX/WP.8. United Nations, Geneva, 30 July 36. Uhlenhaut C (2018) Responsible scientific conduct: perspectives from the world organisation for animal health. In: Paper presented at the international workshop on building a global community of shared future for biosecurity: development of a code of conduct for biological scientists: conference handbook. Tianjin, 25–27, June. (slides 11 and 12) 37. Organisation for the Prohibition of Chemical Weapons (2016) The Hague ethical guidelines: applying the norms of the practice of chemistry to support the Chemical Weapons Convention. OPCW, The Hague 38. See Annex II of reference 35 39. Committee on Assessing Fundamental Attitudes of Life Scientists as a Basis for Biosecurity Education (2009) A survey of attitudes and actions on dual use research in the life sciences: a collaborative effort of the national research council and the american association for the advancement of science. National Academies Press, Washington, DC (See the conclusions on Education and Outreach) 40. Russian Federation (2005) Basic principles (core elements) of the codes of conduct of scientists majoring in biosciences. BWC/MSP/2005/WP.2. United Nations, Geneva 41. Perkins D et al (2018) The culture of biosafety and biosecurity, and responsible conduct in the life sciences: a comprehensive literature review. Appl Biosaf 24(1):34–45 42. Secretary General (2018) Securing our common future: an agenda for disarmament. Office of Disarmament Affairs, United Nations, New York (pages 3, 25) 43. OPCW (2018) Decision: addressing the threat from chemical weapons use. C-SS-4/DEC.3. OPCW, The Hague (page 3) 44. Tass (2018) Diplomat slams decision on OPCW as a blow to chemical weapons prohibition. Rus Polit Dipl 11:07 45. Thomson H (2018) Open your mind: negotiating a new era of psychedelics takes a great guide. Book review of Pollan M How to change your mind: the new science of psychedelics. New Sci, 16 June (page 44) 46. Hambling D (2018) Building an X-ray bomb. New Sci, 16 June (page 6) 47. Krishnan A (2018) Military neuroscience and the coming age of neurowarfare. Routledge, London

Chapter 4

Dual-Use Neuroscience?

Abstract Given that in the future civil neuroscience could be subject to dual use in the development of novel chemical and biological weapons the question for neuroscientists is what should they do to help protect their benignly-intended work from misuse? The dilemma for scientists is illustrated at the start of this chapter by reference to a similar ethical question facing computer scientists after their work was used by Cambridge Analytica to analyse the ‘likes’ of Facebook users and the reaction that produced in democratic societies. The question is then raised as to what extent it is possible to forecast the consequences of technological changes? It is argued that while it is generally difficult to do this, a significant paradigm change has been noted in relation to chemical and biological weapons development as advances in the life sciences will allow weaponeers to change their traditional focus from the agent to the target within the living system for the attack. Changes in our capabilities to manipulate living systems is then illustrated by reference to work on Parkinson’ Disease and to work on two neuropeptides—orexin and oxytocin—that could also perhaps be misused for hostile purposes. In conclusion it is argued that there are serious questions to be asked about how the new brain projects are going to go about protecting their results from such misuse.

4.1 Introduction The main bearing of the last chapter is surely to suggest that while most civil neuroscience should not be of immediate concern in regard to potential dual-use applications in chemical and biological weapons now, some advances might well be of considerable concern in future decades. The question for neuroscientists and neuroethicists then is what should be done to protect benign civil neuroscience from such misuse? In early 2018 during the discussions that arose from the manipulation of democratic elections through data mining John Naughton, the technology expert writing for the London Observer, raised the question of the ethics of the IT specialists involved [1]. He began by recalling Leo Szilard’s realisation in London’s Russell Square in 1933 that if there was an element that would emit two neutrons © Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6_4

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when split by the impact of one neutron a sustainable nuclear chain reaction could be possible, and Szilard’s later regret about this insight leading eventually to Hiroshima and Nagasaki being devastated by atomic bombs. Turning then to the question of the activities of Cambridge Analytica, Naughton pointed out that three young scientists in Cambridge University published a paper in 2013 that demonstrated that ‘likes’ posted on Facebook could be effectively used to predict highly sensitive personal data. As he noted: The work reported in their paper was a paradigm of curiosity-driven research. The trio were interested in social media as a phenomenon and had a hunch about how unintentionally revealing its users’ online activities could be. They found a way of confirming their hunch…

Naughton argued that the trio were smart and probably understood that their work could be of use to advertisers, but they probably did not appreciate, as one of their colleagues did, just how much power their work gave to Facebook. Naughton then suggested that in their own way the trio might be seen as equivalent to Szilard but: …whereas the physicist’s ideas revealed a way to blow up the planet, the Cambridge researchers had inadvertently discovered a way to blow up democracy.

Naughton went on to say that his thoughts about this came about after he had read an essay arguing that “computer science now faces an ethical reckoning analogous to those that other academic fields have had to confront.” He ended his article with the speculation that: Up to now, my guess is that most computer science graduates have had only a minimal exposure to ethical issues such as these. Indeed, it’s possible that they regard ethics as a kind of hobbyhorse for people who don’t have enough to do…

Perhaps then computer scientists are now on the same long road as neuroscientists in trying to work out means of minimising the possible misuse of their benignlyintended work, but how best can we begin to think about what could be of concern in the advances that will be made in neuroscience over coming decades?

4.2 Forecasting Technology Change It is reasonable to assume that in coming decades there will be great improvements in capabilities to disperse chemical agents [2], and our ability to directly target [3] such agents to particular receptors in the brain. It is also to be expected that a wide range of novel agents that may affect the brain will be explored [4]. Moreover, it can be expected that military defence establishments will attempt to monitor these developments, for example using, by an analogy to a weather forecasting methodology, (Futures, Watch, Warning, and Alert) [5] as set out in Table 4.1. Once such a system reaches alert then responses will be obvious as can be seen in the response to the use of fentanyl to break the Moscow theatre siege in 2002. As

4.2 Forecasting Technology Change Table 4.1 Definitions used in a military forecasting methodologya

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Futures: Create a technology roadmap and forecast; identify potential observables to aid in the tracking of technological advances Technology Watch: Monitor global communications and publications for breakthroughs and integrations Technology Warning: Positive observables indicate that a prototype has been achieved Technology Alert: An adversary has been identified and operational capability is known to exist a From

Ref. [5]

scientists from the UK Defence Science and Technology Laboratory at Porton Down noted [6]: …International condemnation of the use of the aerosol, killing 15% of those exposed, was not forthcoming…. A comparison of open literature publications before and after the siege from government scientists from around the world suggests an increased interest in fentanyl compounds and other potential incapacitating agents…

The authors then list some 62 publications from such sources dating from after the use of the aerosolised fentanyl derivatives to break the siege. However, it may not be the dispersal, targeted delivery and agent advances that are of critical concern here in relation to novel chemicals that attack the Central Nervous System (CNS), but our increasing knowledge of the operations of systems with the CNS. If we look at the kinds of incapacitating effects being sought during the early Cold War period [7, 8] we can begin to understand what might well become the objectives of chemical and biological weaponeers later in this century. As is clearly shown in Table 4.2 they were not just seeking simple methods of sedation as their lack of knowledge of the operations of the brain and its receptor systems forced them to do later in the last century [9]. The critical point was made by three US Defence Analysts in the early years of this century. They argued that the threat from traditional biological weapons would level out as this century continued because our countermeasures would become better, and that the same thing would happen later to genetically modified biological weapons However as our science and technology advanced [10]: …Emerging biotechnologies likely will lead to a paradigm shift in BW agent development; future biological agents could be rationally engineered to target specific human biological systems at the molecular level. This is a departure from the traditional model of BW agent development, which is focused on the naturally occurring agent, not the target organism… (emphasis added).

And they elaborated as follows: …Advanced BW agents will be able to target specific biological systems, such as the cardiovascular, immunological, neurological, and gastrointestinal systems. Using an everincreasing information base, BW designers of the future will have the capability to engineer agents that target biological processes, producing a wide range of effects including death, incapacitation, or neurological impairment… (emphasis added).

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Table 4.2 Systems considered for disabling early in the Cold Wara

SIPRI list Hypotension Emesis Body temperature Labyrinthine reflexes Muscular hypotonia Temporary blindness Psychotophic effects US list Fits or siezures Dizziness Fear Panic Hysteria Hallucinations Migraine Delirium Extreme depression Notions of hopelessness Lack of initiative to do simple things Suicidal mania a From

Refs. [7, 8]

Of course, precisely the same argument can be made in regard to future chemical weapons. What we have to watch carefully are the advances being made in the understanding of the neuronal circuits in the brain—just what is being sought in civil neuroscience as described in Chap. 1. Until very recently it was only possible to obtain a mechanistic understanding of the neuronal control of simple behaviours (for example the crustacean stomatogastric ganglion) or in very specialised systems (for example bat echo location systems) [11–13]. But now advances in technologies such as neuroimaging, knock-in and knock-out genetic manipulation, optogenetics and multiple simultaneous recording of neuronal activity has changed that situation radically [14]. It now appears possible to successfully investigate the activity of neuronal circuits that underlie more complex behaviours. As noted in Chap. 1 a report for the US National Institutes of Health stated in 2014 [15]: In considering the goals and the current state of neuroscience, the working group identified the analysis of circuits of interacting neurons as being particularly rich in opportunity, with potential for revolutionary advances…

Indeed, the initiation of multiple State-level brain research projects in recent years [16] and their co-ordination into a global effort [17] indicates clearly that the possibilities of major advances in neuroscience being made for beneficial purposes in the next decade is widely recognised. A further element of considerable importance in the advances in neuroscience has been the realisation that there is much to be gained in the study of the neuronal

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circuits operating in the human brain by the study of such circuits in other animals [18], an approach underpinned by the understanding of the deep homologies in development revealed in studies of evolution and development [19, 20]. Darwin, of course, considered that there was a the link between the expression of emotions in man and other animals [21], and it has been argued [22] that “emotional primitives” such as fear and anger “can be modelled and studied in evolutionary distant model organisms, allowing functional dissection of their mechanistic bases and tests of their causal relationships to behaviour.” More generally the work in the last century by ethologists like Lorenz [23] on species-specific instinctive behaviours, innate releasing mechanism and fixed action patterns suggested that there were neuronal systems underlying complex behaviours that could be open for analysis. The idea that mammals have similar emotional networks in homologous brain regions has been argued strongly by Jaak Pansepp and colleagues. He has stated that [24]: …Seven types of emotional arousals have been described…they are SEEKING, RAGE, FEAR, LUST, CARE, PANIC/GRIEF and PLAY…. These circuits are situated in homologous subcortical brain regions in all vertebrates tested…

Pankepp has also given considerable attention to the implications of these finding for human beings, for example in a detailed exposition written in collaboration with Lucy Biven a psychotherapist [25]. Research on the generation of rhythmic movements by neuronal circuits in invertebrates over the last five decades has also led to an increasing understanding of how such rhythms are produced. As one review concluded in 2015 [26]: … study of small circuits that generate rhythmic movements has revealed principles of circuit organization and function that generalize to the organization of large circuits and the mechanisms by which they combine into functional units. In particular, it is clear that circuit function can be surprisingly robust to variation in many parameters…

This review also notes that: A wealth of data has shown that neuromodulators and modulatory neurons can reconfigure oscillatory networks, changing their frequency, phase relationships, and functional interactions among neurons. Notably, neurons can switch among different rhythms, and the same neuron can be part of oscillatory circuits with very different cycle times.

There is known to be a deep homology of the molecular signalling systems in animals that it seemingly at odds with the wide variations in behaviour of different species. The probable explanation of this paradox is that it involves “changes in the compartmentalization, or subfunctionalization, of neuromodulation; neurons shift their expression of GPCRs [G protein coupled receptors] and the content of monoamines and neuropeptide.” So just as neuromodulation can change the operation of a circuit in an individual species, differences in neuromodulation between species can produce different behaviours [27]. Indeed there is now a good understanding of the general principles of neuromodulation of neurons and circuits [28].

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These can be summarised as including that: every stage of neuronal processing can be under neuromodulatory control; neuromodulators are released in a variety of ways; neuromodulators act in a variety of ways; all neural circuits are multiply modulated and activated differentially through diverging and converging neuromodulatory effects. This developing understanding of neuronal circuits and their modulation is important here because as the report on Emerging Cognitive Neuroscience and Related Technologies stated in 2008 [29] “increased experimentation with neuropeptides will have profound implications for the neuropsychopharmacological modulation of behaviour” and thus for the potential for misuse.

4.3 Modulation of Neuronal Circuits The question then that arises is how far has the study of such circuits and their modulation gone? This section takes up this question in regard to one important disease of the nervous system before an in-depth look is taken at two neuromodulatory systems to illustrate what could be subject to misuse.

4.3.1 Parkinson’s Disease and Drug Delivery Parkinson’s Disease is the second most common neurodegenerative disease worldwide and the prevalence is certain to rise as the population in general ages. The disease is usually characterised by disturbances of the motor control system, but there can be disturbances of other functions so the disease has both motor and nonmotor aspects. The motor system disturbances that characterise Parkinson’s Disease are defined as [30]: …Slowness of initiation of voluntary movements with progressive reduction in speed and amplitude of repetitive actions (bradykinesia) with one additional symptom i.e. muscular rigidity, resting tremor or postural instability…

The cause of Parkinson’s Disease is in most cases, unknown and there is presently no treatment that will halt the progress of the disease that increasingly affects the quality of the affected person’s life. Given these characteristics there have been considerable efforts to find means of helping people with Parkinson’s Disease. In the last century the dopamine system in the CNS was discovered, and it was then found that destruction of the dopamine cells in the substantia nigra of the CNS produced the motor aspects of Parkinson’s Disease [31]. It is estimated that these motor disturbances occur when some 80% of the dopamine cells in the nigro-striatal system are lost. Yet it also is clear that this loss is preceded by disruption of other systems in the brain.

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The mechanism involved in the loss of the motor control has been understood for some time within a simple model in which dopamine is central. The substantia nigra is part of the basal ganglia of the CNS. These ganglia, which have been conserved in the vertebrates, can be subdivided into [32]: …an input region (the dorsal and ventral striatum) activated by the cerebral cortex, thalamus, and an output region referred to as pallidium (globus pallidus interna and substantia nigra reticulate). The output neurons are inhibitory and have a very high activity at rest…

The purpose of this output is to keep the brainstem motor centres quiet at rest. When a motor output is required the pallidal output has to be inhibited by the striatum, but the striatal neurons are silent at rest and not easily activated from the cortex or thalamus. Their level of activity is determined in good part by the dopaminergic input from the substantia nigra. Thus: …If the level of dopamine activity is reduced, as in Parkinson’s disease, it becomes very difficult to activate the striatal neurons and thereby to initiate and carry out most types of movement…

Conversely, it has been possible to alleviate the movement defects in Parkinson’s Disease by supplying a precursor of dopamine (L-DOPA) that passes the Blood Brain Barrier or through supply of various dopamine agonists to the brain. However, these treatments do not halt the progress of the disease and may indeed result in other complications [33]. The mechanisms involved in motor control and the changes in the disease are obviously more complex than the simple model would suggest despite its value in helping to alleviate the symptoms of the disease. It is to be expected that the neuronal circuits involved will be elucidated in more detail both because of the availability of animal models of the disease [34] and because of the advances being made in technologies useful to investigate the diversity of the dopamine neurons involved in the basal ganglia [35]. A further interesting development is that deep brain stimulation which has been found useful in treating the symptoms of the movement disorder has also become useful in investigating the oscillations of the neuronal circuits that appear to be involved in the normal and affected brain and how these can be purposefully altered by carefully designed and monitored stimulation [36, 37]. Clearly precise and effective interventions are crucial to successful treatment of the disease and are likely to become more important as the details of the circuits involved in the breakdown of motor control are clarified. Thus, another technology that is proving useful in developing novel treatments for the disease is nanotechnology. Data from a review of 28 studies involving animal models, most published since 2010, demonstrated a number of improvements [38]: …(i) improvement of pharmacological properties, (ii) more stable drug concentrations, (iii) longer half-life and (iv) attenuation of pharmacological adverse effects…

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As the review points out this is significant because “unfortunately long-term treatment with L-DOPA is associated with motor fluctuations, dyskinesia (abnormal involuntary movements) and psychiatric problems.” These side effects happen for many patients and the treatment often has to be suspended. Nanotechnology can be used to enhance imaging studies and, manipulated in various ways, to improve the delivery of drugs to the brain: for example, to reside longer in the nasal cavity, to help pass the Blood Brain Barrier, and to improve their uptake. The review discusses results involving L-DOPA, and a variety of drugs such as ropinirole and bromocriptine. What is interesting for this paper is that the review notes that of twenty studies that involved in vivo research nine (45%) utilised intranasal delivery and eight of these were published after 2013. The authors state that: …Therefore, intranasal route recently turned into the most used via of administration in studies, maybe for its known advantages, like great surface area, little invasiveness, and BBB and first-pass metabolism evasion…

Indeed, they suggest that there is a good chance that the first nanoparticle drugs for Parkinson’s Disease to reach the market could use intranasal delivery. Clearly, such advances in nanotechnology and drug delivery could have a significant impact on delivery of chemical warfare agents to the brain [39].

4.3.2 Orexin The use of derivatives of the opiate fentanyl by Russian special forces to break the 2002 Moscow theatre siege dramatically demonstrated that one of the aims of developing incapacitating chemical agents has long been to simply render people unconscious. The opioids, however, are dangerous to use in such operations because they also affect the victim’s ability to breath and are thus likely to kill or injure a proportion of those subject to the agent—as indeed happened to many of the hostages in Moscow [40]. It would surely not have escaped the notice of weaponeers that in the late 1990s just a few years before the Moscow siege our understanding of the mechanism of the sleep/wake cycle radically changed [41] with the discovery of the orexin (OX), also known as hypocretin (Hcrt), neuropeptide system in the mammalian brain [42]. As explained in Chap. 1, it was only in 1953 that it was discovered that sleep was not a unitary phenomenon. Recording of brain activity, for example by electroencephalography (EEG), showed that there were two types of sleep: rapid eye movement sleep (REM) and four stages of non-rapid eye movement (NREM) sleep. In NREM sleep our sensations and perceptions are dull or absent and our movements episodic and involuntary, but in REM sleep our sensations and perceptions are vivid (as when we are awake), but they are internally generated not externally generated as when we are awake. Also, and importantly, so that we do not put ourselves in danger most of our voluntary movements are inhibited during REM sleep [43]. Subsequent

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research lead to the development of a ‘flip-flop switch’ model of the control of this system in which [44]: …(A) During waking, monoaminergic neurons…promote waking and inhibit the sleepproducing neurons of the ventrolateral preoptic area (VLPO)…. (B) During sleep, neurons of the VLPO inhibit the wake-promoting monoaminergic neurons…. This mutually inhibitory interaction produces conditions analogous to an electrical flip-flop switch whereby the alternate states of sleep and waking are self-reinforcing but intermediate states are unstable and transient…

The text goes on to explain that this system allows rapid transitions from sleep and the waking state and vice versa. Orexin neurons both excite and reinforce the wakeproducing activities of the monoaminergic neurons and thus serve to stabilise the waking state. The orexin producing cells were found to be located in the lateral hypothalamus and number about 3,200 in the mouse, 6,700 in the rat, and 50–80,000 in the human brain. These cells produce two different peptides and these peptides affect two different orexin receptor types in the brain [45]. Recordings from orexin cells demonstrated that “they are generally quiescent during quite wakefulness… and sleep but show high discharge rates during active wake and in anticipation of … sleep–to-wake transitions. In addition, they show high discharge rates during arousal by environmental stimuli.” Such data suggest that the orexin system is involved in a variety of behavioural control systems including sleep to waking transitions. What was surprising was the finding that disruption of the orexin system quite clearly caused narcolepsy. This is a debilitating sleep disorder “characterised by intrusions of sleep into wakefulness, as well as signs of dysregulated REM sleep and cataplexy, a sudden loss of muscle tone during wakefulness.” The cataplexy can last for minutes but people remain conscious during that period. Clearly it can be very dangerous, for example if the person is driving a car [46]. There are two recognised forms of narcolepsy: Type 1 was previously known as narcolepsy with cataplexy and people suffering the disease have low levels of brain orexin and report having cataplexy and excessive daytime sleepiness. Type 2 narcolepsy was previously known as narcolepsy without cataplexy. People suffering the disease experience excessive daytime sleepiness but do not usually experience cataplexy and have normal levels of brain orexin. People suffering from narcolepsy can also experience sleep paralysis—a temporary inability to move or speak whilst falling asleep or waking, and hallucinations—vivid images that can accompany sleep paralysis. Before reviewing the causes of narcolepsy, it is important to stress the speed of the advances that have been made in our understanding of the sleep/wake mechanism and the role of orexin in the less than 20 years since this neuropeptide was discovered. Two factors have been important in this regard as has been noted by one of the leading groups studying the system [47]. Firstly, sleep seems to have been highly conserved in animal evolution: Sleep is ubiquitous in the animal kingdom, and molecular pathways associated with sleep in the worm, fly, and mammals show much conservation…. For example in both insects

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Thus, there is considerable utility in the study of sleep in model organisms for understanding the mechanisms at play in human beings and what goes wrong in diseases such as narcolepsy. Secondly, of course, there has been acceleration in the development of powerful new techniques in neuroscience such as optogenetics that allow cell specific manipulation and therefore, as noted in Chap. 1, “it is now possible to functionally interrogate the specific roles of, and interactions between, genetically defined neuronal populations across the brain in sleep/wake regulation.” The rate of advances made in our understanding of the control of the sleep/wake cycle and of the orexin neuropeptides within that system are reflected in the number of major publications being produced by the scientists involved. For example, in 2017 two journals produced collections of papers including those on the sleep/wake cycle control system [48, 49] and the role of orexin [50, 51]. These papers illustrate the complexity of the circuits involved but also the rapid increases in our understanding of the circuits. In particular the circuits involved in producing cataplexy are being clarified. For example, one paper [52] specifically reviews “the use of genetically engineered methods as a neurobiological tool to understand the neural circuitry underlying narcoleptic symptoms.” The authors note that, as the orexin neurons project to pontine areas that are known to be involved in muscle tone during waking in addition to other areas involved in arousal, the loss of these orexin neurons will destabilise the maintaining of muscle tone as well as arousal. They also state that “[C]ataplexy in humans and canines is triggered by strong emotions such as laughter (humans) and food (canines). In mice, certain sugary foods or predator odor also triggers cataplexy.” This then indicates that the limbic system is involved in the production of cataplexy when the orexin system is degraded. That and other evidence led them to investigate the involvement of the amygdala, showing first that in orexin knockout mice. “orexin gene transfer into the amygdala… significantly decreased predator odor-induced cataplexy attacks.” This demonstrated that introducing orexin into amygdala circuits was effective but did not identify the specific circuits causing the change. However, it is now possible to make gene transfers specifically to neurons that project to particular areas of the brain and thus further experiments demonstrated that “orexin gene transfer into CeA [central nucleus of the amygdala] neurons projecting specifically to the pons significantly inhibits predator induced cataplexy in narcoleptic mice.” Based on their experiments they suggest a model in which in the normal animal muscle tone regulated by pontine neurons is maintained during emotions because orexin excitatory signals from the hypothalamus neutralises the inhibitory signals from the amygdala. On the contrary, however, in narcoleptic mice the orexin signal is absent and therefore the inhibition from the amygdala overwhelms and prevents pontine neurons maintaining muscle tone. This results in cataplexy. Inserting the orexin genes into the amygdala neurons experimentally thus cancels out the inhibitory effect. Other research indicates that the impact of orexin on the amgdala may naturally be indirect [53]. Indeed, while the

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loss of muscle tone in cataplexy “probably involves brainstem circuits in common with REM-sleep atonia” it seems that [54]: …cataplexy occurs as a multistep process, starting typically after postural collapse with a brief phase of wake-like EEG activity, followed by a phase characterised by high-power theta prefrontal discharges, which then develops into an EEG activity profile indistinguishable from that seen in REM sleep…

Clearly there is much yet to be clarified about the circuits involved [55], but overall the research on sleep/wake cycle and the role of orexin is reaching the stage where scientists feel comfortable in proposing quantitative models of the functions of the circuits [56] and in analysing how the sleep/wake system fits within different animals’ ecology [57]. Such basic research can be expected to continue apace as it has already underpinned the development of orexin antagonist drugs for the treatment of insomnia and might in the future also underpin the development of agonist drugs to help people with narcolepsy [58]. Further research will certainly include investigations into the causes of narcolepsy and these are obviously of particular interest here. Whilst there are a few examples of narcolepsy running in families most cases of narcolepsy are not caused by an obvious genetic mutation. However, there has long been a suspicion that narcolepsy is an autoimmune disease as a recent commentary noted [59]: For decades, narcolepsy has been known to be associated with variants in genes that encode the major histocompatibility complex proteins, also known as HLAs. Almost all patients with narcolepsy with cataplexy (82–99%) are carriers of HLA type DQB1*06:02, whereas only 12–38% of nonnarcoleptic individuals carry this allele…

The idea that there is an autoimmune cause of the disease, which is triggered by something in the environment affecting susceptible individuals, was reinforced by the impact of the 2002 H1N1 influenza epidemic. In northern Europe “[A] six-toninefold increase in new narcolepsy cases in children was observed a few months following vaccination against H1N1 with Pandemrix [vaccine].” The normal incidence of narcolepsy is about 1 in 2,000 individuals so this increase was clearly detectable. However, it has been difficult to prove narcolepsy is an autoimmune process [60]. Another possibility is that the H1N1 virus itself could be the cause [59] because in China where this vaccine was not used “new cases of narcolepsy increased threefold in the 6 months after the peak of the outbreak, then decreased into the normal rate by 2011 after the pandemic had been contained.” Moreover, there is considerable evidence that viruses, including influenza viruses, can enter the CNS via the nasal route [61]. This idea was tested in mice that lacked the ability to produce an adaptive autoimmune response and the authors concluded that the mice [62]: …infected with a H1N1 influenza virus strain developed over time sleep-wake changes described in murine models of narcolepsy and narcolepsy patients. In the brain, the virus infected orexin/hypocretin-producing neurons, which are destroyed in human narcolepsy, and other cells in the distributed sleep-wake-regulating neuronal network…

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They also point out that it is of particular interest that influenza A virus antigens were found in the orexin containing neurons of the hypothalamus and that “[T]hese peptidergic neurons innervate the mitral and granule cell layers of the OB [Olfactory Bulb], and thus represent a target for retrograde axonal transport of viruses along the pathway.” They end by suggesting that this direct affect by a virus should be considered alongside the possible autoimmune causation of narcolepsy in further research. Research into the possibility of autoimmunity continues. For example, a mouse model was produced that expressed [63]: …the hemagglutinin (HA) as a ‘neo-self-antigen’ specifically in hypothalamic orexin+ neurons…which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be in play in narcolepsy…

It was found that “the transfer of cytotoxic CD8 T cells…led to both T-cell infiltration and specific destruction of orexin+ neurons” and that this drastic neuronal destruction caused catalepsy and sleep attacks mimicking human narcolepsy. This and other recent studies [64] suggest that it will not be long before we have a mechanistic understanding [65] of the causes of Narcolepsy Type 1 and thus of the way in which cataplexy is generated.

4.3.3 Oxytocin Oxytocin has long been known for its role in maternal behaviour, pair bonding and social recognition, but as one recent review of the relevance of this peptide to psychiatry noted [66]: A seminal study published in Nature in 2005 suggesting that intranasal administration of oxytocin increases trust in humans was a game changer for human oxytocin research…

As the authors continued: …A surge in intranasal oxytocin studies ensued, with most emphasizing a role for oxytocin in increasing positive behaviors such as trust, altruism, affiliation, empathy…

Not surprisingly this finding attracted military interest and military-funded research [67]. Subsequently mixed results of research led to more careful analysis of the statistical basis of claims and of the precise route by which oxytocin reaches the brain after intranasal delivery [68]. It does, however, seem clear now that oxytocin can reach the human brain via the olfactory nerve and have an impact by reducing amygdala activation following social stimuli, and that the idea of oxytocin being solely a pro-social hormone has had to be abandoned, “with converging evidence suggesting that oxytocin increases social salience and approach-related behaviors regardless of valence.”

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What is important here is that the imaginative use of animal models [69] in research can, because of the homologous nature of the neural systems involved, reveal a detailed mechanistic understanding of the role of oxytocin in such behaviours. Nevertheless, despite such homologies care has to be taken in dissecting the neural circuits involved. For example, while the amygdala is obviously highly involved in processing fear the circuits are complex [70] with “good evidence to support the existence of distinct circuits for fear of pain, fear of predators and fear of aggressive conspecifics.” Modern techniques have been applied to understanding these circuits in rodents and human beings and this has facilitated translation of understanding of the mechanisms involved both from animals to humans and vice versa [71]. Such techniques have also been used to elucidate the action of oxytocin on these circuits [72]. An interesting example is the switching of protective maternal behaviour to a threat recently dissected in rodents. When an animal encounters a threat, it can choose from different responses depending on the circumstances. It can choose to fight or escape if that is possible. Or if escape is not possible it can freeze in the hope that it will not be noticed. However, for a mother rat with very young pups it is not possible to freeze so it has to confront the threat [73]. In this situation the mother takes active defensive measures and the young pups learn to associate the threat with something to be avoided. With older pups the mother is likely to usher them together as they probably can run away if necessary. This switch from freezing to active maternal defence is controlled by oxytocin input to the amygdala [74]. Mother rats in this study were conditioned to associate a peppermint air puff with a foot shock. Then these mothers were tested for their response to the peppermint air puff with or without their pups. When alone these rats responded by freezing, but with young pups they carried out active defensive behaviours. With older pups who were able to move more freely the mothers responded by keeping close to the pups, but not by active defence. The role of oxytocin in the causation of this behaviour was investigated by injecting an oxytocin antagonist into the central amygdala (where the centro-lateral nucleus is known to express oxytocin receptors). The authors noted that the rat mothers injected with the oxytocin antagonist “failed to suppress freezing, displaying robust levels of this behaviour despite the presence of their pups.” The evolution of predatory/prey relationships has led to animals having this range of defensive responses from fighting and fleeing to freezing, and on to immobility when all other options are not available. Complete immobility can sometimes fool a predatory and allow the prey to escape later. So, freezing is not a passive state [75], but “a state of attentive immobility serving to avoid detection by predators and to enhance perception.” The mechanism by which the output from the central nucleus of the amygdala causes freezing “by disinhibition of the ventrolateral periaqueductal grey excitatory outputs to pre-motor targets in the magnocellular nucleus of the medulla” has also been described [76], as has its selection versus flight behaviour within the amygdala [77]. The mechanisms involved in the periaqueductal grey have even been dissected with modern techniques in freely behaving rodents [78], and the role of periaqueductal grey in top-down control of spinal sensorimotor circuits is also being elucidated [79].

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The issue of interest here is not the specifics of the diverse mechanisms involving oxytocin that are being elucidated through the use of modern neuroscience but the fact that the aim in view is an understanding of human social behaviour at a molecular/neural network level. As one review of “[T]he amygdala as a hub in brain networks that support social life” noted [80]: …Studies employing neuropeptide delivery, imaging genetics, and optogenetics provide exciting tools that have already begun mounting evidence for a cellular and molecular understanding of the amygdala-based circuits that make up the social brain.

And the authors continued by stating that: Members of the nonopeptide family, particularly oxytocin (OXT), are promising targets for treatment of disruptions of social behaviour given that the amygdala is one of the core nodes of OXT action in the brain…

Underlying this research is considerable knowledge of the “genetic polymorphisms in the genes encoding oxytocin and vasopressin peptides and/or their respective target receptors” in human beings and the association of such polymorphisms with social behaviours [81] plus the evolutionary history of the oxytocin gene [82]. Of course, there is some way to go before we have a mechanistic understanding of human social behaviour, yet [83]: …Although the large gap between genetic and systems approaches remains a challenge, sophisticated tools for mapping the structural and functional neural circuits that mediate social behaviour will continue to allow the identification of neural substrates of social behaviour…

And in that quest the authors point out: …it is critical to understand how the regulated release of various social neuropeptides coordinates distinct neural circuit dynamics…

So, a continued exploration of the functions of oxytocin in the causation of social behaviour seems certain. More generally the development of research on oxytocin and its role in social behaviour indicates what is likely to happen in relation to other neurotransmitter systems that have not been studied for such a long time or not so intensively. It is clear surely that many of the neuronal networks and their modulation by chemical bioregulators that underlie our behaviour will become better and better understood and open to manipulation - for benign or malign purposes.

4.4 Conclusion In a section on “Potential Intelligence and Military Applications of Cognitive Neuroscience and Related Technologies” the authors of the 2008 US study of Emerging Cognitive Neuroscience and Related Technologies [84] noted that:

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Most advances in cognitive neuroscience and related technologies will have dual uses. Pressures leading to advances will come from the pull of medical necessity and the push of science and technology advancement. Large state-funded programs are possible…. As cognitive neuroscience and related technologies become more pervasive, using technology for nefarious purposes becomes easier…. the triggers and observables become less obvious to the analyst…. The same equipment might be needed for medical and for disruptive neuropsychopharmacological experiments…

The paragraph then ends by suggesting that: …It could be asked, What types of experiments are being done? How are the experiments being controlled and monitored, and why were they chosen? How would human experimentation be conducted outside accepted informed-consent limits? (emphasis added).

These are indeed critical questions, but what else might be best asked about the new State-level funding of brain projects? It is surely necessary to ask first to what extent the new brain research projects have given consideration to the possibilities of dual use of the technologies and results they produce in the development of new chemical and biological weapons that attack the central nervous system? Then if some consideration has been given to this issue to ask what mechanisms have been put in place or are planned to help guard the work from such misuse? It is of course necessary to keep in mind the kinds of agents that have been developed and sometimes used in the past and to be aware of the behaviours and underlying CNS systems they were intended to disrupt in order to know if modern advances have made these agents potentially more attractive to weaponeers [85]. More importantly it is necessary to keep in mind the kinds of behaviours that the original Cold War weaponeers envisaged and the underlying CNS mechanisms that may now be much better understood and potentially open to disruptive assault. Novel results such as the discovery of new powerful neuropeptides should be carefully analysed as should new means of passing agents through the Blood Brain Barrier and of targeted delivery of agents within the CNS. We are not interested here in domestic use of standard riot control agents that are allowed to be used under the Chemical Weapons Convention as long as the types and quantities used are appropriate. These standard agents act peripherally as irritants. However, it is also necessary to be aware of grey areas such as the development of so-called malodorant [86] chemical agents and weapons which can trigger other CNS mechanisms and thus open up the possibility of erosion of the idea that attacking systems within the CNS is not allowed. Perhaps it is best always to keep in mind a longer-term view and understand that what we want to avoid is the continued application of new knowledge in biology and chemistry in the succeeding generations of more powerful weapons as we saw during the twentieth Century [87].

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Part II

The Brain Projects

Chapter 5

The EU Human Brain Project

Abstract It is against the background of rapid advances in neurosciences and the need to find means of protecting this benignly-intended work from misuse that in this chapter begins the second section of the book with an analysis of the European Union (EU) Human Brain Project (HBP). The chapter starts by noting the complexity of the international situation facing policy-makers, particularly in understanding the impact of the rapid advances in science and technology, but stresses that the Scientific Advisory Board of the OPCW has long had a settled view of the dangers that could arise from the development of agents that attack the Central Nervous System. As the EU Human Brain Project clearly had paid attention to the ethical issues involved in its work from the start it was chosen as the starting point for the analysis of what the brain projects were doing to deal with the problem of dual use. This 10 year project began with a very strong emphasis on the idea of building a computer model of the brain but was re-orientated to have a more realistic balanced research objective that included more practical neuroscience. An analysis of some of this research shows quite clearly that it involves issues that could be of dual-use concern. The chapter then turns to the question of what the project is doing about protecting its research from such misuse. As the project was set up with a specific funding stream for the investigation of ethical issues it is not surprising that is has focused on the potential for misuse in political, security, intelligence and military applications. So, these concerns about misuse include the specific issue of the development of novel chemical and biological weapons—the issue of dual-use as understood by the security community. The chapter then outlines how the project set about dealing with this issue through 2016 and 2018 and it ends by assessing how the question of dual use was being dealt with by States Parties to the CWC and the BTWC at the end of 2018.

5.1 Introduction In late July 2018 one of the main UK Sunday papers had a rather unusual title for its compilation of books for summer reading. Titled “[H]ow the ‘brainy book’ became a publishing phenomenon,” the author argued that in these uncertain times © Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6_5

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the popularity of easy reading celebrity biographies had declined, and many people wanted to read serious nonfiction instead. There were obviously several reasons for this, but a major reason was that [1]: …At a time when politics is more furious and fragmented than ever, when technology is colonising our everyday existence, when medicine is reshaping our lives, we still look to books to make sense of things, to feel ourselves part of a great communal effort to understand our age. These are serious times and they demand serious, intelligent and challenging books.

People could well have reason for being concerned at the way the world seemed to be changing when the July/August edition of the major journal Foreign Affairs had the frontpage title “Which World Are We Living In?” The journal had six specialists attempting to explain what is happening in the world from their very different perspectives [2] While these essays were attempting to explain the current evolution of the world system there was also dizzying change going on at other levels. For example, as demonstrated in the headlines reproduced in Table 5.1, the reader of newspapers over the preceding months could hardly have missed the fact that very rapid advances were being made in brain research. Such uncertain times obviously created difficulties for those charged with keeping arms control and disarmament agreements up-to-date and effective. In our analysis Table 5.1 Headlines in the London Guardian and London Observer 2017 November 4. Radical new approach to schizophrenia treatment begins trial in UK hospital: Evidence emerges it could be immune system disease. Trial with antibody drug normally used to treat MS December 16. Genetic breakthrough offers hope to millions: Huntington’s drug success could now be key to treating Alzheimer’s and Parkinson’s 2018 January 5. New hope in fight to end opioid addiction: Scientists a step closer to non-addictive alternatives. Discovery made around brain’s receptor proteins January 25. Genetic science breakthrough: In the footsteps of Dolly: cloned macaques make history February 1. Natural opioids in nasal spray offer safer pain relief February 4. Can a breath test smoke out stoned drivers? February 6. Doctors warn of emerging crisis over anxiety drug. UK accounts for 22% of global ‘darknet’ sales of the highly addictive medication Xanax February 19. New test raises hopes for early diagnosis of autism April 1. How to grow a second brain: A radical technique that makes mature cells act like those in embryos is being used to grow mini-me ‘organoids’ May 12. Scientists set to grow miniature brains using Neanderthal DNA June 1. Daily injection halts hunger pangs for children born with fat genes July 26. Pass notes: Toxoplasma gondiia a Toxoplasma

gondii is a parasite that is thought to manipulate its host’s behavior

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Table 5.2 Groups of Questions facing the CWC 4th Review Conferencea 1. Ensuring CWC Universalisation and Complete Destruction of all Chemical Weapons 2. Maintaining the Comprehensive Nature of the CW Prohibition 3. Strengthening National Implementation and Verification 4. Preventing and Responding to Hostile Uses of Toxic Chemicals a From

Ref. [3]

the States Parties to the Chemical Weapons Convention had four groups of questions to deal with in the 4th Five-Year Review Conference in November 2018 [3]. These groups are set out in Table 5.2 and all involved attempting to deal with rapidly changing situations. For example, there were clearly major difficulties within Group 1 questions in attempting to remove whatever remained of the chemical weapons that had been used in the Syrian civil war, in improving the monitoring and risk assessment of science and technology in Group 2, updating under Group 3 the verification measures agreed almost 30 years previously when the Convention was negotiated, and finding new means of preventing and responding to the hostile use of chemical agents that had become frighteningly more frequent. Yet serious researchers have cautioned that it is wise when thinking about the future to consider things that do not seem likely to change [4]. An example of such stability in the area of interest here can be found in the response of the Director-General of the OPCW to the report of his Scientific Advisory Board (SAB) for the 2018 4th Review Conference of the Chemical Weapons Convention. He noted that [5]: 22. The SAB is of the view that the technical discussion on the potential use of toxic chemicals for law enforcement purposes, specifically central nervous system (CNS)-acting chemicals, has been exhaustive and it continues to recommend that the Secretariat prepare for verification activities involving these types of chemicals…

The response from the Director-General then continued by pointing out that: …The SAB Chairperson had presented the compiled outcomes of the Board’s deliberations on this topic to States Parties at a side event in the margins of the Twenty-Second Session of the Conference of States Parties, in 2017…

The response then encouraged States Parties to review this advice in order to gain greater insight for the discussions at the upcoming Review Conference. What should be understood here is the nature of the “compiled outcomes of the Board’s deliberations” on the topic [6]. The headings of the detailed quotations given by the SAB Chair in 2017 are set out in Table 5.3. Clearly, the SAB had had a settled view on the dangers that such chemicals could cause for over a decade and a half. The issue of the threat that the development, deployment and use of such chemicals posed to the prohibition was not going to be set aside by those charged with giving scientific advice on the future of the Convention.

