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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Page viii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Page xiii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: 10.17226/26078.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

PREPUBLICATION COPY THE EMERGING FIELD OF HUMAN NEURAL ORGANOIDS, TRANSPLANTS, AND CHIMERAS: SCIENCE, ETHICS, AND GOVERNANCE Committee on Ethical, Legal, and Regulatory Issues Associated with Neural Chimeras and Organoids Committee on Science, Technology, and Law Policy and Global Affairs A Consensus Study Report of This prepublication version of The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance has been provided to the public to facilitate timely access to the report. Although the substance of the report is final, editorial changes may be made throughout the text and citations will be checked prior to publication.

PREPUBLICATION COPY | UNCORRECTED PROOFS THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 This activity was supported by contracts from the National Institutes of Health (Sponsor Award Number HHSN263201800029I/75N98019F00861) and The Dana Foundation. This Project has been funded in whole or in part with federal funds from the National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN263201800029I. Any opinions, findings, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project. International Standard Book Number-13: 978-0-309-XXXXX-X International Standard Book Number-10: 0-309-XXXXX-X Digital Object Identifier: https://doi.org/10.17226/26078 Cover image: High-magnification view of a neural organoid modeling early stages of development of the cerebral cortex. Image courtesy of Silvia Velasco and Paola Arlotta, Department of Stem Cell and Regenerative Biology, Harvard University Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2021 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2021. The Emerging Field Of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance. Washington, DC: The National Academies Press. https://doi.org/10.17226/26078.

PREPUBLICATION COPY | UNCORRECTED PROOFS The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies.org.

PREPUBLICATION COPY | UNCORRECTED PROOFS Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of experts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the presentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nationalacademies.org/about/whatwedo.

COMMITTEE ON ETHICAL, LEGAL, AND REGULATORY ISSUES ASSOCIATED WITH NEURAL CHIMERAS AND ORGANOIDS Co-chairs BERNARD LO (NAM), Professor Emeritus, University of California, San Francisco and President and CEO Emeritus, The Greenwall Foundation. JOSHUA R. SANES (NAS), Jeff C. Tarr Professor of Molecular and Cellular Biology and Paul J. Finnegan Family Director, Center for Brain Science, Harvard University Members PAOLA ARLOTTA, Chair, Harvard Department of Stem Cell and Regenerative Biology and Golub Family Professor of Stem Cell and Regenerative Biology, Harvard University R. ALTA CHARO (NAM), Warren P. Knowles Professor Emerita of Law and Bioethics, University of Wisconsin Law School JOHN H. EVANS, Professor; Tata Chancellor’s Chair in Social Sciences; Associate Dean of Social Sciences; and Co-director of the Institute for Practical Ethics, University of California, San Diego FRED H. GAGE (NAS, NAM), President; Professor, Laboratory of Genetics; and Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease, Salk Institute for Biological Studies HENRY T. GREELY, Deane F. and Kate Edelman Johnson Professor of Law; Professor, by courtesy, of Genetics, Stanford School of Medicine and Director, Center for Law and the Biosciences, Stanford University PATRICIA A. KING (NAM), Professor Emerita, Georgetown University Law Center WILLIAM T. NEWSOME (NAS), Harman Family Provostial Professor of Neurobiology, Stanford University School of Medicine and Vincent V.C. Woo Director, Wu Tsai Neurosciences Institute, Stanford University SALLY TEMPLE, Scientific Director, Principal Investigator, and Co-Founder, Neural Stem Cell Institute S. LAWRENCE ZIPURSKY (NAS), Distinguished Professor, Department of Biological Chemistry, University of California, Los Angeles and Investigator, Howard Hughes Medical Institute Staff ANNE-MARIE MAZZA, Study Director and Senior Director, Committee on Science, Technology, and Law STEVEN KENDALL, Program Officer, Committee on Science, Technology, and Law ANITA EISENSTADT, Program Officer, U.S. Science and Innovation Policy VERN DUNN, Program Officer, U.S. Science and Innovation Policy v

PREPUBLICATION COPY | UNCORRECTED PROOFS DOMINIC LOBUGLIO, Senior Program Assistant, Committee on Science, Technology, and Law SARAH CARTER, Consultant Writer vi

PREPUBLICATION COPY | UNCORRECTED PROOFS COMMITTEE ON SCIENCE, TECHNOLOGY, AND LAW Co-Chairs DAVID BALTIMORE (NAS/NAM), President Emeritus and Robert Andrews Millikan Professor of Biology, California Institute of Technology DAVID S. TATEL, Judge, U.S. Court of Appeals for the District of Columbia Circuit Members JOE S. CECIL, Senior Fellow, Civil Justice Research Initiative, University of California, Berkeley School of Law ERWIN CHEMERINSKY, Dean and Jesse H. Choper Distinguished Professor, University of California, Berkeley School of Law ELLEN WRIGHT CLAYTON (NAM), Professor of Law and Professor of Health Policy, Vanderbilt University Medical Center JOHN S. COOKE, Director, Federal Judicial Center JOHN DABIRI, Centennial Professor of Aeronautics and Mechanical Engineering, California Institute of Technology JENNIFER EBERHARDT (NAS), Professor of Psychology, Stanford University FEI-FEI LI, Sequoia Capital Professor, by courtesy, of Operations, Information and Technology, Stanford University JUDITH MILLER, Independent Consultant MARTHA MINOW, 300th Anniversary University Professor, Harvard Law School KIMANI PAUL-EMILE, Professor of Law, Fordham University Law School NATALIE RAM, Associate Professor of Law, University of Maryland Francis King Carey School of Law LISA RANDALL (NAS), Professor of Theoretical Physics, Harvard University PAUL M. ROMER, Professor of Economics and Director, The Urbanization Project, New York University WILLIAM B. SCHULTZ, Partner, Zuckerman Spaeder LLP JOSHUA SHARFSTEIN (NAM), Vice Dean and Professor, Johns Hopkins Bloomberg School of Public Health SUSAN S. SILBEY, Leon and Anne Goldberg Professor of Humanities, Professor of Sociology and Anthropology, and Professor of Behavioral and Policy Sciences, Massachusetts Institute of Technology SRI SRINIVASAN, Judge, U.S. Court of Appeals for the District of Columbia Circuit GREGORY STONE, Partner, Munger, Tolles & Olson LLP SUSAN WESSLER (NAS), Neil and Rochelle Campbell Presidential Chair for Innovation in Science Education, University of California, Riverside and Home Secretary, U.S. National Academy of Sciences vii

PREPUBLICATION COPY | UNCORRECTED PROOFS Staff ANNE-MARIE MAZZA, Senior Director STEVEN KENDALL, Program Officer DOMINIC LOBUGLIO, Senior Program Associate viii

PREPUBLICATION COPY | UNCORRECTED PROOFS Preface More than any other organ, the brain gives human beings their unique identities. The complexity of the human brain has perplexed researchers, and its central role in the mystery termed consciousness continues to challenge the boundaries between science and philosophy. Conversely, devastating neurological and psychiatric diseases and disorders not only cause untold suffering but can also rob people of their identity. For many of these diseases, treatments are completely unavailable, and for others they are hopelessly inadequate. Research over the past several decades has greatly advanced understanding of the brain and begun to provide new therapeutic approaches to brain diseases. However, progress in this area is stymied by the practical and ethical difficulties of studying the human brain and by serious limitations of existing tools and models. In response, researchers have worked to develop new models that promise a deeper understanding of the human brain and new treatments for brain disorders. These new models include human neural organoids, transplants of human stem cells into nonhuman animal brains, and human neural chimeras. However, as models of the brain improve to better reflect the characteristics of actual human brains, they also raise profound ethical questions. It has become clear that in using these models to advance understanding of the brain, it will be necessary to pay attention to what lessons they might teach about consciousness and what it means to be human. For the past year, at the request of the National Institutes of Health and the Dana Foundation and under the auspices of the National Academies of Sciences, Engineering, and Medicine’s Committee on Science, Technology, and Law, we co-chaired a committee of scientists, ethicists, and legal scholars that explored recent scientific advances and ethical and ix