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Table 5.3 Central nervous system acting chemicals: considerations by the OPCW SABa SAB S&T report to RC-1 dated 23 April 2003 (RC-1/DG.2 paragraph 3.14) SAB S&T report to RC-2 dated 28 February 2008 (RC-2/DG.1 paragraph 2.3 and 3.14) Director-General statement to RC-2 dated 7 April 2008 (RC-2/DG.2 paragraph 57) Director-General statement to CSP-14 dated 30 November 2009 (C-14/DG.13 paragraph 161) SAB Report of 15th Meeting dated 14 April 2010 (SAB-15/1 paragraph 13.2) SAB Report of 16th Meeting dated 6 April 2011 (SAB-16/1 paragraph 10.4) SAB S&T Report to RC-3 dated 29 October 2012 (RC-3/DG.1 paragraph 12) Director-General response to SAB dated 31 January 2015 (RC-3/DG.2 paragraph 15) SAB Temporary Working Group Report on Verification dated June 2015 (page 7) Executive Council, Medium Term Plan 2017–2021 dated 8 April 2016 (EC-83/S/1 paragraph 13) SAB response to the Director-General’s request to provide consideration on which Riot Control Agents are subject to Declaration under the Chemical Weapons Convention dated 27 March 2017 (SAB-SAB-25/WP.1) a From

Ref. [6]

This point was made very obvious in the recommendations of the Open-Ended Working Group on Future Priorities for the 4th Review Conference. Under the section on future policy discussion their report stated that [7]: Aerosolising central nervous system-acting chemicals in law enforcement scenarios 53. Noting the increasing concern, notwithstanding Convention Article II, paragraph 9 (d), among States Parties that toxic chemicals which target the central nervous system (CNS), and their potential use in aerosolised form in certain law enforcement scenarios, undermine the object and purpose of the Convention, as well as the OPCW’s Scientific Advisory Board conclusion that CNS-acting chemicals cannot be used safely for law enforcement purposes, the Organisation should commence an inclusive policy discussion in its PMOs [Policy Making Organs] without pre-empting its outcome. Such a policy discussion could take into account the implications of any interpretative statements on the use of CNS-acting chemicals for law enforcement purposes for the implementation of the Convention, including its verification regime. 54. States Parties in a position to do so should make known their national positions on these chemicals for law enforcement purposes.

What then had been the response and what would be the response to this rather clear example of the potential misuse of benignly-intended work by the new Statelevel brain projects? Given that it was nearest to home and that I had an idea that the problem may have been given more attention in the EU-funded project than elsewhere I decided to begin my investigations of the different brain projects with the EU project. It has to be understood that there were many new synthetic psychoactive substances being manufactured at that time [8] and that such substances were causing concerns about social misuse [9], but also that there was continued interest and research into the development of psychoactive substances for medical treatments [10].

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5.2 The EU Human Brain Project In 2017 the EU Human Brain Project issued a summary of facts and figures related to the project for the period April 2016 to March 2018 (SGA1). The introduction stated that [11]: The Human Brain Project (HBP) is a European Commission Future and Emerging Technologies (FET) Flagship. The HBP aims to put in place a cutting-edge, ICT-based scientific Research Infrastructure for brain research, cognitive neuroscience and brain-inspired computing. The 10-year Project began in 2013, and involves scientists and developers at 116 universities and research centres across Europe.

Clearly, the project is a major initiative by the European Union involving 19 countries, 116 institutions and the expenditure of 89 million Euros during the report period. The objectives of this Flagship project were stated to be to: Create and operate a European scientific Research Infrastructure for brain research, cognitive neuroscience, and other brain-inspired sciences; Gather, organise and disseminate data describing the brain and its diseases; Simulate the brain; Build multi-scale scaffold theory and models of the brain; Develop brain-inspired computing, data analytics and robotics; Ensure that the HBP’s work is undertaken responsibly and that it benefits society.

It is not difficult to see from this listing that the project has a major interest in information technology as a means of investigating the brain and using the results. However, that is only part of the story. The project was launched in October 2013 with an expected expenditure of 1 billion Euros over a ten-year period and with a much more information technology orientation. As Henry Markram, one of the initial leaders of the project, explained in an article in the Scientific American in 2012 the aim was to change the paradigm by which neuroscience research was carried out [12]. In his view “[B]uilding a vast digital simulation of the brain could transform neuroscience and medicine and reveal new ways of making more powerful computers,” and “[B]uilding this instrument is the goal of the Human Brain Project.” Now it may not be theoretically possible to build anything like a realistic simulation of the brain [13], but you did not have to hold that view to believe that doing it in the near future was not very likely. Therefore, if that had remained the goal of the project it would seem that concerns about the project opening up routes to new forms of chemical and biological weapons were rather farfetched and therefore the project would not be of much immediate concern here. However, that was not what happened. Many practicing scientists felt that the objective was far from achievable at the present time and that the huge amounts of money being spent could in part be better spent on further direct biological research on the brain, and they also had questions about the management of the project as it got underway.

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For example, in a 2014 comment in Nature titled “Where is the brain in the Human Brain Project?” two eminent European neuroscientists were scathing about the state of the project [14]: Contrary to public assumptions that the HBP would generate knowledge about how the brain works, the project is turning into an expensive database management project with a hunt for new computing architectures…

And they added: …In recent months, the HBP executive board revealed plans to drastically reduce its experimental and cognitive neuroscience arm, provoking wrath in the European neuroscience community. (emphasis added)

This reaction put the leaders of the HBP in a very difficult position for, as the authors pointed out: …About 430 million Euros (US$570) of the European Commission funding goes to the HBP’s ‘core team’. The remainder of the 1-billion Euros budget depends mostly on scientists throughout Europe raising partnership funds from sources such as regional governments, and then being selected by the HBP management on the HBP’s terms…

Why, they asked, “would people want to join the project under such conditions?” Inevitably, therefore, there was a substantial reorganisation of the project and its management. In March 2017 an editorial in The Lancet: Neurology summarised the objections made and the responses that led to an independent review of the project. The review published in 2015 suggested the following lines of reorganisation [15]: …the HBP should provide a new governance structure: reintegrate cognitive neuroscience into the core projects; refocus the project on technology development jointly with the neuroscience community; and improve communication with the general public, based on realistic goals. (emphases added)

At that time in 2017 the editorial suggested that the HBP should be commended “for taking a more democratic approach to reorganising its governance structure and reintroducing cognitive neuroscience as one of 12 core subprojects,” but also made it clear that the project had more work to do to convincingly balance the various interests involved and that achieving that balance was crucial for the overall success of the project. However, it was already obvious that the Human Brain Project, while heavily involved in computing, was not going to just be a huge data management project and that it would involve extensive practical research work on the structure and function of the brain. Table 5.4 was taken from the overview given on the website of the HBP in September 2018 [16] and clearly indicates both the main information technology orientation and the funding of practical neuroscience research. So, the HBP could be of immediate concern to those worried about how neuroscience research on the brain was to be protected from dual-use applications. This becomes very clear when the reinstated Subproject 3 on Systems and Cognitive Neuroscience in the core of the HBP is examined. As the HBP website also stated in September 2018 in regard to this subproject [16]:

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Table 5.4 The Human Brain Project in mid-2018a “Six ICT research Platforms form the heart of the HBP infrastructure: Neuroinformatics (access to shared brain data), Brain Simulation (replication of brain architecture and activity on computers), High Performance Analytics and Computing (providing the required computing and analytics capabilities), Medical Informatics (access to patient data, identification of disease signatures), Neuromorphic Computing (development of brain-inspired computing) and Neurorobotics (use of robots to test brain simulations) The HBP also undertakes targeted research and theoretical studies, and explores brain structure and function in humans, rodents and other species In addition, the Project studies the ethical and societal implications of HBP’s work.” a From

Ref. [16]

Our goal is to uncover neural mechanisms underlying cognitive processes …. How is consciousness generated by the brain? …. Similarly, how can disparate phenomena such as sleep and wakefulness emerge from the same cortico-thalamic systems in the brain? …. SP3 also investigates brain mechanisms of memory …. In summary, by its cross-disciplinary approach to multiple levels of neural and brain organization, we will work to elucidate mind–brain relationships that have eluded explanation for centuries. (emphases added)

The possibility that some aspects of the subproject could be of interest to those concerned with potential dual-use applications was also obvious from some of the references given in the overview [17, 18]. However, the Human Brain Project also has connections outside of 12 the core subprojects of the project first in its in its CoDesign projects which integrate across the core projects and in Partnering projects. These were defined as follows on the HBP website in September 2018 [16]: CoDesign Projects Co-design projects are multi-disciplinary and cross Subprojects. They are led by senior scientists from the HBP and are designed around collaboration, data gathering and simulation between the HBP’s Platforms. Partnering Projects Partnering Projects create synergies between the core HBP and activities receiving funding at regional, national or transnational level. The projects and their partners already have their own funding and join with the HBP to together make a new and significant contribution to the HBP’s strategic research roadmap.

Even a brief examination of these aspects of the whole HBP reveals much that could be of concern in regard to dual-use applications. For example, Co-Design Project 6 on “Modelling Drug Discovery” has the objective of developing new strategies for drug development stating that [16]: The aim of this CDP is to develop new strategies for more effective drug treatments of major brain diseases such as Alzheimer’s, Schizophrenia, Epilepsy, Parkinson’s, glioblastoma and rare diseases using computational models.

And that:

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5 The EU Human Brain Project Innovative neuromedicine approaches require a detailed understanding of the molecular and systems-level organisation of the human brain, the causes and mechanisms of diseases, their progression, and the response to treatments. Because of the high level of complexity of the nervous system and the inter-subject variability in molecular brain organisation, behaviour and disease, addressing these issues for any neuropathology appears a daunting task…

And the statement continued: …Indeed, for most neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, there is currently no cure in spite of the very large investments from academia and industries. The discovery of new drugs against brain diseases is thus viewed as an ethical priority for ongoing neuroscience research.

We would surely all agree with that view, but we should also be aware of the possibilities that the knowledge and techniques that result from this civil work could be applied in the search for novel chemical and biological weapons. Similarly, studies in some of the Partnering Projects, for example those shown in Table 5.5 on brain networks and rhythms, are clearly related to issues of interest to those who might be seeking novel chemical and biological means of incapacitation [16]. In short then, the EU Human Brain Project could obviously give rise to a range of dual-use concerns in the longer term for example about how the rich and powerful Table 5.5 HBP Partnering Projectsa RobotBodySchema Studying the mechanisms of how the brain represents the body to make robots more autonomous and safe CANON Shedding light on the multiscale organisation of cortical computation by integrating neuronal and population activities with inter-areal interactions CHAMPMouse Investigating multi-areal visual perception in the mouse FIIND Developing a Ferret Interactive Integrated Neurodevelopment Atlas FUSIMICE Ultrafast Functional Ultrasound (fUS) Imaging for Highly-Resolved Targeted Mapping of Functional Connectivity in the Awake Mouse Brain MULTI-LATERAL Analysis of Brain Lateralization for Language SloW-Dyn Slow Wave Dynamics: from experiments, analysis and models to rhythm restoration MoCoTi Motor Control and Timing in the Cerebellum: Spatio-Temporal Integration in Complex Neuronal Networks a From

Ref. [16]

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might use knowledge of the operations of the brain to distort democracy [19], but also in the more immediate future in regard to novel chemical and biological weapons targeted at the CNS. What was being done within the whole project to address such concerns?

5.3 Dealing with Dual Use By the autumn of 2018 the Human Brain Project was nearing the half way point of its 10-year funding having completed the Ramp-Up Phase (October 2013 to March 2016), its First Specific Grant Agreement (SGA1 from April 2016 to March 2018) and had embarked on its second two-year tranche of funding from the EU. It was also a closely co-ordinated project [20]: Three bodies are responsible for coordinating the HBP: the Stakeholder Board, the Science and Infrastructure Board and the Directorate. The Stakeholder Board is the project’s ultimate decision-making body…. The Science and Infrastructure Board is central to the HBP, providing scientific leadership of the Core Project…. The Directorate is responsible for the management of the Core Project…

Moreover, it is clear that the objective is to create a legal entity from the project to ensure the continuation of an “enduring, federated, ICT-based research infrastructure for advanced brain research.” It will have been noticed in Table 5.4 that the HBP also aims to study the ethical and social issues involved in the project’s activities. This is carried out in Subproject 12 “Ethics and Society” of the core project which focuses on the implications of HBP research and in mid- 2018 the HBP website stated that [16]: …Our methods include conceptual and philosophical analyses, organizing workshops and webinars, and performance of interviews with experts. We aim to develop better foresight and ethical analysis, to promote engagement with broader audiences, and to raise awareness among researchers on how to recognise ethical issues and the possibilities for action when they arise.

These objectives are carried out in a series of work packages as set out in Table 5.6. I first encountered the HBP when I was asked to present a paper at a meeting on dual use organised under WP 12.3 “Public Dialogues and Engagement” in Paris in March 2016. The meeting was reported in a briefing by the HBP in October 2016 [21]. The WP 12.3 is run by a group based in Denmark and they have continued to work on this issue. The HBP, however, has argued that the use of the concept of dual use has not always been helpful as misuse of civil research can also take place in other domains. Therefore, they state that [22]: To help in clarifying matters, we argue that policy makers and regulators need to identify and focus on specific harmful or undesirable uses in the following four domains: political, security, intelligence and military (PSIM)…

That seems a very sensible view, but it runs into a problem in regard to misuse in relation to chemical and biological weapons in that the “dual use” terminology

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Table 5.6 HBP subproject 12 work packagesa “Work Package (WP) 12.1 Foresight. This WP identifies potential ethical and social concerns at an early stage by producing scenarios of potential developments and implications, produces reports and publications, and feeds these back to the HBP researchers to build capacity to adapt to differing uncertain futures WP12.2 Neuroethics and Philosophy. We perform philosophical, ethical, and social analyses of HBP key activities and issues, thereby furthering conceptual clarity in the analysis of the neuro- and computational sciences and the issues they raise and promoting the reflective capacity of HBP researchers and others in addressing societal implications WP12.3 Public Dialogue and Engagement. This WP assists the HBP in creating a constructive dialogue not only with public and private stakeholders, but also with the general public. This WP maintains an intense engagement with points of view external to the HBP, thereby identifying emerging controversies and formulating recommendations for HBP research organisation and research priorities WP12.4 Ethics Management. We develop ethics governance measures to ensure compliance, reflection, and engagement with ethics among the entire HBP community. We work with all ethics stakeholders, notably the Ethics Advisory Board and Ethics Rapporteurs, to ensure that ethics-related activities of the scientific and technical SPs are collected and communicated, and ensure open interaction between SP12’s wider research and that of other SPs. These activities ensure that ethical issues are managed to the highest standards within the HBP and that international best practice is developed.” a From

Ref. [16]

has become so embedded in the discourse of the security community over the last 20 years that changing the terminology in this area is likely to cause more confusion than clarification. So, to my mind it is best to accept the clarification, but to keep the use “dual use” as a specific type of misuse in the area of military misuse. Perhaps in recognition of this difficulty the summary of the then latest work under WP 12.3 used the PSIM system to describe its research but had dual use in the title [23]. The research is of considerable interest here as a wide-ranging internet survey followed up by two workshops in different parts of Europe provided a picture of what citizens thought about the potential misuse of neuroscience and of what might be done about it. It was found that “they have serious concerns about the potential PSIM use of this research and call for action, particularly from policy makers” and the authors of the summary paper added that “[I]t is important that HBP and similar research projects take these concerns seriously and address them.” Although the military applications discussed did not focus specifically on chemical and biological weapons the citizens’ conclusions about what might be done were familiar to those who had been involved in the discussions about what to do to prevent the re-emergence of chemical and biological weapons. The report stated: …For the regulation to have the desired impact, it should not be confined to single countries or projects but be international in scope. To facilitate practical implementation, it should contain ethical guidelines stipulating what constitutes ethically sound research and use. Enforcing the regulation should not just be left to the individual scientist…

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What seemed new to me was that “[A] recurrent suggestion was that there should be enforcement and steering mechanisms, for instance in the shape of a standing committee under EU auspice.” (emphasis added). A key feature of the material produced on the aims of the HBP is to stress that the whole project is integrated. By the autumn of 2018 it was possible to see how this kind of integration was being carried out within the ethics and society subproject. A paper published in the journal Futures described how during the ramp-up phase and the first strategic grant award period (that is from 2013 to 2018) [24]: …Collaborators from two tasks and work packages in SP12, Foresight, Researcher Awareness, and Ethics Management use the case of machine intelligence to illustrate key aspects of the dynamic process through which questions of ethics and society… are approached in the HBP organisation… (emphasis added).

The paper then shows how the recommendations of the work by the foresight group during the ramp-up phase were developed into actions by the ethics management and researcher awareness teams. In conclusion the authors identify two different challenges, as they put it “to differentiate between ethics compliance and broader reflection upon ethics and society.” They argue that this differentiation “is achieved in the HBP through a demarcation between compliance activities, which are structured according to a self-assessment survey and a round of approval-checking meetings, and subsequent activities with a broader mandate.” These broader mandate activities include “[T]eleconferences and other forms of interpersonal interaction involving researchers, ethics rapporteurs, Ethics Advisory Board members.” I think it is fair to say that the paper strongly suggests that the first of these activities—compliance management—proved much less difficult to deal with than the broader issue—of broader reflection on ethics and society—of the kind of interest here in relation to dual use. The need to carefully distinguish between compliance management and the broader question of ethics and society was made very strongly in a second reflection on the experience of these initial stages on the HBP by members of the foresight team in 2018. In their view [25]: …it was necessary to keep these two dimensions distinct, so that interactions through more informal channels with collaborators across the HBP with the aim of trust building and capacity building do not become identified with formal ethical oversight…

Clearly to become enforcers of ethics would not be easily compatible with open discussion with those to be enforced about what should be done! However, the reasons for this approach are underpinned by a specific choice of how ethical analysis should be carried out. The authors say that widespread dissatisfaction with the ELSI (Ethical, Legal, Social, Implications) approach of the Human Genome project which was widely felt to have been used to justify what had already been produced led them to adopt the very different AREA (Anticipate, Reflect, Engage and Act) approach. They stressed additionally that this approach should be practiced in an integrated way across the whole of research practice. Thus, in their view:

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5 The EU Human Brain Project …Anticipation occurs by inclusively engaging researchers with stakeholders and experts to think reflexively about the research…. Possible outcomes become apparent when people from different parts of the research programme interact - not just amongst themselves but with others outside of the programme. Taking action (being mutually responsive to different actors’ concerns i.e. social learning) happens when research strategies and intended outcomes are adjusted based on these dialogues… (original emphases)

Of course, they are not blind to the difficulties of doing this in practice referring to the “Collingridge Dilemma” that suggests that in the early stages of technological development when change is easy the need for it cannot be foreseen and when the need for it becomes clear change is difficult and costly. Moreover, even when researchers appreciate that malign military applications may be possible, they rarely see any need for action to be taken by them, in part because they feel that they have little influence on the application of their work. Finally, they note that the HBP like other such projects rarely has the opportunity start research programmes that are just beginning. Most such research has been underway before and has a certain trajectory before the project funding is awarded. As the authors point out: …Indeed closing the AREA loop is the hardest challenge, and to find mechanisms whereby the recommendations and opinions of SP12 actually do influence, and in some cases determine, the directions and management of the HBP research.

Opinions are a mechanism by which recommendations for action can be given and as the authors note “[T]he topic chosen to be the focus of our next opinion, developed in this way, will be ‘dual use’—that is to say, the potential military uses of research and development initially designed for non-military purposes.” So, investigating how this opinion was developed, what it recommended and how such recommendations were to be implemented was of particular importance to this study. The HBP should have been well placed to produce an effective opinion as the SP12.2 “Ethics and Philosophy” group had produced an extensive study of Dual Use in Neuroscientific and Neurotechnological Research in early 2017 [26] and the main author of the study was Professor James Giordano who, as we saw in Chap. 3, had written extensively on the problem of dual use and particularly on the dangers of the development of novel chemical and biological weapons. This extensive report makes three points of considerable interest in relation to dual use and novel chemical and biological weapons. First it is clear that we are not without some means of assessing the most immediate dangers, noting that “it is practical to determine which efforts are most likely for dual use, and therefore of highest priority for ethical address.” Secondly it lists what needs to be done to assess and provide guidance in relation to such dual-use research of concern, listing: realistic assessment; research to more accurately determine potential use; responsiveness to the burdens that might result; revisions to research practices; and regulation to ensure rigour in governing such research. Finally, the report concludes with a series of specific recommendations to deal with the problem and these recommendations are summarised in Table 5.7.

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Table 5.7 Recommendations for dealing with dual-use neurosciencea 1. Establishment of a permanent working group dedicated address and to make assessments of HBP activities with potential for DURC/military-warfare uses 2. Engagement of this working group in proactive discourse with relevant interest groups 3. Development of an educational program that provides material addressing DURC/military-warfare use of HBP efforts 4. Formulation of an updated mission statement that affirms the intent of all HBP research for civilian biomedical purposes and proscribes intent for specific dual use(s) of concern, inclusive of military-warfare applications 5. Establishing requirements that HBP research personnel: (a) participate in these educational activities on a defined, regular basis; (b) explicitly affirm intent of purpose; (c) explicate such intent in a formal statement to be included on any/all publications and proposals; (d) be prohibited from receiving military funding both during their tenure in an HBP-supported activity, and for a defined period of time subsequent to termination of such involvement 6. Development of white papers and position statements to more effectively guide and govern dual use(s) of both HBP research, and brain science, writ large a From

Ref. [26]

5.4 Conclusion While not directly involved, I was aware of the efforts being made to achieve such objectives within the HBP as I had taken part in the earlier meeting on these issues organised by the HBP in Paris in March 2016 [27] and a roundtable on dual use to discuss a draft Opinion on ‘Responsible Dual Use’ held in Brussels in March 2018 [28]. I had also given a lecture on dual use in the Research, Ethics and Societal Impact section of the HBP web-based educational programme and helped to run a TeamBased Learning exercise on dual use in the First HBP Curriculum Workshop Series [29]. However, I was also well aware from the experiences recorded in earlier chapters that even within a co-ordinated and integrated project achieving the outcomes set out in Table 5.7 was not going to be an easy task. Discussions at an EU Human Brain Project Workshop in Stockholm in November 2018 [30] left me with the impression that these far reaching proposals were but one of a variety of possibilities under discussion and that there was not much chance of a decision being rapidly made about what should best be done. Fortunately, I was wrong and not only was the Opinion published in December 2018 but, crucially from my perspective, the recommendations for the EU Human Brain Project included a strong version of a required educational programme which stated that [31]: 7.5 We recommend that the Human Brain Project develops an educational programme concerning the political, security, intelligence and military uses of brain inspired research and development:

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5 The EU Human Brain Project a. that provides ongoing seminars/symposia, webinars, publications, and online informational material addressing the potential irresponsible uses of HBP research in political, security, intelligence and military domains b. that directs this educational material to all HBP researchers as well as members of the public, governmental agencies, policy makers, regulators, research funders, etc. c. that establishes requirements that any/all HBP research personnel participate in these educational activities on a defined, regular basis. (original emphases)

In the early years of this century, when the problem of dual-use of advances in the life and associated sciences and technologies was clearly recognised in producing possibilities for the development of novel chemical and biological weapons, it was frequently thought that the development of codes of conduct related to dual use would also be an effective mechanism for scientists to become engaged in protecting their work from such misuse [32]. At the end of the second decade of the century that view could no longer be sustained. It had become clear that, as in many other fields, just producing a code of conduct was not sufficient to achieve changes in behaviour as a great deal of hard work was needed to embed the code in the hearts and minds of professionals and institutions [33]. Careful research has shown that there are many ways that researchers can address codes of conduct other than seeing them as guidelines for behaviour if the codes are not carefully constructed and continuously explained [34]. This point about the foundational need for effective education was made very clearly in the conclusions of the Zagreb meeting described in Chap. 3 [35] as can be seen in the extract of the conclusions of the meeting shown in Table 5.8. Indeed, it seemed to me that without a very determined educational programme the kind of dual-use ethical competence suggested by Kuhlau and her colleagues [36] (see Chap. 3) was unlikely to be achieved. Thus, there are a series of questions that can reasonably be asked about the intended educational programme. For example: Table 5.8 More conclusions from the Zagreb meetinga Building Success and Sustainability in Dual use Governance “As discussed frequently during the workshop, effective governance requires more than “check-box” compliance with regulations, policies, and practices. Acceptance and engagement by the affected communities are essential and this requires sustained and continuing effort in fostering and promoting governance Many participants raised the topic of education and training, with education of scientists as a foundational element for the governance of dual use research. Education was seen as an ongoing activity, not something that happens once and for which researchers will never need additional engagement as science advances. This includes building networks of faculty who can support each other, share best practices, and sustain capacity-building efforts. It requires modules and courses, as well as materials that can be used to teach and engage with scientists about dual use issues. Activities that introduce dual use issues and biosecurity within a wider context, such as the responsible conduct of science, can serve as the basis for more advanced and specialized training.” (emphases added) a From

Ref. [35]

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1. How will the present state of knowledge about dual use of members of the HBP be assessed; 2. What will be the content (curriculum) of this educational programme; 3. How will the course material be produced; 4. By what method(s) will this educational material be conveyed to participants; 5. How will the members of the HBP who will deliver the material be trained; 6. How will participation in this educational programme be ensured and assessed; 7. How will be impact of the educational programme be evaluated. For example, as I think it is clear that scientists responsibility for their research cannot sensibly be confined to just the individual experiment within the laboratory [37] and extends to having some responsibility to help protect their work from misuse by understanding and supporting the international prohibitions on chemical and biological weapons, the educational programme should extend to include the history of the development of such weapons and the efforts to prevent their further development by the international community. Similarly, as it is quite evident that active learning methods have to be employed to effectively engage scientists in educational efforts on dual use issues what material will be produced, and by whom for this education programme? Moreover, it seems to me that participation in the education programme would need to be mandatory at all levels for it to be effective—in short that given the increasing dangers of serious misuse a scientist should not be allowed to take part in the EU Human Brain Project without certification of completion and continuous updated involvement in the programme. Finally, it has to be understood that while evaluation of the programme will not be simple, there are means by which it could be achieved if sufficient attention is given to the very important issue of whether it was having the desired impact [38]. At the international level the situation in regard to development of effective regulation of the dangers of dual use at the end of 2018 was probably worse than within the Human Brain Project. Prior to the Review Conference of the Chemical Weapons Convention in November 2018 there were strong suggestions for the need for action on dealing with incapacitants in major scientific journals [39, 40]. At the Executive Council meeting a month before the Review Conference the Ambassador of the United States put the point very clearly [41]: The RevCon will also provide an opportunity to address the critical threat posed by central nervous system chemicals such as the pharmaceutical anesthetic fentanyl. The United States and many other States Parties are seriously concerned that some States may be developing these chemicals for warfare and other harmful purposes, while cloaking their efforts as legitimate activities such as law enforcement or medical research. This Organisation’s efforts working towards a world free of chemical weapons demand that we adapt and address new and emerging threats, such as those posed by central nervous system acting chemicals…

The same point was made at the Review Conference in papers, for example, by Switzerland [42] and in a joint paper by 43 States Parties [43]. However, Russia argued that it was premature to act on this issue, and listed some of the issues that would need to be discussed and agreed as follows [44]:

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5 The EU Human Brain Project To achieve a common understanding of the provisions of the Chemical Weapons Convention by all its States Parties it is necessary to define such concepts and terms as ‘law enforcement purposes’, ‘aerosolisation of chemicals’, ‘incapacitating chemical agents’, and ‘temporary incapacitation’ as well as ‘central nervous system-acting’ toxic chemicals.

In one sense that could be seen as an attempt to set out some of the issues that would need to be sorted out in order to deal with this issue. But although there were sections of the Chairman’s report on the proceedings of the review on the issue of incapacitating chemical agents [45], the political disagreements that were noted in Chap. 2 prevented an agreed consensus report being produced at the end of the Review Conference. Thus, nothing was actually decided on this and other pressing issues. The situation in regard to the Biological and Toxin Weapons Convention was even less satisfactory. The report on MX2 of the Meeting of Experts did contain reference to the development of an international code of conduct, singling out that topic along with risk assessment and management [46]: 6. A recurring debate took place during MX2 on how to strike the right balance between ethics and scientific freedom, in a context in which innovative technologies are being developed outside the reach of current regulations. Notwithstanding the existence of national and professional codes of conduct, or similar instruments as ethical guidelines, several delegations expressed interest in discussing a ‘Code of Conduct’ within the Intersessional Programme of the BWC, under a negotiation process led by States Parties which would allow for the participation of the scientific community and other relevant players.

And the report suggested that these as potential issues that could be profitably addressed in future meetings: 7. The Chair sees the two topics above as those that could lead to a meaningful discussion during the remaining meetings of the ISP, in 2019 and 2020. They seem to present the best prospect for an agreed outcome on S&T issues in the 2021 Review Conference of the BWC. The Meeting of Experts on Science and Technology is the available format for discussions, but State Parties should not rule out other possibilities, such as working groups in parallel and complementary to MX2.

Unfortunately, the whole meeting was bedevilled by the financial constraints that arose from the failure of a number of States Parties to pay their assessed contributions to the running of the Convention and its meetings. Indeed, it appears that dealing with this problem took up most of the time in a shortened meeting and the report of the meeting [47] bleakly noted in regard to the substance of the issues brought forward from the Meeting of Experts that “[N]o consensus was reached on the deliberations including any possible outcomes of the Meeting of Experts.” Thus, again, nothing was decided apart from the dates of the meetings for 2019. Thus, even though major scientific journals were recognising the dangers of new biological weapons being developed using CRISPT/Cas technology [48], and a Chinese scientist was reported to have crossed the widely accepted red line and made hereditable changes to human beings using this technology [49], nothing resulted from the agreed concentration of the specific focus on CRISPR/Cas for the meetings in 2018.

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It looked very unlikely that much progress was going to be made on the international level during 2019, particularly as the United States seemed to be turning sharply away from the support of multilateral international agreements as a means of ensuring stability in the international system [50]. More, rather than less responsibility therefore would inevitably rest in the near future on other actors—such as practicing scientists - who could help to fashion effective regulation at other levels. Much therefore seemed to depend on progress in the US BRAIN project in addressing these issues. I therefore began to investigate the US project at the start of 2019 as set out in Chap. 6.

References 1. Preston A (2018) How the ‘brainy’ book became a publishing phenomenon. In: The observer: new review. pp 18–23. (29th July, page 20) 2. Rose G (2018) Which world are we living in? Introduction to the set of essays. Foreign Affairs 97(4), 10–55 3. Crowley M et al (2018) Preventing chemical weapons: arms control and disarmament as the sciences converge. Royal Society of Chemistry, London. (See Chapter 21: Conclusions and Recommendations) 4. See for example the introductory sections of Friedman G (2010) The next 100 years: a forecast for the 21st century. Anchor Books, New York 5. Director-General (2018) Response by the Director-General to the Report of the Scientific Advisory Board on Developments in Science and Technology for the Fourth Special Session of the Conference of the States Parties to Review the Operation of the Chemical Weapons Convention. RC-4/DG.2 OPCW, The Hague, 1 June (page 6) 6. Chair of the Scientific Advisory Board (2017) Central Nervous System Acting Chemicals– Considerations from the OPCW Scientific Advisory Board. Conference of States Parties (CSP22), 28 November 7. Open-Ended Working Group on Future Priorities of the OPCW (2018) Recommendations to the Fourth Special Session of the Conference of the States Parties to Review the Operation of the Chemical Weapons Convention. RC-4/WP.1. OPCW, The Hague, 16 July (page 9) 8. Zuba D et al (2016) 25C-NBOMe as a New Hallucinogen. In VR Preedy (ed) Neuropathology of Drug Addictions and Substance Misuse, chapter 92, vol 3. Academic Press, Amsterdam 9. Marsh S (2018) Police link surge in use of monkey dust drug to social media. The Guardian, London, 18th August (page 19) 10. Sample I (2018) Study reveals how cannabis extract may help treat psychosis. The Guardian, London, 20th August (page 12) 11. Human Brain Project (2017) HBP facts and figures, HBP in Europe, SGA1 April 2016–March 2018. https://www.humanbrainproject.eu/en/follow-hbp/sfn2017/ (pages 3 and 5) 12. Markram H (2012) The human brain project. Scientific American, June 50–55 (pages 50 and 51) 13. Nicolelis MAL (2018) The human brain, the creator of everything, cannot be simulated by any turing machine, chapter 20. In: Linden DJ (ed) Think tank: forty neuroscientists explore the biological roots of human experience. Yale University Press, New Haven and London, pp 263–269 14. Frégnac YL (2014) Where is the brain in the Human Brain Project? Nature 513:27–29 (pages 27 and 28) 15. Editorial (2017) The human brain project: adjusting the flagship’s course. Lancet Neurol 16:171 16. Available at https://www.humanbrainproject.eu/. Accessed 14th Sept 2018 17. Bregestovski P et al (2017) Light-induced regulation of ligand-gated channel activity. Br J Pharmacol 117(11):1892–1902

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18. Sanchez-Vives MV et al (2017) Shaping the default activity pattern of the cortical network. Neuron 94(5):993–1001 19. Harari YN (2018) The myth of freedom. The Guardian Review, 32–35 (15 Sept) 20. Amunts K et al (2018) The human brain project: creating a European research infrastructure to decode the human brain. Neuron, 92, 574–581 (page 575) 21. Human Brain Project (2016) Opening up the discussion on dual use in the Human Brain Project (HBP), Briefing No.4, October. Danish Board of Technology Foundation. www.tek no.dk. Accessed 18th Sept 2018 22. Mahfoud T et al (2018) The limits of dual use. In: Issues in science and technology, 73–78 (Summer, page 73) 23. Human Brain Project (2018) Dealing with dual use of HBP research–the citizens’ perspective. Briefing No. 7, August. Danish Board of Technology Foundation. www.tekno.dk. Accessed 18th Sept 2018 (pages 1 and 2) 24. Aicardi C et al (2018) Accompanying technology development in the Human Brain Project: from foresight to ethics management. Futures 102:114–124 (pages 115 and 122) 25. Aicardi C et al (2018) The integrated ethics and society programme of the Human Brain Project: reflecting on an ongoing experience. J Responsible Innovat 5(1):13–37 (pages 28, 17 and 29) 26. Evers K et al (2017) Dual use in neuroscientific and neurotechnological research: a report on background, developments, and recommendations for ethical address, assessment and guidance of human brain project activities. Human Brain Project Neuroethics and Philosophy Group, Uppsala University. 31st March. http://www.crb.uu.se/research/neuroethics/ (pages 14, 40 and 15) 27. Human Brain Project (2016) Dual use, future computing, neurorobotics and the Human Brain Project (HBP): expert seminar. Danish Board of Technology Foundation, HBP Foresight Lab and European Institute for Theoretical Neuroscience, Paris 10–11 March 28. Human Brain Project (2018) Seminar on dual use and research policy. Danish Board of Technology Foundation. Hotel Leopold, Brussels, 22nd, March 29. Whitby S, Dando MR (2018) Ethics, neuroscience, and public policy: a case study of raising neuroscientists’ awareness of the problem of dual use. In: A Poama, A Lever (eds) The routledge handbook of ethics and public policy. Routledge Handbooks in Applied Ethics, Taylor & Francis Ltd, London 30. Human Brain Project Education Programme (2018) 2nd HBP curriculum workshop series: dual use and responsible research: ethical challenges. Karolinska Institute, Stockholm, Sweden, 15–17 Nov 31. Human Brain Project (2018) Opinion on ‘Responsible Dual Use’: political, security, intelligence and military research of concern in neuroscience and neurotechnology. Danish Board of Technology Foundation, Copenhagen, Denmark 32. See for example, Royal Society (2005) The roles of codes of conduct in preventing the misuse of scientific research. The Royal Society, London 33. Consultative Committee of Accounting Bodies (2014) Developing and implementing a code of ethical conduct: a guide for businesses and other organisations. CCAB, London 34. Giorgini V et al (2015) Researcher perceptions of ethical guidelines and codes of conduct. Account Res 22(3):123–138 35. US National Academies (2018) Governance of Dual Use Research in the Life Sciences: Advancing Global Consensus on Research Oversight: Proceedings of a Workshop Highlights. National Academies, Washington, D.C. December 36. Kuhlau F et al (2012) Ethical competence in dual use life science research. Appl Biosaf 17(3):120–127 37. Douglas T (2014) The dual-use problem, scientific isolationism and the division of moral labour. Monash Bioeth Rev 32:86–105 38. Perkins D et al (2018) The culture of biosafety and biosecurity, and responsible conduct in the life sciences: a comprehensive literature review. Appl Biosaf 24(1):34–45 39. Shang L et al (2018) Close loophole for chemical weapons. Nature 562:344

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40. Crowley M et al (2018) Preventing chemical weapons as sciences converge: focus must extend beyond 20th-century technologies. Policy forum: science and security. Science 362:753–755 41. United States (2018) Statement by H.E. Ambassador Kenneth D. Ward. EC-89/Nat.10, 9th October. Organisation for the Prohibition of Chemical Weapons, The Hague (page 3) 42. Switzerland (2018) Strengthening the OPCW’s Verification Regime. RC-4/WP.9, 14th November. Organisation for the Prohibition of Chemical Weapons, The Hague 43. Joint Paper (2018) Aerosolisation of Central Nervous System-ACTING chemicals for Law Enforcement Purposes. RC-4/NAT.26, 30th November. Organisation for the Prohibition of Chemical Weapons, The Hague 44. Russian Federation (2018) Aerosolisation of Central Nervous System-Acting Chemicals for Law Enforcement Purposes. RC-4/NAT.9, 21 November. Organisation for the Prohibition of Chemical Weapons, The Hague (page 3) 45. OPCW (2018) Chairperson’s Report of the Proceedings of the Fourth Special Session of the Conference of the States Parties to Review the Operation of the Chemical Weapons Convention (Fourth Review Conference). RC-4/3/Rev.1, 30th November. Organisation for the Prohibition of Chemical Weapons, The Hague. (See section 9.57) 46. Chair of the Meeting of Experts on Review of Developments in the Field of Science and Technology Related to the Convention (2018) Meeting of Experts on Review of Developments in the Field of Science and Technology Related to the Convention: Reflections and proposals for possible outcomes. BWC/MSP/2018/CRP.3. United Nations, Geneva, 4th December (page 2) 47. BWC (2018) Report of the Meeting of States Parties. Advanced Version (page 6) 48. Reeves RG et al (2018) Agricultural research, or a new bioweapon system: Insect-delivered horizontal genetic alteration is concerning, Policy Forum: Dual-Use Research. Science 362(6410):35–37 49. Sataline S, Sample I (2018) Chinese scientist faces wrath of his peers over editing of babies’ DNA. The Guardian, 29th November (page 4) 50. Borger J (2018) Trump is building “new liberal order’ declares Pompeo. The Guardian, 28, 5th December

Chapter 6

The US BRAIN Initiative

Abstract At the 4th Five-Year Review Conference of the Chemical Weapons Convention in November 2018 the United States reiterated that it had concerns about non-compliance by some States and noted specific concerns about the pursuit of agents that could attack the Central Nervous System. This issue was strongly reinforced in a US presentation in which attention was given to the dangers that fentanyl and other similar chemical agents could cause. The point was clearly backed up by the Department of Defense seeking to develop and field capabilities to detect exposure to this “ever growing” class of so-called non-lethal incapacitating agents. That then was the context in which the US Brain Initiative was functioning at the start of 2019. The chapter asks how the project was organised at that time, what was it researching and publishing, and what was it doing about the dangers of dual use? It is clear from the full name of the US project—the Brain Research through Advancing Innovative Neuroechnologies—BRAIN Initiative that the underlying aim was to develop new technologies for brain research, but the project also had a well-crafted biological research programme designed to advance knowledge of the neuronal circuits of the brain. It also has an excellent website where the progress of the project, including webcasts of key meetings, can be followed. In early 2019 it was clear that after 5 years of operation ethical issues were beginning to be more effectively considered. That was necessary because the project was obviously involved in research that could have an impact on the real world, including research that could be of dual-use concern. Some examples of such research are reviewed in the chapter. The conclusion is that the work of the BRAIN Initiative does indeed raise issues that could be of dual-use concern, but that by mid-2019 no effective means were in place within the Initiative to deal with the problem.

6.1 Introduction At the Fourth Review Conference of the Chemical Weapons Convention on 22 November 2018 the US Ambassador’s Statement noted that [1]:

© Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6_6

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6 The US BRAIN Initiative One of the founding principles of the Convention is to ‘exclude completely the possibility of use of chemical weapons, through implementation of the provisions’ of the Convention. The success of this principle depends entirely on all States Parties’ compliance with their obligations. When States Parties fail to meet these obligations, they must be held accountable. No one should think that they can develop, retain, use, or transfer chemical weapons and get away with it. Unfortunately, there are States Parties in this room that think their conduct has no consequences and that they can act with impunity.

He then went on to specify non-compliance concerns in regard to Syria, Russia and Iran. In regard to Iran he stated that: …The United States has had longstanding concerns that Iran maintains a chemical weapons programme that it failed to declare to the OPCW. The United States is also concerned that Iran is pursuing central nervous system-acting chemicals for offensive purposes. (emphasis added).

And he proposed dealing immediately with this problem, stating that: The United States calls on responsible States to endorse a non-use policy regarding aerosolisation of CNS- acting chemicals. This endorsement would include international support recognising that the aerosolised use of CNS-acting chemicals is not consistent with the law enforcement exception to the Convention. The United States proposed taking this step last year, and we propose it once again. Let us not wait to take action on this issue until it is too late.

There are certainly reports available in the open literature of work in Iran on CNSActing chemicals that could be a cause of concern [2]. Official US concerns were clearly shown in a presentation by a US military spokesman at the Review Conference [3]. One slide of the presentation noted that “[The] 2017 United States Department of Homeland Security (DHS) Chemical Terrorism Risk Assessment placed fentanyl and fentanyl-analogues at the top of the U.S. chemical threat list.” Indeed, as was clear from the subtitle of the presentation—Central Nervous system (CNS)-Acting Chemicals—the stress in the presentation was on incapacitants, particularly fentanyl, with 10 of the 18 slides devoted to this subject. Against that background it is hardly surprising that the US Department of Defense put out a solicitation in October 2018 for a means of defence against fentanyl attack. The objective of the work required was [4]: To provide passive, on-warfighter diagnostic capability for intoxication subsequent to exposure to opioid threat agents. Capabilities sought are intended for use in far-forward deployed settings and must be effective and suitable to diagnose intoxication (disease) with high clinical sensitivity within a timeframe from exposure up to presentation of outward symptoms (i.e. the detectable pre-clinical phase).

It will be noted that the system was to function in “far-forward” deployments and to detect the agent quickly in order that counteraction was possible. In the detailed description the threat from this “ever-growing opioid chemical threat agents” is noted: The U.S. Department of Defense (DoD) seeks to develop and field diagnostic capabilities for detection of exposure to the ever-growing opioid class of chemical threat agents. Opioids

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are a drug class that includes heroin, synthetic opioids such as fentanyl (and analogues), and pain relievers such as oxycodone, hydrocodone, codeine, morphine, and others. Side effects of opioids include sedation, nausea, respiratory depression, and euphoria. Fentanyl and its analogues have rapid onset of symptoms and vary in duration of action. They are 50– 10,000 times more potent than morphine, which suggests quantities leading to accidental life-threatening exposure may occur on the level of an individual even within groups in confined spaces…

The potency of these agents is obvious, so the eventual aim is to have a fully automatic system that will also directly inject the treatment to the individual attacked. Defence organisations would be failing in their duties if they did not examine credible threats and what might be done to counter such threats. However, in a tense international context [5] and with rapidly advancing science [6] where new possibilities are likely to arise [7] there is always the danger of misperceptions and overreactions to defensive measures. As a major US report noted in 2008 that in such a ‘degradation market’, where customers were seeking advantage by degrading the cognitive abilities of others, examination of such possible agents that needed to be defended against might lead to the discovering of an effective agent with few side effects. That would likely lead to an escalating—self-fulfilling—arms race [8]. Of course, the involvement of the US Defense Advanced Research Projects Agency (DARPA) in the work could increase such suspicions even if the work was intended to be benign [9]. Just imagine the view that would be taken of the involvement of a similar agency in a brain project in other countries. That then is the context in which the US BRAIN Initiative was situated at the beginning of 2019. How was the project organised then, what was it researching and publishing, and, in particular, what was it doing about the dangers of dual use?

6.2 Neuroethics Developments in the BRAIN Initiative As we saw in Chap. 3 H Greely, Khara Ramos and Christine Grady, prominent members of the US BRAIN Initiative, stated in a 2016 review of Neuroethics in the Age of Brain Projects [10] that the projects “have so far done little to investigate the likely effects of neuroscience advances on society.” While accepting that the EU Human Brain Project may have supported more research on this than the BRAIN Initiative, they also concluded that none of such subjects “seem likely to be addressed any time soon by the ethics components of the brain projects.” However, despite such issues appearing “too far downstream and beyond the scope of brain projects” at that time they did see that changing in the future. That change was quite apparent in a paper titled Neuroethics and the NIH BRAIN Initiative [11] that was posted online in May 2017 and also authored in part by Khara Ramos and Henry Greely. The Brain Initiative, the authors explain, includes five Federal Agencies including the National Institutes of Health (NIH) and other entities such as private firms and universities. The NIH component is guided by the BRAIN 2025: A Scientific Vision report produced for the Advisory Committee to the NIH Director in 2014 [12]. They suggest that this report emphasises the importance of ethical considerations for the success of the

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Table 6.1 Explicit ethical goals of the BRAIN Initiativea Goals (Years 1–10) 1

Joint neuroscience/ethics training programs and meetings to consider the unique issues raised by human neuroscience research, and to establish a shared vision for the ethical conduct of such research

2

Resources for collecting and disseminating best practices in the conduct of ethical scientific research, particularly for the conduct of clinical research

3

Support for data-driven research to inform ethical issues arising from BRAIN Initiative research, ideally with integrated activities between ethicists and neuroscientists

4

Opportunities for outreach activities focused on engaging government leaders, corporate leaders, journalists, patients and their advocates, educators, and legal practitioners in discussion of the social and ethical implications of neuroscience research

a From

Ref. [12]

initiative and that it states four explicit goals for the ethical component of the project. These are set out in Table 6.1. Clearly there was room for progress in dealing with the problem of dual use within these guidelines, for example under the first point with its reference to ethics training programmes. Ramos and her colleagues went on to explain that oversight of the Brain Initiative was provided by a Multi-Council Working Group (MCWG) and that the MCWG had an ethics division (subsequently renamed the Neuroethics Working Group), which served as “a resource to help navigate ethical issues” that were associated with the research carried out under the initiative. While the NIH work was focused on ethical issues related to medicine the authors note also that “ethical issues around nonmedical applications are inevitable.” Furthermore, they make clear that the division would address such issues. From the perspective adopted here it is most important that they recognised that: Engagement and education are two pillars that will be key to successfully integrating neuroethics into neuroscience research programs…. Engagement refers to enabling interactions among the public, scientists, bioethicists, policy-makers, and members of congress, regarding neuroscience research and its associated ethical, legal, and social implications…

And Education goes hand-in-hand with engagement…. Ethicists who understand the scientific questions that neuroscientists are pursuing are better positioned to help responsibly guide research. And scientists who are well-educated about the implications of their work can be good stewards of their own research… (emphasis added)

At the time this paper was written the NIH had already hosted three meetings of scientists and ethicists in pursuit of these goals. Details of these meetings are available on the NIH website. So, for example, it is clear from the summary of the meeting on August 3, 2016 that the problem of dual use was under consideration [13]. The representative of the Defense Advanced Research Projects Agency (DARPA):

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…discussed DARPA’s efforts towards integrating ethical, legal, and societal implications (ELSI) of new technologies into their BRAIN-funded research, through a neuroethics ELSI panel. A member of that panel, Dr. Jim Giordano, discussed a recently developed operational neurotechnology risk assessment and mitigation paradigm (ON-RAMP), which entails querying, framing, and modelling patterns and trajectories of neuroscience and neurotechnology research and translational uses, and the ELSI generated by such advancements and their applications…

As noted in previous chapters Dr Giordano has contributed to the open literature warning about the need to deal effectively with the problem of dual use. The representative of the Intelliegence Advanced Research Projects Agency (IARPA) also made direct reference to this issue: Dr. Jeannotte explained that IARPA has a smaller footprint for programs that intersect with neurotechnology, and focuses more on human neuroscience and enhancement. Dr. Jeannotte added that IARPA is concerned with the ethical aspects of research application in addition to ethical conduct of research, especially regarding dual use. She expressed interest that a partnership with the Neuroethics Workgroup will aid incorporation of neuroethics into their research programs. (emphasis added).

So, it is reasonable to assume that dual use was one of the problems the ethics group would have on its continuing agenda. In late 2018 two papers were published in the Journal of Neuroscience that provided an update on this work on neuroethics. The first paper [14] noted that over the 5 years since the initiation of the initiative the NIH had spent over $950 million on the development of new tools and technologies and that, as in the past history of medicine, the application of these new technologies and capabilities required an evolution of ethics to guide what should be done. Moreover, it noted that work on this development of ethics was taking place not only in the USA but around the world. The set of Guiding Principles for the NIH Initiative were then set out as in Table 6.2. The second paper discussed these principles in some detail. Obviously, of main interest here is principle 4 which stated that [15]: Novel tools and technologies, including neurotechnologies, can be used both for good ends and bad. Researchers should be mindful of possible misuses that might range from intrusive surveillance of brain states to efforts to incapacitate or impermissibly alter a person’s Table 6.2 Neuroethics guiding principlesa 1

Make assessing safety paramount

2

Anticipate special issues related to capacity, autonomy and agency

3

Protect the privacy and confidentiality of neural data

4

Attend to possible malign uses of neuroscience tools and neurotechnologies

5

Use caution when moving neuroscience tools and neurotechnologies into medical or non-medical uses

6

Identify and address specific concerns of the public about the brain

7

Encourage public education and dialogue

8

Behave justly and share the benefits of neuroscience research and resulting technologies

a From

Ref. [14]

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behavior. Researchers have a responsibility to try to predict plausible misuses and ensure that foreseeable risks are understood, as appropriate, by research participants, IRBs, ethicists, and government officials. When possible, misuse should be prevented, for example, through design of the technology, such as ensuring secure wireless device connections.

These seem eminently sensible objectives, but the statement leaves aside the question of how they are to be achieved. The first paper by Diana Bianchi and colleagues sets out how this was to be done. First an internal team in the NIH had been tasked to ensure the integration of the principles throughout the grant cycle. This internal group is charged with growing an ethics research portfolio and interfacing with the external Neuroethics Working Group. Secondly, the high-level NIH Advisory Committee to the Director (ACD) was looking again at the initial set of priorities set for the Initiative and how they now might be adjusted. A Neuroethics Subgroup of this Advisory Committee had been tasked with producing a Neuroethics Roadmap to help guide future development of the BRAIN Initiative. The paper concludes that [16]: It is anticipated that the ACD working group will deliver its final report, including the Neuroethics Roadmap, to the full ACD in June 2019. The Neuroethics Working Group will then inform the NIH BRAIN Initiative’s implementation of the Roadmap by providing ongoing input on the neuroethical implications of the Initiative’s evolving research portfolio, continuing to host topical workshops on issues as they arise, and helping to shape the Initiative’s neuroethics research portfolio…

At that stage it would become clearer what it is intended to do practically about the problem of dual use. In early 2019 it was possible given the 5 years of operation of the BRAIN Initiative to ask if there was any work being done that could cause concerns to arise about dual use.

6.3 The BRAIN Initiative and Dual Use Given its full name the Brain Research through Advancing Innovative Neurotechnologies, the BRAIN Initiative might be seen as a purely technology development project. Even if that was all it was that would not exempt its participants from some responsibility for the implications of the application of these technologies because, as a report on the implications of genome editing technologies cogently pointed out [17]: Finally, stakeholders must recognize that many of the issues identified here are not unique to genome editing. Instead, they are representative of broader systemic challenges created by advances in the life sciences and biotechnology; challenges that will only grow more complex over the long-term. Unless the process of modernizing existing governance measures to ensure the safe, secure, and responsible use of biology begins today, the scientific and policy communities will find it even more difficult to take effective action in the future.

The work of the BRAIN Initiative is mainly being carried out in the United States where the predominant characterisation of the dual-use issue has been to concentrate on Dual Use Research of Concern (DURC) restrictively defined as [18]:

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Dual Use Research of Concern (DURC) is life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security. (emphases added)

Thus, it might be argued that it is unlikely that very much of the work would have those characteristics and if they did that would likely be spotted by those involved. Leaving aside the question of whether DURC would be spotted by those involved (maybe not a likely event given the history of controversy over such research during this century) [19], it is surely necessary to insist that the time for a concentration solely on single experiments is over and that now we have to be concerned also about is the growth of overall capabilities and what might be done with such capabilities in the future. The difference between the situation today and that of the Cold War weaponeers seeking novel incapacitating agents is well illustrated by reference to the agent BZ (3-quinuclidinyl benzilate) that was weaponised by the United States. The nerve agents like Sarin and VX act at synapses involving the acetylcholine neurotransmitter by blocking the enzyme that destroys the transmitter. So, they act at all synapses involving acetylcholine. During the early Cold War extensive investigations were carried out to find less lethal agents and many different chemicals were tested. As there are two types of receptor for acetylcholine—those affected by nicotine and those affected by muscarine—and as we now know many subtypes of each type, the work eventually led to the discovery of a class of agent that was incapacitating. We know a lot about the work that was done on this agent by the United States because of a detailed historical account given by one of the key scientists involved [20]. As this account makes clear BZ was being investigated as a treatment for gastrointestinal diseases when it was found to cause confusion and hallucinations in the people being treated. So, it came to the attention of the army and its effects on volunteers was subject to considerable testing. Moreover, the weaponeers could generate numerous different chemical agents with similar structures and test the effects of these compounds in a similar manner even though they were far from clear about the mechanism of action of these compounds. The peripheral actions of the fungal extract muscarine in slowing the heart and of atropine-like compounds blocking its actions were clarified in the early years of the last century, particularly after Loewi and Dale had identified acetylcholine as chemical neurotransmitter in the 1920s [21], but the Cold War weaponeers still had little understanding of the acetylcholine system within the central nervous system. It was not until the late 1970s that understanding of the cholinergic pathways in the central nervous system, apart from within the spinal cord, began to be clarified [22] and later still that the various sub-types of the muscarinic acetylcholine receptor were identified to eventually produce our present understanding of the acetylcholine system of the brain [23]. We can expect the process of developing a more detailed understanding of this important system to continue including within the various brain projects. The excellent informative website for the BRAIN Initiative sets out the aims current in early

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2019 in some detail [24]. The headings for the descriptions of these objectives are shown in Table 6.3. The website also lists the funded grants and the publications produced by scientists funded by the Initiative. It is therefore possible to look and assess the possible dual-use implications of the research. The interesting question is how to make such an assessment. One way to interrogate this information might be to think in terms of agents: current agents of concern, old agents, and novel agents becoming of potential interest because of advances in our understanding of the brain [6, 25]. However, a more appropriate approach to this benignly-intended research might be to follow the approach taken in a study published in 2000 by a group at Pennsylvania State University College of Medicine in a publication titled The Advantages and Limitations of Calmatives for Use as a Non-Lethal Technique [26]. They defined calmatives as pharmaceutical agents producing a calm-like behavioural state and considered a range of drugs including those that affected the central nervous system such as: …sedative-hypnotic agents, anesthetic agents, skeletal muscle relaxants, opioid analgesics, anxiolytics, antipsychotics, antidepressants and selected drugs of abuse…

Table 6.3 Objectives of the Brain Initiative in 2019a 1

Cell Type Discovering diversity: Identify and provide experimental access to the different brain cell types to determine their roles in health and disease

2

Circuit Diagrams Maps at multiple scales: Generate circuit diagrams that vary in resolution from synapses to the whole brain

3

Monitor Neural Activity The brain in action: Produce a dynamic picture of the functioning brain by developing and applying improved methods for large-scale monitoring of neural activity

4

Interventional Tools Demonstrating causality: Link brain activity to behavior with precise interventional tools that change neural circuit dynamics

5

Theory & Data Analysis Tools Identifying fundamental principles: Produce conceptual foundations for understanding the biological basis of mental processes through development of new theoretical and data analysis tools

6

Human Neuroscience Advancing human neuroscience: Develop innovative technologies to understand the human brain and treat its disorders; create and support integrated human brain research networks

7

Integrated Approaches From BRAIN Initiative to the brain: Integrate new technological and conceptual approaches produced in Goals #1–6 to discover how dynamic patterns of neural activity are transformed into cognition, emotion, perception, and action in health and disease

a From

Ref. [24]

6.3 The BRAIN Initiative and Dual Use Table 6.4 Some agents and receptors considered for production of a Calmative Statea

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Benzodiazepines: GABA receptors Alpha2 Adrenergic Receptor Agonists: Alpha2 adrenergic receptors Dopamine D3 Receptor Agonists: D3 receptors Selective Serotonin Reuptake: 5-HT transporter Serotonin 5-HT1A Receptor Agonists: 5-HT1A receptor Opioid Receptors and Mu Agonists: Mu receptor a From

Ref. [26]

Clearly therefore they were considering a variety of circuits that might be attacked to produce the so-called calmative state. They produced a table listing the drugs that might produce such effects and the receptors that would be affected by each agent to achieve the intended effect (Table 6.4). So, to use the same kind of approach we would need to survey the research of the BRAIN Initiative looking for different behavioural outcomes that might be of interest for incapacitation (such as a calm-like behavioural state), the different circuits that might be attacked to produce the intended state, the drugs that would be required to produce such a change in such circuits and the receptors that the agents would affect. At the time of this survey in early February 2019 the NIH website listed 552 grants and numerous publications. The following sub-sections give an overview of some examples of the awards and publications that could rather obviously raise concerns about possible misuse. This, of course, should not be taken to imply that any dual use was intended in any of the research discussed, or, on the other hand, that other aspects of the research programme are necessarily free of such concerns.

6.3.1 Structure and Function of Opioid Receptors Opiates are natural substances like morphine derived from the opium poppy. These chemicals have been used by human beings for thousands of years, particularly for the relief of pain but they can also be powerfully additive. The term opioid covers such natural opiates but also includes synthetic chemicals like fentanyl [27] which have similar effects on the nervous system by acting via the same neuroreceptors. The Mu receptor has a high affinity for opioid drugs and at lower concentrations the drugs can cause drowsiness and sleep as well as pain relief. However, at higher concentrations there is danger of respiratory depression and death. At the present time there is considerable concern in the United States and other countries over the number of people being killed by overdoses of strong opioids like fentanyl taken for pain relief or for recreational purposes. As a recent review noted that in the United States there were 33,091 deaths in 2015 due to taking opioids, and stated that [28]:

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…The increased demand for opioids has led to the increased availability of heroin and the proliferation of real and counterfeit opioid pills in the illicit drug market…. clandestine manufacturers are able to produce drug analogues at a faster rate than these compounds can be controlled, or scheduled…

An insight into how this can come about was given in a paper concerned with a similar misuse of cannabinoids [29]. The paper was titled Hijacking of Basic Research: The Case of Synthetic Cannabinoids and told the story of how benignly-intended scientific work “[O]riginally developed for the legitimate research purpose of furthering understanding of the cannabinoid system” ended being used to make drugs that could be very harmful to human health. The argument can be followed in Fig. 6.1. A 2008 US report on Emerging Cognitive Neuroscience and Related Technologies, as noted previously, suggested different types of markets could be involved in the use of drugs developed for medical purposes [30]. The central column of Fig. 6.1 shows how medical interest in a class of drugs such as cannabinoids or opioids can lead to research on the systems in the brain affected by the drugs including the neurotransmitters and the receptors affected and chemical modifications of the drugs. This research can then produce a better understanding of the whole system and new drugs for medical use. On the righthand side of the figure part of the enhancement market is shown. Clearly, some use of novel drugs for enhancement, while perhaps not needed for medical purposes, is not illegal. However, there is also an illicit market for drugs and what the hijacking paper shows is how new cannabinoid drugs were developed and used in this market and, further, how banning of these drugs in an attempt to prevent such use led to illegal chemists using the knowledge gained in the benignly-intended health research to make modifications of the drugs so that they kept ahead of the law. The end result has been a severe social problem with people using very potent synthetic cannabinoids [6]. As just noted, a similar argument can be applied to the present problem with fentanyl and derivatives. However, there is also another point to be made about the degradation market as shown on the left-hand side of the figure. We know that the use of fentanyl derivatives to halt the Moscow theatre siege led to considerable interest in fentanyl amongst defence scientists. Indeed, a recent review of incapacitating chemical agents by two US defence scientists only considered BZ and fentanyl in any detail [31]. So, there is clearly a danger that an action-reaction race to produce new incapacitants could break out because of misperceptions and concerns about what other States might be doing in such research. As the authors of Emerging Cognitive Neuroscience and Related Technologies put it [32]: …The fear that this approach to fighting war might be developed will be justification for developing countermeasures to possible cognitive weapons. This escalation might lead to innovations that could cause this market area to expand rapidly…

And they continued: …Tests would need to be developed to determine if a soldier had been harmed by a cognitive weapon. And there would be a need for a prophylactic of some sort. If a particularly effective

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Enhancement Market

Medical Interest in a class of chemicals

Research on the system affected by the drug: Including the structure of the receptors and development of novel drugs of different design

Interest in novel incapacitant chemicals

Development of countermeasures to new the new incapacitant

Development of new incapacitants based on the knowledge gained in the medical research Fig. 6.1 The Hijacking process

Improved knowledge of the system involved and development of new drugs for medical use

Illicit drug use

Illicit use of novel drugs

Banning of novel drugs for illicit use

Illicit development of new drugs based on the knowledge gained in the medical research

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degradation product is developed that has few side effects, escalation of this market will be self- fulfilling…

In short, people carrying out benignly intended civil research on fentanyl and other opioids need to be aware of the possibility of dual-use and take some responsibility for helping to protect their work from being misused. So if the BRAIN Initiative has projects involving fentanyl and other opioids it is reasonable to ask if those involved are carrying out the research responsibly in regard to the potential dangers of dual-use applications in the future [33]. One publication listed on the NIH BRAIN website is titled “New Technologies for Elucidating Opioid Receptor Function” and would appear to raise just such concerns [34]. The paper provides “a brief description of our understanding of opioid receptor function from both molecular and atomic perspectives as well as their role in neural circuits in vivo,” and discusses new technologies for investigating these topics in a series of sections titled, for example, “Functionally-selective opioid ligands” and “High resolution structures of opioid receptors and relevance to chemogenetics”. The paper concludes that: …Although the field of opioid receptor pharmacology will always rest on pharmacological methods and concepts for its foundation, these emerging technologies provide unparalleled opportunity for addressing key enigmas in opioid receptor structure and function.

It might be argued that as this is a review paper and does not involved reporting of any empirical research it is less subject to criticism, but there is no problem in finding publications from the project that involved empirical research and given clear medical concerns, for example in regard to treating pain, so such research is likely to continue [35]. One factor that also needs to be kept in mind when examining work funded by the BRAIN Initiative is that the researchers being funded are very unlikely to view this as the only source of funding for their research programmes. So, it is important to view the brain project funding and the publications it produces in the light of the other work on the same subject being carried out by the investigators under other funding in order to obtain a proper rounded appreciation of the work and its potential implications. It is a straightforward matter to interrogate the BRAIN Initiative website and find more examples of work by scientists involved on the structure and function of receptor systems that might be of interest to weaponeers [36]. However, it is clear that weaponeers were driven to seek simple effects such as sedation by aerosolised fentanyl as their understanding of the brain was not sufficient to achieve the much more complex types of incapacitation that they had in mind in the early days of the Cold War. In that context the obvious emphasis in the BRAIN Initiative on elucidation of the neuronal circuits underlying behaviour has to be taken particularly into account in regard to potential misuse in the future. The question is whether our increased understanding of the mechanism underlaying behaviours that could be of dual-use concern might open up possibilities well beyond what can be achieved by the largescale misuse of medical applications of aerosolised fentanyl [37] and its derivatives? To illustrate such possibilities we can look at behaviours such as arousal, fear, reward and trust.

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6.3.2 BRAIN Research on Circuits: Sleep/Wake In Chap. 1 we briefly reviewed how the use of novel technologies has radically altered our understanding of the mechanisms underlying sleep and arousal. The chapter particularly focused on work on the role of hypercretin (orexin) a neurotransmitter chemical that was only discovered some 20 years ago. The loss of the relatively small number of neurons that produce this transmitter has been found to cause narcolepsy which is a very debilitating disruption of the normal sleep and wake cycle. One paper on the BRAIN list of publications gives a comprehensive update on the growing knowledge of these neurons in a widening range of behaviours [38]. The paper notes that the hypocretin cells are located in the lateral hypothalamus which is a key region for the integration and regulation of behaviours such as sleep, feeding and motivation. It also notes that the hypocretin secreting neurons have direct excitatory effects on the noradrenaline producing cells of the locus coeruleus and that the output from these noradrenaline producing neurons are critical for the production of the change from the sleep state to wakefulness. What might be of particular interest for those with malign intent is that narcolepsy involves not just disruption of the sleep/wake cycle but also cataplexy. The cause of the loss of hypocretin neurons is not certain, but it is generally thought to be an autoimmune disease or perhaps a direct response to a viral infection [39]. Cataplexy occurs in about 70% of people who suffer from narcolepsy and if it occurs the narcolepsy is termed Type 1. As a review of the mechanisms causing cataplexy argued [40]: …Cataplexy is incapacitating because it leaves the affected individual awake, but either fully or partially paralyzed. The mechanism responsible for muscular paralysis is unknown, but is hypothesized to result from intrusion of REM sleep paralysis (atonia) into wakefulness…

It will be recalled from Chap. 1 that during Rapid Eye Movement (REM) periods of sleep most of our muscles are paralysed, presumably to protect us from dangerous movements when we are asleep. However, the intrusion of such muscular paralysis during normal waking is very distressing even though the person affect is fully conscious unlike the situation during REM sleep. Two interesting recent papers reported investigations of the possible mechanisms involved by the use of novel neurotechnolgies like those described in Chap. 1 on model organisms such as mice [41, 42]. What is particularly interesting is that cataplexy is often triggered by strong positive emotions such as laughter in human beings suggesting that the cause is more complex than just the shutting down of the muscle tone. It is obviously clear that in the lower parts of the brain there is a system that does shut down the movements of the muscles in order to produce atonia during REM sleep, and that the same system operates to produce the atonia of cataplexy in people suffering from Type 1 narcolepsy. In people who do not have narcolepsy, as we have seen, it appears that the activation of systems such as the noradrenaline producing cells of the locus coeruleus by input from the hypocretin producing cells helps to stop the output from the lower brain system that inhibits muscular activity in cataplexy.

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The investigation of genetically modified mice lacking hypocretin neurons in these two papers led to the general conclusion that when presented with a positive situation (such as pleasant food or activity) the higher parts of the brain activates cells within the amygdala and these cells produce inhibition of systems such as the noradrenaline neurons of the locus coeruleus by GABA neurotransmission. That then cuts the inhibition of the system in the lower part of the brain that produces atonia, thus allowing the production of cataplexy. The entire system is no doubt more complex than this simplified explanation would suggest, but the point is that the mechanism producing cataplexy is being dissected and that there is every reason to expect that process to continue because it will eventually help people with narcolepsy and the new techniques available to neuroscientists are obviously capable of being used to further such investigations. This point is made very clearly in a major review of the present state of our understanding of the cause of narcolepsy and its treatment in Sleep Medicine Reviews. The authors make use of the recent research literature including the two just mentioned and note that [43]: …The discovery of the Hcrt [hypocretin] neuron loss as the proximate cause of narcolepsy has enabled the creation of animal models with both construct and face validity, thereby enabling assessment of currently used medications to determine predictive or pharmacological validity of these models as well as assessment of the utility of these models to help identify new therapeutic paths for treatment of both EDS [excessive daytime sleepiness] and cataplexy…

We still do not know the cause of the loss of the hypocretin neurons and therefore cannot treat that aspect of the disease therefore most current treatments are aimed at increasing the availability of neurotransmitters such as noradrenaline. However, the authors see future improvements in this situation stating that: …Treatments directed at neurobiological circuits that can be translated clinically and tethered to specific symptom management may lead to personalised approaches. This approach is consistent with the Research Domain Criteria initiative spearheaded by the National Institutes of Mental Health.

The importance of this approach was discussed in Chap. 1 and the kind of outcome intended is shown by the authors noting that that the first small molecule hypocretin agonist and its effectiveness in a mouse model is a welcome development. We should of course welcome that advance and also expect more such advances as there is a great deal of other work being carried out on the hypocretin system within the BRAIN Initiative [44], but also note that inhibition of the output of noradrenaline was also seen as a potential method of incapacitation earlier in this century [45].

6.3.3 BRAIN Research on Circuits: Threat, Fear and Anxiety The amygdala is better known as a key element in the circuits that underpin responses to negative circumstances such as threat, fear and anxiety. As these circuits have great similarities in mammals a standard method of investigation has been to subject a

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mouse or rat to a sound paired with an electrical shock to its feet. The rodent quickly associates the sound with the footshock and reacts by freezing just to the sound. If the sound is repeated without the footshock it also eventually learns not to freeze just to the sound. In the past there were many investigations of the operations of the different parts of the amygdala in such fear memory, but [46]: …Until recently researchers have been limited in their ability to investigate the varying contributions at a molecular level, of different subtypes of cells within a brain region…

Now, however, because of the development of new investigative techniques such as optogenetics [47] that allow the manipulation of identified types of neurons in behaving animals these circuits are being dissected despite the complexity of the cell types involved. Research on topics such as fear are funded by the BRAIN Initiative, and while such funding can be predominantly for technology developments, it is not surprising to find that the researchers funded are also publishing the results of the use of such novel technologies. For example, it is not hard to link a project [48] titled “Genetic Tools and Imaging Technology for Mapping Cholinergic Engrams of Anxiety” to a publication [49] titled “Cholinergic signalling controls conditioned-fear behaviors and enhances plasticity of cortical-amygdala circuits” through the project leader of the grant. The authors of this paper explain that cholinergic signalling has been known for a long time to be involved in the amygdala network for the formation, recall and extinction of fear memories, but that: …The NBM [Nucleus Basalis] cholinergic neurons and their projections to the BLA [Basal Lateral Amygdala] are interspersed with neurons and fibres of other transmitter phenotypes, preventing selective stimulation or inhibition by standard electrophysiological or pharmacological techniques…

However, in this study they “used optogenetic techniques to specifically stimulate or inhibit cholinergic inputs within the BLA” in mice. This enabled them to assess the impact of this specific input in fear memories. They were able to conclude, for example that cholinergic signalling is needed for normal fear learning and that this input is not just a modulator of fear memories but is a necessary component of such conditioned fear learning. A similar pattern of an investigator having a BRAIN Initiative grants for technological developments [50] and making investigations dissecting neuronal circuits in the amygdala can be seen in regard to work on noradrenaline input from the locus coeruleus and anxiety-like behaviour [51]. In commenting on another important paper on the brainstem noradrenaline system [52] this investigator jointly authored a paper that made an interesting observation about how we now understand the operations of the locus coeruleus (LC). As the authors noted in regard to fear learning [53]: …These observations suggest that LC neurons can exhibit distinct response modes modulated by the sensory experience: a global broadcast mode evoked by intense aversive stimuli and a discrete coding mode related to cognitive processes.

And they note the similarity of this organisation to the:

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…modern concept of a polymorphic computer, which can dynamically arrange computational tasks under a computing architecture consisting of multiple arranged modules that efficiently process information matching the computational demands of the moment…

They point out that this system gives the LC maximal flexibility in matching behavioural responses to different environmental circumstances. Indeed, it would seem that the original objectives set out in the 2015 report to take advantage of the novel technologies in neuroscience to in order to achieve an “qualitative shift” in our understanding of neuronal circuits [54] is coming to fruition with all of the benefits and risks of dual-use applications that involves [6]. We now turn to an aspect of brain research in the United States where there might be even more reason for dual-use concerns.

6.3.4 BRAIN Research on Circuits: Aggression It might be argued that the association of the Defense Advanced Projects Research Agency (DARPA) and the Intelligence Advanced Research Project Agency (IAPRA) with the NIH BRAIN Initiative should be a cause of concern about dual-use applications. Such an association would certainly raise concerns if it happened in other countries. On the other hand, as we have seen, representatives of these two agencies drew attention to the problem of dual use in early meetings about the ethical implications of the research. Additionally, the projects related to the BRAIN Initiative that were listed on the DARPA and IAPRA websites at the start of 2019 did not seem to me to raise any direct issues in relation to potential chemical and biological weapons. However, a somewhat different view can arise if a broader view of the links between wider DARPA research interests and the BRAIN initiative is taken. For example, it is known that DARPA has had an interest in funding research on the neuropeptide oxytocin [25] possibly in relation to its potential role in building trust and DARPA’s interest in narrative networks [55]. But oxytocin has very wide-ranging functions in the mammalian nervous system and one of the projects listed on the NIH BRAIN Initiative website is concerned with oxytocin and its role in aggression [56]. Funding totalling some $2.9million was awarded to a group at the New York School of Medicine and the project description states correctly that: Oxytocin is a peptide hormone synthesized and released from the hypothalamus for reproduction and maternal behavior. Recent studies have tagged oxytocin as a ‘trust’ hormone, promising to improve social deficits in various mental disorders, such as autism…

And suggests that the overarching goal of the project: …is to achieve a better understanding of the oxytocin modulation in socio-spatial behaviors, which we define as social interactions within a specific context or behavioral environment…

What is of particular interest here is that the final part of the project description that states that it:

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…will combine the knowledge and techniques developed … to investigate the statedependent oxytocin modulation of aggressive behaviors at a brain site essential for aggression, the ventrolateral part of the ventromedial hypothalamus (VMHvl)…

And crucially, the description continues: …Intriguingly, a group of oxytocin neurons are found neighboring the VMHvl, potentially providing a local source of oxytocin although its behavioral relevance is currently unknown. Together the [whole project will] develop new tools, use cutting-edge techniques, and largescale methods to provide an in-depth description of the neural circuitry for maternal sociospatial behavior.

We can obtain an idea of what the project involves from publications made by this and other groups on the mechanism underlying the production of aggression since the specific role of the VMHvl was described in 2011 [57]. The work of interest here was summarised in a paper titled “Ventromedial Hypothalamus and the Generation of Aggression” in 2017 [58]. The authors describe a model in which the firing of the VMHvl neurons depends on three factors which together drive the aggressive behaviour. These three factors are set out in Table 6.5. The authors argue that, as has been shown in other systems such as hunger and thirst, the activity of these specific cells, driven, for example by olfactory information or precise experimental manipulation can be sufficient to cause an attack and they are able to describe in some detail the natural input and output from these neurons in the behaving animal. The neurons involved in the VHMvl have high levels of expression of the oxytocin receptor and oxytocin is known to cause excitation of these neurons. Furthermore, although the natural source of oxytocin activation of these cells is not known they note that there are oxytocin expressing cells lying next to the VMHvl and that “[G]iven that oxytocin can be released from not only axons but also dendrites local oxytocin release from those …oxytocinergic cells are likely to have strong influence on the adjacent cells in the VMHvl.” More generally, they conclude that: After decades of relative quiescence, aggression research has regained its momentum. Recent studies using genetically precise cell-type specific manipulation, tracing, and in vivo recording have quickly advances our knowledge regarding the neural substrates relevant for aggression…

Table 6.5 Factors driving the VMHvl Cell Firinga

Motivation Overall aggressive state of the animal Sensation Detection of sensory clues provoking aggression Action Initiation and execution of aggression-seeking behaviours and attack a From

Ref. [58]

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Moreover, it seems likely that this knowledge can already help to deal with medical problems such as “sundowning” the early evening agitation and aggression in people suffering from dementia and Alzheimer’s disease [59].

6.4 Conclusion In mid-12019 it appeared that the objectives set out in the original 2015 report BRAIN 2025 have been at least partially achieved. It also seemed very likely that the review of the BRAIN Initiative would propose that funding should continue to be allocated and this would lead to a further increase in our understanding and capabilities to manipulate the Central Nervous System of animals and ourselves over the following five years. On the other hand, while impressive efforts were being made to anticipate and deal with the neuroethical issues that these scientific and technological developments would produce, it was also clear that an effective response to the problem of dual use had not been found by the beginning of 2019.