PREPUBLICATION COPY | UNCORRECTED PROOFS governance issues associated with human neural organoids, transplants, and chimeras. The committee heard from numerous experts and reviewed relevant scientific literature, religious scholarship, and current laws and policies. We are grateful for the individuals who spoke to and engaged in thoughtful discussions with the committee. Their expertise contributed greatly to the committee’s deliberations. In particular, interactions among biomedical scientists, ethicists, religious scholars, and legal experts provided the committee with important insights. We are deeply indebted to the committee members for the time and effort they devoted to reading and reviewing background materials; preparing for discussions with invited experts; attending virtual meetings; and engaging in thoughtful, critical analysis and discussion with each other. This report is a reflection of their commitment to understanding the issues under consideration. We greatly appreciate as well the efforts of study director Anne-Marie Mazza and study staff Steven Kendall, Anita Eisenstadt, Vern Dunn, and Dominic LoBuglio and of consultant writer, Sarah Carter. Bernard Lo and Joshua R. Sanes, Committee co-chairs x

PREPUBLICATION COPY | UNCORRECTED PROOFS Acknowledgments Acknowledgment of Presenters The committee gratefully acknowledges the thoughtful contributions of the following individuals who made presentations before the committee: Megan Albertelli, Stanford University; Mark Barnes, Ropes & Gray LLP; Allan Basbaum (NAS/NAM), University of California, San Francisco; Valerie Bonham, Ropes & Gray LLP; Emery Brown (NAS/NAM/NAE), Massachusetts Institute of Technology; I. Glenn Cohen, Harvard Law School; Charles Camosy, Fordham University; David DeGrazia, George Washington University; Frans B. M. de Waal, Emory University; Nita Farahany, Duke University School of Law; Guoping Feng, Massachusetts Institute of Technology; Steven Goldman, University of Rochester Medical Center; Steven E. Hyman (NAM), Harvard University and Dana Foundation; Eva Jablonka, Tel-Aviv University; Kathleen Hall Jamieson (NAS), University of Pennsylvania; Christof Koch, Allen Institute for Brain Science; Arnold Kriegstein (NAM), University of California, San Francisco; Margaret Landi, GlaxoSmithKline; Robin Lovell-Badge, The Francis Crick Institute; Brad Margus, Cerevance; Sergiu Pasca, Stanford University; James Peterson, Roanoke College; Mu-Ming Poo (NAS), Institute of Neuroscience of the Chinese Academy of Sciences; Margaret Foster Riley, University of Virginia School of Law; Dietram Scheufele, University of Wisconsin-Madison; Bjoern Schwer, University of California, San Francisco; Anil Seth, University of Sussex; Sarra Tlili, University of Florida; Gordana Vunjak-Novakovic (NAE/NAM), Columbia University; and Carrie Wolinetz, National Institutes of Health. Acknowledgment of Reviewers This Consensus Study Report was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published report as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following individuals for their review of this report: Charles Camosy, Fordham University; Patricia Churchland, University of California, San Diego; xi

PREPUBLICATION COPY | UNCORRECTED PROOFS Ellen Wright Clayton (NAM), Vanderbilt University; I. Glenn Cohen, Harvard University; Jonathan Flint, University of California, Los Angeles; Michael Goldberg (NAS), Columbia University; Steven Goldman, University of Rochester Medical Center; Gillian Hue, Emory University; Insoo Hyun, Case Western Reserve University; Madeline Lancaster, University of Cambridge; Margaret Landi, GlaxoSmithKline; James Peterson, Roanoke College; Alex Pollen, University of California, San Francisco; Anil Seth, University of Sussex; Hongjun Song (NAM), University of Pennsylvania; and Robert Streiffer, University of Wisconsin, Madison. Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report nor did they see the final draft before its release. The review of this report was overseen by Wylie Burke (NAM), University of Washington and Thomas D. Albright (NAS), Salk Institute for Biological Studies. They were responsible for making certain that an independent examination of this report was carried out in accordance with the standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the authoring committee and the National Academies. xii