References 1. United States of America (2018) Statement by H. E. Ambassador Kenneth D. Ward. RC4/NAT.7. OPCW, The Hague, 22 Nov (pages 1, 2, 4) 2. Crowley M, Dando M (2014) Down the slippery Slope? A study of contemporary dual-use chemical and life science research potentially applicable to incapacitating chemical agent weapons. Policy Paper No. 8. Biochemical Security 2030 Project, University of Bath, UK. October (pages 34–38) 3. Simpson, Lt Col M A (2018) The National Guard Weapons of Mass Destruction (WMD) Civil Support Team (CST) and Central Nervous System (CNS)–Acting Chemicals. In: Presentation at the CWC fourth review conference, The Hague, November (Slide 12) 4. Department of Defense (2018) Wearable medical device to diagnose in-theatre opioid intoxication of the warfighter. DoD 2018.3 SBIR Solicitation. https://www.sbir.gov/sbirsearch/det ail/1508759. Accessed 10 Aug 2018 (pages 1 and 2) 5. Editorial (2019) Nuclear weapons: with Donald Trump in charge, it is harder to hold back the arms race clock. The Guard J (page 2, 21 January) 6. Nixdorff K et al (2018) Dual-use nano-neurotechnology: an assessment of the implications of trends in science and technology. Politics Life Sci 37(2):180–202 7. Corriveau J, Feasel M (2014) Incapacitating Agents. In: H. Salem, S.A. Katz (eds.) Inhalation toxicology, 3rd edn (pages 245–255) 8. Dando MR (2015) Neuroscience and the future of chemical-biological weapons. Palgrave Macmillan, Basingstoke (See Chapter 6: Novel Neuroweapons, pages 76–96) 9. Reeves RG et al (2018) Policy forum: agricultural research, or a new bioweapon system? Science 362:35–37 10. Greely HT et al (2016) Neuroethics in the age of brain projects. Neuron 92:637–641 (page 640) 11. Ramos KM et al (2018) Neuroethics and the BRAIN Initiative. J Responsible Innov 5(1):122– 130 (pages 125, 126, 127) 12. Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Working Group (2014) BRAIN 2015: A Scientific Vision. Report to the Advisory Committee to the Director, NIH. National Institutes of Health. Washington DC. 5th June

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13. Available at https://www.braininitiative.nih.gov/about/neuroethics-working-group (page 4) 14. Bianchi DW et al (2018) Neuroethics for the National Institutes of Health BRAIN Initiative. J Neurosci, 38(50):10583–10585 (pages 1, 3, 4) 15. Greely HT et al (2018) Neuroethics guiding principles for the NIH BRAIN Initiative. J. Neurosci 38(50):10586–10588 (page 4) 16. Bianchi DW et al (2018) Neuroethics for the National Institutes of Health BRAIN Initiative. J. Neurosci, 38(50):10583–10585 (page 5) 17. Kirkpatrick J et al (2018) Editing biosecurity: needs and strategies for governing genome editing. Institute for Philosophy and Public Policy, Stanford University, Stanford (page 85) 18. Avaiable at https://osp.od.nih.gov/biotechnology/dual-use-research-of-concern/ 19. Van der Bruggen K (2015) Biosecurity challenges in the 21st century: the case of gain-offunction experiments, Chapter 2. In: S. Whitby et al (eds) Preventing biological threats: what you can do. University of Bradford, Bradford. https://www.bradford.ac.uk/…/preventing-bio logical-threatswhat-you-can-do.php. (See, for example) 20. Ketchum JS (2006) Chemical warfare secrets almost forgotten: a personal story of medical testing of army volunteers with incapacitating chemical agents during the cold war (1955– 1975). Private Publication, Santa Rosa, California. ISBN 1-4243-0080-0 21. Finger S (2000) The minds behind the brain: a history of the pioneers and their discoveries. Oxford University Press, Oxford (See, Chapter 16, Otto Loewi and Henry Dale: The Discovery of Neurotransmitters, pages 259–280) 22. Iversen LL et al (2009) Introduction to neuropsychopharmacology. Oxford University Press, Oxford (Chapter 6: Acetylcholine, page 135) 23. Meyer JS, Quenzer LF (2013) Psychopharmacology: drugs, brain and behavior. Sinauer Associates, Sunderland, Mass (See, Chapter 7, Acetylcholine, pages 185–201) 24. Available at https://www.braininitiative.nih.gov/. Accessed 6 Feb 2019 25. Dando MR (2018) Chapter 8: advances in understanding targets in the Central Nervous System (CNS). In: Crowley M et al (eds) Preventing chemical weapons: arms control and disarmament as the sciences converge. Royal Society of Chemistry, London (pages 228–258) 26. Lakoski JM, Murray WB, Kenny JM (2000) The advantages and limitations of Calmatives for use as a non-lethal technique. College of Medicine, Applied Research Laboratory, Pennsylvania State University. October, 3rd; See for a similar approach, Holstage CP et al (2017) CBRN– Opioids/Benzodiazepines Poisoning. Medscape, July 17th. https://emedicine.medscape.com/ article/834190-print 27. Stanley TH (2014) The fentanyl story. J Pain 15(12):1215–1226 28. Armenian P et al (2018) Fentanyl, fentanyl analogs and novel synthetic opioids: a comprehensive review. Neuropharmacology 134:121–132 (page 122) 29. Wiley JL et al (2011) Hijacking of basic research: the case of synthetic Cannabinoids. Methods Rep RTI Press, Nov. https://doi.org/10.3768/rtipress.2011.op.007.1111 (page 1) 30. Committee on Military and Intelligence Methodology for Emergent Neurophysiological and Cognitive/Neural Sciece Research in the Next Two Decades (2008) Emerging cognitive neuroscience and related technologies. National Academies Press, Washington, D.C. 31. Corroiveau JL, Feasel M (2015) Incapacitating agents. In: Salem H, Katz SA (eds) Inhalation toxicology, 3rd edn. CRC Press, Boca Raton (pages 245–255) 32. Committee on Military and Intelligence Methodology for Emergent Neurophysiological and Cognitive/Neural Science Research in the Next Two Decades (2008) Emerging cognitive neuroscience and related technologies. National Academies Press, Washington, D.C. (page 133) 33. InterAcademy Partnership (2016) Doing global research: a guide to responsible conduct in the global research enterprise. Princeton University Press, Princeton (See Chapter 3: Preventing the Misuse of Research and Technology, pages 21–30) 34. Bruchas MR, Roth BL (2016) New technologies for elucidating opioid receptor function. Trends Pharmacol Sci 37(4):279–289 (pages 1, 8) 35. Grace PM et al (2016) Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation. Proc Natl Acad Sci 113(24):E3441–E3450

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36. McCorvy JD, Roth BL (2015) Structure and function of serotonin G protein coupled receptors. Pharmacol Ther 150:129–142 (See, for example) 37. MacLeod DB et al (2012) Inhaled Fentanyl Aerosol in Heathy volunteers: Pharmacokinetics and Pharmacodynamics. Anesth Analg 115(5):1071–1077 38. Tyree SM et al (2018) Hypocretin as a hub for arousal and motivation. Front Neurol 9:1–16. https://doi.org/10.3389/fneur.2018.00413. (June 6) 39. Dando MR (2018) Advances in understanding targets in the central nervous system. Chapter 8. In: Crowley M et al (eds) Preventing chemical weapons: arms control and disarmament as the sciences converge. Royal Society of Chemistry, London (pages 228–258) 40. Pintwala S, Peever J (2017) Circuit mechanisms of sleep and cataplexy in narcolepsy. Curr Opin Neurobiol 44:50–58 (pages 33, 31) 41. Mahoney CE et al (2017) GABAergic neurons of the central amygdala promote cataplexy. J Neurosci 37(15):3995–4006 42. Snow MB et al (2018) GABA cells in the central nucleus of the amygdala promote cataplexy. J Neurosci 37(15):4007–4022 43. Szabo ST et al (2019) Neurobiological and immunological aspects of narcolepsy: implications for pharmacotherapy. Sleep Med Rev 43:23–36 44. Project Number 1F32MH115431-01 on Investigating the hypocretin to VTA circuit in memory consolidation during sleep. (See for example) 45. Lakoski JM, Murray WB, Kenny JM (2000) The advantages and limitations of calmatives for use as a non-lethal technique. College of Medicine, Applied Research Laboratory, Pennsylvania State University (3 Oct) 46. Gafford GM, Ressler KJ (2016) Mouse models of fear related disorders: cell-type specific manipulations in amygdala. Neuroscience 321:108–120 (page 109) 47. Sprangler SM, Bruchas MR (2017) Optogenetic approaches for dissecting neuromodulation and GPCR signalling in neural circuits. Curr Opin Pharmacol 32:56–70 48. Project Number 1U01MH109104-01 49. Jiang L et al (2016) Cholinergic signalling controls conditioned-fear behaviors and enhances plasticity of cortical-amygdala circuits. Neuron 90(5):1057–1070 (page 2) 50. See Project Numbers 1R01MH111520-01 and 1R21EY027612-01 to Michael R. Bruchas 51. McCall JG et al (2017) Locus coeruleus to basolateral amygdala noradrenergic projections promote anxiety-like behaviour. eLife 2017; 6:e18247. https://doi.org/10.7554/elife.18247 52. Uematsu A et al (2017) Modular organisation of the brainstem noradrenaline system coordinates opposing learning states. Nat Neurosci 20(11):1602–1611 53. Seo D-oh, Bruchas MR (2017) Polymorphic computation in locus coeruleus networks. Nat Neurosci 20(11):1517–1519 (page 1519) 54. Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Working Group (2014) BRAIN 2015: a scientific vision. Report to the Advisory Committee to the Director, NIH. National Institutes of Health. Washington DC. 5 June (page 5) 55. Sanchez J (2019) Narrative networks. https://www.darpa.mil/program/narrative-networks. Accessed 23 Feb 2019 56. See Project Number 1U19NS107616-01 to Richard W. Tsien 57. Lin D et al (2011) Functional identification of an aggression locus in the mouse hypothalamus. Nature 479:221–226 58. Hashikawa Y et al (2017) Ventromedial hypothalamus and the generation of aggression. Front Syst Neurosci 11:94. https://doi.org/10.3389/fnsys.2017.00094 (page 10) 59. Todd DW et al (2018) A hypothalamic circuit for the circadian control of aggression. Nat Neurosci 21(5):717–724

Chapter 7

Global Neuroethics in Early 2019

Abstract This chapter reviews how the brain projects were dealing with neuroethics in early 2019, and, in particular, how they were attempting to deal with the problem of dual use. After briefly reviewing the scientific objectives of the projects as set out in a series of articles in 2016, the answers given by the different projects in early 2019 to the question “What applications might be considered misuse or best uses beyond the laboratory” in a series of articles in the journal Neuron titled “Neuroethics Questions to Guide Ethical Research in the International Brain Initiatives” are analysed. It was clear from the articles on the Australian, Canadian, Chinese, Japanese, and Korean projects that the question of dual use had yet to be addressed. The EU Human Brain Project had clearly devoted more attention to this issue and had produced an Opinion on Dual Use in December 2018. This Opinion indicated that an educational programme would be needed as part of a strategy to deal with dual use. The US BRAIN Initiative had also produced a set of guiding principles which included “Attend to the possible malign uses of neuroscience tools and neurotechnologies,” but was still working out how that might be done. So progress was being made, and as the brain projects were linked together in the International Brain Initiative it was to be hoped that good practice would progressively spread, but the chapter ends by noting the unstable and uncertain state of the international system at that time and the possible attraction of novel chemical and biological weapons within modern methods of hybrid warfare.

7.1 Introduction An opportunity arose in early 2019 to take stock on how well all of the brain projects were coping with the problem of dual use as they began to bring together their joint thinking about dual use in the context of how they were developing their ideas and programmes on neuroethics. In October 2018 the journal Neuron carried an article on “Neuroethics Questions to Guide Ethical Research in the International Brain Initiatives” [1]. These questions are set out in Table 7.1.

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Table 7.1 Neuroethics questions to guide ethical research in the international Brain projectsa Q1. What is the potential impact of a model or neuroscience account of disease on individuals, communities, and society? Q2. What are the ethical standards of biological material and data collection and how do local standards compare to those of global collaborators? Q3. What is the moral significance of neural systems that are under development in neuroscience research laboratories? Q4. How could brain interventions impact or reduce autonomy? Q5. In which contexts might a neuroscientific technology/innovation be used or deployed? Q5a. Which applications might be considered misuse or best use beyond the laboratory? a From

Ref. [1]

The fifth of the five questions (NeQNs) listed asked, “In which contexts might a neuroscientific technology/innovation be used or deployed?” and specifically, in question 5a, “Which applications might be considered misuse or best uses beyond the laboratory?” (emphases added). Given the past history of the misuse of advances in neuroscience in the development of chemical and biological weapons it would thus appear that the international brain research initiatives intended to make an important contribution to dealing with the problem of dual use, the fact that, as the UK Royal Society [2] put it in 2012, “knowledge and technologies used for beneficial purposes can also be misused for harmful purposes.” Given that, even after the multiple uses of chemical weapons in recent years, the States Parties to the Chemical Weapons Convention (CWC) and the Biological and Toxin Weapons Convention (BTWC) were unable to agree any significant strengthening of the Chemical and Biological Non-Proliferation regime at their respective meetings in 2018, it was reasonable to question in early 2019 whether we could deal effectively with such potentially malign applications of the life and associated sciences. Indeed, given the then state of international arms control and international relations more generally, it was surely reasonable to ask if a future series of missteps and misunderstandings might end up less fortuitously than NATO’s “Able Archer” exercise [3] did in 1983? Then, as a major 1990 US review released only in 2015 concluded [4]: “In 1983 we may have inadvertently placed our relations with the Soviet Union on a hair trigger.” While it may not be as easy to communicate concerns about biological threats as it is for nuclear threats there can be little doubt that global catastrophic threats could arise in dual-uses of advances in the life sciences [5]. If we are to avoid further such dangerous interactions life scientists surely have a role to play in making the world a safer place as the revolution in biotechnology continues through coming decades. The international workshop organised in collaboration with the InterAcademy Partnership in Zagreb during 2018 (see Chap. 3) made this quite clear in concluding that a layered system of governance measures will be required to prevent the misuse of advances in the life sciences in the development of new chemical and biological weapons. The report stating that [6]:

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…Governance of life science research that raises dual use concerns is likely to require a complex layered system that occurs at multiple stages across the research process…. stakeholder communities can include government policy makers, research-conducting institutions, practicing researchers from academia and industry, biosafety officers, laboratory risk management professionals, journal publishers, specialists in education and outreach…

How then are the brain research projects setting about their part of this task?

7.2 Objectives of the Brain Projects in 2016 Of course, for the very good reason of the need to help people with medical problems there was a great deal of research on the Central Nervous System before the Statelevel brain initiatives began to be funded over the last few years, but the initiation of these projects signalled that there was a real opportunity for making rapid progress in understanding the neuronal mechanisms underlying such problems and how they might best be treated. An editorial and a collection of articles (Table 7.2) in 2016 [7] set out the main research themes of these initiatives as they were seen at that stage. The editorial in the journal Neuron emphasised that there had been an “explosion of growth in neuroscience” over the preceding 5 years based on major technological developments and that the application of these new capabilities was likely to be transformative for neuroscience and for its ethical and social implications. The editorial also anticipated that gaps in appreciation [8] were to be expected and adaptations would be required in the initiatives to deal with the new problems as they became understood. The article in the collection on the US BRAIN Initiative made its central aim clear by spelling out the initiative’s full title: Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative and stating its explicit objective first to develop new technologies to “enable scientists to monitor and modulate brain circuit activity” and then to apply these novel capabilities in hypothesis-driven investigations of brain structure and functions. In conclusion the authors also noted that although Table 7.2 Articles on the Brain initiatives in Neuron November 2016a

Editorial: Global Neuroscience The BRAIN Initiative: Building, Strengthening, and Sustaining The Human Brain Project: Creating a European Research Infrastructure to Decode the Human Brain Brain/MINDS: A Japanese National Brain Project for Marmoset Neuroscience China Brain Project: Basic Neuroscience, Brain Diseases, and Brain-Inspired Computing Australian Brain Alliance Brain Canada: One Brain One Community Korea Brain Initiative: Integration and Control of Brain Functions a From

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the Initiative was benignly-intended there could also be risks that would have to be dealt with as they arose. The European Union’s Human Brain Project (HBP) was initiated in late 2013 at the same time as the US project was announced (see Appendix 1) and like the US project was intended to have a central objective of technology development. However, as the authors of the article on the HBP emphasised, it had an Information Technology orientation in aiming to understand the structure and function of the brain “across all levels of brain organisation, from genes to the whole brain”. This needed an interdisciplinary approach “joining neuroscience, computer science, informatics, physics and mathematics.” Another feature of the EU HBP was that it had a specific sub-project on Ethics and Society tasked with exploring the project’s “social, ethical and philosophical implications” which aimed to foster responsible research and innovation by raising “social and ethical awareness among the project participants”. The authors of the article on the Japanese Brain/MINDS project indicated that the initiation of the US and EU projects in 2013 led to a consideration of what Japan might be able to contribute to an international neuroscience effort and the conclusion that it would be possible to use Japan’s long experience of investigations of marmoset biology to use these non-human primates “to bridge fundamental advances from current animal models, such as the mouse, to an accurate understanding of the human brain.” Thus, the Brain Mapping by Integrated Neurotechnologies for Disease Studies Brain/MINDS project involves four major groups studying “(A) Structural and functional mapping of the marmoset brain, (B) Development of innovative neurotechnolgies for brain mapping, (C) Human brain mapping and clinical research, and (D) Advanced technology and application development.” No mention was made in this account of potential ethical and social implications of the research. Consideration of the US, EU and Japanese projects in China led to a “consensus that understanding the neural basis of human cognition… should form the central pillar of the China brain project”, and that resources should be devoted to dealing with the immediate problems caused by major brain disorders. Thus “the basic research on neural circuit mechanisms underlying cognition provides input to and feedback from the two applied wings of brain disease/intervention and brain inspired intelligence technology”. Given the concentration on higher cognitive functions the authors explain that the project would focus on “the mesoscopic circuit analysis of the macaque brain.” They also stated that with this focus on non-human primate (NHP) research the project “aims to establish nationwide ethical regulations for NHP experiments that are compatible with international standards”, but they did not mention other ethical issues that may arise. The article on the Australian Brain Alliance stated that it had only been established recently, but it was clear from the account that with its aim of cracking the brain’s code it would be working with the overarching goal of “understanding the mechanisms…that underlie how neural circuitry develops, how it encodes and retrieves information, how it underpins complex behaviors, and how it adapts to external and external changes”. It would therefore, like the other brain projects, likely be involved in areas of research where dual-use concerns could arise. The articles on the Canadian and Korean brain projects both explained that the current initiatives to link up

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with the new international brain projects followed on from long histories of national cooperation in neuroscience research and therefore, not surprisingly, both articles noted the possibility of ethical issues arising as the initiatives developed. However, although the point was made in regard particularly to the US and EU projects, the overall situation in 2016, as noted in Chap. 2, was perhaps best summed up in one of the accompanying articles [9] titled “Neuroethics in the Age of Brain Projects” in which it was concluded that the brain projects had understandably “focused on the ethics of the research they are supporting or, sometimes, their near term consequences”, but that “they have so far done little to investigate the likely effects of neuroscience advances on society”.

7.3 Neuroethics in the Brain Projects in 2019 The chance to assess the progress of the application of neuroethics in these brain initiatives in regard to the problem of dual use (particularly under the agreed NeQN 5a) came in early 2019 when a further collection of articles (Table 7.3) was published in the journal Neuron. The lead editorial noted that each of the initiatives now had its own neuroethics team and that following the recent linking up of the nationallevel initiatives into the International Brain Initiative (IBI) these national ethical approaches had also been linked together in the Neuroethics Working Group of the IBI [10]. The following articles then described developments within each nationallevel project. Clearly, the overall objective is to produce a systematic approach that applies within each initiative, allowing, of course, for cultural differences where necessary. The article on the Australian project explained that a Neuroethics and Responsible Research and Innovation Committee (NRRIC) had been set up within the initiative to try to meet the ethical challenges that arise as a result of the research. The article then discussed the five questions set out in the 2018 guidelines, but I could find no Table 7.3 Articles on global neuroethics in Neuron February 2019a

Edirorial: Neuroethics: Think Global A Neuroethics Framework for the Australian Brain Initiative A Neuroethics Backbone for the Evolving Canadian Brain Research Strategy Responsibility and Sustainability in Brain Science, Technology, and Neuroethics in China—a Culture-Oriented Perspective The Human Brain Project: Responsible Brain Research for the Benefit of Society Neuroethical Issues of the Brain/MINDS Project of Japan Korea Brain Initiative: Emerging Issues and Institutionalization of Neuroethics The NIH BRAIN Initiative: Integrating Neuroethics and Neuroscience a From

Ref. [10]

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direct reference to question 5a, and specifically in regard to the problem of dual use. The article on the Canadian project concentrated on describing how the research strategy is being developed and some ethical issues that it is seen to involve. The questions agreed internationally were only addressed briefly at the end of the article and the issue of dual use was not mentioned, the article stating that “We defer the fifth question… to later phases of work and ongoing engagement with the International Brain Initiative”. The article on the brain project in China gives an interesting insight into the social and cultural situation in which the project is embedded and the ethical issues that are thought likely to arise, and it is made clear that an ethics committee is to be integrated into the project. What is interesting here is that although the problem set out in question 5a is not specifically addressed, the possibility of learning from other international experience is stressed. For example, the authors state that “Due to a current lack of a neuroethics speciality and expertise in China, learning from the international community is imperative for us”. It is obvious from the article on the Brain/MINDS project that a great deal of work has been done in Japan on the ethical issues involved in doing the research and detailed answers are given, for example in regard to NeQNs 1, 2 and 4 in the guidance list. However, the authors state more research is needed in regard to neuroenhancement and only that “we will be exploring NeQN 5 … as we develop this technology”. The article on the Korean Brain Initiative made clear that it had a strong interest in ethics, but noted the “priority of implementing neuroethics is to establish an education and training program due to the absence of neuroethics expertise,” but there was no mention of question 5a or of dual use. So, it is possible to conclude that the question of dual use had not yet been addressed within these projects when the articles on Australia, Canada, China, Japan and Korea were written. The situation in regard to the EU and US initiatives was rather different and much more encouraging. The article on the EU HBP emphasised that ethical considerations were central to the project from the beginning, noting that “[T]he Ethics and Society Subproject is not external to the HBP but embedded in it: it is part of the core research project itself, funded with approximately 4.5% of the overall budget.” The subproject is involved in the production of consensus opinions on issues of key neuroethical concern and the article noted that in regard to NeQN5 it had produced an Opinion on Responsible Dual Use dealing with issues such as “international frameworks for regulating and governing both research and the use of weaponizable brain science.” As discussed in Chap. 5 this opinion was published in December 2018 [11] and included recommendations such as that “the HBP develops an educational programme concerning the political, security, intelligence and military uses of brain inspired research and development.” An implementation plan for the recommendation in the opinion was then being developed. Yet, as pointed out in Chap. 5, it seems to me that without a very determined educational programme dualuse ethical competence is unlikely to be achieved, and there are a series of difficult questions that can reasonably be asked about the intended educational programme. Again, as discussed in Chap. 6 the article on the US Initiative similarly stresses that the external Multi-Council Working Group that provides an overall perspective on

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the evolution of the initiative has a dedicated Neuroethics Working Group (NEWG) and that the NEWG had recently published a set of neuroethics guiding principles for the initiative to help participants frame and navigate neuroethical questions involved in their work [12]. These principles include “4. Attend to possible malign uses of neuroscience tools and neurotechnologies.” The high-level Advisory Committee to the NIH Director (ACD) was due to report on updating the initiative for the coming years in June 2019 and a neuroethics subgroup of the ACD has been tasked to produce a Neuroethics Roadmap as part of that report. This roadmap would presumably include an analysis of key ethical questions and educational recommendations similar to the EU Opinion on dual use and thus the same kind of questions as listed about the HBP programme of education in Chap. 5 would also apply.

7.4 Assessment of the Progress in Dealing with Dual Use Thus, in early 2019 it might well have been possible to conclude that international cooperation in neuroethics could not deal with the entirety of the problem of dual use, but it could certainly make an important contribution if scientists in this field were able to agree and implement an effective international system to help protect their benignly-intended work from dual use. To achieve that end the next steps required seemed to be that the EU HBP decided on an effective means of implementing its Opinion on Dual Use and the US BRAIN Initiative came up with a plan similar to the EU opinion and then an effective action plan to implement it. That would then provide a framework within which the other brain projects could find their own culturallyspecific means of proceeding along the same trajectory. It also seemed possible to work from the international level and for the International Brain Initiative to link up with Advisory Board on Education and Outreach of the Organisation for the Prohibition of Chemical Weapons [13] and elements associated with the Biological and Toxin Weapons Convention such as the InterAcademy Panel and States Parties such as China and Pakistan [14] that are interested in developing an international code of conduct dealing in part with dual use so as to add to and learn from these different experiences of trying to deal with this important and difficult issue. Yet there were real reasons for concern that international co-operation would not be easy to achieve in the international situation at that time.

7.5 Strategic Interactions in 2019 In a collection of essays on The New Nationalism Carla Norrlof argued that the wave of nationalism sweeping the western world was so disturbing because all of the populist movements rejected liberal values. As she put it [15]:

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…If the world once seemed to be moving inexorably toward greater political and economic freedom, human dignity, tolerance, equality, nondiscrimination, open markets, and international cooperation, all are now under threat…

She argued further that the impact of the new nationalism went beyond individual states: …Because the countries that uphold the liberal international order, especially the United States, are turning against liberalism, they risk undermining the order they built, ushering in a more antagonistic and dangerous world.

This strategic theme was taken up in another of the essays in which Michael Mandelbaum discussed the problem that the United States will have in dealing with the raising power of Russia, China and Iran. Referring back to the epic struggle of the second half of the last century and the United States policy of containment of the Soviet Union he noted that [16]: …if today’s challenges are less epic, they are far more complicated. The old containment was simple, if not easy. The new containment will have to blend a variety of policies, carefully coordinated with one another in design and execution. This will tax the ingenuity and flexibility of the Unites States and its allies.

It is not difficult to see how these dilemmas were playing out in international diplomacy in early 2019. On March 19th, 2019 Yleem D.S. Poblete, Assistant Secretary, Bureau of Arms Control, Verification and Compliance of the United States gave an address to the UN in Geneva as the United States took over the Presidency of the Conference on Disarmament in Geneva [17]. The address noted that the Conference on Disarmament and its predecessors had been successful, for example, in agreeing the Biological and Toxin Weapons Convention and the Chemical Weapons Convention, but that in recent decades it had fallen into deadlock and achieved very little. The address went on to argue that this was regrettable and that the United States was keen to make progress. It then laid the blame for the lack of progress on certain “MALIGN ACTORS” and focused on a long series of allegations against Russia, China and Iran. In regard to Iran the address again noted that “the United States is gravely concerned that Iran is pursuing pharmaceutical-based weapons for offensive purposes.” While the address ended by calling for everyone to work together to develop further international arms control and disarmament agreements it did not seem likely that would be easily achieved in the context set out in the address. A further indication of the probable lack of progress at the international level had been given by Dr. Christopher Ashley Ford, Assistant Secretary, Bureau of International Security and Nonproliferation in an address on March 14th in Washington D.C. [18]. Titled Re-Learning a Competitive Mindset in Great-Power Competition and focused on “Strategic Weapons in the 21st Century: The New Dynamics of Strategic Conflict and Competition” the speaker noted that it was a year since the US National Security Strategy had warned that China and Russia were “actively competing against the United States and our allies and partners.” He went on to

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suggest that America had been too cooperative since the end of the Cold War and had forgotten the need for a competitive mindset to guide its overall strategic policy. He then focused specifically on the raising power of China and argued that: …America’s strategic holiday is over…as we try to devise a competitive strategy appropriate to this new era, we at least finally admit that we need one, and we are now working hard to meet the challenge. That, I believe, represents a sea change in U.S. foreign and national security policy, and “mindset’ is leading the way. (original emphasis)

Against that background it seemed that progress in strengthening the chemical and biological non-proliferation regime at the international level would be hard going over the next few years and strengthening other aspects of the overall preventive policies were likely to be the best way to make progress. That meant that scientists could be one group that would be well placed to lead efforts to make progress in protecting their benignly-intended work from dual-use.

7.6 A Potential Opening for Scientists? The United States had produced a National Biodefense Strategy in 2018 [19]. This strategy stated on page 1 that its purpose was to put in place for the first time: …a single coordinated effort to orchestrate the full range of activity that is carried out across the United States Government to protect the American people from biological threats…

The strategy had five goals as set out in Table 7.4. On April 17th 2019 a Biodefense Summit was held in at the National Academy of Sciences in Washington D.C. on the implementation of this strategy and the whole of the meeting was made available on a webcast. In relation to Goal 2 of the strategy one of the sub-goals was set out as shown in Table 7.5. As the agenda for the summit noted: …This goal also recognises the ‘dual use’ natures of the life sciences and biotechnology, in which the same science and technology base that improves health, promotes innovation, and protects the environment, can also be misused to facilitate a biological attack. The United

Table 7.4 Goals of the US biodefense strategya

Goal 1: Enable Risk Awareness to Inform Decision-Making Across the Biodefense Enterprise Goal 2: Ensure Biodefense Enterprise Capabilities to Prevent Bioincidents Goal 3: Ensure Biodefense Enterprise Preparedness to Reduce the Impacts of Bioincidents Goal 4: Rapidly Respond to Limit the Impacts of Bioincidents Goal 5: Facilitate Recovery to Restore the Community, the Economy, and the Environment After a Bioincident a From

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Table 7.5 Sub-goal 2.4.2 of the US national biodefense strategya 2.4.2 Support and Promote the Responsible Conduct of the Life Science and Biotechnology Enterprise • Support and promote a culture of global biosafety, biosecurity, ethical, and responsible conduct in the life sciences • Promote effective global oversight of: Dual-use research, to prevent misuse; and Research for which biosafety lapses could have very high consequences, such as with potential pandemic pathogens Encourage engagement among the health, scientific, biotechnology, enthusiast, and security communities in the United States, and with international partners, to reduce the risk of misuse Promote the development and implementation of relevant national and international policies, guidance, training, and other resources across the health, scientific, biotechnology, enthusiast, and security communities to reduce the risk of misuse a From

Ref. [19]

States seeks to prevent the misuse of science and technology while promoting and enhancing legitimate use and innovation.

Unfortunately, very limited consideration was given to point 2.4.2 Support and Promote the Responsible Conduct of the Life Science and Biotechnology Enterprise during the meeting. But the organisers made clear throughout the meeting that they would like comments on the implementation of the strategy from participants at the meeting or those watching the webcast. An interesting question therefore was whether scientists were prepared to comment on this point, what the content of the comments were and the extent to which the US Government acted on the comments, but it is necessary here to refer to another webcast from Washington D.C. produced the following day.

7.7 Hybrid Warfare and Chemical and Biological Weapons The lecture was given at the US National Academies in the Bio/Chem Defense Discussion series by Professor James Giordano. Professor Giordano’s important work on neuroethics and dual use was discussed in Chap. 3. The advertisement for the lecture stated that “[N]euroscience and technology (neuroS/T) is increasingly being considered and employed for warfare, intelligence, and national (WINS) security operations.” And that neuroS/T could be used “as weapons to affect adversaries’ thoughts, feelings, actions and health (neuroweapons).” The lecture gave a frank overview of the current and possible future of such operations as for example in his paper on “Battleship Brain” [20]. This method of considering the wide-ranging use of diverse means of affecting adversaries’ behaviour fits into the view increasing being taken of what is happening in recent conflicts such as in Syria where all out conventional (or nuclear) war is avoided by the use of a combination of lesser means in order to eventually achieve

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the adversaries’ objective through disruption rather than force destruction. The idea here has been described as hybrid warfare. What needs to be understood is that the usual description of chemical and biological weapons as weapons of mass destruction tends to distract attention from the fact that these weapons can be used on a huge range of scales from assassination through conventional warfare as well as perhaps for mass destruction [21]. So, these weapons, broadly conceived could indeed be used as a component of such hybrid warfare. For example, one analysis of the Russian invasion of Eastern Ukraine suggests that a combination of tailored propaganda, manipulation of medical infrastructure and the possible use of psychotrophic substances should be considered [22]. Of course, that line of thinking takes us back to the objectives of the early Cold War weaponeers, who certainly had the intention of interfering with much higher order aspects of the CNS than simple sedation [23], and thus raises the question of how far modern neuroscience and specifically the new State-level brain projects could enable manipulation of thoughts, feelings, actions and health. That needs to be kept in mind as we turn our attention in the next two chapters to the projects that have a focus specifically on the brains of animals much closer to us than rodents like mice and rats.

References 1. Global Neuroethics Summit Delegates (2018) Neuroethics questions to guide ethical research in the international brain initiatives. Neuron 100:19–36 2. Royal Society (2012) Neuroscience, conflict and security. Brain Waves Module 3. Royal Society, London (page 60) 3. Dowling T (2018) 1983: the world at the brink. Little, Brown, London 4. Jones N (2016) Able Archer 83: the secret history of the NATO exercise that almost triggered nuclear war. The New Press, New York (page 80) 5. Schoch-Spana M et al (2019) Risk communication strategies for the very worst cases: how to issue a call to action on global catastrophic biological risks. Center for Health Security, Bloomberg School of Public Health, John Hopkins University 6. National Academies of Sciences, Engineering, and Medicine (2018) Governance of dual use research in the life sciences: advancing global consensus on research oversight: proceedings of a workshop. The National Academies Press, Washington, DC (page 96) 7. Editorial (2016) Global neuroscience, Neuron 92, 557 and the following articles on the US BRAIN Initiative, 570–581 (page 570), the EU Human Brain Project, 574–581 (pages 574, 577), the Japanese Brain/MINDS project, 582–590 (page 582), the China Brain Project, 591– 596 (pages 591, 592,594) the Australian Brain Alliance, 597–600 (page 597), Brain Canada (601–606) and the Korean Brain Initiative (607–611) 8. Novossiolova T et al (2019) Altering an appreciation system: lessons from incorporating dual use concerns into the responsible science education of biotechnologists. Futures 108:53–60 9. Greely HT et al (2016) Neuroethics in the age of brain projects. Neuron 92:637–641 (page 640) 10. Editorial (2019) Neuroethics: think global. Neuron 101:363–364 and the following articles on the Australian Brain Initiative, 365–369 (page 365), the Canadian, 370–374 (page 373), China, 375–379 (page 378), the EU, 380–384 (pages 381, 383) Japan, 385–389, (389), Korea, 390–393, (393) and the US (394–398)

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11. Ethics and Society (2018) Opinion on ‘Responsible Dual Use’: political, security, intelligence and military research of concern in neuroscience and neurotechnology. Human Brain Project (page 11) 12. Greely HT et al (2018) Neuroethics guiding principles for the NIH BRAIN initiative. J Neurosci 35:10586–10588 13. Advisory Board for Education and Outreach (12 February 2018) Report on the role of education and outreach in preventing the re-emergence of chemical weapons. ABEO-5/1. OPCW, The Hague 14. China and Pakistan (9 August 2018) Proposal for the development of a model code of conduct for biological scientists under the biological weapons convention. BWC/MSP/2018/MX.2/WP.9 15. Norrlof C (2019) Educate to liberate: open societies need open minds. Foreign Aff, 132–141 (page 132) 16. Mandelbaum M (2019) The new containment: handling Russia, China, and Iran. Foreign Aff, 123–131 (page 216) 17. Poblete YDS (19 March 2019) Arms control and international security: remarks at the conference on disarmament. https://www.state.gov/t/avc/rls/2019/290475.htm. Accessed 3 April 2019 (page 8) 18. Ford CA (14 March) Re-learning a competitive mindset in great-power competition, Washington, DC. https://www.state.gov/t/isn/rls/rm/2019/290438.htm. Accessed 3 April 2019 (page 5) 19. United States (2018) National biodefense strategy. Office of the President, Washington, DC (pages 1 and 15) 20. Giordano J (2017) Battleship brain: engaging neuroscience in defense operations. HDIAC J 3(4):13–16 21. Robinson J (2008) Difficulties facing the chemical weapons convention. Int. Aff 84:223–239 22. Barna C, Dugan C (2016) The ukrainian hybrid warfare and neuroscience–dismantling some facets of the psychosphere. In: Iancu N et al (eds) Countering hybrid threats: lessons learned from Ukraine. E book, IOS Press, pp 115–140 (page 115) 23. Dando MR (2018) Chapter 8: advances in understanding targets in the central nervous system (CNS). In: Crowley M et al (eds) Preventing chemical weapons: arms control and disarmament as the sciences converge. Royal Society of Chemistry, London (page 258)

Chapter 8

Japan’s Brain/MINDS Project

Abstract This chapter focuses on Japan’s BRAIN/Minds project and in particular its concentration on studies of the Non-Human Primate (NHP) marmoset monkey. It is pointed out that while the EU and US brain projects are certainly interested in the functions of the human brain the model organisms studied are mostly lower mammals such as rodents. So, the focus on NHPs opens up the possibility of greater understanding of higher-level brain functions—and consequently of attacking such systems through dual-use applications by those with hostile intent. The chapter gives an account of the reasons why Japan chose to concentrate on marmoset research and also raises some questions about the utility of research on NHPs, particularly in regard to the ethics of such research. It also notes that Japan’s project has an excellent informative website in English so that its work can easily be followed. Consideration is the given to the use of animal models and it is noted that marmosets are New World monkeys much less closely related to humans than Old World monkeys and apes. So, while we can gain insight from studies of marmosets, care has to be taken in drawing direct analogies to human brains and behaviour. Nevertheless, it is argued that the possibility of research on such NHPs being useful for those with malign objectives cannot be ruled out. Certainly, the United States again made it clear in mid-2019 that it and other States intended to try to tighten restraints on chemical agents that could attack the Central Nervous System during meetings in 2020. The chapter then reviews some of the work being carried out in Japan’s BRAIN/minds project to illustrated that the work could clearly be of dual-use concern, and argues that these concerns are likely to increase given the continued technical developments, for example in genome editing of marmosets. The chapter ends by returning to the question of the level of ethical analysis in relation to dual-use issues within the project and contrasts the low level of concern within the project with Japan’s interest and activities within the Biological and Toxin Weapons Convention on this issue and asks whether in the future national level concerns over biosecurity and dual use will come to impinge on the project.

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8.1 Introduction Civil scientists involved in the brain projects undoubtedly have the intention of contributing to the development of means to help people with brain injuries or disorders. So far in this book we have concentrated on their efforts to follow up on the ideas of people like Panksepp [1], and those who designed the Research Domain Criteria (RDoC) described in Chap. 1, to take advantage of the fact that some of our basic functions like sleep are caused by neuronal mechanisms that have been highly conserved in the mammals. Therefore, it has been possible to discover a great deal about these mechanisms by studies of rodents such as mice and rats. The early Cold War weaponeers were certainly very interested in targeting such basic functions, but they were also interested in the possibility of attacking much higher-level function of our Central Nervous Systems like our ability to think critically. That is why the brain projects in Japan and China are important here. Of course, the scientists involved in the EU and US projects are studying the higher order functions of the brain, but in Japan and China there are specific aims to further our understanding of primate brains—marmoset New World monkey in Japan and macaque Old World monkey in China. This is important because, by analogy to the idea that there has been a conservation of neuronal mechanisms throughout the mammals, it can be argued that there has been conservation of some features of primate neuronal mechanisms throughout the primates. So, the intensive study of the brains of these Non-Human Primates (NHPs) is likely to enable considerable insights into the mechanisms of the higher order neuronal mechanisms of our brains even though there will be specific features of the brain functions of different species that will not generalise across the primate group [2]. For example, while we have learned a great deal about how the mammalian brains of rodents deal with threats and fear it is necessary to be able to study such systems in NHPs in order to get a better understanding of how we exert top down control of these lower-level emotional systems [3]. Clearly then, it is also essential to protect such research from the dangers of misuse, and particularly of concern here is the danger of hostile dual use of the knowledge gained in these projects. Anyone who doubts that there are such dangers might search one of the standard databases of life science publications for recent studies of marmoset brain and behaviour. It is obvious from such sources that there are many studies using these monkeys for analysis of the effects of potential biological weapons agents such as Anthrax [4], Melioidosis [5], Marburg Virus [6] and Eastern Equine Encephalitis [7]. These published studies were done for legitimate defence purposes, but it is not difficult to imagine other studies being carried out for other purposes.

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8.2 Japan’s National Brain Project for Marmoset Neuroscience As noted in the previous chapter, Japan’s Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) project was initiated in 2014 after careful consideration of the US and EU projects and of what Japan might best be able to contribute to the overall effort to understand the human brain and how to deal with its medical deficiencies. The project has been carefully described in a number of publications, for example in the Philosophical Transactions of the Royal Society in 2015 [8]. The project involves some 65 laboratories in 47 institutions and has a projected budget of 40 billion Yen over 10 years [9]. The 10-year roadmap for the project envisions “the creation of a clinical data centre using translational biomarkers for the diagnosis and treatment of human brain diseases.” The marmoset was chosen as the major focus for the project as it can be used to bridge what is known from rodent models to the human brain. The detailed description of the project in 2016 noted, for example, that [10]: …the primate prefrontal cortex responsible for cognitive process like prefrontal-based working memory, and the expression of some psychiatric disorders, has no clear homolog in rodents … suggesting advantages of non-human primate models for modelling the human brain and mental illness…

The description also stated that the marmosets were chosen because of the specific advantages they have for brain mapping noting that [11]: …various research tools and resources including genome sequence information, anatomical and MRI atlases and genome modifying technologies have been developed for marmoset. Importantly, this technological foundation makes the marmoset a potentially useful species for neurological disease models, such as stroke, Parkinson’s disease, spinal cord injury… and new models for psychiatric, neurodevelopmental and neurodegenerative diseases… that are in the pipeline…

Moreover, Japan has a long history of research in marmoset breeding and reproductive studies. Marmosets additionally have a shorter gestation period than macaques and being smaller are easier to house in large social groups. However, it is clearly envisaged that close links will be maintained with the Chinese project on macaques. When it was announced [12] the project did not go uncontested. Patrick Bateson and Ian Ragan referred to their 2011 Review of Research Using Non-Human Primates [13] which included UK research between 1997 and 2006, and judged that NHP research was “of high quality, yet few projects showed evidence of biomedical benefit” and that sometimes “the case for using non-human primates—rather than other species, including humans—was not well made.” These authors went on to state further that: It could be argued that the unavailability of suitable GM animals at that time might account for the poor translation into health benefits. But the justification for using GM marmosets in research today needs to be much stronger, because of the substantial ethical issues at stake.

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Whist noting the view that such ethical issues could be considered as they arise the authors contended that these ethical issues “should be considered before the journey starts,” and, as we saw in the last chapter, dealing with the problem of dual use within this BRAIN/Minds project remained a work in progress four years later. Nevertheless, the project has an excellent website in English with detailed information on the research being carried out, but before looking closely at the work of the project it is necessary to analyse more carefully why the focus on NHPs, and particularly the marmoset, is so important in consideration of the potential for dual-use dangers.

8.3 Research on Non-human Primate Models Mammals are thought to have appeared towards the end of the Triassic geological period about 225 million years ago and then to have diversified particularly rapidly after the mass extinction that led to the demise of all of the dinosaurs (except birds) 66 million years ago [14]. As noted above, mammals have conserved many of the basic physiological systems essential for survival. Therefore, it has been possible to examine these systems—which are still present in modern humans—in model animal systems such as mice and rats, and because crucial physiological mechanisms are highly conserved across animal groups even in worms and flies. This point was stressed by the Nobel Prize winner Eric Kandel in his 2018 book The Disordered Mind: What Unusual Brains Tell Us about Ourselves [15]. In his view our current view of the brain derives from advances in three areas of research: genetics, brain imaging and the study of animal models. In regard to animal models he stated in his introductory chapter that: …Animal models have proven invaluable in studies of psychiatric disorders, providing insights into how genes, the environment and the interaction of the two can disrupt brain development, learning and behaviour. Animal models, such as mice, are particularly useful for studying learned fear or anxiety because these states occur naturally in animals…

But he added that: …mice can also be used to study depression or schizophrenia by inserting into their brain altered genes that have been shown to contribute to depression or schizophrenia in people.

Indeed, there are references to the use of animal models in all but one of the thirteen chapters of the book. For example, in his chapter on movement disorders like Parkinson’s and Huntington’s diseases, which are characterised by misfolded proteins, Kandel discussed conserved physiological mechanisms—molecular chaperone pathways—that help proteins take their normal shape and can sometimes reverse misfolding [16]. Scientists inserted a mutant gene for such proteins into flies and found that they compromised the dopamine producing cells and cause a movement disorder that was “strikingly similar to the effects of Parkinson’s disease in people.” Moreover, increasing

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the amount of helper molecules prevented the dopamine-producing cells becoming compromised. Indeed, he noted that: …This technique also works in fruit-fly models of other neurodegenerative diseases – of which there are many now – as well as in mouse models of some degenerative disease, illustrating once again the utility of animal models for the study of human disease.

Yet, it is striking that despite the emphasis given to the importance of animal models throughout the book there are very few mentions of Non-Human Primate models in the almost 300 pages. This raises the question of just how useful such models can be in the search for means of dealing with the disordered human mind. The primate order of mammals arose during the diversification of the phylum about 85–55 million years ago. There are various ways in which the primates such as lemurs, galagos lorises, tarsiers, monkeys, apes and humans can be named and divided, but the broad outlines are now agreed. Monkeys and apes are classified together as simians and this group includes catarrhines (narrow nosed) Old World monkeys and apes of Africa and Asia, and platyrrhines (flat nosed) New World monkeys of South America. The split between these two groups is thought to have taken place about 60 million years ago. Marmosets are one group of the New World monkeys. The apes and humans are thought to have divided some 25 million years ago from Old World monkeys. Macaques are one group of the Old World monkeys. An important point that needs to be borne in mind is that we used to think that there was a steady development over time in which we gradually ascended: lemurs followed by tarsiers then monkeys, apes and finally humans. In this earlier understanding monkeys could be seen as a single group. Modern understanding, of course, sees each of these different types of animal evolving as branches of a tree rather than as a single ladder. Thus, it is not correct to see monkeys as a single group, in particular the New World and Old World monkeys have evolved separately for some 60 millions years and the apes and humans are much more closely related to Old World monkeys that to the New World monkeys. Apes are classified in two families: the gibbons, and the great apes including orangutans, gorillas, chimpanzees, and humans. The gibbons are thought to have diverged from us about 15–20 million years ago and the orangutans diverged about 14–17 million years ago. The gorillas then diverged about 8 million years ago and the chimpanzees about 6–7 million years ago [17]. In general terms primates have larger brains in relation to body size than other mammals and much increased reliance on vision rather than the sense of smell—features that are most developed in monkeys and apes. Apes are distinguished from monkeys as, for example, they do not have tails. Primates exhibit strong social behaviour of different forms and most are at least partly arboreal, but there are exceptions such as apes, baboons and human beings. While these estimates for the evolution of the primates cannot be precise it is clear that there have been millions of years of evolutionary change between marmosets and human beings. We are all familiar with the idea that what happens during this evolutionary process is that the relative size of the cortex of the brain to the body size simply gets bigger and bigger until it reaches the size in human beings and that this is the fundamental

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reason why we have so much more complex behaviours than other NHPs. However, this idea that the cortex is relatively uniform and simply gets bigger does not really stand up to the comparative approach of modern biology. Todd Preuss made this very clear in a 2010 [18]: …Cortex varies across mammalian taxa at just about any level or dimension of organisation one cares to consider, from transmitters and receptors; to cell types, cell morphologies, and cell numbers…to the ways in which different layers are interconnected to form local processing architectures…

That is not, of course, to say that there are no widely shared features of cortical organisation amongst mammals, but, as this account continues to point out, the idea that there is an ancestral organisation from which there has been descent with modification is “a very different proposition than the claim that important features of cortical organisation are invariant across mammalian groups, which is the main point of ‘basic uniformity’.” So, the question is whether it is as profitable to study the higher functions of the human nervous system in NHPs as it has clearly been to study the basic physiology and survival mechanisms in simpler organisms? One way to think about this question is in terms of two hypotheses that seek to explain the evolution of the brain. The mosaic brain hypothesis [19]: …argues that variation in the size of individual brain components reflect adaptive divergence in brain function mediated by selection…. On this view, major brain components evolve together because functional systems cut across and connect them…

This model is contrasted by the concerted brain hypothesis: …which instead argues that brains evolve predominantly by global alterations to the duration of neurogenesis, increasing or decreasing all components together…. with structures completing neurogenesis late in development (such as the neocortex) growing disproportionately large with evolutionary increases in brain size…

Clearly the second hypothesis allows for less effect of selection pressures on brain changes over time in different species and thus more possibility of relating simpler model systems to human brain operations. Whilst it is possible to see some overlap between the two hypotheses, it seems that recent work on genetics and neurodevelopment lead to the conclusion that “functional rather than developmental constraints are the main cause of observed patterns.” Thus, it may be argued that care has to be taken in making comparisons between human and other NHPs brain structures and functions. Certainly, recent work strongly supports the contention made by Preuss in 2010 [20, 21]. The argument is that the recent evolution of modern humans have produced a situation in which selection has so altered our capabilities, for example in the use of language and the advantages that gives us to think conceptually [22] that there is a vast gap between the structure and function of our brains and those of apes—let alone monkeys—so comparisons with NHP models are far from straightforward in regard to these essentially human capabilities. On the other hand, there are

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strong arguments in favour of the study of brain and behaviour in NHPs in general [23] and marmosets in particular [24, 25] both for what we can learn that will be of utility in understanding human disease and in testing of drugs before clinical trial in humans. One scientist at a 2018 workshop at the US National Academies probably summarised the situation as seen by the scientific community correctly [26] by saying that we cannot tell how useful NHP models will be, but NHPs will be studied as part of the range of models because they are nearer to us in evolutionary terms. Therefore “the increasing use of animals such as marmosets and macaque for research is both justified and necessary.” In that context it is hardly surprising that in mid-2019 the US BRAIN Initiative put out a request for applications for grants to expand marmoset colonies and create a marmoset coordination centre in order to further such research [27].

8.4 The Dangers of Dual Use We can summarise the preceding arguments as follows. On the one hand, given the vast differences between human brains [28, 29] and behavioural capabilities [30] as compared with apes let alone monkeys, it is unlikely that studies of monkey brains and behaviour could enhance the possibilities of interference with sophisticated aspects of human behaviour. In that case the dual-use potential would not appear to be very different from that of other brain projects that are not so focused on NHPs. On the other hand, it might be argued that view would be to ignore the expansive aims of the early Cold War weaponeers in considering such possibilities. As Colonel Yanka, then commander of the US Chemical Warfare Laboratories, pointed out in 1960 [31]: Disabling chemical compounds fall into two broad classes: those which temporarily immobilize the mental faculties – in effect, neutralizing a person’s will to resist; and those which produce physical distress for a significant period, such as severe discomfort, anesthesia, paralysis or immobility.

And he went on to state that, in regard to such physical distress: …compounds are known which irritate the lungs, temporarily lower the blood pressure, induce severe vomiting, disturb body temperature, physiologically impair vision, or bring on involuntary bowel movement or temporary anesthesia…

Yanka’s colleagues at the Chemical Warfare Laboratories at that time differentiated these two classes of effects [32] as “Off the Rocker” and “On the Floor” and suggested that besides physically incapacitating compounds: “[P]sychotomimetic drugs are those which induce a temporary state mimicking one of the psychoses or states of insanity, such as schizophrenia.” Moreover, while vision could be blocked by optical means for example by clouding the cornea, it could also be blocked “through interference with the complex nervous pathways involved in the visual process” so that while the eyes were functional “the man does not see.” As a report on such psychochemical agents concluded in 1955 [33]:

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Psychiatrists, pharmacologists and biochemists are actively investigating the problem of the mechanism of mental illness, and as these studies progress leads to more effective psychochemical agents will undoubtedly become available. As this occurs, our program will be modified accordingly…

Fortunately, it did not prove that easy to investigate the basis of complex human behaviour and its defects at that time and such levels of manipulation were not possible. But can we be sure that soon the necessary advances will not be made given current rates of technological progress in investigating brain circuits, for example even in our understanding of very sophisticated aspects of human behaviour such as language from the study of monkeys and apes [34]. In that case the dual-use potential would appear to be of a quite different order that in the other brain projects in opening up much more far reaching possibilities for mind manipulation in the future. It has also to be kept in mind that different countries can have very different views on what kinds of research are permissible and whether, for example, human-monkeys chimera embryos can be developed for research purposes [35]. What is clear is the continued concern amongst States Parties to the Chemical Weapons Convention about current interest in such so-called non-lethal CNS-acting chemical agents. As the US Ambassador stated in a meeting of the Executive Council in July 2019 [36]: … The United States remains concerned that States are deliberately developing CNSacting chemicals for warfare or other harmful purposes, cloaking these efforts under the guise of non-prohibited purposes, such as law enforcement or medical research. It is an Administration priority to address this concern by taking concrete action here at the OPCW…

The Ambassador continued his presentation with a proposal for action on this issue: The United State is pleased to announce, together with other State Parties, that we intend to put forward an initiative, in the form of a decision, to make clear that the aerosolized use of CNS-acting chemicals is understood to be inconsistent with law enforcement as a purpose not prohibited under the Convention…

Thus, this issue of the potential development of novel CNS-acting chemicals was certain to become a priority focus in discussions amongst State Parties during the following year.

8.5 Research in the Brain/MINDS Project Hideyuki Okano, one of the leaders of the Japanese project gave an admirably concise and clear account of the goals of the research in a paper published in Nature Neuroscience in 2016. He pointed out that the aim of mapping the brain of the common marmoset Callithrix jacchus was intended to be [37]: …an important step toward gaining a better understanding of the human brain and toward developing knowledge-based strategies for the diagnosis and treatment of human psychiatric and neurological disorders…

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Table 8.1 Major research groups in the Brain/MINDS project in 2016a Group 1: Structural and Functional Mapping of Marmoset Brain “…will undertake macro-, meso- and microscale mapping of the marmoset brain…” Group 2: Development of Innovative Neurotechnologies for Brain Mapping “…will develop high-resolution, wide-field, deep, fast and long imaging techniques for brain structures and functions…” Group 3: Human Brain Mapping and Clinical Research “…will map patient-derived human brains and will work with the marmoset brain-mapping group to create ‘translatable brain markers’ that bridge the gap between human and non- human primates…” And “…One of the most important aims of the clinical research teams is to develop translatable brain markers that are useful in research on neuropsychiatric disorders” a From

Ref. [38]

This objective was to be reached by the work of three major groups of researchers, as set out in Table 8.1 and these research groups intended to use the best available cutting-edge techniques. Clearly the work of the third group with its aim to “develop translatable brain markers that are useful in research on neuropsychiatric disorders” is of particular interest here. The paper also set out some of the achievements of these groups at the time that the paper was written. For example, in regard to the work of Group 3 it pointed out that following earlier success in generating transgenetic marmosets: …they have been generating genetically modified marmosets that model neurodevelopmental and neurodegenerative diseases such as autism spectrum disorders and Parkinson’s disease…. These models have begun to show several behavioural and neuronal phenotypes typical of human disease symptoms.

Moreover, the paper sets out the impact aims over a 10–15 year period and these included: …improvements in diagnosis and treatment of human psychiatric and neurological disorders based on outputs of Brain/MINDS, such as identification of translatable brain markers.

We can all agree that these are laudable benignly intended research objectives, but on the face of it there would appear to be rather obvious dual-use dangers if the results of such research were misapplied for hostile purposes. The questions at issue here is how easily could the results of such research be misused and what is the Brain/MINDS project doing, and intending to do, to protect its benignly intended work from such misuse? Clearly, that requires first a more detailed look at the research being carried out and then the neuroethical measures in place and planned. In the autumn of 2019, the excellent website of the Brain/MINDS project announced its objective clearly at the top of the Homepage [38]: Studying the neural networks controlling higher brain functions in the marmoset, to gain new insights into information processing and diseases of the human brain.

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Then on the next page the Program Supervisor, Shigeo Okabe of the Graduate School of Medicine at the University of Tokyo, provided a general introduction to the project. In this introduction he suggested that the improvements in available technology has given neuroscientists cause to “think that it is time for a major paradigm shift in research, with its goal of elucidating the full mechanisms of the brain” (emphasis added). He then noted that: …Dubbed Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS), this new project was launched in fiscal 2014 and started to integrate new technologies and clinical research. In this program, challenging goals will be achieved through long-term researches carried out by linking core research institutions nationwide…

Illustrating the rate of change in neuroscience research, he then added that: …In 2018, a sister program called ‘Brain/MINDS Beyond’ was initiated and expected to facilitate international collaboration and data sharing. From 2019, the second half of the research term started with appointment of new research teams for clinical neuroscience and innovative neurotechnologies.

To assess the dual-use possibilities inherent and efforts to deal with it in the Brain/MINDS project we therefore have to look in addition at the Brain/MINDS Beyond project. The website very helpfully has an Organisational Chart showing the component parts of the Brain/MINDS project and its links both to higher governmental levels and the link to the Brain/Minds Beyond project (Fig. 8.1). Concentrating first then on the original Brain/MINDS project we can see, from the Organisational Chart, that in 2019 the research groups had become more complex with elements both inside/linked to the core RIKEN Center for Brain Research and three other groups outside of the RIKEN center. On the face of it, if we keep in mind the far-reaching aims of the early Cold War Weaponeers, some parts of this research might well be of concern in regard to potential dual-use applications. For example, within RIKEN there is work on “Structure, Function, and Molecular Mechanisms of the Brain”, and within Marmoset Research group there is work on “Neurodegenerative Disease Marmoset Models” and within Clinical Research there is a group working on “Psychiatric disorders.” The specific investigations on such psychiatric disorders mentioned on the website are set out in Table 8.2. The recent initiation of the partner Brain/Minds Beyond project should remind us that while the Brain/MIND project may have been on a smaller scale at the start than the EU and US projects, it now has a more significant scale. More importantly, perhaps, it emphasises that the brain projects are all taking place against a background of already largescale investment in research on the brain, and furthermore that Meselson was right when he stated that we are really dealing with a revolution across the whole of the life sciences that will undoubtedly open up significant avenues for potential misuse. As noted in Chap. 2, in his view [39]: …During the century ahead, as our ability to modify fundamental life processes continues its rapid advance, we will be able not only to devise additional ways to destroy life but will also become able to manipulate it – including the processes of cognition, development,

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MEXT*

AMED*

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Project for Psychiatric and Neurological Disorders: Program Director

Program Supervisor – Program Director

Project Leaders

Research and Development Teams

Central Ins tute RIKEN Center for Brain Science

Brain/MINDS Office

Research on Neurodegenera ve Disease Marmoset Models Group

Research on Wild Type Marmosets Group Coopera on

Clinical Research Group

Technology Development Group

*MEXT: Life Sciences Division, Ministry of Educa on, Culture, Sports, Science and Technology *AMED: Division of Neurological, Psychiatric and Brain Research, Japan Agency for Medical Research and Development

Fig. 8.1 The Brain/MINDS organisational chart (From Ref. [38])

The Strategic Interna onal Brain Research Promo on Program: Brain/MINDS Beyond

138 Table 8.2 Work of the psychiatric disorders groupa

8 Japan’s Brain/MINDS Project Study for impairment of predictive function in psychiatric disorders using a bi-directional translational approach Studies on psychiatric disorders using mutant marmosets generated by autologous embryo transfer Identification and functional analysis of neural circuit responsible for mental disorders based on genomic information of brain Studies on neural circuit and molecular pathology based on human genome mutations in psychiatric disorders a From

Ref. [38]

reproduction and inheritance…. Therein could lie unprecedented opportunities for violence, coercion, repression, or subjugation…

What then will this new partner project add to the original project? The website of the project starts its overview as follows [40]: The Strategic International Brain Science Research Promotion Program (Brain/MINDS Beyond) was launched in June 2018 as an initiative to contribute to … brain research globally by enhancing collaboration with domestic projects of other countries across the world…

The text later elaborates: …we aim at revealing human intelligence, sensitivity and sociality at brain circuit level for early detection and intervention of psychiatric and neurological disorders by fostering: comprehensive analysis of brain images from healthy to diseased states, developing AIbased brain science technologies, and comparative study of neural circuitry of human and non-human primates.

At first sight then, this project appears to have objectives that will require research that could well be subject to later dual-use application because, while the development, production and use of CNS-acting agents requires much more than just a knowledge of susceptible neuronal circuits, that knowledge would be foundational for the consideration of novel agents in the future. This project is organized from the Division of Neurological Psychiatric and Brain Research of the Japan Agency of Medical Research and Development (AMED) and the core of the organization is located in the National Institute for Physiological Sciences. In summary of the organization chart the website states that: Japan fosters a research program of ‘Psychiatric and Neurological Disorders’ as one of the projects of integrated disease area. This project aims to the elucidation of the structures and functions of all of the circuits of the brain as well as the promotion of infrastructure for the development of biomarkers. In addition, it focuses on revealing the pathological basis, diagnosis and appropriate treatment of dementia and depression. The Brain/MINDS Beyond is embraced in this project… (emphasis added)

Brain/Minds Beyond has a core organization, three research groups and an innovative research group for young investigators [41] as set out in Table 8.3.

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Table 8.3 Research groups of the Brain/MINDS-Beyond projecta Research Group 1 A comprehensive study involving longitudinal analyses of cerebral images from healthy to pathological states by life stages (developmental, adulthood, and senile stages) Research Group 2 Research involving an inter-species comparison of human and non-human primate brains Research Group 3 Development and application of technologies such as neuro-feedback through collaboration with artificial intelligence (AI) research projects Innovative Research Group Internationally collaborative pioneering and multidisciplinary researches by young investigators aimed at paradigm shift by innovative ideas and technologies a From

Ref. [41]

Importantly, from the perspective taken here the page of the website that deals with the Core Organisation has a statement by Junichi Nabekura, the Director General of the National Institute for Physiological Sciences, which makes specific mention of neuroethical issues involved in non-human primate research: We work as a response window for the promotion of entire brain science research in Japan by domestic coordination along with enhancing collaboration with International Brain Initiative (IBI) and other countries across the world. In order to run the Brain/MINDS Beyond smoothly and foster the globally collaborative innovations, we are supporting the neuroethical aspects of human and non-human primate research as well as promoting outreach activities for the stakeholders… (emphasis added)

We will return to the issue of neuroethics at the end of the chapter after an examination of the research work published by the Brain/MINDS and Brain/MIND Beyond. The question at issue here is not, of course, whether this benignly-intended work should or should not have been carried out, but whether some of the work could reasonably be seen to have dual-use implications and therefore that the researchers in these projects should be aware and well educated about this aspect of biosecurity. There is a large and growing literature on the brain and behaviour of marmosets and members of the Brain/Minds projects have made important contributions [42] to this literature. A simple way to answer our question is to ask whether neuroreceptor/neurotransmitter systems that are known to have been of interest to weaponeers in the past or that might reasonably be supposed to be of interest to them in the future [43] feature in papers listed as published by members of the Brain/MINDS project on the website. That is indeed not a difficult task with work related, for example, to norepinephrine (noradrenaline) [44], tetrahydrocannabinol [45], and orexin [46] in the papers listed. Similarly, it is not difficult to find work on neurotransmitters and neuroreceptors in the work of the Brain/MINDS Beyond project, for example in the sections of the innovative Research Group set out on the website [47]. Some such examples are shown in Table 8.4. A second way to attempt to answer our question is to ask if any of the neuronal circuits that we have discussed as being of potential interest in regard to dual use are subjects of research in the Brain/MINDS and Brain/MINDS Beyond projects. It

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Table 8.4 Sections of the Brain/MINDS Beyond innovative research groupa Analysis for pharmacological mechanisms of psychoactive drugs In this research, we analyze the phosphorylation signals induced by neuropsychiatric drugs in the brain comprehensively for each brain region, and use the optogenetic method to manipulate the phosphorylation signals as a disease model mouse and to mimic the effect of therapeutic drugs. Finally, we will elucidate the brain region where the therapeutic drugs works and the mechanism of action that improves the symptoms Generation of whole brain atlas for monoamines and anti-depressants localisations Due to recent advances in sample preparation protocols, current imaging mass spectrometry (IMS) allows for the visualization of small molecule tissue localization, including that of monoamine neurotransmitters like serotonin, dopamine, and norepinephrine. Although monoamine-producing neurons, as well as their projections and synapses, have been thoroughly characterized, monoamine localization within these circuits remains unclear. Moreover, it is worth studying the fluctuations in local monoamine concentration in response to physiological stimuli, drug administration, and neurodegenerative disease progression, which can be achieved by analyzing the in situ concentration maps afforded by coupling IMS with on-tissue derivatization protocols a From

Ref. [47]

is again quite easy to ascertain that research on such circuits is being carried out, for example into the control of the sleep/wake (level of awareness) circuits and the mechanisms underlying Parkinson’s Disease. A concise review of our present state of knowledge of the sleep/wake system was produced by William Joiner in 2018. He noted that continued agreement on a model based on the opposition of sleep and wake producing processes, and that although we still lack a good understanding of the sleep producing process we have gained a good deal of knowledge of the wake producing process (although how the two processes are integrated is still unclear). As he explains, monoaminergic and cholinergic modulatory inputs proceed from the brain stem to the forebrain by two routes [48]: …The dorsal pathway modulates the thalamus, which receives much sensory information before passing it on to the cortex for further processing…. The ventral pathway leading through the basal forebrain also includes nodes in the lateral hypothalamus and tuberomammillary nucleus that releases orexin…and histamine respectively. The orexinergic neurons enhance activity in many arousal-promoting nuclei, thus stabilizing and enhancing waking.

The activity of these different pathways can then explain waking and the different types of sleep. In waking both pathways are active, so the cortex is excited and input to the thalamus also allows sensory information to flow to the cortex. During REM sleep cholinergic signals through the ventral pathway continue to activate the cortex but lower monoaminergic activity reduces thalamic input to the cortex. At the same time cholinergic signalling also activates a descending pathway that inhibits motor neurones in the spinal cord and thus produces muscle atonia. In contrast during NREM sleep both cholinergic and monoaminergic signalling are reduced and this both lowers cortical activation and heightened filtering out of sensory information

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in the thalamus. So far so good, but as Joiner comments while there has been identification of some of the molecules involved in these circuits, we still lack a coherent understanding of even the arousal aspect of the system. Given that sleep is so highly conserved, and its disruption is clearly associated with many psychiatric and neurodegenerative diseases research in this area remains a priority. It is therefore no surprise to find Japan’s brain projects have publications in this area of research [49]. As with the state of research into the neuronal mechanisms underlying sleep, we have gained much knowledge about then role of the basal ganglia of the brain and the causes of Parkinson’s disease, but still are far from having a comprehensive understanding that would allow it to be effectively treated. It is clear that the basic mechanisms of central control of our movement capabilities has been conserved from the earliest vertebrates through to the primates over the last 500 million years [50]. In summary it is known that [51]: …This network helps make goal-directed behaviour and habits rapid and ‘automatic.’ When the BG [basal ganglia] is impaired, control becomes slower and less efficient; moreover, the ability to generate rapid, stimulus-driven, habitual motor sequences is largely lost…

When the higher levels of the brain initiate movement, it acts on the basal ganglia via the Striatum [52]: The output of the basal ganglia is from the Globus Pallidus interna (GPi) and from Substantia Nigra pars reticulata (SNr)…Neurons in these structures are all inhibitory (GABA) and have a high level of tonic activity under resting conditions…

So, under such resting conditions the net effect is to inhibit the activity of the lower motor centres which these basal innervate. If action is undertaken the Stratum’s direct inhibitory connections to the GPi and SNr can themselves be inhibited and thus the inhibition of the lower motor centres is removed. However, while almost all of the neurons in the Striatum are inhibitory and produce GABA at their terminals they are of two different types The GABA neurons that directly innervate SNr and GP have dopamine D1 subtype receptors themselves and dopamine input increases the activity of these neurons (thus acting eventually leading to the disinhibition of the lower motor centres). Other GABA producing neurons express a different D2 dopamine receptor and input to these neurons decreases their activity. These neurons act only indirectly on the neurons of the SNr and GP and actually this indirect input enhances the inhibition of the neurons affected. The system therefore allows for some motor centres to be activated while others are inhibited and coordinated action to be achieved. The dopamine input is crucial for the effective operation of the system and it is this input that is destroyed in Parkinson’s disease. Parkinson’s disease has two striking characteristics. First it is a specific human disease. Whilst some of its characteristics can be replicated in animal models, it does not occur naturally in other animals. Secondly the incidence of the disease seems to have greatly increased over the last 200 years. This may be because of many of us living longer or some change in our lifestyles such as being less active or encountering more toxins in the environment. What we do know is that the vast increase in size of

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the higher reaches of the brain during primate evolution has not been matched by an equal expansion of the basal ganglia system [53]: …the volume of the striatum has increased by 300-fold from rats (20 mm3 ) to humans (6,280 mm3 ), but the number of dopamine neurones in the (SNpc) [Substantia Nigra pars compacta that provides the dopamine innervation] has increased by only 32-fold (rats, 12,000, humans, 382,000). Thus, human dopamine nigral neurons must give rise to axons 10 times the size and 10 times the number of synapses compared to rats… (original emphasis)

Thus, the dopamine neurons in humans could be on the edge of their functional capabilities and this “overload may partly explain the selective fragility of the human dopaminergic …neurotransmission and the unique presence of PD [Parkinson’s Disease] in humans.” Given the undoubted importance of Parkinson’s Disease it is hardly surprising that a great deal of research on the disease is being carried out by members of the Brain/MINDS projects [54], or that such work [55] could be viewed by others as having some potential dual-use implications. The two approaches to answering the question about dual use implications of the brain projects in Japan that we have just discussed are obviously useful, but the most interesting aspect of these projects is that they have also begun to explore the neural mechanisms underlying more complex human behaviour and it is to the potential dual-use aspects of this part of the research that we must try to analyse. There is no problem in finding research in the Brain/MINDS project that involves work on higher brain functions in primates [56] as is clear from Table 8.5. Table 8.5 Studies listed as ‘Finished Research’ on the Brain/MINDS websitea Neural mechanisms subserving Marmoset social behaviours Investigator Atsushi Iriki Neural networks underlying higher brain functions in common marmosets Investigator Katsuki Nakamura Elucidation of neural circuit responsible for cognition and behaviour in disease pathology Ryota Hashimoto Elucidation of neural networks associated with mood disorders by analysing neuroimaging Yasumasa Okamoto Developing innovative therapeutic interventions for frontotemporal lobar degeneration based on elucidation of neural circuit disruption Gen Sobue Development of technologies for pathway specific manipulation and structural analysis of neural circuits aiming at functional brain research of common marmosets Kazuto Kobayashi Multidisciplinary analyses of neural circuits and structures to understand marmoset brain functions Atsushi Nambu Development of optical techniques to manipulate and measure cortical circuits with higher brain functions Masanori Matsuzaki a From

Ref. [56]

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We have to understand, of course, that underpinning of this research on the higher brain functions is the extensive efforts both within the Japanese projects and elsewhere to understand the structure and functions of the marmoset and other primate brains. It is against that general background that the specific work on accessing, assessing and affecting the operations of higher brain functions must be considered. Accounts of the research being undertake on marmosets has been regularly reported in academic papers, but the general objectives are perhaps best understood from the short accounts given on the RIKEN website by specific investigators. For example the summary of research given on by the Laboratory for Symbolic Cognitive Development [57] states that “[W]e aim to find out evolutionary and neurobiological mechanisms that lead human mind to emerge in the primate brain that subserves our modern civilized societies” and that [58] “we will elucidate the neurobiological mechanisms of evolutionary and developmental processes that give rise to the symbolic cognitive functions subserving inference, empathy, imagination, metaphysical thoughts, etc. that characterize human intelligence.” Given that the Japanese projects, in line with the other brain projects, are strongly orientated to the introduction and use of significantly greater technical capabilities in neuroscience it can be seen that we are just at the start of the process of achieving such aims. Illustrations of what has been achieved so far in attempting to develop capabilities for genome editing for marmosets that could be equivalent to those that underpinned the successful research on brain and behaviour in rodents [59, 60] are showing us where we are at the beginning of a long road [2] which must lead increasingly to a much better understanding of our brains and how our behaviour is produced [61]. Given these greatly improved and improving technical capabilities there is obviously a danger that this will lead to a very reductionist approach that misses the significance of understanding the natural behaviour of the animals studied. This need to ensure against this danger has been well argued in a paper titled “Neuroscience Needs Behavior: Correcting a Reductionist Bias” that suggests that, in fact, understanding the natural behaviour should come first stating that [62]: …the detailed analysis of tasks and of the behaviour they elicit is best suited for discovering component processes and their underlying algorithms. In most cases, we argue that study of the natural implementation of behaviour is best investigated after such behavioural work… (original emphasis)

This approach work seems to be particularly appropriate in dealing with complex behaviour such as social interactions in the marmoset—one of the key features that is suggested to make these primates attractive as a model to help us understand human behaviour. A review of social learning noted that [63]: …social learning progressively pervades the infant and juvenile phases of primates’ lives…and…it recurs to play an important role in later life events too, notably when individuals mature and disperse to new groups.

This review makes particular note of earlier work on social learning and even teaching in marmosets, and such work has continued, for example in studies of vocal development [64] and vocal learning in marmosets [65].

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Such research could clearly have important implications for our understanding of the foundations of human language and culture. The Brain/MINDS project has funded work on such social issues, for example in the recognition of marmoset calls [66], possibly on the impact of oxytocin on eye contact marmosets [67], marmosets’ understanding of equal sharing [68] and on the impact of persuasion on human social norms [69]. It would be hard to argue that none of this research work could not have dual-use implications in the future even if it did not have implications today.

8.6 Neuroethics and Dual Use in Japan’s Brain Projects In 2018 a paper reviewed an attempt to investigate neuroethics in Japan against the background of the foundation of neuroethics as an academic discipline in this century in North America and Europe. Intriguingly titled “Looking for Neuroethics in Japan” the author suggested that neuroethics was prominent in Japan in the early part of this century and was integrated within a number of major projects, but then did not become institutionalised [70]. Therefore it follows that whatever neuroethics does exist in Japan will be found within specific research projects not in neuroethics departments in universities. Taking that approach, we have looked at the brain projects in Japan and found ample evidence of the need for attention to be given to the problem of dual-use, but although there is certainly evidence of ethical concerns, for example about research on NHPs there is no evidence that could be found at this stage of concern or action in relation to neuroethics and dual use within these projects. That reinforces the conclusions reached in the last chapter. That is somewhat surprising as Japan has championed the development of education and codes of conduct at meetings of the Biological and Toxin Weapons Convention (BTWC) for over a decade [71], produced high level proposals for dealing with the problem of dual use within Japan in 2012 [72] and has continued to contribute to discussions on these issues in recent working papers [73] and presentations [74, 75] showing substantial levels of awareness of the problem of dual use amongst scientists [76] at BTWC meetings through to the present time. The question that remain is whether the situation in regard to these projects could change over the next 5 years. Given that a number of countries have initiated comprehensive national strategies to deal with biological security, and that national legislatures were beginning to investigate the aims and effectiveness of these national strategies in the latter part of 2019 [77], it remained to be seen how long such national decisions would take to begin to impact on these brain projects or whether the scientists involved would take the necessary action more quickly on their own initiative.

References

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27. BRAIN Update (2 July 2019) Two new RFAs seek to expand marmoset colonies and create a marmoset coordination center. NIHNINDS 28. Schneider GE (2014) Brain structure and its origins in development and in evolution of behavior and the mind. The MIT Press, Cambridge, Mass 29. Passingham R (2008) What is special about the human brain?. Oxford University Press, Oxford 30. Tomasello M (2019) Becoming human: a theory of ontology. The Belknap Press of Harvard University Press, Harvard 31. Yanka CDE (April 1960) Mickey finn on the battlefield. Army, 28–29 (page 29) 32. Lindsey D el at (May–June 1960) “Off the Rocker” and “On the Floor”: non-lethal chemical agents. Armed Forc J, 8–9 (page 8) 33. Office of the Assistant Secretary of Defense Research and Development (19 November 1955) Report of the ad hoc study group on psychochemcial agents. PBC 206/1, Technical Library Army Chemical Center, Maryland (page 33) 34. Ghazanfar AA, Eliades SJ (October 2014) The neurobiology of primate vocal communication. Curr Opin Neurobiol 128–135 35. Drury C (31 July 2019) Human-animal hybrid research approved. The Independent (page 22) 36. United States (9 July 2019) Statement by H. E. Ambassador Kenneth D. Ward permanent representative of the United States of America to the OPCW at the ninety-first session of the executive council. EC-91/NAT.8, OPCW, The Hague (page 3) 37. Grillner S et al (2016) Worldwide initiatives to advance brain research. Nat Neurosci 19(9):1118–1122 (page 120) 38. See https://brainminds.jp/en/overview/greetings. Accessed 10 September 2019 39. Meselson M (2000) Averting the hostile exploitation of biotechnology. Chem Biol Weapons Convent Bull 48:16–19 (page16) 40. See https://brainminds-beyond.jp/about/. Accessed 10 September 2019 41. See https://brainminds-beyond.jp/aboutstructure.html. Accessed 10 September 2019 42. See for example, Okano H, Mitra P (2015) Brain-mapping projects using the common marmoset. Neurosci Res 93:3–7, and Okano H, Kishi N (2018) Investigation of brain science and neurological/psychiatric disorders using genetically modified non-human primates. Curr Opin Neurobiol 50:1–6 43. Nixdorff K et al (2018) Dual-use nano-neurotechnology: an assessment of the implications of trends in science and technology. Politi Life Sci 37(2):180–202 44. Moriguchi S et al (2017) Norepinephrine transporter in major depressive disorder: a PET study. Am J Psychiatry 174(1):36–41 45. Sugaya Y et al (2016) Crucial roles of the endocannabinoid 2-arachidonoylgycerol in the suppression of epileptic seizures. Cell Rep 16:1405–1415 46. Inutsuka A et al (2016) The integrative role of orexin/hypocretin neurons in nociceptive perception and analgesic regulation. Sci Rep 6:29480. https://doi.org/10.1038/srep29480 47. https://brainminds-beyond.jp/research/innovative. Accessed 10 September 2019 48. Joiner WJ (2018) The neurobiological basis of sleep and sleep disorders. Physiology 33(5):317– 227 (page 319) 49. See for example, Niwa, Y et al (2018) Muscarinic acetylcholine receptors Chrm 1 and Chrm 3 are essential for REM sleep. Cell Rep 24:2231–2247 50. Grillner S, Robertson B (2016) The basal ganglia over 500 million years. Curr Biol 26:R1088– R1100 51. Diederich NJ et al (2019) Parkinson’s disease: is it a consequence of human brain evolution. Mov Disord 43(4):463–459 (page 463) 52. Grillner S, Robertson B (2015) The basal ganglia downstream control of brainstem motor centres–an evolutionary conserved strategy. Curr Opin Neurobiol 33:47–52 (page 47) 53. Garcia-Ruiz PJ, Espay AJ (2019) Parkinson disease: an evolutionary perspective. Front Neurol 8:157. https://doi.org/10.3389/fneur.2017.00157 (page 2) 54. Araki K et al (2019) Parkinson’s disease is a type of amyloidosis featuring accumulation of amyloid fibrils of alpha-synuclein. PNAS 116(36):17963–17969

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55. Andres DS, Merello M, Darbin O (2017) Editorial: pathophysiology of the basal ganglia and movement disorders: gaining new insights from modelling and experimentation, to influence the clinic. Front Hum Neurosci 11:466. https://doi.org/10.3389/fnhum.2017.00466 56. https://brainminds.jp/en/completed. Accessed 4 April 2020 57. http://www.bdr.riken.jp/en/research/labs/iriki-a/index.html. Accessed 4 April 2020 (page 1) 58. http://www.bdr.riken.jp/en/research/labs/iriki-a/index.html. Accessed 4 April 2020 (page 2) 59. Izpisua Belmonte JC et al (2015) Brains, genes and primates. Neuron 86(3):617–631 60. Kishi N, Okano H (2017) Neuroscience research using non-human primate models and genome editing. In: Jaenisch R et al (eds) Research and perspectives in neurosciences. https://doi.org/ 10.1007/978-3-31960192-2_7 61. O’Day E et al (2019) Are we there yet? How and when specific biotechnologies will improve human health. Biotechnol J 14(1):1800195, 1–11 62. Krakauer JW et al (2017) Neuroscience needs behavior: correcting a reductionist bias. Neuron 93:480–490 (page 480) 63. Whiten A, Van de Waal E (2018) The pervasive role of social learning in primate lifetime development. Behav Ecol Socilbiol 72(6):80. https://doi.org/10.1007/s00265-018-2498-3 (page 1) 64. Ghazanfar AA, Liao DA (2018) Constraints and flexibility during vocal development: insights from marmoset monkeys. Curr Opin Behav Sci 21:27–32 65. Takahashi DY et al (2017) Vocal learning via social reinforcement by infant marmoset monkeys. Curr Biol 27:1844–1852 66. Kato M et al (2018) Individual identity and affective valence in marmoset calls: in vivo brain imaging with vocal sound playback. Anim Cogn 21:331–343 67. Kotani M et al (2017) An eye tracking system for monitoring face scanning patterns reveals the enhancing effects of oxytocin on eye contact in common marmosets. Psychoneuroendocrinology 83:42–48 68. Yasue M et al (2018) Inequality aversion is observed in common marmosets but not in marmoset models of autism induced by prenatal exposure to valproic acid. Behav Brain Res 343:36–40 69. Yukihito Y et al (2017) The neural basis of changing social norms through persuasion. Sci Rep 7:16295. https://doi.org/10.1038/s41598-017-16572-2 70. Gaillard G (2018) Looking for neuroethics in Japan. Neuroethics 11:67–82 71. Japan (14 August 2008) Oversight, education, awareness raising, and codes of conduct for preventing the misuse of bio-science and bio-technology. BWC/MSP/2008/MX/WP.21, United Nations Geneva 72. Center for Research and Development Strategy (2012) Strategic proposal: preparedness framework and its governance of dual use research of concern for promising progress of life sciences. CRDS-FY2012-SP-02, Japan Science and Technology Agency, Japan 73. Ukraine, Japan and the United Kingdom (6 December 2017) Awareness-raising, education and outreach: recent developments. BWC/MSP/2017/WP.22. United Nations, Geneva 74. Shinomiya N et al (9–10 August 2018) Cutting edge life science and dual use issues–how should we have a dialogue with society? Presentation to MX2, United Nations, Geneva 75. Shinomiya N (31 July–2 August 2019) Biological risk assessment of leading-edge life science and its management. Presentation to MX2, United Nations, Geneva 76. See slide 12 of the 2019 presentation in Ref. [74] 77. Joint Committee on National Security Strategy (2019) Biosecurity and human health: preparing for emerging infections and bioweapons. www.parliament.uk

Chapter 9

China’s Brain Project

Abstract This Chapter on China’s Brain Project begins by giving some examples of how scientists are finding more and more examples of complex behaviour in lower animals and then briefly discusses why the study of macaque Non-Human Primates (NHPs) is considered to be so important for understanding the human brain. The structure of the China Brain Project is then described. This was not easy to do in late 2019 because I could not find a dedicated website for the project in English. However, there was enough published in English for me to outline the basic structure of the project, and there was no shortage of research publications in English about the work that was being financed. Some of the research work being carried out in the project is concerned with lower animals and examples of such work are noted, but the aim to study more complex behaviour in NHPs is emphasised. Before looking specifically at the research being done on NHPs in the project examples of the kind of work being carried out on macaques around the world are used to illustrate how sophisticated this research can be. Examples of studies of circuits of neurons, modulation of such circuits, and of genes, neuronal mechanisms and behaviour are given to illustrate this point. Then examples of NHP primate research being carried out within the project are reviewed, particular attention being given to work on genome editing of NHPs and studies of consciousness. Finally, the disjunction between the lack of concern with dual use within the project and the efforts of China to achieve an international code of conduct in support of the Biological and Toxin Weapons Convention is noted and it is suggested that at some time in the future this disjunction could be closed.