PREPUBLICATION COPY | UNCORRECTED PROOFS Contents Summary ........................................................................................................................................... 1 1 Introduction ............................................................................................................................... 18 Overview of Brain Research .................................................................................................... 19 Study Charge ............................................................................................................................ 25 Organization of the Report ...................................................................................................... 27 2 The Science of Human Neural Organoids, Transplants, and Chimeras ............................. 29 Human Neural Organoids ........................................................................................................ 39 Human Neural Transplants ...................................................................................................... 47 Human Neural Chimeras ......................................................................................................... 49 Capacities of Human Neural Organoids, Transplants, and Chimeras .................................... 51 Measuring Characteristics of Human Neural Organoids, Transplants, and Chimeras ........... 62 3 Ethical Concerns ....................................................................................................................... 67 Issues Common to All Three Models ...................................................................................... 68 Issues Specific to Human Neural Organoids, Transplants, and Chimeras ............................. 79 Ethical Issues Specific to Neural Organoids ........................................................................... 95 Summary .................................................................................................................................. 97 4 Oversight and Governance ....................................................................................................... 99 Use of Human Stem Cells ................................................................................................... 100 Informed Consent ................................................................................................................ 105 Use and Care of Animals in Research ................................................................................... 109 Use of Nonhuman Primates in Research ............................................................................... 112 U.S. Policy and Guidance Specific to Neural Transplants and Chimeras ............................. 115 Graded Oversight: A Three-Tiered Approach ....................................................................... 122 International Policy Specific to Neural Organoids, Transplants, and Chimeras ................... 124 Future Oversight .................................................................................................................... 129 5 Public Engagement.................................................................................................................. 137 Public Engagement Internationally and in the United States ................................................ 137 Potential Contribution of Social Science Research ............................................................... 140 Nomenclature ......................................................................................................................... 141 6 Findings of the Committee ..................................................................................................... 143 References ..................................................................................................................................... 155 xiii

PREPUBLICATION COPY | UNCORRECTED PROOFS Appendixes Appendix A: Biographies of Committee and Staff Members ............................................... 171 Appendix B: Committee Meeting Agendas .......................................................................... 184 xiv

PREPUBLICATION COPY | UNCORRECTED PROOFS Boxes, Figures, and Tables Boxes 2-1 The Nervous System .................................................................................................................. 31 4-1 Illustrative Oversight Scenarios ............................................................................................... 120 Figures 1-1 Human neural organoids and assembloids .............................................................................. 22 1-2 Human neural transplants and chimeras .................................................................................. 24 2-1 Architecture of the human nervous system ............................................................................. 34 2-2 Cells of the nervous system ..................................................................................................... 35 2-3 Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)............................. 40 2-4 Use of induced pluripotent stem cells ( iPSCs) to analyze mechanisms of brain disease ...... 43 2-5 Distinct evolutionary views of consciousness ....................................................................... 58 Tables 3-1 The Three R’s........................................................................................................................... 87 4-1 Oversight of Research Based on the Use of Human Stem Cells ......................................... 103 4-2 Oversight of Research on Human Neural Cell Transplants and Neural Chimeras ............... 116 4-3 Examples of Human Neural Organoid, Transplant, and Chimera Research Subject to Different Levels of Scrutiny .................................................................................................. 123 xv

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Each year, tens of millions of individuals in the U.S. suffer from neurological and psychiatric disorders including neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease, and psychiatric disorders such as autism spectrum disorder, depression and schizophrenia. Treatments for these diseases are often completely lacking or only partially effective, due in large part to the difficulty of conducting brain research and the complexity of the brain itself.

Researchers in recent years have developed new models to better represent and study the human brain. The three models considered in this report, all of which generate and use pluripotent stem cells from healthy individuals and patients, are human neural organoids, human neural transplants, and human-animal neural chimeras. The Emerging Field of Human Neural Organoids, Transplants, and Chimeras: Science, Ethics, and Governance reviews the status of research, considers its benefits and risks, discusses associated ethical issues, and considers governance mechanisms for this type of research.

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