9.1 Introduction Newspaper readers in the early autumn of 2019 could easily find intriguing stories of animal behaviour: crabs that could run mazes [1]; rats that could be taught to drive tiny cars [2]; and supposedly vegetarian macaque monkeys found to be eating large numbers of rats and thus acting as a natural anti-pest measure and protecting palm oil plantations from the rats [3]. Clearly, we have a lot more to learn about animal behaviour [4]. The last example concerning macaque monkeys is most relevant here © Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6_9

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because it is a primary focus of the research project in China. There are obviously differences between the brain of human beings and macaque, but that does not mean that the macaque brain cannot be used in some respects in order to better understand the human brain. As Richard Passingham argued a decade ago [5]: …Evolution is a historical process. It works in two ways. Where something works it retains it; where novel changes are required, they are typically made by adapting what was there in the first place. It is for this reason that the macaque monkey model can remain productive even in cases where humans have cognitive abilities that have not developed in other animals.

After reviewing a number of relevant examples, he asked why bother with monkeys anyway and immediately pointed out the answer “[T]he reason is that recordings from electrodes in the human brain is always going to be restricted for ethical and practical reasons.” So, in order to really understand what is happening animal models will always be needed. Passingham concluded that the message was clear: …Work on monkeys is essential for understanding the mechanisms of the brain. But whenever possible, one should test whether the results can be generalised to the human brain…. After all Kandel and coworkers had to check whether the molecular mechanisms that they had established for learning in the sea slug (Aplysia) were also involved in memory in a mammal, such as the mouse…

On these grounds the choice made to focus on the macaque makes good sense. However, there could be other possible objections. In the UK for example there are government moves to ban the owning of primates as pets because of concerns about the animals’ welfare [6] and alarm about Chinese scientists using modern genome editing technologies on human babies [7]. There could certainly be some people needing to be convinced that there is no issue to debate in regard to cloning gene-edited monkeys in order to study mental illnesses [8]. The issue was set out quite clearly in a press report. The scientists involved wanted to create primates with identical genes in order to test new treatments. In this case they knocked out a gene responsible for the production of a substance that affects the body’s circadian rhythms, then they: …took cells from one of the donor monkeys that had been gene edited and who displayed symptoms including reduced sleep time and those associated with mental health problems. They used these donor cells to clone a group of monkeys with the same disease-causing mutation.

So far so good, but as the report pointed out, there were ethical issues as “the scientists went through dozens of cloned embryos and monkeys that only survived for a few days.” Indeed, the report concluded that “[P]rimate research is tightly controlled, meaning that it is unlikely such techniques will be widely applied.” However, that may be an incorrect estimate of future research possibilities, while there are reports of scientists having to locate their work in China in part to avoid restrictions [9] on my reading it is likely that the use of these techniques will become more and more prevalent, for example in the US. As one recent review concluded [10]:

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In summary, there is a bright and promising future for the generation of transgenic and gene-edited NHP. NHP have an essential role in the study of human diseases and for the development of effective therapeutic strategies…in neuropsychiatric disorders that affect cognitive function and behaviour. Much of the initial work to adopt and adapt genetic and gene-editing tools to NHP was done in macaques…

However, such work is very expensive, and the report ends by stressing the importance of support from public agencies such as the us NIH, Japan’s Brain/Minds project and for the research in China. It is against that background that we can take a first look at the brain project in China. Then we will need to get a better idea of just what kinds of sophisticated behaviour it is now possible to examine in macaques before we take a more detailed look at the dual-use possibilities involved in the project and finally ask what kinds of precautions are being put in place to deal with the issue of dual use.

9.2 China’s Brain Project At the time of writing this chapter in the autumn of 2019 China’s Brain Project was still undergoing rapid expansion so it was not so easy to describe what was happening because, for example, I could not find a dedicated website for the whole project in English. Nevertheless, enough information was available to be able to describe its objectives and basic structure in this section of the chapter. There was obviously also enough research published in English to allow an assessment to be made of potential dual-use concerns later in the chapter. The objectives of the project were clear in China’s contribution to the set of papers in the journal Neuron in 2016 [11]. The authors, led by Mu-ming Poo, were mainly based in institutes in Shanghai at that time. Their paper was divided into eight roughly equal parts (Table 9.1). The introduction stated that extensive strategic discussions led to a consensus that: …understanding the neural basis of human cognition, a universal goal of neuroscience, should form the central pillar of the China Brain Project…

Table 9.1 Description of the China Brain Project, 2016a

1. 2. 3. 4. 5. 6. 7. 8.

Introduction Neural Circuit Mechanisms of Cognition Early Diagnosis and Intervention of Brain Disorders Input from Chinese Medicine Non-human Primate Research Brain-Inspired Computation Machines and Human Intelligence Concluding Remarks

a From

Ref. [11]

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And further that the project had to address the pressing social needs resulting from mental illnesses. This led to an overall structure of the project in which: …the basic research on the neural circuit mechanisms underlying cognition provides inputs to and receives feedback from the two applied wings of brain disease diagnosis/intervention and brain inspired intelligence technology.

This scheme was described as “one body, two wings” as shown in Fig. 9.1. The paper stated that this was a 15 year project (2016–2030) with the first five years timed to coincide with China’s 13th five—year plan for social and economic development. The second section of the paper will come as no great surprise in view of what we have learned of the other major brain projects in previous chapters. While noting the great progress that has been made in recent years, the authors are quite clear about the major gap in our current knowledge: …there is an enormous gap in our knowledge at the mesoscopic level. We know very little about how neural circuits are assembled from specific types of neurons in different brain regions and how specific neural circuits perform their signal processing functions during cognitive processes and behaviors…

They argue that study of simpler systems will help us to understand how such circuits produce behavior in lower animals but functions such as “[C]ognition of self and nonself, empathy, and theory of mind, on the other hand, are likely to be present only in non-human primates.” Therefore, they conclude that:

Understand the Neural Basis of Cogni ve Func ons Develop Effec ve Approaches in Early Diagnosis/Interv en ons of Brain Disorders

Develop BrainMachine Intelligence Technologies

Develop Brain Research Technology Pla orms

One Body Two Wings Building the Core and Developing the Applica ons

Fig. 9.1 The design of the China brain project (From Ref. [11])

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…In our opinion, given the rich resources of NHPs in China, the China Brain Project should include a substantial NHP component on the mesoscopic circuit analysis of the macaque brain, in parallel with other programs that focus on non-primate animal models…

And that: …In line with the main focus of Japan’s Brain/MIND project on marmosets, the China Brain Project could make a significant contribution in studying cognition in macaque monkeys…

The utility of research on NHPs is stressed in the third section of the paper which deals with early diagnosis and prevention of brain disorders. The section notes, for example, that: …Gene-edited NHP models of brain diseases, based on identified molecular targets, will provide further information for understanding the pathogenesis mechanisms and for developing pharmacological and physiological intervention approaches…

The fifth section of the paper on Non-human Primates enumerates some of the resources China had at that time and was further developing to carry out such research: …the Kunming Institute of Zoology of Chinese Academy of Sciences (CAS), which already has a large colony of macaque monkeys for research purposes, is in the process of further expansion into the National Primate Resource Center…. Yunnan Key Laboratory of Primate Biomedical Research in Kunming now houses a collection of gene-edited monkeys …

And … A NHP facility maintained by Chinese Academy of Medical Sciences in Kunming … is now shifting its interest toward developing NHP models for brain diseases. Finally, the Institute of Neuroscience of Chinese Academy of Sciences in Shanghai has established the largest NHP research facility in East China for both macaque and marmoset monkeys…

So, in 2016 it was abundantly clear that a largescale research project on the neuronal circuit basis of sophisticated behavior and its deficits would be carried out in this brain project. In February 2017 Mu-ming Poo gave a long interview for the National Science Review in China in which he elaborated his views on the China Brain Project (CBP) and the future of neuroscience in China [12]. At that time Professor Poo was Director of the Chinese Academy of Sciences (CAS) Center for Excellence in Brain Science and Intelligence Technology (CEBSIT) and had been the founding Director of the CAS Institute of Neuroscience (ION), also located in Shanghai, since 1999. CEBSIT had been founded in 2014 and he described it as: …a cross-disciplinary, multi-institutional organization that aims to consolidate existing research strength of CAS laboratories via the formation of collaborative research teams, in order to address major future questions in brain science and intelligence technology involving brain-inspired computing methods and devices.

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Table 9.2 Key points of the China brain projecta 1. Emphasis on Current Applications “…CBP puts the research on brain disorders and brain-inspired artificial intelligence (AI) as immediate high-priority areas, rather than remote goals after we understand the brain more completely…” 2. A Large Population with Mental Illnesses “…China has the largest patient populations in the world for all brain disorders, making research on prevention, early diagnosis and early intervention particularly urgent and, in the meantime, offering the largest data base for researchers to work on…” 3. Most Neuroscience Uses Rodent Models “…the current international neuroscience community mostly uses rodents (mice and rats) as animal models for studying the neural mechanisms underlying brain functions under both normal and pathological conditions…” 4. Non-Human Models Are Needed for Neuroscience “…it has become increasingly clear that to understand both human cognition and pathogenesis of brain diseases, especially psychiatric disorders, non-human primates are likely to be more appropriate experimental animal models…” 5. China has Major Resources of Macaque Monkeys and Rapidly Advancing Research “…China has large macaque monkey resources, and research on developing human disease models using macaque monkeys is advancing at a rapid rate…” a From

Ref. [12]

Poo emphasized the comprehensive approach being taken in the China Brain Project which he said had the aim of covering basic research on the brain, applied research on brain diseases and brain-inspired computing methods and devices. He also argued that although all of the brain projects had similar long term aims China had some unique advantages (as set out in Table 9.2). Given these advantages he argued that China had the chance to “play a leading role in studying higher cognitive functions, such as empathy, consciousness and language, as well as pathogenic mechanisms and intervention approaches for brain disorders.” What was striking throughout the interview was Professor Poo’s stress on the need to build up a cadre of new young investigators doing collaborative research by paying careful attention to the incentives offered to them, including by attracting outstanding scientists from China who were in the West back to China to continue their careers over the longer term. By early 2018 Nature was reporting on a plan to build a new research institute for the China Brain Project in Beijing [13]. The China Institute for Brain Research was established by an agreement between seven institutes in the capital and the Beijing municipality. The two co-Directors were Rao Yi from Peking University and Luo Minmin of the National Institute of Biological Sciences. The report stated that: Luo says that he will oversee the roughly 50 principle investigators who will have laboratories at the new centre, with Rao taking charge of external grants that will support around 100 investigators throughout China…

Liu also stated that he would have 180 million Chinese yuan (US$29million) to install the first five or six groups in 2018 and that he expected to have some 400 million yuan per year within five years to run the institute. Then in the middle of

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2018 it was reported in Science that the Shanghai Research Centre for Brain Science was to be developed in Shanghai, and that [14]: …The new center, and its Beijing counterpart, launched two months ago, are both expected to become part of an ambitious national effort to bring China to the forefront of neuroscience. Government planners called for brain research to be a key science and technology project in the nations 13th Five-Year Plan in Spring 2016. But details of the project…are still being worked out.

While the project is still a work in progress it is clear that there will be two major components of the China Brain Project, one in Beijing in the North and one in Shanghai in the South of the county but these institutes would be linked to major research on the brain in other parts of the country. Furthermore, it was clear that a great deal of work would be carried out and that much of that work would be published in English. Therefore, it should be possible to assess whether the project raises potential issues of dual-use application across the range of possibilities— sophisticated and unsophisticated—considered by the weaponeers during the Cold War of the 20th Century. Given what we have seen in previous chapters on the EU, US and Japan brain projects, it is obviously easy to show that scientists involved in the China Brain Project are carrying out work on the kinds of simpler systems and signaling molecules that could be of concern in relation to dual use. For example, the authors who contributed to the early description of the project in the 2016 edition of the journal Neuron were largely located in Shanghai. They included Jui-lin Du who has recently published on the operation of the Locus Coeruleus during general anesthesia in Zebrafish [15]. Similarly, the 2018 report in Nature on the launch of the Beijing centre mentioned two leading neuroscientists who would lead the work: Rao Yi of Peking University and Luo Minmin of the National Institute of Biological Sciences in Beijing. Professor Rao Yi has recently published on the role of a specific 5HT receptor in sleep homeostasis in Drosophlia, [16] and Professor Luo Minmin has published on the role of serotonin in the regulation of defensive behavior in mice [17]. It would be possible to multiply such examples many times. For example, Min Xu of the Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academies of Sciences was a member of a multi-authors team who recently published on the role of orexin (hypocretin) neurons on wakefulness in mice [18]. However, what is of particular interest about the project in China is the stress on investigations of the nervous system and behaviours of Non-Human Primates— specifically macaque monkeys. As Professor Mu-ming Poo, one of the key scientists, noted in late 2018 [19]: …Over the past 30 years, neuroscientists have made tremendous progress in understanding the structure and function of the brain using various model organisms, focusing mainly on conserved mechanisms. For the next 30 years, I would like to see more attention paid to the diversification rather than conservation of brain functions in different species…

In short, as he pointed out:

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…It is great to know rodents have some innate behaviors that may be conserved in primates, but it seems equally important to know how cortical control of innate behaviors emerged in primates when substantially larger cortices had evolved.

So, if we want to understand what the brain projects are likely to discover about the operations of our nervous systems in coming decades, we should look at the work on NHPs as well as on simpler model organisms. Before looking specifically at the work being carried out in China on NHPs it is useful to examine the kind of investigations that have now become possible around the world using macaques as a model to set the work in China within a wider context.

9.3 Macaque Neuroscience Today Macaques are part of a group of Old World monkeys that radiated out of Africa into Asia [20]. These monkeys “comprise a bewildering variety of variously adapted arboreal and terrestrial forms, including some 20 recognized species… of … Macaca [Macaques].” Several of the species have long been the subject of medical research and for studies of behavior. For example, the index of the 1987 edition of the Oxford Companion to Animal Behaviour lists 40 separate entries under the topic of macaques, [21] with most entries being for the Japanese Macaque Macaca fuscata and the Rhesus monkey Macaca mulatta. Clearly, complex social behavior is one of the chief distinguishing characteristics of primates. As a 2013 review of the Neuroethology of primate social behavior concluded [22]: …The social environment is rife with information and tinged with uncertainty, and as a result much of our mental machinery is applied to reducing the cognitive load of social interaction…

Moreover, the review added that: …Biological mechanisms that primarily functioned to mediate nonsocial behaviors in the ancestral state have been repurposed in some species, like humans and rhesus macaques, to mediate social behavior. Biological mechanisms are redirected and further modified for social functions at multiple levels of organization, from neurons and circuits to hormones and genes…

So, there is much that can be gained by the study of macaque brain and behavior, but Fans De Wall recently reinforced the message that we have to be very careful about the assumptions we bring to such investigations by illustrations from a wide variety of investigations [23]. For example, a study of macaque assaults on tourists found that the monkeys not only stole valuable items like glasses from the humans but also bartered them back in exchange for food items [24]. So how much do we actually understand about macaques’ capabilities without very careful investigation?

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While keeping that caution in mind we will briefly detail some example that show how scientists are gaining a better understanding of the neuronal mechanisms underlying complex social behavior in NHPs and then give some examples of Chinese Brain Project research in this area. The aim here is to ask whether, particularly in later decades of this century, such work could be subject to hostile dual use? However, it is necessary also to be clear that there is no implication being made here that the work is being done for anything other than benign civil purposes. For ease of comparison with earlier chapters we will divide these examples into three parts dealing with neuronal circuits, modulation of circuits and the genetics underlying neuronal circuits and behaviour.

9.3.1 Circuits of Neurons A review published in 2017 was titled “Social decision-making and the brain: a comparative perspective” and explained why studies of the neurophysiology of primate social decision making had recently come to the fore [25]. The paper began by asking the reader to imagine that he or she was visiting a local fruit market where they usually bought from a particular vendor and received a discount. However, on this day the fruit did not look in the best condition and the usual vendor was not in a good mood. The question then posed was whether to go to another vendor where the fruit looked in better condition at the risk of losing the relationship built up, and the discounts obtainable from the usual vendor. The authors explained that the visitor to the market brain would be required to take a series of steps as set out in Table 9.3. The important point is that the authors go on to state that functional magnetic resonance imaging (fMRI) of human beings while undertaking such tasks has “uncovered a set of brain regions reliably engaged” at these stages of social decision-making. However, limitations, for example in the detail that it is possible to discern from fMRI Table 9.3 Social decision-making stagesa

Step 1 Identify the social context, the vendors involved and your past interactions with them Step 2 Infer the state of mind of the vendor based on observation of his or her current behaviour Step 3 Estimate the value of the goods on offer to you based on your current preferences Step 4 Compute the best buy for you at this time Step 5 Update your model of this decision context based on how your decision turns out a From

Ref. [25]

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scans and ethical considerations “make animal models of social interactions critical for developing a fully mechanistic account of human social behavior” (emphasis added). They go on to give examples of the deeper insights that become available from recording of neurons in analogous regions of the brain in monkeys. They review one published paper on an experiment in which macaques were trained to play the interactive Prisoners Dilemma game while recordings were made from the dorsal anterior cingulate cortex (dACC) of one of the players. The players have to decide on a small certain reward for defecting or a larger, but uncertain, reward for cooperating with the other player. The experiment identified: …some neurons selective for the monkey’s own choice, some selective for the partner’s choice, and a third subgroup of neurons selective for the predicted choice of the partner monkey… (original emphasis)

The original experimenters considered that the predicted intentions of other might contribute to the computations of future strategic social behavior and tested this idea by disrupting the normal neuronal activity in the dACC by microstimulation and found that this specifically impaired cooperation with the partner. Numerous other such experiments to investigate the operations of aspects of NHPs brains during complex social behavior [26] are now becoming possible in the emerging field of primate social neurophysiology [27]. Some such experiments involve gaining a better understanding of the role of the primate amygdala in the recognition of faces and clearly have relevance to our own neuronal circuits [28]. Strikingly scientists, who began by taking a reductionist approach to investigate what was happening in the monkeys’ brain, are now beginning to use much more naturalistic experimental circumstances, for example substituting videos for the monkeys to study rather than still pictures and eventually clearly aim to investigate what is happening in the brains of freely interacting monkeys [29].

9.3.2 Modulation of Circuits A particular interest in the use of NHP models is for the study of human social behavior and its disfunctions. As we have seen in previous chapters, there has been extensive work on how the neurotransmitter/hormone oxytocin affects rodent social behavior, for example in causing specific alterations to maternal behaviour towards young pups and their distress calls. This kind of work led to the suggestion that oxytocin functions to increase the salience of socially important signals. At the same time, as we have also seen, studies of the impact of oxytocin, delivered by intranasal administration to humans, led, despite variability of the results, to the suggestion that oxytocin could profoundly affect mechanisms within the human brain concerned with social interactions. Therefore, there has been increased interest in how such oxytocin influenced mechanisms work, and go wrong, in human beings. However, given the wide evolutionary gap between rodents and humans, there may well be

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major differences between the mechanisms at play in humans and in rodents and in how such mechanisms are affected by oxytocin. So, scientists have seen good reason to attempt to study these mechanisms in NHP models such as macaque monkeys. These animals have much more comparable social behaviours to those of humans, whilst also increasingly being open to the kinds of detailed mechanistic studies which have been so useful in rodent research. A recent review of such research on NHPs [30] strongly suggested that oxytocin “enters the CSF [cerebrospinal fluid] of primates and elevates OT [oxytocin] levels in the brain when peripherally administered in appropriate doses.” However, it is also quite clear that the distribution of oxytocin receptors in the primate brain differs substantially from that of the rodent. This review pointing out that: …Just as rodents express OXTRs [oxytocin receptors] in the brain regions dedicated to their primary sensory modality (olfaction) NHPs express OXTRs in regions devoted to attention and visual and/or multisensory processing…

Moreover, whilst it is obvious that the function of the amygdala is affected by oxytocin input it appears that this could be an indirect effect via the critical acetylcholine input from the nucleus basalis of Meynert where oxytocin receptors are strongly expressed in NHP species. The review concludes that the NHP research has shown that oxytocin does impact the brain when administered peripherally, but that oxytocin receptors are much sparser than in the rodent brain and expressed particularly where they could impact powerful cholinergic modulatory mechanisms. However, while oxytocin does affect social behavior considerable new methodological work will be required to study oxytocin’s effect on neuronal mechanisms in animals involved in natural settings [31].

9.3.3 Genes, Mechanisms and Behaviour In 2016 the American Psychological Association announced its Distinguished Scientific Contribution award to Avshalom Caspi and Terrie E. Moffitt [32] for “innovative research and theory on mental health and human development” in which they had demonstrated “how early life experiences shape health disparities and how genetic factors shape and are shaped by environmental factors.” Caspi is particularly well known for work on how the serotonin transporter mechanism functions and affects behavioural outcomes under different early environmental variations. The serotonin transporter gene’s transcription can be modulated by a polymorphic region upstream of the promotor of the gene and this region has two forms. The short form leads to reduced expression of the gene and thus decreased serotonin reuptake compared to the long form. So, an individual can have two long alleles (l, l), two short alleles (s, s) or one of each (l, s). In humans Caspi demonstrated that people with short forms of this region (s, s or l, s) were susceptible to the impact of early life stress and this had consequences for their later behavior whereas those with the long form only were not so affected. This suggested that the short form and early

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stress influenced the later difficulties and raised the question of why the short form persisted at high levels in the human population. It has been found that macaque monkeys have much the same system and prevalence of the short form of the promotor as in the human population. This allowed investigators to ask a different question—rather than being a damaging susceptibility could the short form be a means of increasing the range of adaptability in a population and thus be an advantage rather than a deficit? In a natural population of rhesus macaque monkeys, they tested whether young short form carriers showed increased sensitivity to high investment in their social care? Specifically, they asked whether there could be a gene times environmental effect in which individuals with short forms of the promotor region would be influenced by high quality mother attachment. The experimenters found that there was such an effect, stating that [33]: …we found a G times E [Gene times Environment] interaction whereby rhesus macaque s-allele carriers which experience enhanced maternal protection during the first 12 weeks of life, exhibited the highest levels of social play at 2 years of age. L-allele homozygotes [l, l], by contrast, were comparatively insensitive to the effects of their early environment…

In their discussion the authors show how other hypotheses than susceptibility or adaptability (plasticity) might also be tested. The point is that the macaque monkey model not only opens up the genetics and neural mechanisms for investigation but also the natural behavior that is affected. This could be extremely valuable, for example, in the study of autism which is almost certainly a developmental disorder with multiple different genetic and environmental causes [34].

9.4 Examples of Chinese Investigations Again, the intention here is not to review all of the work being done on NHPs within the China Brain Project but rather to give some illustrative examples of what is being done and to raise the question of whether the project participants should be giving greater consideration to the possibilities of dual use.

9.4.1 Genome Editing Technology A short review of an important aspect of work on NHP brain research was given by two members of the Shanghai Institute for Biological Sciences in 2017. The paper was titled “Non-human Primate Models for Brain Disorders—Towards Genetic Manipulations via Innovative Technology” and described pharmacological and environmental approaches, genetic approaches based on viral transduction, genetic approaches based on genome-editing and a connectomic view of the psychiatric brain [35]. From our point of view here the key point is the obvious involvement of

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Table 9.4 The rapid evolution of capabilities to manipulate NHP genomesa Genetic Approaches Based on Viral Transduction 2001 In seminal work rhesus monkey oocytes infected with a green fluorescent gene followed by in vitro (IVF) fertilisation and transgenic monkeys produced by surrogate mothers 2008 Lentivirus harbouring the Huntingtin mutant gene used to infect monkey oocytes and transgenic monkeys carrying the mutant gene produced. The monkeys shown to have symptoms of Huntington disease 2009 Taking advantage of the shorter reproduction time of marmosets, transgenic monkeys produced by lentiviral methods bred to obtain a new generation of affected monkeys and thus demonstrating the utility of this method for producing NHP model organisms 2016 Similar work using lentiviral/IVF methods produced monkey models of autism disorders and then xenograft methods used to transfer testicular tissues from immature transgenic monkeys to nude mice. After 9 months mature sperm collected and used for IVF. Second generation trans genetic monkeys produced in a much shorter time. Genetic Approaches Based on Genome-Editing Methods 2011 The emergence of genome-editing methods (e.g., CRISPR/Cas) from 2011 onwards means that genetic engineering of NHPs becomes feasible and relatively easy a From

Ref. [35]

Chinese scientists in the very rapid evolution of capabilities set out in the middle two sections as summarised in Table 9.4. While problems of inadequate effects, or off-target effects causing mosaic consequences, in transgenic monkeys produced by CRISPR/Cas remain the review concluded that: …With the rapid development of genetic-engineering technology, such as lentiviral transduction and genome-editing, it is foreseen that non-human primates will play a crucial role as animal models in the near future…

The review also noted that with technical advances such as brain imaging and ultrasound stimulation also being applied successfully to such transgenic monkeys these non-human primate models will become increasingly important in researching the causes and treatment of brain disorders. Much has been written about the CRISPR/Cas system for genome editing in recent years. It is sufficient to say here that it was discovered as a bacterial defence system that targets and destroys invading phages by attacking specific genome sequences and bringing a cutting mechanism to bear on that sequence—thus preventing its activity. Following this discovery, the system was rapidly developed so that it could be applied by scientists in almost any cell. Another paper, again by scientists from the Shanghai Institute for Biological Sciences, showed how the mosaic effects of the CRIRPR/Cas system applied to monkeys could be overcome by successful multiple attacks on a specific gene sequence [36].

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In 2019 Chinese researchers from Yunnan provided a detailed review of the use of CRISPR/Cas-mediated genome editing on NHPs which carefully described the history of research in this area, its positive prospects and the difficulties that have been encountered [37]. The paper has sections on gene disruption, gene introduction, off-target effects and mosaic mutations, but it concludes that: …Overall, advances in the CRISPR/Cas genome editing technique have made it possible to generate genetically modified NHPs, which provide a new and exciting way to explore gene functions, disease mechanisms and human therapy strategies in modern translational medical research…

Moreover, while noting the need to pay attention to serious safety and ethical questions, it looks forward to further rapid developments in the use of these NHP models.

9.4.2 Research on Consciousness and Self Awareness Clearly there are many higher order functions that could be investigated here—for example language or social interactions—however two issues that leaves little doubt on the seriousness of research on core aspects of human brain functions are surely the consideration of mechanisms underlying our consciousness and awareness of ourselves. In 2019 Chinese researchers from Fudan University in Shanghai published a paper [38] titled “Consciousness: New Concepts and Neural Networks” that provided a short introduction to modern work in this field which it describes as currently “an intensively focused area of neuroscience.” The paper begins by pointing out that previously it was thought that midline brain structures (the reticular activation system) was vital to maintaining arousal, but that more recently other proposals have been put forward and there is no clear conclusion at this time. However, they state that there is agreement that there are two key features of consciousness “(1) the state of consciousness (i.e. wakefulness) and (2) the content of consciousness (i.e. awareness),” and they argue that a scientific investigation of consciousness should logically begin by investigating the state of wakefulness, particularly as we presently have some useful means of investigating this aspect of consciousness. We have certainly considered aspects of this state of consciousness in previous chapters when reviewing papers on research of the mechanisms underlying the generation of sleep and awaking. This paper builds on builds on such studies (for example on the role of orexin) and concluded that the paraventricular nucleus of the thalamus (PVT) plays a key role and that the projection of orexin-secreting neurons from the lateral hypothalamus to the PVT glutamatergic neurons represents one of the pathways that control arousal. They also suggest that the claustrum, which is suspected to be present in all mammals, may play an important, but as yet undefined, role and that a large network is required to generate the content of consciousness.

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One particular concern to the medical community is how to diagnose and deal with patients suffering from chronic disorders of consciousness following brain damage. A detailed review of this problem by Chinese researchers included a section on the results of functional magnetic resonance imaging (fMRI). The authors suggested that [39]: … The best-studied network is the default mode network (DMN), which includes the medial predial prefrontal cortex, the posterior mid-brain regions, the medial temporal lobes and the lateral parietal cortex…

And they note that in healthy individuals the DMN has high levels of recordable activity when no explicit task is being undertaken. Moreover, they state that: …recent studies have found that the activity of the DMN is closely associated with specific states of consciousness, such as anesthesia and sleep. In DOC [Disorders of Conscious], studies have shown that the resting-state functional connectivity within the DMN is decreased and proportional in the degree of consciousness impairment…

Indeed, in their view studies have suggested that opposition between the DMN and the executive control network could be a distinguishing feature to predict the outcome for DOC patients. Yet, while such indicators are still far short of being good enough to be taken as biomarkers intensive research is likely to continue apace. An important component of adult human consciousness is surely self-awareness and researchers have tried to detect it in other animals by asking if they respond by touching an ink spot placed (without their knowledge) on their face when they look in a mirror. Chimpanzees and a few other species such as elephants pass this test, but monkeys have not been found to respond. So that would suggest that they are not self-aware in the way that we are and therefore that self-awareness cannot be studied in monkeys like macaques. However, Chinese researchers at the Shanghai Institutes for Biological Sciences (including Mu-ming Poo) thought that it perhaps not be that the monkeys were not self-aware but rather that the test was inappropriate [40]. They set out to test this idea by training monkeys to touch a spot placed by a laser light on a board behind them when they saw it in a mirror in front of them. The monkeys were trained to sit in a chair which restrained their head before they were trained to touch the spot for a food reward. After training to touch the spot on the board behind them they were able to do the same for a spot located on their face when it was seen though the mirror. Moreover, these monkeys used a mirror placed in their cage to spontaneously explore parts of their bodies that they could not normally see. A control group of monkeys that sat in the training chair for the same number of periods but did not get training remained unable to pass the mirror test. The researchers suggested that maybe the monkeys needed to link the visual input with their internal proprioceptive system to be able to handle the mirror test requirements and that the monkeys in fact have self-awareness. Indeed, one commentary on these experiments suggested that the DMN, which may be partially involved in these kinds of self-awareness activities, and as the DMN has been found in rodents as well as macaques that self-awareness

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capabilities could be much more widespread than implied by the standard mirror test results [41]. Frans de Waal adds to that idea in a commenary on another experiment that suggested that cleaner wrasse fish may have elements of self-awareness [42]. de Waal’s argument is that given that evolution tends not to proceed in great disjunctions but rather through gradual change it seems unlikely that most animals lack self-awareness and that just a few species have taken a great leap to this level of consciousness. Whatever the eventual outcome of this kind of research it seems clear that it casts new light on important elements of human cognitive capabilities. What needs to be added again is that all of the work described clearly is motivated by beneficial intentions even if we might have concerns about the ethics of working on NHPs. Equally, it is also clear that the more we understand about the neuronal mechanisms involved in producing our behavior the greater care we need to exercise in order to minimize the possibilities of dual-use applications.

9.5 China and Dual Use Given the kind of research we have just discussed it is hardly surprising that serious questions have been asked about the dual-use implications of the China Brain Project [43]. Yet, Chinese scientists had been involved in discussions of the potential misuse of biotechnology earlier during this century [44] and quite recently in specific discussion of neurotechnology and societal impacts [45] in cooperation with the Organisation for Economic Cooperation and Development [46]. Thus, the lack of progress in dealing with dual use within the brain project in China is surprising, and even more surprising because China has recently taken a leading role in trying to bring the longstanding interest in developing an International Aspirational Code of Conduct in the context of the Biological and Toxin Weapons Convention to a successful conclusion. This saga began almost two decades ago after the effort to agree a verification system fell apart at the Fifth Five Year Review Conference in 2001. It was rumored the UK Foreign Secretary at the time asked to take material on the Convention home with him over the Christmas holiday. This is not documented in the open literature as far as I am aware, but the UK government did produce a review (a Green Paper) of the available options for developing the Convention in the run up to the recommencement of the meeting in late 2002. A review of this paper [47] noted that one option was “codes of conduct for professional bodies” but also noted that “[W]hile there would be benefits from such an international code of ethics, the Green Paper says nothing as to how such a code might be developed or implemented.” Nevertheless, at the meeting in Geneva States Parties to the BTWC agreed that as part of the new Intersessional Process of annual meetings at Expert level (in the summer) and State Party meetings late in the year the content, promulgation, and adoption of codes of conduct for scientists would be the subject for the meetings in 2005 [48]. These annual meetings in 2003, 2004 and 2005 would be used to discuss, and promote common understanding and effective actions to support the Convention.

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Table 9.5 Papers produced for the 2005 discussions on codes of conducta Background Papers Four Papers by the Secretariat One Presentation by the United States State Working Papers (Total 35) Argentina 1, Canada 7, UK 4, Germany 6, Russia 2, China 1, Japan 2, India 1, Indonesia 1, South Africa 1, Iran 1, Australia 4, Cuba 2, Korea 1, Italy 1 Additional Working Papers at the MSP India 1, Russia 1 a Data

from the UN website in Geneva under Biological Weapons Convention

By the time of the 2005 Meeting of Experts the difficulties encountered in the later stages of the attempt to negotiate a verification system during the 1990s had reduced and there was certainly an attempt to deal seriously with the issue of codes of conduct with large numbers of papers being produced for the meetings in 2005 (Table 9.5). One particularly interesting point was raised by Australia in its Working Paper 29 [49]. This stated that: 1. Amongst the Australian scientific community, there is a low level of awareness of the risk of misuse of the biological sciences to assist in the development of biological or chemical weapons. Many scientists working in ‘dual-use’ areas simply do not consider the possibility that their work could inadvertently assist in a biological or chemical weapons programme. For most of these researchers, biological weapons issues may seem irrelevant and therefore strong advocacy is required to overcome natural resistance or ignorance…

The paper therefore continued by reasoning it followed that: … Introducing Codes of Conduct that highlight these issues is an important step in raising awareness. However, it is not enough simply to put such Codes in place. Without effective measures to educate scientists about the existence and importance of such Codes, attitudes and awareness will remain largely unchanged. (emphasis added).

A similar point was made by the Russian Federation in a paper for the Meeting of States Parties later in the year [50]. Russia supported the idea of a code and gave as the first core element that scientists should “[B]e well informed of, and apply in their practice, international and national regulatory legal instruments on the prohibition of biological and toxin weapons.” So even in 2005 just introducing a code of conduct was not seen to be sufficient to deal with the problem of the potential misuse of research by some of the States Parties. Given this level of interest it was unsurprising that the 6th Review Conference in 2006 decided that in 2008 during the Second Intersessional Process States Parties would focus on two topics, the second of which being [51]: …Oversight, education, awareness raising, and adoption and/or development of codes of conduct with the aim of preventing misuse in the context of advances in bio-science and bio-technology research with the potential of use for purposes prohibited by the Convention.

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Again in 2008 there were numerous contributions by States Parties, including by China, [52] on this topic. However, the most significant contribution was by the Netherlands. Their Working Paper stated that [53]: A code is a set of principles and instructions that are binding on members of a particular group in a profession or industry.…Moreover, codes can be classified into different types. Brian Rappert developed this typology… (emphasis added).

Brian Rappert, as a Sociologist, had suggested the typology that the Working Paper then set out. This typology can be summarised as follows: Aspirational Codes (Set Standards); Advisory Codes (Provide Guidelines) Enforceable Codes (Make Legal Requirements). Rappert also argued that it could be very confusing if different people were discussing different types of codes! It has become clear that the discussions in Geneva are best related to an Aspirational Code that could be agreed at this international level and then implemented to fit the different requirements in various countries. What it is important to understand is that in 2008 it was widely thought that developing a code could be a means to raise awareness of the problem of dual use amongst scientists. This idea which was in direct contradiction to the view put forward in 2005 by Australia. As was quite clearly stated in the Netherlands paper as “[T]he main aim of the Dutch Code of Conduct on Biosecurity is to be seen as a contribution to awareness raising.” The code developed by the Netherlands was widely circulated for example by the InterAcademy Panel, but while the need for education was noted in the code there was no requirement for it to be in place to support the code. The impact of the lack of education was illustrated by the account given by Koos van der Bruggen of the surprise of the young researchers in the Netherlands who carried out the research on airborne transmission of highly pathogenic avian influenza in 2011 at the consternation caused by the submission of their work for publication. According to this account one of the researchers said that [54]: …he never imagined that the paper would get a red light from the NSABB [National Science Advisory Board for Biosecurity in the United States] and become the focus of a heated international debate about the limits of academic freedom. Watching the flood of news coverage, ‘it was strange to think that we had created all of that in our lab’…

That in regard to an experiment that many would see as raising very obvious dual-use concerns. This lack of education about dual use was brought to the attention of States Parties in a contribution by Japan in a joint Working Paper by eleven States Parties at the Seventh Review Conference in 2011. The paper stated that [55]: …the National Defense Medical College (NDMC) in Japan and the University of Bradford in the UK conducted collaborative research to analyse the current state of biosecurity education in Japan. The research found that there was a lack of educational topics on biosecurity despite a certain level of presence of dual-use references, mainly due to an absence of space in the

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existing curricula, an absence of time and resources to develop new curricula, an absence of expertise as well as doubt about the need for biosecurity education…

The paper also noted that “[P]arallel to this survey, the NDMC and the University of Bradford also jointly developed an online learning module in applied dual-use biosecurity education.” Moreover, given that level of interest in the topic amongst States Parties it was not surprising that the Review Conference decided that, under the Standing Agenda on developments in the field of science and technology related to the Convention, the Third Intersessional Process would consider [56]: (d) voluntary codes of conduct and other measures to encourage responsible conduct by scientists, academia and industry; (e) education and awareness-raising about risks and benefits of life sciences and biotechnology…

Thus, the Meeting of States Parties in 2015 concluded that [57]: To further address education and awareness-raising about risks and benefits of life sciences and biotechnology, States Parties recognized that the continuous and accelerating rate of progress in scientific knowledge requires the necessity of deepening a culture of responsible use of this knowledge, which takes into account the object and purpose of the Convention without undermining peaceful uses. In order to further efforts on education and awarenessraising about risks and benefits of life sciences and biotechnology, States Parties discussed the need to share information and knowledge on these developments, including dual-use research of concern. (emphasis added).

Then in 2016 at the Preparatory Committee for the Seventh Review Conference China and Pakistan put forward a significant proposal for the development of a template for a code of conduct. Their Working Paper stated that [58]: With the aim to prevent abuse and misuse of bioscience and technology, fulfil the aims and objectives of the Convention and strengthen global biosecurity governance, China has proposed the development of a template of biological scientist code of conduct within the framework of the Convention in December 2015… (emphasis added)

The paper went on to point out that many States had indicated support for the idea and provided suggestions. So, it proposed that States Parties should “[F]ully exchange views on the issue ‘the development of the template of biological scientist code of conduct under the framework of the BWC’ under relevant agenda of the Eighth Review Conference.” At the Review Conference itself Ukraine and the UK, reflecting on their own joint studies and research, pressed the case for serious attention to be given to the education of scientists given the current lack of awareness of the Convention and its implications. Their joint Working Paper argued that [59]: 18. The Conference should therefore adopt the following language in the Final Declaration text for Article IV:

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9 China’s Brain Project The Conference stresses the critical importance of biosecurity education and awarenessraising in achieving effective implementation of the Convention, which should be put into effect through national implementation measures, as appropriate, in accordance with the constitutional process and practices of each State Party.

19. The Conference notes that such measures could include… (c) promoting the development and implementation of training and education programmes as well as training guides, handbooks and course materials, including raising awareness of the implications of dual use research and technology, for those granted access to biological agents and toxins relevant to the Convention, and especially for those with the knowledge or capacity to modify such agents and toxins… (emphases added).

The Ukraine, Japan and the UK again pressed the case for serious attention to be given to education at the 2017 Meeting of States Parties in a Working Paper on Awareness-raising, education and outreach: recent developments. The joint paper suggested that [60]: 19. There are a number of key points that States Parties might draw from these experiences, taking into account what is most appropriate given their own national structures and organisations: The need to reach out and engage with stakeholders over a period, obtain their interest and support, and build networks; it is especially important to engage with staff who will deliver the teaching, and students who will study the materials, to ensure that learning will be effective. The need to develop appropriate teaching materials, adapting what is already available for their own national circumstances and developing complementary material where necessary. The benefits of international collaboration and shared experience and expertise. The benefits of using websites and online techniques to facilitate communication and learning. The importance of continuing efforts to ensure sustainability. (emphases added)

Finally, China and Pakistan made a clear-cut proposal for bringing this long period of development to a conclusion at the Ninth Review Conference in 2021. At the 2018 Meeting of Experts they presented a Working Paper that stated [61]: 9. Hereby, we propose to: Continue in-depth discussion on the topic of ’development of a model code of conduct for biological scientists’, with a view to reaching consensus on the content of the model code of conduct. Facilitate the approval of the model code of conduct for biological scientists by the Ninth Review Conference, as well as the authorization by the Review Conference to work on implementation and promotion of the model code of conduct in the future inter-sessional process. (emphasis added).

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Crucially, following the meeting in Tianjin (see Chap. 3), the envisaged code of conduct had a key element concerned with emplacement of an effective system of education for scientists: 8. (Education and training) Scientific community and professional associations should play an active role in education and training. Increase public awareness of the Convention, and establish a safety education and training system for all parties involved in biotechnology research. Biological scientists should be encouraged to engage in dialogue and cooperation with social scientists, philosophers and anthropologists, so as to have a better understanding of the possible ethical and social implication of relevant biological research and its outcome. (emphasis added).

Then in his report of the meeting the Chair of the MX2 Session on science and technology concluded that such a code of conduct would be one of the elements that had most chance of being agreed at the Ninth Review Conference [62]: …It is the Chair’s view that…activities of the ISP should focus on issues that achieved greater commonality of approaches among delegations. In this regard, two areas could be explored: (i) risk assessment and management, and (ii) a voluntary code of conduct for biological scientists and relevant personnel. The Chair sees the two topics above as those that could lead to a meaningful discussion during the remaining meetings of the ISP, in 2019 and 2020. They seem to present the best prospect for an agreed outcome on S&T [Science and Technology] issues in the 2021 Review Conference of the BWC… (emphasis added).

How this played out would depend on how well meetings of the BTWC succeeded in 2020 and 2021 in the lead up to the decision making 9th Review Conference. However, China’s attitude to the misuse of biotechnology became very much clearer at the end of 2019 when the scientist who used CRISPR/Cas technology to edit the genomes of three human babies was sentenced to 3 years in jail and a large fine by a court in Shenzhen for illegal medical practice [63].

References 1. Bawdon T (23 October 2019) Crustacean education: brainy shore crabs learn to navigate a maze. The Independent, London (page 13) 2. Crawford LE et al (2019) Enriched environment exposure accelerates rodent driving skills. Behav Brain Res 79(1–2):219–225 3. Holzner A et al (21 October 2019) Macaques can contribute to greener practices in oil plantations when used as biological pest control. Curr Biology 29:R1055–R1069 (pages 1066–1067) 4. De Waal F (2016) Are we smart enough to know how smart animals are?. W.W. Norton, New York 5. Passingham R (2009) How good is the macaque monkey model of the human brain? Curr Opin Neurobiol 19(1):6–11 (page 7) 6. Bawdon T (25 October 2019) Ban on keeping primates could put an end to pet shop monkey business. The Independent, London (page 21)

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7. Cookson C (4 July 2019) Experts sound alarm on gene editing babies: biophysicist under attack for using human embryos. The Independent, London (page 21) 8. Gabbatiss J (25 January 2019) Researchers clone monkeys in effort to study mental health disorders. The Independent, London (page 27) 9. Zhang S (8 June 2018) China is genetically engineering monkeys with brain disorders. The Atlantic, 1–16 10. Park JE, Silva AC (2019) Generation of genetically engineered non-human primate models of brain function and neurological disorders. Am J Primatol 81(2). https://doi.org/10.1002/ajp. 22931 (page 8) 11. Poo M et al (2016) China brain project: basic neuroscience, brain diseases, and brain-inspired computing. Neuron 92:591–596 (pages 591, 592, 593) 12. Wang L (2017) Mu-ming Poo: China brain project and the future of Chinese neuroscience. Nat Sci Rev 4(2):258–263 13. Cyrandski D (2018) Beijing launches pioneering neuroscience centre: large research facility will be key part of much-anticipated brain initiative. Nature 356:157–58 (page 157) 14. Normile D (2018) China’s ambitious brain science project inches forward. Science 360:840– 841 (page 840) 15. Wen-jei Du et al (2018) The locus coeruleus modulates intravenous general anesthesia of zebrafish via a cooperative mechanism. Cell Rep 24:3146–3155 16. Qian Y et al (2017) Sleep homeostasis regulated by 5HT2b receptor in a small subset of neurons in the dorsal fan-shaped body of drosophila. eLife 6:e26519. https://doi.org/10.7554/ eLife.26519 17. Huang Lu et al (2017) A retinoraphe projection regulates serotonergic activity and loomingevoked defensive behaviour. Nat Commun 8:14908. DOI:https://doi.org/10.1038/ncomms 14908 18. Shuancheng Ren et al (2018) The parventricular thalamus is a critical thalamic area for wakefulness. Science 362:428–434 19. Poo M (2018) Interview. Neuron 99:884–886 (page 884) 20. Cartmill M (2010) Primate Classification and Diversity. Chapter 2. In Platt ML, Ghazanfar AA (eds) Primate neuroethology. Oxford University Press, Oxford (page 27) 21. McFarland D (ed) (1987) The oxford companion to animal behaviour. Oxford University Press, Oxford (page 652) 22. Chang SWC et al (2013) Neuroethology of primate social behaviour. Proc Natl Acad Sci 110(Suppl 2):10387–10394 (page 10390) 23. De Wall F (2019) Mama’s Last Hug: Animal emotions and what they teach us about ourselves. W. W. Norton, New York (page 138) 24. Brotcorne F et al (2017) Intergroup variation in robbing and bartering by long-tailed macaques at Uluwata Temple (Bali, Indonesia). Primates 58(4):505–516 25. Tremblay S et al (2017) Social decision-making and the brain: a comparative perspective. Trends Cogn Sci 21(4):265–276 (pages 2 and 5) 26. Isoda M et al (2018) Development of social systems neuroscience using macaques. Proc Jpn Acad Ser B Phys Biol Sci 94(7):305–323 27. Chang SWC (2017) An emerging field of primate social neurophysiology: current developments. ENeuro 4(5):1–8. https://doi.org/10.1523/eneuro.0295-17.2017 28. Chang SWC et al (2015) Neural mechanisms of social decision-making in the primate amygdala. Proc Natl Acad Sci 112(52):16012–16017 29. Gothard KM et al (2018) New perspectives on the neurophysiology of primate amygdala emerging from the study of naturalistic social behaviors. Wiley Interdiscip Rev Cog Sci 9(1). https://doi.org/10.1002/wcs.1449 30. Putnam PT et al (2018) Bridging the gap between rodents and humans: the role of non-human primates in oxytocin research. Am J Primatol 80(10):e22756. https://doi.org/10.1002/ajp.22756 (page 5) 31. Bauman MD et al (2018) Opportunities and challenges for intranasal oxytocin treatment studies in nonhuman primates. Am J Primatol 80(10):e22913. https://doi.org/10.1002/ajp.22913

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32. Anon (2016) Award for distinguished scientific contributions: Terrie E. Moffitt and Avshalom Caspi. Am Psychol 71(8):658–662 33. Madrid JE et al (2018) Adaptive developmental plasticity in rhesus macaques: the serotonin transporter gene interacts with maternal care to affect juvenile social behaviour. Proc Biol Sci 285(1881):20180541 (page 2) 34. Zhang R et al (2017) Genes related to oxytocin and arginine-vasopressin pathways: associations with autism spectrum disorder. Neurosci Bull 33(2):238–246 35. Qin Z, Li X (2017) Non-human primate models for brain disorders–towards genetic manipulations via innovative technology. Neurosci Bull 33(2):247–250 (page 249) 36. Zuo E et al (2017) One-step generation of complete gene knockout mice and monkeys by CRISPR/Cas9-mediated gene editing with multiple sgRNAs. Cell Res 27:933–945 37. Kang Y et al (2019) CRISPR/Cas9-mediated genome editing in nonhuman primates. Dis Model Mech 12(10):dmm039982 (page 6) 38. Zhao T et al (2019) Consciousness: new concepts and neural networks. Front Cell Neurosci 13(302). https://doi.org/10.3389/fncel.2019.00302 (page 1) 39. Song M et al (2018) Brain network studies in chronic disorders of consciousness: advances and perspectives. Neurosci Bull 34(4):592–604 (page 594) 40. Chang L et al (2017) Spontaneous expression of mirror self-recognition in monkeys after learning precise visual-proprioceptive association for mirror images. Proc Natl Acad Sci 114(12):3258–3263 41. Huttunen AW et al (2017) Can self-awareness be taught? Monkeys pass the mirror test–again. Proc Natl Acad Sci 114(13):3281–3283 42. de Waal FBM (2019) Fish, mirrors, and a gradualist perspective on self-awareness. PLoS Biol 17(2):e3000112 43. Palchik G et al (2018) Monkey business? Development, influence, and ethics of potentially dual-use brain science on the world stage. Neuroethics 11:111–114 44. Smithson AE (ed) (August 2007) BEIJING ON BIOHAZARDS: Chinese experts on bioweapons nonproliferation issues. James Martin Center for Nonproliferation Studies, Monterey, USA 45. Garden H et al (2019) Responsible innovation in neurotechnology enterprises. OECD Science, Technology and Industry Working Papers 2019/05. Report of a workshop on “Minding neurotechnology: delivering responsible innovation for health and well-being”, 6–7 September 2018. Shanghai, China 46. OECD (2017) Neurotechnology and society: strengthening responsible innovation in brain science. OECD Science, Technology and Innovation, Policy Paper No. 46. OECD, Paris. November 47. Pearson GS (2002) Return to Geneva: the United Kingdom Green Paper. Review Conference Paper No. 6. University of Bradford, UK (page 23) 48. United Nations (2002) Final report of the fifth review conference of the states parties to the convention on the prohibition of the development, production and stockpiling of bacteriological (biological) and toxin weapons and on their destruction. BWC/CONF.V/17. United Nations, Geneva 49. Australia (2005) Raising awareness: approaches and opportunities for outreach. BWC/MSP/MX/WP.29. United Nations, Geneva (page 1) 50. Russian Federation (2005) Basic principles (core elements) of the codes of conduct of scientists majoring in biosciences. BWC/MSP/2005/WP.2. United Nations, Geneva (page 1) 51. United Nations (2006) Final report of the sixth review conference of the states parties to the convention on the prohibition of the development, production and stockpiling of bacteriological (biological) and toxin weapons and on their destruction. BWC/CONF.VI/6. United Nations, Geneva 52. China (2008) Oversight of science, education and awareness raising, coders of conduct. BWC/MSP/2008/MX/WP.18. United Nations, Geneva 53. Netherlands (2008) Development of a code of conduct on biosecurity. BWC/MSP/2008/MX/WP.8. United Nations, Geneva (page 2)

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54. van der Bruggen K (2005) Gain-of-Function experiments, Chapter 2 (Box 2.3: young scientists who did the job). In Whitby S et al (eds) Preventing biological threats what you can do. University of Bradford, UK 55. Australia et al (2011) Possible approaches to education and awareness-raising among life scientists. BWC/CONF/VII/WP.20/Rev.1. United Nations, Geneva (page 9) 56. United Nations (2011) Final report of the seventh review conference of the states parties to the convention on the prohibition of the development, production and stockpiling of bacteriological (biological) and toxin weapons and on their destruction. BWC/CONF.VII/7/ Corr.1. United Nations, Geneva 57. United Nations (2015) Report of the meeting of states parties. BWC/MSP/2015/6. United Nations, Geneva (pages 8, 9) 58. China and Pakistan (2016) Proposal for the development of the template of biological scientist code of conduct under the framework of biological weapons convention. BWC/CONF.VIII/PC/WP.31. United Nations, Geneva (page 2) 59. Ukraine and UK (2016) Awareness-raising, education, outreach: an example of best practice. BWC/CONF.VIII/WP.10. United Nations, Geneva (page 6) 60. Ukraine, Japan and the UK (2017) Awareness-raising, education and outreach: recent developments. BWC/MSP/2017/WP.22. United Nations, Geneva (page 5) 61. China and Pakistan (2018) Proposal for the development of a model code of conduct for biological scientists under the biological weapons convention. BWC/MSP/2018/MX.2/WP.9. United Nations Geneva (pages 2, 4) 62. United Nations (2018) Chair’s report on MX2. BWC/MSP/2018/CRP.3. United Nations, Geneva (page 2) 63. Sample I (31 December2019) Chinese scientist who edited babies’ genes jailed for three years. The Guardian, London

Part III

Possible Futures

Chapter 10

Conclusion

Abstract The concluding this Chapter begins by returning to Professor Meselson’s question of whether the 21st Century biotechnology revolution will inevitably be turned in a major way to hostile purposes. The Chapter then notes that the fundamental aim of the brain projects is to gain a mechanistic understanding of the operations of the brain and that this is likely to be progressively achieved over coming decades. The questions that were set out in at the start of the book are restated and it is concluded that the results of the brain projects will undoubtedly raise more and more concerns about dual-use applications and that neuroscientists will have to confront such potential implications of their work. In early 2020 some 5 or 6 years after the start of the projects in the USA, the EU, Japan, China, Australia, Canada and South Korea it was clear that although some progress was being made there was a long way to go before the clear responsibilities of the participants in the projects for dealing with dual use was going to be adequately met. However, it was also noted that top-down developments at national and international levels could make it easier for scientists to discharge their responsibilities and that new analyses by neuroethicists could provide avenues that would help neuroscientists engage in this process of protecting their benignly intended work from misuse. Finally, it is pointed out that although the devastating COVID-19 outbreak brought the research on the book to premature end, it could also open up the possibility of a much more rigorous and rapid strengthening of the Chemical and Biological Weapons Non-Proliferations Regime and thus facilitate life scientists playing an increasing role in maintaining and developing the Chemical Weapons Convention and the Biological and Toxin Weapons Convention.

10.1 Introduction Chapter 2 of this book began with a reference to Meselson’s turn of the century essay on Averting the Hostile Applications of Biotechnology and his warning [1] that as the biotechnology revolution advances during this century there could be “unprecedented opportunities for violence, coercion, repression, or subjugation” © Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6_10

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and that dangerous capabilities could be available to a much wider range of actors than were available in relation to nuclear weapons. Moreover, when he referred to these new capabilities for hostile dual use reaching “deeply into what we are and how we regard ourselves” he must have had advances in neuroscience at least partly in mind. The current dangers of the development of so-called non-lethal incapacitating chemical agents for the future of the Chemical Weapons Convention are amply demonstrated by the concerns amongst many States Parties that the potential loophole in Article II.9(d) should now be closed [2]. However, as we have seen, the UK pointed out in a Working Paper in Geneva in 2012 that in the longer term there must also concerns about how dual-use applications of advances in neuroscience could affect the Biological and Toxin Weapons Convention as well as the Chemical Weapons Convention [3]. As noted in Chap. 4, J. B. Petro and his colleagues argued, again almost two decades ago, there is likely to be a paradigm shift in chemical and biological warfare as increasing capabilities of the life sciences allow a focus on the target to be attacked rather than the agent of attack [4]. This shift in would not eliminate the threat from traditional agents and genetically modified traditional agents, but would open up an expanding range of novel advanced agents. Petro and his colleagues’ argument focused on microbiological agents but could clearly be seen to apply across the range of potential dual-use applications of the life sciences— including neuroscience. The United States BRAIN Initiative was preceded by a very careful analysis of what might best be done by a working group of neuroscientists. Members of that working group published an article on their findings in the Philosophical Transactions of the Royal Society (see Appendix 1) in 2014 [5]. The main thrust of the initiative was made clear in the title of the article which read as follows “The BRAIN Initiative: developing technology to catalyse neuroscience discovery” and in the very start of the article which stated that: …The evolution of the field of neuroscience has been propelled by the advent of novel technological capabilities, and the pace at which these capabilities are being developed has accelerated dramatically in the past decade…

We have frequently seen the stress placed on the need to understand the neuronal circuits underlaying natural behaviours and in this early paper the need for further technical development was prominent: …To enable the immense potential of circuit manipulation, a new generation of tools for optogenetics, chemogenetics and biochemical and electromagnetic modulation should be developed for use in animals and eventually human patients.

The final result of the application of such techniques was stated without reservation as: “The most important outcome of the BRAIN Initiative will be a comprehensive, mechanistic understanding of brain function that emerges from synergistic application of the new technologies and conceptual structures developed under the Brain Initiative.” (emphasis added)

10.1 Introduction Table 10.1 Problems that we should be able to solve in the next 50 yearsa

177 How do circuits of neurons compute? What is the complete connectome of the mouse brain (70,000,000 neurons)? How can we image a live mouse brain at cellular and millisecond resolution? What causes psychiatric and neurological illness? How do learning and memory work? Why do we sleep and dream? How do we make decisions? How does the brain represent abstract ideas? a From

Ref. [8]

It is also necessary to recognise, as we have also seen, that neuroscience is evolving away from a reductionist bias [6] by taking a much more comparative approach [7] that emphasises the need to consider natural behaviour. The question then is what kind of mechanistic understanding will we have of brain functions that might easily be subject to malign misuse? In 2015 Ralph Adolphs published a study that looked at the unsolved problems of neuroscience [8]. He divided the problems into four sections: those that were already solved or would be solved soon; those that we should be able to solve in 50 years; those that we should be able to solve sometime; and those that we may never be able to solve. The second section in this listing is of particular interest here and the topics are set out in Table 10.1. Two points are worth noting about this list. First that some of these issues are obviously related to potential misuse such as understanding what causes psychiatric and neurological illness, how learning and memory work and how we make decisions. Secondly, we are now one tenth of the way thought the 50 year period that Adolphs was considering and that now the initial ramp-up phases of the major brain research projects has significantly increased the technological capabilities available to neuroscientists and therefore the pace of advances is likely to increase. In the Preface of this book I suggested that I had three questions in mind in my investigation: 1. How were the major State-level brain projects organised and what was their objective? 2. Was any of the research being carried out within these major projects likely to raise concerns about potential dual-use applications by others in the future? 3. If there were likely to be such concerns about dual use in relation to these projects what policies were being developed and implemented within these major projects, and other announced brain projects, to help protect the work from future dual use?

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In short, the answer to the first two questions is undoubtedly that these are major projects with largescale organisational and funding resources which aim to develop and use advances in technology to gain a mechanistic understanding of the operations of the Central Nervous System that produces our behaviour, and that such mechanistic understandings are likely to cause increasing concerns about dual-use applications as the underpinning of more and more complex behaviour is clarified. Although in regard to the third question it might have been hoped that more progress had been made in the initial stages of the projects in developing and implementing policies to deal with dual use, the actual situation in mid-2020 was more complex, and perhaps more encouraging because of movements within and outside of the projects. Some reservations are in order before we attempt to draw conclusions from the evidence assembled here. First, of course, there is a great deal of neuroscience research being done outside of these projects and in countries not examined here, and some of that work has clearly raised dual-use concerns amongst well-qualified experts [9]. Secondly, the problem of dual use is not dealt with by practicing scientists alone. As members of the ethics group of the EU Human Brain Project pointed out, there are powerful commercial interests for the States that are providing the funding for these projects and such interests can cut across participants’ concerns about dual use [10]. Yet as the Inter-Academy Panel pointed out in Chap. 3 “Preventing the Misuse of Research and Technology” of its 2016 guide to responsible conduct in the global research enterprise [11]: “The difficulty of predicting the future course and applications of research does not absolve researchers of responsibility for participating in venues to explore these issues. Researchers need to participate in discussions about the possible consequences of their work, including harmful consequences, in planning research projects…” (original emphasis)

While the problem of dual-use may be increasingly recognised amongst biotechnologists [12], it is far from clear that they have the expertise to judge when research they are carrying out may raise concerns in the future [13]. Indeed, although States may be able to specify that some experiments are off limits, the discussion of microbiological experiments that have caused considerable concern amongst security analysts since the turn of the century also indicates that many scientists saw these as necessary and beneficial. The problem then is not just about taking care in regard to individual experiments (although that is certainly needed) but critically also to think about other ways—such as raising awareness, education and mentoring—in which scientists can carry out their obligations to help prevent the future misuse of their work. The difficulty is compounded by the fact that the issue to be assessed may not just be about the increasing knowledge of a particular system such as means of penetrating the Blood-Brain Barrier [14], but of a rapidly developing new enabling technologies that could have widespread applications [15], and, of course, one group’s essential experimental programme could look to have decidedly dual-use implications to others [16]. Moreover the context in which neuroscience and our increasing knowledge of the brain takes place may be decidedly unstable over the next decades.

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10.2 The International System and Advances in Neuroscience As we moved into the third decade of the 21st Century it was not hard to find influential sources expressing concerns about the stability of the international system and the potential for conflict and war. The New Atlanticist carried a listing [17] of the “Top ten risks of 2020” as set out in Table 10.2. So, under the topic of “The great unravelling” the article states that “[W]ith the demise of its disputes mechanism, the World Trade Organisation—the lynchpin of seventy years of prosperity and a rules-based economic order—may also become defunct,” and under the topic “Nuclear stability unravels” it states that “the United States is ending the architecture of restraint, and starting a Hobbesian world of allagainst all, un-learning the lessons from the Cold War of avoiding an arms race.” Even Alex Bellamy, in his detailed description about how we have managed slowly over the last few centuries, and particularly over the last bloody century, to build a less war prone world, sees the present situation as being at a very dangerous turning point [18]: …State consolidation, trade, democracy, the diminution of ideological struggles, and sustained efforts in peace-making and peace building have made the world a more peaceful place than it once was…. But the ideas and social forces that give rise to war now seem to be in the ascendancy. Unless they are met with countervailing activism for peace, our future may become more violent than our immediate past…

Bellamy then directly calls for us all to think about what to do and to take appropriate action to help prevent the possible calamity that he foresaw. On the other hand, the chemical and biological non-proliferation regime does not just rest on the CWC and BTWC as these are part of a set of international and national treaties and regulations that together could provide a resilient web of prevention against natural dangers and accidental or deliberate misuse of the life and associated sciences [19]. If the UK working paper was correct in 2012 in suggesting Table 10.2 Top ten risks of 2020a

2020 elections Brexit The great unravelling A bifurcated world North Korean defiance Nuclear stability unravels Demise of US traditional alliances Nuclear proliferation Post-US Middle East Gray Swan: A China reckoning/world financial crisis a From

Ref. [17]

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that most of the advances in neuroscience that could be of dual use concern lie in the future then there is still time to strengthen the regime against misuse. What then can we conclude about how well the recently initiated State-level brain projects are prepared to deal with this problem of dual-use applications of their benignly-intended research?

10.3 The Role of Neuroscientists In such circumstances the questions of interest here are what role will life and associated scientists play in protecting their work from misuse, and what can neuroethicists do to help steer the brain projects in useful directions? Probably the most extensive study of ethics in relation to dual use was carried out by Frida Kuhlau and her colleagues at Uppsala University in Sweden [20, 21]. In 2012 these studies were brought together in a paper on ethical competence [22] described (Chap. 3) as “the different capacities required to handle tasks and situations in the working life.” Thus “ethical competence in dual use research concerns the capacity of life scientists to manage dual use research dilemmas.” In the view of these authors therefore: “…Ethical competence can be said to involve three core capabilities: 1) awareness, to initially recognize an ethically challenging situation; 2) reflection, to ethically reflect upon it; and 3) action, to adapt one’s behaviour to it.” (original emphases).

This perspective agrees with Sir Geoffrey Vickers’ view that only when a problem is recognised and felt to be important will action be taken—as we have also tried to point out in regard to dealing with the problem of dual use [23]. Unfortunately, there is overwhelming evidence that most life scientists know very little about the problem of dual use. As noted previously, a striking recent example of this situation was presented by Professor Tim Stearns, Chair of the Department of Biology at Stanford University in an invited paper [24] for a US National Academies study of Dual Use Research of Concern in the Life Sciences: Current Issues and Controversies [25]. There have been efforts to improve the awareness and education of life scientists about the problem of dual use [26, 27]. However, these efforts have not been nearly as systematic and organised as the work of the International Nuclear Security Education Network (INSEN) has been under the funding from the IAEA (International Atomic Energy Agency) and what is very likely to develop under the Advisory Board on Education and Outreach (ABEO) under funding from the OPCW [28]. This despite the probability that relevant scientific and technological advances will continue at a much faster rate in the life sciences than in chemistry or physics [29]. In January 2020 I asked the corresponding authors for each of the papers on the different brain research projects in the collection in the journal Neuron in February 2019 under the editorial “Neuroethics: Think Global” [30] to let me know what policies were being developed and implemented within their project to deal with the set question 5a which included misuse. I then put the responses I received into a

10.3 The Role of Neuroscientists Table 10.3 The International Brain Projects and Dual Use: Policy Developments in Early 2020

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Dual-Use Issues are seen to come under question 5a as set out in October 2018 Q5. In which contexts might a neuoroscientific technology/innovation be used or deployed? 5a. Which applications might be considered misuse or best uses beyond the laboratory? Policy Developments are considered to develop as follows Stage 0. No consideration being given to dual-use issues within the project Japan’s Brain/MINDS Project; China Brain Project; Korea Brain Initiativea Stage 1. Discussions of a policy on dual use taking place within the project Australian Brain Initiative; Canadian Brain Research Strategy; US BRAIN Initiative Stage 2. A policy agreed and published Human Brain Project Stage 3. Discussions on the implementation of the published policy taking place within the project Human Brain Project Stage 4. Policy on implementation agreed and published Stage 5. Implementation of the policy taking place and effectiveness being monitored aI

was unable to get a reply to my enquires from Korea so this is an assumption.

simple format of how an organisation might move from recognition of a problem to implementing a potential solution to the problem. The result of this analysis is set out in Table 10.3. I think it is clear that in early 2020 some five to six years after the initiation of these projects dealing with dual use was in the very early stage of a work in progress. It would seem fairly obvious that the first step that needs to be made is for all of the projects to develop education policies on responsible conduct in regard to dual use. There is certainly now a good literature that could be drawn on to carry out that work both in regard to life sciences [31] and chemical sciences [32]. Once there is wider recognition of the problem of dual use then there is also a considerable literature on how the risks might be managed [33] that informed scientists could use to help decide what best might be done within the various projects. Obviously, also, the projects would benefit from following the discussions within the meetings of States Parties to the Chemical Weapons Convention on what to do about the current issue of Article II.9(d) and incapacitating chemical agents and factor that into their thinking about the longer-term issue of how to help prevent more complex forms of hostile manipulation based on advances in neuroscience. The idea of using developments in

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top down regulation to help design and implement this kind of bottom-up regulatory activities can also be used more generally if current developments within and among States are understood.

10.4 Top Down Developments By the end of the second decade of the 21st Century States were beginning to respond to the threat of natural, accidental and deliberate disease to humans, animals and plants in a more and more integrated way. For example, the UK Biological Security Strategy of 2018 defines biological security to [34]: …cover the protection of the UK and UK interests from biological risks… whether these arise naturally, or through the less likely event of an accidental release of hazardous biological material from laboratory facilities or a deliberate biological attack. These risks could affect human, animals and plants.

As such integrated strategies evolve to counter the perceptions of an increasing threat there are bound to be discussions about how to ensure both freedom of research investigations and protection of the public from harm. Well prepared scientists could make valuable contributions to such discussions and policy developments. At the OECD (Organisation for Economic Cooperation and Development) there have been discussions about dealing with neurotechnology and dual use in which members of the International Brain Initiative have taken part, and in 2019 the OECD adopted recommendations for responsible innovation in neurotechnology [35] these included a recommendation (number 9) to anticipate and monitor potential unintended use and/or misuse of neurotechnology as detailed in Table 10.4. Following the recommendation to “take active steps to protect against potential misuse of neurotechnology” this will similarly require more attention from scientists to the implications of their work outside of the laboratory, particularly as the Table 10.4 OECD Recommendations for Preventing the Misuse of Neurotechnologya To this end, relevant actors should (a) Promote mechanisms to anticipate, and prevent, potentially harmful, short and long-term unintended uses and impacts before neurotechnologies are deployed (b) Implement safeguards and consider mechanisms to support integrity, autonomy, protection of private life, non-discrimination and dignity of the individual or of groups in the short and/or long term (c) Anticipate and prevent activities that seek to influence decision processes of individuals or groups by purposely affecting freedom and self-determination through, for example, intrusive surveillance, unconsented assessment, manipulation of brain states and/or behaviour (d) Where possible, take active steps to protect against potential misuse of neurotechnology. (emphasis added) a From

Ref. [35]

10.4 Top Down Developments

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Table 10.5 The Chairman’s aide memoire on the States Parties’ discussions on science and technologya “MX2 - Review of Developments in the Field of Science and Technology Related to the Convention • Establishing a Scientific and Technological Experts Advisory Forum or Committee to analyze benefits and risks of new S&T developments… • Developing a model code of conduct for biological scientists and all relevant personnel, and biosecurity education, adaptable to national requirements, in order to preventing the misuse of dual-use research while ensuring that research for peaceful purpose is not hampered… (emphasis added) • Considering the applicability of already available frameworks and principles to the BTWC context, including by tapping into academic material when relevant…” a From

Ref. [36]

document notes it is the first international standard in this domain and is intended to “guide governments and innovators to anticipate and address the ethical, legal and social challenges raised by novel neurotechnologies while promoting innovation in the field.” Finally, the efforts within the orbit of the BTWC by countries like China and Pakistan to have an Aspirational Code of Conduct agreed at the 2021 Review Conference could possibly lead to further developments in awareness raising and educational projects at national and international levels. Relevant conclusions were detailed in the report of the 2019 Meeting of Experts adopted by the Meeting of States Parties in December 2019 and summarised informally in an Aide Memoire by the Chair [36] of the meeting as shown in Table 10.5. The section of the adopted report of the Meeting of Experts dealing with codes of conduct stated, in part, that [37]: A number of States Parties stressed the crucial importance of awareness-raising and education as a complementary and effective measure to reduce risks regarding dual-use research of concern. Some also remarked on the benefits of open online training and education material. Additionally, some States Parties emphasized the importance of incorporating the Convention’s provisions as well as biosafety and biosecurity related topics into university curricula.

This clearly indicated that progress was indeed possible in 2021.

10.5 A Role for Neuroethics Meselson argued that as all previous technological revolutions had been applied in major ways for hostile purposes the same could well happen to biotechnology, if we were not very careful, as it was certain to be a core technology revolution during this century [38]. Given that chemical and biological weapons would be relatively easy to develop and would have advantages of stealth, deniability and cause considerable fear

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and disruption, they could be increasingly attractive to those involved in the hybrid, asymmetric wars likely to characterise coming decades. Moreover, as members of the European Brain Project have argued, such weapons systems could find applications in other fields such as politics, security and intelligence besides the dual-use military applications that are the focus here [39]. Such widespread application, however, would seem to be much more likely to happen if the chemical and biological conventions are eroded and chemical and biological weapons were to become commonplace in conflicts and warfare. While all biotechnologists should be concerned about such misuse it seems particularly pernicious for neuroscientists’ benignly-intended work aimed at alleviating the suffering of people with brain injuries and diseases to be so misused. Towards the end of the last century Stuart Croft in his study of Strategies of Arms Control: A History and Typology suggested that the international community has developed a varied toolkit related to the different arms control problems that have arisen at different times [40]. Today new forms of weapons systems may well need not just the strengthening of current international agreements but the development of new means of regulation [41]. It may also require the involvement of new actors to help shape these new systems of control. The argument here is that neuroscientists, particularly those funded in the cutting-edge brain projects, have a role to play in this process. This will not be a straightforward task. The concept of dual-use research of concern has been useful in delineating some experiments in microbiology that should not be undertaken without great care, but even in this field there has often been debate about the utility of the concept and the potential limitation of freedom of enquiry [42]. It seems less likely that the concept will be useful in fields such as neuroscience where there are not specific organisms that can be identified from previous offensive programmes as potentially of concern for instance in regard to genetic engineering. Indeed, it is likely that there will be a need for significant work by ethicists, risk analysists and informed neuroscientists to assess how scientists can best act at the different levels of national and international policy levels to help guard their work from misuse. At the present time the role of neuroscientists may best be to find ways to raise awareness of the potential for misuse and thus to involve more practicing scientist in thinking through the problem, but what should they do then? In 2008 when education and awareness-raising was a focus of interest at meetings of States Parties to the BTWC James Revill and I published a paper in which we tried to answer the question of what scientists might be able to do to help strengthen the Convention once they had become aware and educated about the problem of dual use [43]. Using Nicholas Sims’ concept of the Convention having four dimensions (development, research, compliance and institutionalisation) we suggested a range of possible activities within these dimensions as set out in Table 10.6. Given the obvious difficulties being experienced by those involved in the brain projects in dealing with the problem of dual use, it might again be asked now, over a decade later, what neuroscientists might be able to do to help strengthen the prohibition against chemical and biological weapons in future decades if all of the brain projects did successfully launch effective dual-use education initiatives over the next few years? An obvious place to look for indications

10.5 A Role for Neuroethics Table 10.6 Roles that scientists can play in strengthening the BTWCa

185 Development Assist in capacity building Facilitating peaceful cooperation and identifying where technology can be transferred legally and safely Building trust between scientists on a bilateral basis Research Helping to differentiate between permitted and prohibited research Contributing to the development of research oversight committees and pre-project reviews Compliance Contribute to biosafety and biosecurity Support the implementation of national measures Ensure States are aware of their responsibilities Ensure scientists are aware of their responsibilities Institutionalisation Contribute to the Inter Sessional Process Build relations between scientists internationally a From

Ref. [43]

of what might be possible is to follow the development of ideas about responsible conduct of research since 2008. Interestingly, in 2009 the US National Academies produced the third edition of On Being a Scientist: Responsible Conduct in Research and this had a section on “The Researcher in Society” and a separate text box telling the story of the use, by the US military, of Agent Orange to destroy plants in the Vietnam War and Arthur Galston’s efforts to stop what he considered to be a misuse of his discoveries about plant growth factors [44]. The text quotes Galston saying that he used to think scientists could avoid such misuse of their work by not becoming involved in projects that could be misused for evil ends but realised that things were not so simple and that it was necessary for a scientist “to remain involved with it to the end.” Galston’s longer paper on Science and Social Responsibility: A Case History sets out the detail of how he organised and lobbied in order to stop the massive use of herbicides and the destruction of ecosystems [45]. He felt, in particular, that the 1925 Geneva Protocol should have been applied and stopped such hostile use of the chemical herbicides. Yet his action was taken after the dual-use application of science had taken place and it would surely be better if such misuse was prevented before it happened. However, the 2009 text of On Being a Scientist does not elaborate on what actions might have been used to achieve that end. This issue was taken up by Sankar and Cho in a paper in the American Journal of Bioethics in 2015 [46]. They noted the lack of a guiding definition of social responsibility in the third edition of On Being a Scientist, suggested a framework

186 Table 10.7 A social responsibility analytical frameworka

10 Conclusion Basis Values investigators use for their research Approach Reasoning used to identify and manage benefits and harms in research Timing At what stage in the research are social responsibility issues addressed? Participants Who takes part in the discussion of social responsibility? Transparency How easy is it for others to ascertain how questions of social responsibility were addressed in the research process? a From

Ref. [46]

for further research and development and illustrated the use of the framework to analyse two different recent life science experiments. The basic framework is set out in Table 10.7. Whilst the focus is still on the single experiment the framework does open up the possibility of much wider monitoring of what is being done and what impact it might have. However, a follow-up paper in the same journal later reflected on 25 years of efforts apply Corporate Social Responsibility in the commercial world and cautioned that changing the guiding model there from one in which the only stakeholders were the shareholders to one in which a wider conception of relevant stakeholders had not been easy to achieve. In fact, these authors state that such initiatives can be a force for good [47]: …But they can also become empty rituals that provide PR cover and a defense against threats of hard regulation, while accomplishing little of tangible value…

And they conclude that advocates of a broader concept of socially responsible science would do well to bear this history in mind. In order to understand a subject Toshio Kuroki argued in 2018 that a critical initial question that needs to be addressed is classification [48]. He then suggested that around the world it is usual to distinguish two categories of research misconduct: Fabrication, Falsification and Plagiarism (FFP) and Questionable Research Practice (QRP). However, he then points out that this is a rather unsatisfactory classification system that muddles different things and misses out important issues such as risk. In his view a better system would be the one summarised in Table 10.8. From our point of view this is very helpful because it clearly separates out a category of risk (Category III Misconduct) that can be isolated for focused attention. From this perspective dual use research would be judged to be a form of research misconduct in that it involves the creation of risk. An experiment which clearly falls into the category of dual use can easily be understood to create a potential risk and surely requires that those involved consider what they should do to reduce that risk. However, if we draw back from a focus on single experiments and consider the general evolution of the

10.5 A Role for Neuroethics Table 10.8 A classification of research misconducta

187 Class I Misconduct Regarding Truth i. Fabrication ii. Falsification Class II Misconduct Regarding Trust i. Plagiarism ii. Irreproducibility iii. Inadequate Research Practice Class III Misconduct Regarding Risk i. Risk to health ii. Risk to industrial products a From

Ref. [48]

life and associated sciences then almost all modern life science research can be seen to contribute to an increasing capability for misuse and this therefore obliges all of those involved to consider what they should do about dual use. The reason for this is that there exists another group of stakeholders who are not involved in the research, but who may be affected by it—those who could in the future be affected by the dual use of civil research like those people who suffered from the destruction caused by herbicide use during the Vietnam War. The nature of the dual use risk that we have concentrated on here is primarily that of novel chemical and biological weapons that could affect the Central Nervous System and that would clearly come under the purview of the CWC and the BTWC. More generally as Professor Giordano and his colleagues have also pointed out, it is necessary again to stress that advances in neuroscience can be expected to raise increasing questions about novel weapons in wider warfare and security applications and that such applications could well encompass weapon systems that are not covered by the chemical and biological non-proliferation regime [49]. So the risks of to be considered in regard both to single potentially dual use experiments and in the overall advances in neuroscience are much greater that just those being focused on here. However, the risk is not really in single experiments or even in the application of empowering new technologies such as CRISPR/Cas, but rather in the potential for the fears and uncertainties about what others are doing [50] leading to an arms race in novel neuroweapons and then such weapons becoming commonplace in warfare, terrorism and criminality. As some well-informed commentators concluded recently after a review of a Chinese scientist’s use of CRISPR/Cas to modify human babies [51]: In the military domain, the logic of strategic balance of power dictates likely emergence of genetic warfare arms race, with some form of involvement of all major powers…

And in their paper these authors give believable examples, for example of targets for germ line the modification of friendly forces and of enemy forces. As they suggest, the implications of the first use of CRISPR/Cas to gene edit human beings “may

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be more profound, far reaching, and impactful than the recent nuclear escalations for humanity.” So, the risks to other stakeholders who are not involved in modern neuroscience research, including the brain projects, could hardly be higher if this prognosis is correct. One of the authors, writing earlier in 2015 about the possibility of an engineered influenza causing an unnatural pandemic, pointed out that the people affected probably would never have been consulted about the original work that was misused and that besides those involved in that work [52]: …The community is also a stakeholder with rights, and DURC [Dual Use Research of Concern] done in the country could cause harm to people in other countries who were never included in the debate…

Thus, the paper continued by adding that: …The first requirement is to inform and engage the public as a stakeholder in such research, and to make deliberations about DURC public and transparent…

The authors added that the second requirement was to make the structures and guidelines uniform and enforceable internationally. We are still obviously a long way from achieving such objectives but a 2018 paper put forward a process by which scientists could begin to work out how to deal with what they admitted was a “complex ethical question” of “[W]hat protections are owed to nonparticipants” including those affected by animal studies on transmissible pathogens [53]. These authors suggested a pilot study in which granting bodies required applications to consider this issue using a series of steps as set out in Table 10.9. The results of this part of the application would not be used in the judgement of the application, but would be used to inform the deliberations of a working group that would draft guidelines that attempted to balance the rights of the stakeholders not involved in the research with the administrative burden for the researchers. These guidelines would then be implemented and progressively modified so that over time Table 10.9 A procedural approach to dealing with other stakeholdersa

Stage 1. Statement of Possible Risks Applications required to state if risks to nonparticipants were expected Stage 2. Estimate of Risks Where risks were expected a rough estimate of the scale of the risk to be given Stage 3. Dealing with the Risk A plan for dealing with the expected risks to be given and a justification for any remaining risks provided Stage 4. Justification for remaining risks Explanation to be given of why the remaining risks should be accepted in order for the benefits of the research to be attained a From

Ref. [53]

10.5 A Role for Neuroethics

189

Table 10.10 The possible future of dealing with dual use in the BRAIN Initiativea “First, neuroscientists and neuroethicists should convene to consider the potential for dual use of fundamental BRAIN initiative-supported research…” “Second, neuroscientists and neuroethicists should expand dialogue between NIH staff, the NIH-associated community and other entities exploring the challenge of dual use neurotechnology both domestically and internationally…” “Finally, more specific guidance should be provided to BRAIN Initiative-funded researchers on potential ways their research could be used for military or national-security purposes. At present, the BRAIN Initiative does not have a formal dual-use education and awareness training program. Development of such materials could be integrated into BRAIN 2.0.” (emphasis added) a From

Ref. [56]

a comprehensive policy and understanding would emerge. Of course, it would be sensible to accept that using this process would not be straightforward in a rapidly changing research landscape involving converging technologies [54], but it would be a system of engagement and learning for both the participants in the research and the other stakeholders. These examples suggest that something important has happened since James and I listed points in the regulatory system where scientists might be able to act to help prevent their work from misuse. Rather than just pointing to the possibilities more recent work has shown ways in which scientists can be engaged in thinking about how they might act during their ordinary day-to-day working lives. This approach seems to me to fit into the more general approach being taken in other areas such as microbiology where detailed check lists are being put forward so that individual scientists can investigate in detail how well placed their laboratory is to deal with the requirements of the Responsible Conduct of Research [55]. Welcome signs of changing thinking can be seen in the report on The BRAIN Initiative and Neuroethics: Enabling and Enhancing Neuroscience Advances for Society? by the Neuroethics Subgroup of the Working Group on BRAIN 2.0 in the United States [56] (Table 10.10). If such policies on dual use are undertaken in the US BRAIN Initiative, they are likely to be followed up in the other projects. Particularly, the final point on the need for education and awareness potentially being addressed in the next phase of the initiative could be critical for the future of all of the projects.

10.6 Conclusion It will be evident to readers who have reached this concluding section of the book that I had an underlying intention of telling, and commenting on, a story of how one group of scientists—neuroscientists in the brain projects—have attempted to deal with the problem of dual use in order to learn lessons that could be useful in the future. It is clear from this account that the problem of dual use, and of biological security more

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generally, rarely comes to the top of the political agenda and allows decisive and coordinated action to be taken. Indeed, useful progress on biological security can often be blown off course by other events higher up on the political agenda. Nevertheless, it does seem possible that progress in strengthening the BTWC, particularly in regard to codes of conduct and education, could be achieved at the upcoming Review Conference in 2021. Additionally, perhaps before then progress could also be achieved in dealing with CNS-acting toxic chemicals under the CWC. My approach was based on the assumption, and hope, that no major natural, accidental or deliberately caused biological calamity would occur and that the story would be helpful both to the scientists directly affected, and to other groups of scientists facing similar problems as the biotechnology revolutions proceeds in coming decades. Therefore, I planned to try to follow the story through to the end of 2020 when we would be on the threshold of the 9th Review Conference in late 2021, and to present a summary of my research at the Preparatory Committee Meeting for the Review Conference that would take place in the Spring. This gradual approach seemed realistic given my experience of following the difficulties of making progress in strengthening the Chemical and Biological Non-Proliferation Regime since the mid-1990s. Progress during that time has been slow and incremental, but not impossible as we have seen recently in the solution found to dealing with Novichoks under the Chemical Weapons Convention [57]. Then in early 2020, as I considered my research plans for rounding up my investigation, the COVID-19 outbreak struck and dramatically demonstrated how fragile our health, social and economic systems are to such a biological threat. Given that it was unlikely that any major developments in dealing with dual use would occur during the months that would be required to bring the epidemic under control, I decided to write up at that stage in April and May 2020. So that is where my story ends with its conclusion that work is being done, but that it will take time for the brain projects to find effective ways of dealing with dual use. The world may slip back into a gradualist approach to strengthening the Chemical and Biological Non-Proliferation Regime when the COVID-19 outbreak is over despite the inevitable serious national and international investigations of what went wrong that will take place. My view is that would be a mistake and that we should take the opportunity to act on this warning of the dangers and quickly substantially strengthen this regime—and that as part of that process neuroscientists should now face up to their responsibilities to help prevent the dual use of their benignlyintended work by seeing the Chemical Weapons Convention and the Biological and Toxin Weapons Conventions as their Conventions which require their particular and continuing attention. Should this much more immediate action be undertaken I hope some of the lessons gained from the story of the last few years that I have told here will be of more immediate utility.

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43. Revill J, Dando MR (2008) Life scientists and the need for a culture of responsibility: after education… what? Sci Public Policy 35(1):29–35 44. National Academies of Science (2009) On Being a Scientist: Responsible Conduct of Research, 3rd edn. National Academies, Washington, DC (page 49) 45. Galston AW (1972) Science and social responsibility: a case history. Ann New York Acad Sci 96:223–235 46. Sankar PL, Cho MK (2015) Engineering values into genetic engineering: a proposed analytical framework for scientific social responsibility. Am J Bioeth 15(12):18–24 (page 21) 47. Conley JM et al (2015) Scientific social responsibility: lessons from the corporate social responsibility movement. Am J Bioeth 15(12):64–66 48. Kuroki T (2018) New classification of research misconduct from the viewpoint of truth, trust, and risk. Accountab Res 25(7–8):404–408 49. DeFranco J at al (2020) Redefining Neuroweapons: emerging capabilities in neuroscience and neurotechnology. PRISM 8(3):49–63 50. Eastwood BM (2017) Gene-Editing in China: Beneficial Science or Emerging Military Threat? Available at http://www.atlanticcouncil.org/blogs/futuresource/gene-editing-in-chinabeneficial-science-oremerging-military-threat 51. Heslop DJ, MacIntyre CR (2019) Germ line genome editing and the emerging struggle for supremacy in the Chemical, Biological and Radiological (CBR) balance of power. Global Biosecur 1(1):1–5 (page 3) 52. MacIntyre CR (2015) Re-thinking the ethics of dual-use research of concern on transmissible pathogens. Environ Syst Decis 35:129–132 (page 129) 53. Eyal N et al (2018) Risk to study nonparticipants: a procedural approach. PNAS 115(32):8051– 8053 (pages 8051, 8052) 54. MacIntyre CM et al (2018) Converging and emerging threats to health security. Environ Syst Decis 38:198–207 55. Culture of Biosafety, Biosecurity, and Responsible Conduct in the Life Sciences: (Self) Assessment Framework (2019) Based on A Guide to Training and Information Resources on the Culture of Biosafety, Biosecurity, and Responsible Conduct in the Life Sciences, 2019, developed by the International Working Group [formerly known as the Federal Experts Security Advisory Panel (FESAP) Working Group] on Strengthening the Culture of Biosafety, Biosecurity, and Responsible Conduct in the Life Sciences, available online at: https://absa.org/wpcontent/uploads/2019/04/CULTURE_TRAINING_CATALOGUE.pdf 56. Neuroethics Subgroup (2019) The BRAIN Initiative and Neuroethics: Enabling and Enhancing Neuroscience Advances for Society. The Brain Initiative, Washington D.C (pages 53 –54) 57. Costanzi S, Koblentz GD (2020) Updating the CWC: How We Got Here and What is Next. Arms Control Today, April, 16–20

Appendix

Timelines of Some Relevant Events and Documents

A1.1 Meetings of the Biological and Toxin Weapons Convention and Associated Documents 2016 Preparatory Committee for the Eighth Review Conference: 26–27 April China and Pakistan, Proposal for the Development of the Template of Biological Code of Conduct under the Framework of Biological Weapons Convention: 11 August 8–12 August Ukraine and UK, Awareness-Raising, Education, Outreach: An Example of Best Practice: 19 October Eighth Review Conference: 7–25 November agrees new InterSessional Process through to the 2021 9th Review Conference 2017 Russia, UK and USA, Elements of a Possible Intersessional Process: 30 November Meeting of States Parties: 4–8 December 2018 Applied Biosafety volume 23 publishes paper by Perkins et al on The Culture of Biosafety and Biosecurity and Responsible Conduct in the Life Sciences: A Comprehensive Literature Review: 7 June China hosts a meeting in Tianjin on Building a Global Community of Shared Future for Biosecurity: Development of a Code of Conduct for Biological Scientists: 25–27 June China and Pakistan, Proposal for the Development of a Model Code of Conduct for Biological Scientists under the Biological Weapons Convention: 9 August © Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6

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Appendix: Timelines of Some Relevant Events and Documents

Meeting of Experts: 7–16 August US National Academies publishes report on the meeting in Zagreb under the title Governance of Dual Use Research in the Life Sciences: Advancing Global Consensus on Research Oversight: November Meeting of States Parties: 4–7 December 2019 Meeting of Experts: 29 July–8 August Report of the Meeting of Experts to the Meeting of States Parties notes that “Many States Parties spoke in favour of a code of conduct for scientists under the Convention and referred to a joint proposal made by two States Parties,” and that “A number of States Parties stressed the crucial importance of awareness-raising and education as a complementary and effective measure to reduce risks regarding dual-use research of concern.” Meeting of States Parties: 3–6 December

A1.2 Meetings of the Chemical Weapons Convention and Associated Documents 2014 Australia, Weaponisation of Central Nervous System Acting Chemicals for Law Enforcement Purposes: 14 November Conference of States Parties CSP-19: 1–5 December 2015 Joint Paper, Aeroslisation of Central Nervous System-Acting Chemicals for Law Enforcement Purposes: 24 November Conference of States Parties CSP-20: 30 November–4 December 2016 International Union of Pure and Applied Chemistry (IUPAC) Endorses The Hague Ethical Guidelines of the OPCW: 4 May Joint Paper, Aeroslisation of Central Nervous System-Acting Chemicals for Law Enforcement Purposes: 2 December Conference of States Parties CSP- 21: 29 November–2 December 2017 Joint Paper, Aeroslisation of Central Nervous System-Acting Chemicals for Law Enforcement Purposes: 28 November Conference of States Parties CSP-22: 27 November–1 December

Appendix: Timelines of Some Relevant Events and Documents

197

2018 ABEO, Report on the Role of Education and Outreach in Preventing the ReEmergence of Chemical Weapons: 12 February United States reiterates its view that a decision should be taken that “use of CNSacting chemicals is not consistent with law enforcement” in official statement to the Review Conference: 22 November Chair of the SAB, Central Nervous System Acting Chemicals–Considerations from the OPCW Scientific Advisory Board: 28 November Conference of States Parties CSP-23: 19–30 November Fourth Review Conference RC-4: 21–30 November 2019 United States again expresses concern that “some States are deliberately developing CNS-acting chemicals for military warfare, under the guise of law enforcement.” (EC-92/NAT.13): 8 October Conference of States Parties CSP-24: 25–29 November

A1.3 The Brain Projects and Associated Documents 2013 Launch of the US BRAIN Initiative: April Launch of the EU Human Brain Project: October 2014 US NIH publishes BRAIN 2025: A Scientific Vision: June Launch of Japan’s Brain/MINDS Project: June Philosophical Transactions of the Royal Society publishes an article by Jorgenson et al on the US BRAIN Initiative titled The Brain Initiative: Developing Technology to Catalyse Neuroscience Discovery: 23 December 2015 Philosophical Transactions of the Royal Society publishes an article by Okano et al on Brain/MINDS: brain-mapping project in Japan: 29 January 2016 China Brain Project Approved: March Neuron publishes an article by Miller et al on Marmosets: A Neuroscientific Model of Human Social Behavior: 20 April Korean Brain Initiative Announced: May

198

Appendix: Timelines of Some Relevant Events and Documents

Neuron volume 92 publishes descriptions of the Brain Projects under title Global Neuroscience: 2 November Neuron volume 92 includes paper by Greely et al on Neuroethics in the Age of Brain Projects: 2 November 2017 Neuroethics publishes an article by Palchik et al titled Monkey Business? Development, Influence, and Ethics of Potentially Dual-Use Brain Science on the World Stage: 11 February US HDIAC Journal publishes a paper by Giordano on Battleship Brain: Engaging Neuroscience in Defense Operations, includes a table on “Weaponizable NeuroS/T”: Winter Issue 2018 The Atlantic publishes an article by Zhang titled China is Genetically Engineering Monkeys with Brain Disorders: 8 June OECD holds a workshop meeting in Shanghai on Minding Neurotechnology: Delivering Responsible Innovation for Health and Well-Being: 6–7 September Neuron volume 100 publishes a paper by the Global Neuroethics Summit Delegates on Neuroethics Questions to Guide Ethical Research in the International Brain Initiative, this includes a question on misuse: 10 October Launch of the International Brain Initiative: November EU Human Brain Project publishes the Opinion on ‘Responsible Dual Use’: Political, Security, Intelligence and Military Research of Concern in Neuroscience and Neurotechnology: December Journal of Neuroscience publishes a paper by Greely et al on Neuroethics Guiding Principles for the NIH BRAIN Initiative, these include attending to the possible malign misuse of neuroscience: 12 December 2019 Neuron publishes a set of papers in which the various Brain Projects provided answers to the questions on neuroethics set out in the journal in October 2018: 6 February US NIH announces two Requests for Applications on expanding marmoset colonies and creating a marmoset coordination center: 2 July The US Brain Initiative publishes The BRAIN Initiative and Neuroethics: Enabling and Enhancing Neuroscience Advances for Society. This report states that “At present, the BRAIN Initiative does not have a formal dual-use education and awareness training programme. Development of such materials could be integrated into BRAIN 2.0”: 11 October OECD publishes the Recommendation of the Council on Responsible Innovation in Neurotechnology which includes “Anticipate and monitor the potential unintended use or misuse of neurotechnology”: 11 December

Appendix: Timelines of Some Relevant Events and Documents

199

2020 PRISM the US Journal of Complex Operations publishes a paper by DeFranco et al on Redefining Neuroweapons: Emerging Capabilities in Neuroscience and Neurotechnology: January

Index

Page numbers followed by f indicate figures; those followed by t indicate tables. A Acetylcholine neurotransmitter, 101 Action, 180 Active learning methods, 26, 89 Adolphs, R., 177 Advantages and Limitations of Calmatives for Use as a Non-Lethal Technique, The (2000), 102 Advisory Board on Education and Outreach (ABEO), 25, 26t, 121, 180 Advisory Codes, 44, 166 Advisory Committee to the NIH Director (ACD), 100, 121 Aerosolisation of Central Nervous SystemActing Chemicals for Law Enforcement Purposes (2015), 25 Aerosolised fentanyl, 55, 106 Aggression, 110–112 Airborne transmission, 166 Alzheimer’s disease, 112 American Journal of Bioethics (2015), 185 American Psychological Association, 159 Amygdala, 62, 65–66, 108–109, 159 Anderzhanova, E., 6 Andreasen, N., 3–4, 14 Animal behaviour, 149 Animal models, 130–131 Anthrax, 128 Apes families, 131 Anticipate, Reflect, Engage and Act (AREA) approach, 85–86 Arms Control Today, 28 Aspirational Code of Conduct, 44, 166, 183

Australia, 24–25, 165 Australian Brain Alliance, 118 Autism, 110, 160 Averting the Hostile Applications of Biotechnology (Meselson), 175 Avian influenza, 166 Awake state, 8, 8t, 11 Awareness, 162–164, 180

B Bartolucci, V., 35 Basal Ganglia (BG), 59, 141–142 Basal Lateral Amygdala (BLA), 109 Bateson, P., 129 Bellamy, A., 179 Belmont Report, 37 Bianchi, D., 100 Biodefense strategy, goals of (US), 123–124t Biodefense Summit (2019), 123 Biological and Toxin Weapons Convention (BTWC), 18, 19–22, 34, 90, 116, 121, 122, 144, 176, 179, 183, 187, 190 8th Five Year Review Conference of, 20 Depositary Working Paper, 20–21 Implementation Support Unit in Geneva, 33, 43 meetings and associated documents, 195–196 strengthening, 185t, 190 Biological mechanisms, 156 Biological security, 144, 182, 189–190 Biosecurity education, 166–167

© Springer Nature Switzerland AG 2020 M. R. Dando, Neuroscience and the Problem of Dual Use, Advanced Sciences and Technologies for Security Applications, https://doi.org/10.1007/978-3-030-53790-6

201

202 Biven, L., 57 Blood-Brain Barrier, 59, 60, 67, 178 Bolton, J., 27 Brain acetylcholine system of, 101 basal ganglia of, 141–142 disorders, early diagnosis and intervention of, 153 evolution of, 131–132, 142 healing, 3–7 of human beings and macaque, differences, 150 orexin receptor in, 61 recording of activity, 60 research, for people with mental illnesses and injuries, 3 social decision-making and, 157 understanding structure and function of, 118 use of imaging, 6 BRAIN 2025: A Scientific Vision report, 97 BRAIN Initiative and Neuroethics, The (2019), 189 BRAIN Initiative, US, 4, 36, 95–112 agents and receptors for production of Calmative State, 103t articles on (2016), 117t developing technology to catalyse neuroscience discovery, 176 and dual use, 100–106, 121, 189, 189t ethical goals of, 98t Guiding Principles for NIH Initiative, 99t hypocretin system within, 107–108 neuroethics developments in, 97–100 objectives (2019), 102t opioid receptors, structure and function of, 103–106 research on NHPs, 133 research on sleep/fear/aggression, 107– 112 Brain Mapping by Integrated Neurotechnologies for Disease Studies project.See Brain/MINDS project Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative.See BRAIN Initiative, US Brain Waves Module 3 on Neuroscience, conflict and security (2012), 23 Brain/MINDS Beyond project, 136, 138– 139 research groups of, 139t sections of innovative Research Group, 140t

Index Brain/MINDS projects and associated documents, 197–199 four major groups, 118 neuroethics in (2019), 119–121 objectives (2016), 117–119. See also China’s Brain Project (CBP); Human Brain Project (HBP), EU; Japan’s Brain Project Brave New Brain: Conquering Mental Illness in the Era of the Genome (Andreasen), 3 Brenton, A., 28 Bromocriptine, 60 Brose, K., 35 BTWC.See Biological and Toxin Weapons Convention (BTWC) BW agents, 39, 55, 176 BZ (3-quinuclidinyl benzilate), 101, 104

C Callithrix jacchus, 134 Calmative state, 103 Cannabinoids, 104 Caspi, A., 159 Cataplexy, 13, 61–64, 107–108 Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), 153 Central Nervous System (CNS), 117, 178, 187 acetylcholine system within, 101 acting chemicals, 24, 77, 78t, 89, 134, 138 agents affecting, 55, 102 dopamine system in, 58 operations of, 6 Chemical and Biological Non-Proliferation Regime (2018), 17–18, 27, 116, 190 BTWC, 19–22 CWC, 23–26 Novichocks, 26–29 Chemical Terrorism Risk Assessment, 96 Chemical Warfare Laboratories, 133 Chemical Weapons Convention (CWC), 18, 23–26, 34, 45, 67, 90, 116, 122, 134, 176, 179, 181, 187, 190 4th review conference, 77t Article IX, 28, 28t meetings and associated documents, 196–197 Chimpanzees, 131 China

Index codes of conduct, 43–48, 45t, 164 and dual use, 164–169 Institute for Brain Research, 154 China’s Brain Project (CBP), 151–156 article on, 120 description of, 151t design of, 152f dual-use implications of, 164–169 early diagnosis and intervention of brain disorders, 153 examples of investigations, 160–164 genome editing technology, 160–162 introduction, 149–151 key points of, 154t macaque neuroscience, 156–160 neural circuit mechanisms of cognition, 152–153 new research institute for, 154–155 NHPs research, 151, 153, 155–156 research on consciousness and selfawareness, 162–164 Chinese Academy of Sciences (CAS), 153 Cho, M. K., 185 “Cholinergic signalling controls conditioned-fear behaviors” (2016), 109 Circuits modulation of, 158–159 of neurons, 157–158 Civil biotechnology, revolution in, 18 Clapper, J. R., 19 Claustrum, 162 Clozapine-N-oxide (CNO), 11t CNS.See Central Nervous System (CNS) Codes of conduct development, Tianjin (China), 43–48, 44t discussions on, 88, 164–169, 165t, 183 Cognition, neural circuit mechanisms of, 118, 152–153, 154 Cognitive neuroscience, 67 Cold War, 34, 48, 55, 56t, 101, 106, 155, 179 Collingridge Dilemma, 86 Complex social behaviour, in primates, 143, 155–158 Compliance management, and broader question of ethics and society, 85 Consciousness and awareness, 162–164 “Consciousness: New Concepts and Neural Networks” (2019), 162 Corporate Social Responsibility, 186 Cortex, 59, 131–132, 140 COVID-19 outbreak, 190

203 Cre recombinase, 10 CRISPR/Cas genome editing technology, 20, 22, 41, 90, 161–162, 169, 187 Croatian Society for Biosafety and Biosecurity, 38 Croft, S., 184 Cerebrospinal Fluid (CSF), 159 CWC.See Chemical Weapons Convention (CWC) Cytotoxic CD8 T cells, 64

D Dan, Y., 7 Declaration Assessment Team (DAT), 28, 29 De Waal, F., 156, 164 Deep brain stimulation, 59 Default Mode Network (DMN), 163 Defence Science and Technology Laboratory, UK, 55 Defense Advanced Research Projects Agency (DARPA), US, 97, 98–99, 110 Degradation market, 24, 97, 104 Dementia, 112 Department of Defense (DoD), US, 96 Department of Homeland Security (DHS), US, 96 Depression, 4, 130 Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) technology, 10, 11t Development, Historical Use and Properties of Chemical Warfare Agents (2016), 26 Diagnostic and Statistical Manual (DSM), 4 Diphtheria toxin A (DTA), 12 Disordered Mind: What Unusual Brains Tell Us about Ourselves, The (Kandel), 130 Disorders of Conscious (DOC), 163 Division of Neurological Psychiatric and Brain Research of Japan Agency of Medical Research and Development (AMED), 138 Dopamine, 58–59, 140t, 141 Dorsal anterior cingulate cortex (dACC), 158 Doxycycline (DOX), 12–13 Drosophlia, 5HT receptor role in sleep homeostasis in, 155 Drug delivery, Parkinson’s Disease and, 58– 60

204 Dual use assessment of progress in dealing with, 121 BRAIN Initiative and, 100–106, 189t of brain projects in Japan, 142, 144 China and, 164–169 dangers of, 133–134 governance of, 38–42, 41t, 88t Human Brain Project and, 83–87 international brain projects and, 181t neuroethics and, 35–42, 144 problem of, 180–181, 184 Dual Use in Neuroscientific and Neurotechnological Research (2017), 86 Dual Use Research of Concern (DURC), 20, 100–101 concept of, 184, 188 policies, 38–39 Dual Use Research of Concern in the Life Sciences (2017), 180

E Eastern Equine Encephalitis, 128 Education about biosecurity, 21, 22, 43, 46, 166– 167 and codes of conduct, 144, 190 and engagement, 98 about problem of dual use, 42 about risks and benefits of life sciences, 167 and training, 39, 46, 88t, 120, 169 Education and Outreach (E&O) theory and practice, 25 Electroencephalography (EEG), 8, 60, 63 Ethical, Legal, Social, Implications (ELSI) approach, of Human Genome project, 85 Emerging Cognitive Neuroscience and Related Technologies (2008), 58, 66, 104 Emotional arousals, types of, 57 Emotional primitives, 57 Enforceable Codes, 44, 166 Engagement and education, 98 Ethical competence, in dual use research, 42, 180 EU Human Brain Project (HBP).See Human Brain Project (HBP), EU Evans, S. W., 42 “Ever-growing opioid chemical threat agents”, 96

Index Evolution, of brain, 131–132, 142 Excessive Daytime Sleepiness (EDS), 108

F Fabrication, Falsification and Plagiarism (FFP), 186 Fear, 57, 65, 109 Fentanyl, 24, 54, 89, 96–97, 103–104, 106 Fact-Finding Mission (FFM), 28, 29 Fifth Five Year Review Conference (2001), 164 5HT receptor in sleep homeostasis, in Drosophlia, 155 Ford, CA, 122 Forecasting technology change, 54–58, 55t Foreign Affairs journal, 76 Foreign Secretary, UK, 164 Fourth Review Conference of the Chemical Weapons Convention (2018), 95–96 Freezing suppression, 65 Fu Cong, 43 Fuller, P., 9, 11 Functional Magnetic Resonance Imaging (fMRI), 157, 163 Futures journal, 85

G G times E (Gene times Environment) interaction, 160 Gamma aminobutyric acid (GABA) neurons, 9–10, 103t, 108, 141 Galston, A., 185 Gene-edited NHP models, of brain diseases, 153 Genes, 159–160 Geneva Protocol (1925), 19, 185 Genome editing technology, 19–20, 160– 162, 161t Germany, 26–27 Gibbons, 131 Gill, S., 21 Giordano, J., 37–38, 86, 99, 124, 187 Global neuroethics articles on (2019), 119t assessment of progress in dealing with dual use, 121 Brain initiatives articles (2016), 117t hybrid warfare and chemical and biological weapons, 124–125 neuroethics in brain projects (2019), 119–121

Index

205

objectives of brain projects (2016), 117– 119 strategic interactions (2019), 121–123 Global Neuroscience (2016), 36 Globalization, Biosecurity, and the Future of the Life Sciences (2006), 42 Globus Pallidus interna (GPi), 141 Glutamate neurons, 10 Goering, S., 36 Gorillas, 131 Governance of Dual Use Research in the Life Sciences (2018), 38 G Protein Coupled Receptors (GPCRs), 57 Grady, C., 97 Greely, H., 36, 97 Guardian, headlines in (2017–18), 76t GV nerve agent, 27 H H1N1 influenza epidemic, 63 Hague Ethical Guidelines, 45, 45t, 48 Hemagglutinin (HA), 64 Herbicides, 185, 187 Higher brain functions in primates, 142–143 Hijacking of Basic Research: The Case of Synthetic Cannabinoids (2011), 104, 105f Holistic Arms Control (HAC), 34, 34t Human brain and genome, 3–7 Human Brain Project (HBP), EU, 36, 79–83, 118, 120, 178 article on, 120 bodies responsibility, 83 CoDesign Projects, 81 dealing with dual use, 83–87, 87t feature of, 118 in mid-2018, 81t Opinion on ‘Responsible Dual Use’ from, 87 Partnering Projects, 81, 82t recommendations for, 87–88, 87t series of work packages, 84t Huntington’s disease, 130 Hybrid warfare and chemical and biological weapons, 124–125 Hypocretin (Hcrt).See Orexin (OX) Hypothalamus, 8, 11, 62, 64, 107, 162 I International Atomic Energy (IAEA), 180 Illicit market for drugs, 104

Agency

Incapacitating chemical agents, 23–24, 60, 90, 104, 181 Incapacitating Chemical Agents: Implications for International Law (2010), 23 Incapacitation, 103, 106, 108 Influenza A virus antigens, 64 Institute of Neuroscience of Chinese Academy of Sciences, 153 Intelligence Advanced Research Projects Agency (IARPA), 99, 110 InterAcademy Panel, 38, 121, 166, 178 InterAcademy Partnership in Zagreb during 2018, 116 International Aspirational Code of Conduct, 164 International Brain Initiative (IBI), 119, 121, 139 International brain projects and dual use, 181t International Committee of the Red Cross, 23 International Nuclear Security Education Network (INSEN), 180 International system and advances, in neuroscience, 179–180 International Union of Pure and Applied Chemistry (IUPAC), 45 Iran, on CNS-acting chemicals, 96 Islamic State of Iraq and Syria (ISIS), 18 J Japanese Macaque (Macaca fuscata), 156 Japan’s Brain Project, 12, 118, 127–144, 151 ‘Brain/MINDS Beyond’ project, 136, 138–139, 139–140t dangers of dual use, 133–134 ‘Finished Research’ on Brain/MINDS website, 142t for marmoset neuroscience, 128–130 neuroethics and dual use in, 144 NHP models research, 130–133 organisational chart, 136–138, 137f research in Brain/MINDS Project, 134– 144, 135t Joiner, W., 140–141 Journal of Neuroscience, 99 Jui-lin Du, 155 K Kandel, E., 130 Kilduff, T., 7

206 Korean Brain Initiative, article on, 120 Krishnan, A., 49 Kuhlau, F., 42, 88, 180 Kuroki, T., 186 L Laboratory for Symbolic Cognitive Development, 143 Lancet: Neurology, The, 80 Language, 134, 144 Law enforcement chemical agents, 24–25, 77, 78 L-Dihydroxyphenylalanine (L-DOPA), 59– 60 Locus Coeruleus (LC) noradrenaline producing cells of, 107– 108 operations of, 109, 155 “Looking for Neuroethics in Japan” (2018), 144 Lorenz, K., 57 Luo Minmin, 154, 155 M Macaque monkeys circuits of neurons, 157–158 genetics underlying neuronal circuits and behaviour, 159–160 modulation of circuits, 158–159 nervous system and behaviours of, 155 neuroscience, 156–160. See also NonHuman Primates (NHPs) Malodorant chemical agents, 67 Mandelbaum, M., 122 Marburg Virus, 128 Markram, H., 79 Marmoset neuroscience, Japan’s national brain project for, 129–130 Mass destruction, 18, 125 Meeting of States Parties (MSP), 22, 43, 77, 121, 164–168, 181, 183t Meetings of Experts (MXs), 21–22, 43, 44, 90 Melioidosis, 128 Meselson, M., 17–18, 136, 175, 183 Military forecasting methodology, 55t Military Neuroscience and the Coming Age of Neurowarfare (2018), 49 Min Xu, 155 Mind Wars: Brain Research and National Defense (2006), 35 Mirror test, for monkeys, 163–164

Index Mirzayanov, V., 27 Modern neuroscience, 3–14 Moffitt, T. E., 159 Monoamines and anti-depressants localisations generation of whole brain atlas for, 140t Moreno, J., 35 Moscow theatre siege (2002), 23, 60 Movement disorders, 59, 130 Mu receptor, 103 Multi-Council Working Group (MCWG), 98, 120 Muscarine, 101 Muscular paralysis, 107 N Nabekura, J., 139 Nanotechnology, 59–60 Narcolepsy, 61–64, 107–108 National Academies (US), 19, 38, 124, 133, 185 National Academy of Sciences, in Washington D.C., 123 National Biodefense Strategy, US, 123, 123–124t National Defense Medical College (NDMC), Japan, 166–167 National Institute for Physiological Sciences, Japan, 138 National Institute of Mental Health, US, 4, 5 National Institutes of Health (NIH), US, 56, 97 National Scientific Academies, 34 National Security Strategy of the United States of America (2017), 18 Nature report, 80, 154, 155 Naughton, J., 53–54 Neocortex, 132 Nerve agents, 26–27 Netherlands, the codes of conduct development, 166 “Raising Awareness” element, 46 Working Paper at 2008 Meeting of Experts, 44, 166 “Neurodegenerative Disease Marmoset Models”, 136 Neuroethics in brain projects (2019), 119–121 code of conduct development, Tianjin (China), 43–48, 44t concerns, 35t developments, in BRAIN Initiative, 97– 100

Index and dual use, 35–42, 144 introduction, 33–35 and regulation of misuse, 33–49 role for, 183–189. See also Global neuroethics Neuroethics and Responsible Research and Innovation Committee (NRRIC), 119 Neuroethics and the NIH BRAIN Initiative (2017), 97 Neuroethics: Anticipating the Future (2017), 34 Neuroethics in the Age of Brain Projects (2016), 36, 97, 119 “Neuroethics Questions to Guide Ethical Research in the International Brain Initiatives” (2018), 115, 116t “Neuroethics: Think Global”, 180 Neuroethics Working Group (NEWG), 100, 119, 121 Neuroethology of primate social behavior review (2013), 156 Neuromodulators, 58 Neuron (journal), 35–36, 115, 151, 155, 180 articles on Brain initiatives in (2016), 117t articles on global neuroethics in (2019), 119t Neuronal circuits, 157–158 modulation of, 58–66 understanding of, 58 Neuropeptide oxytocin, 110 Neuroscience defined, 7 international system and advances in, 179–180 towards mechanistic, 7 modern, 3–14 revolution in, 14 sleep research, 7–13 and technology (neuroS/T), 124 “Neuroscience Needs Behavior: Correcting a Reductionist Bias” (2017), 143 Neuroscientists, role of, 180–182 Neurotechnology, OECD recommendations for preventing misuse of, 182t Neurotransmitters, 101, 104, 107–108, 139 New Atlanticist, 179 New Nationalism, The, 121–122 New Technologies for Elucidating Opioid Receptor Function (2016), 106 New York School of Medicine, 110 NHPs.See Non-Human Primates (NHPs)

207 Non-human Primate Models for Brain Disorders—Towards Genetic Manipulations via Innovative Technology (2017), 160 Non-Human Primates (NHPs) brain structures and functions of human and, 132 complex social behaviour in, 143, 155– 158 genome editing of, 151 models, 158–159, 161 neuroethical issues in NHP research, 139 in neuroscience research, 38 rapid evolution of capabilities to manipulating genomes, 161t research on, 118, 129–133, 153, 159 role in study of human diseases, 151 study of brain and behaviour in, 128, 132–133 use of CRISPR/Cas-mediated genome editing on, 162 Non-lethal CNS-acting chemical agents, 134 Non-Rapid Eye Movement (NREM) sleep, 8, 8t, 12, 60, 140 Norepinephrine (noradrenaline), 107–108, 139, 140t Norrlof, C., 121–122 Novel CNS-acting chemicals, 134 Novichoks, 26–29, 190 NREM sleep, 8, 8t, 12, 60, 140 National Science Advisory Board for Biosecurity (NSABB) in the United States, 166 Nuclear weapons, 18, 176 O Observer, headlines in (2017–18), 76t Okabe, S., 136 Okano, H., 134 Olfaction, 159 On Being a Scientist: Responsible Conduct in Research (2009), 185–186 Ono, D., 12 Open-Ended Working Groups (OEWGs), 20–21 on Future Priorities for 4th Review Conference, 78 Open Forum on the Chemical Weapons Convention (hosted by Technical Secretariat), 23 Operational neurotechnology risk assessment and mitigation paradigm (ONRAMP), 99

208 Opiate fentanyl, use of, 23, 60 Opioid receptors, structure and function of, 103–106 Optogenetics, 62, 109 Orangutans, 131 Orexin (OX), 11–12, 60–64, 107–108, 139, 155 Organisation for Economic Cooperation and Development (OECD), 164, 182 Organisation for the Prohibition of Chemical Weapons (OPCW), 23, 29, 180 Executive Council of, 25 Scientific Advisory Board of, 24, 77–78 ORX2, 11 OXR1, 11 Oxytocin (OXT), 64–66, 110–111, 144 effect on neuronal mechanisms, 158–159 receptors (OXTRs), 159

P Pallidium, 59 Pandemrix, 63 Panksepp, J., 6, 57, 128 Paraventricular nucleus of the thalamus (PVT), 162 Parkinson’s disease, 58–60, 130, 140–142 Passingham, R., 150 Pennsylvania State University College of Medicine, 102 Petro, J. B., 176 Pharmacological treatments, 7 Philosophical Transactions of the Royal Society (2015), 129, 176 Phosphorylation signals, 140t Physical distress, 133 Poblete, Y. D. S., 122 Political, Security, Intelligence and Military (PSIM) system, 84 Pontine neurons, 62 Poo, Mu-ming, 151, 153–154, 155, 163 Preparatory Committee for the Seventh Review Conference (2016), 167 Preuss, T., 132 Prisoners Dilemma game, 158 “Psychiatric and Neurological Disorders” research programme, 138 Psychiatric disorders, 136, 138t Psychoactive drugs, pharmacological mechanisms of, 140t Psychotomimetic drugs, 133

Index Q Questionable Research Practice (QRP), 186

R Ragan, I., 129 Ramos, K., 97, 98 Rao Y. I., 154, 155 Rapid Eye Movement (REM) sleep, 8, 8t, 12, 60, 63, 107, 140 Rappert, B., 166 Re-Learning a Competitive Mindset in Great-Power Competition (Ford), 122 Reflection, 180 Relman, D. A., 37 REM sleep, 8, 8t, 12, 60, 63, 107, 140 “Replace, Reduce and Refine” idea, 42 Research Domain Criteria (RDoC) approach, 4–7, 108, 128 dimensions and constructs, 5t units of analysis, 5t Research misconduct, classification of, 186– 187, 187t Responsible Conduct of Research, 189 Review Conference of the Chemical Weapons Convention (2018), 89 Review of Research Using Non-Human Primates (2011), 129 Revill, J., 184 Rhesus monkey (Macaca mulatta), 156 Rhythmic movements, 57 RIKEN Center for Brain Research, 136 Risks of 2020 (ten), 179t Roadmap for Mental Health Research (ROMER) strategy, 6–7 Ropinirole, 60 Rose, S., 34 Russia, 27, 46, 46t Russian Federation, 165 Ryabkov, S., 49

S Sankar, P. L., 185 Saper, C., 9, 11 Schizophrenia, 4, 130, 133 Science and Social Responsibility: A Case History (Galston), 185 Scientific Advisory Board of OPCW, 24, 77–78 Scientific community, 25, 26t, 37, 133, 165, 169

Index Second Intersessional Process States Parties, 165 “See no evil” syndrome, 29–30 Self-awareness, consciousness and, 162– 164 Serotonin, 140t role in regulation of defensive behaviour in mice, 155 transporter mechanism, 159 Shanghai Institute for Biological Sciences, 161, 163 Shanghai Research Centre for Brain Science, 155 Sims, N., 184 Skripal, S., 26, 28 Skripal, Y., 26, 28 Sleep neurobiology of, 7–13 paralysis, 61 state, 8, 8t types of, 60 and wake mechanism, 61–62, 107, 140 Sleep Medicine Reviews, 108 Social decision-making stages, 157, 157t Social learning, 143 Social responsibility analytical framework, 185–186, 186t Stakeholders, 25, 100, 187–189 States Parties Meeting, 22, 43, 77, 121, 164–168, 181, 183t Stearns, T., 39, 180 Stirling, A., 29 Strategic International Brain Science Research Promotion Program (Brain/MINDS Beyond, 2018), 138 “Strategic Weapons in the 21st Century: The New Dynamics of Strategic Conflict and Competition”, 122 Strategies of Arms Control: A History and Typology (Croft), 184 Stratified medicine, 6, 7t Striatum, 59, 141–142 “Structure, Function, and Molecular Mechanisms of the Brain”, 136 Substantia nigra, 59 Substantia Nigra pars reticulata (SNr), 141 Sundowning, 112 Switzerland, 24 Syria, 18, 27, 28–29 Systems neuroscience, 7 Szilard, L., 53–54

209 T Tabuchi, S., 12 Tet-off system, 12, 13t Tetrahydrocannabinol, 139 Tianjin (China), code of conduct development in, 43–48, 44t Top down developments, 182–183 Transgenic mouse lines, 10, 10t Translatable brain markers, 135 “Triune Brain” evolutionary development of, 6 Type 1 narcolepsy, 61, 64, 107 Type 2 narcolepsy, 61 U United Kingdom ban on keeping pet primates, 150 Biological Security Strategy of 2018, 182 Defence Science and Technology Laboratory, 55 Foreign Secretary, 164 Royal Society’s Brain Waves Module, 23–24, 29, 34, 116 against Russian nerve agents, 26–27 United States Defence Analysts, 55 Defense Advanced Research Projects Agency (DARPA), 97, 98–99, 110 Department of Defense, 96 Department of Homeland Security (DHS), 96 National Academies, 19, 38, 124, 133, 185 National Biodefense Strategy, 123, 123–124t National Institute of Mental Health, 4, 5 National Institutes of Health (NIH), 56, 97 policy of containment of Soviet Union, 122. See also BRAIN Initiative, US University of Bradford, 166–167 V Van der Bruggen, K., 166 Ventrolateral preoptic area (VLPO), 61 Ventromedial hypothalamus (VMHvl) neurons, 111, 111t “Ventromedial Hypothalamus and the Generation of Aggression” (2017), 111 Vesicular GABA transporter (Vgat), 10 Vesicular glutamate transporter (Vglut), 10

210

Index

Vickers, G., 180 Vietnam War, 187 Viral transduction, genetic approaches based on, 161t VX nerve agent, 27

Working Groups (Breakout Sessions), 40, 40t World Organisation for Animal Health, 45 World Trade Organisation, 179 Worldwide Threat Assessment of the US Intelligence Community (2016), 19

W Wakefulness, 9, 12, 61, 162 Warfare, Intelligence, and National (WINS) Security operations, 124 Weaponisation of Central Nervous System Acting Chemicals for Law Enforcement Purposes (2014), 24 Weapons of mass destruction, 18, 125 “Weapons of Mass Destruction and Proliferation”, 19 Weapons systems, new forms of, 184

Y Yamanaka, A., 12 Yanka, C., 133 Yunnan Key Laboratory of Primate Biomedical Research, in Kunming, 153 Yuste, R., 36

Z Zagreb meeting, on governance of dual use, 38–42, 41t, 88t