National Academies Press: OpenBook

Heritable Human Genome Editing (2020)

Chapter: Front Matter

Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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Suggested Citation:"Front Matter." National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.
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PREPUBLICATION COPY Heritable Human Genome Editing International Commission on the Clinical Use of Human Germline Genome Editing A Consensus Study Report of the and This prepublication version of Heritable Human Genome Editing 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 Contract No. HHSN263201800029I / Order No. 75N98019F00852 from the U.S. National Institutes of Health, Grant No. 2019 HTH 009 from the Rockefeller Foundation, and Grant 218375/Z/19/Z from the Wellcome Trust, with additional support from the Royal Society of the U.K., the Cicerone Endowment Fund of the U.S. National Academy of Sciences, and the NAM Initiatives Fund of the U.S. National Academy of Medicine. 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/10.17226/25665 Library of Congress Control Number: xxxxxxxx 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 2020 by the National Academy of Sciences and the Royal Society. All rights reserved. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of the license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/. Printed in the United States of America Suggested citation: National Academy of Medicine, National Academy of Sciences, and the Royal Society. 2020. Heritable Human Genome Editing. Washington, DC: The National Academies Press. doi: 10.17226/25665.

PREPUBLICATION COPY | UNCORRECTED PROOFS INTERNATIONAL COMMISSION ON THE CLINICAL USE OF HUMAN GERMLINE GENOME EDITING KAY E. DAVIES, D.Phil. (Co-Chair), Professor of Genetics, University of Oxford, U.K. RICHARD P. LIFTON, M.D., Ph.D. (Co-Chair), President, The Rockefeller University, USA HIDENORI AKUTSU, M.D., Ph.D., Director, Department of Reproductive Medicine, National Center for Child Health and Development, Japan ROBERT CALIFF, M.D., Verily Life Sciences, USA DANA CARROLL, Ph.D., Distinguished Professor, University of Utah School of Medicine, USA SUSAN GOLOMBOK, Ph.D., Professor of Family Research and Director of the Centre for Family Research, University of Cambridge, U.K. ANDY GREENFIELD, Ph.D., Programme Leader, MRC Harwell Institute, U.K. RAHMAN A. JAMAL, M.D., Ph.D., Professor of Paediatric Haematology, Oncology and Molecular Biology, Universiti Kebangsaan Malaysia JEFFREY KAHN, Ph.D., M.P.H., Andreas C. Dracopoulos Director, Berman Institute of Bioethics, Johns Hopkins University, USA BARTHA MARIA KNOPPERS, JD, Ph.D., Director of the Centre of Genomics and Policy and Canada Research Chair in Law and Medicine, McGill University, Canada ERIC S. LANDER, Ph.D., President and Founding Director, Broad Institute of MIT and Harvard University, USA JINSONG LI, Ph.D., Professor, State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, China MICHÈLE RAMSAY, Ph.D., Director and Research Chair, Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, South Africa JULIE STEFFANN, M.D., Ph.D., Professor of Genetics and Head of the Molecular Genetics Department, Paris University and Necker-Enfants Malades Hospital, France B.K. THELMA, Ph.D., Professor, Department of Genetics, University of Delhi, India DOUG TURNBULL, M.D., Ph.D., Director, Wellcome Trust Centre for Mitochondrial Research and Professor of Neurology, Newcastle University, U.K. HAOYI WANG, Ph.D., Professor, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, China ANNA WEDELL, M.D., Ph.D., Professor and Head of Clinic, Centre for Inherited Metabolic Diseases, Karolinska Institute and Karolinska University Hospital, Sweden Study Staff KATHERINE W. BOWMAN, Senior Program Officer (Commission Co-Director), NAM/NAS JONNY HAZELL, Senior Policy Adviser (Commission Co-Director), The Royal Society MEGHAN ANGE-STARK, Associate Program Officer, NAM/NAS (from Januray 2020) SARAH BEACHY, Senior Program Officer, NAM/NAS CONNIE BURDGE, Policy Adviser, The Royal Society DEBBIE HOWES, Personal Assistant and Events Coordinator, The Royal Society STEVEN KENDALL, Program Officer, NAM/NAS DAVID KUNTIN, Intern (April-July 2019), The Royal Society DOMINIC LOBUGLIO, Senior Program Assistant, NAM/NAS (from November 2019) iii

PREPUBLICATION COPY | UNCORRECTED PROOFS ROB QUINLAN, Intern (July-September 2019), The Royal Society FLANNERY WASSON, Senior Program Assistant, NAM/NAS (until November 2019) ISABEL WILKINSON, Intern (September-December 2019), The Royal Society EMMA WOODS, Head of Policy, The Royal Society Consultants STEVE OLSON, Writer iv

PREPUBLICATION COPY | UNCORRECTED PROOFS INTERNATIONAL OVERSIGHT BOARD VICTOR DZAU, M.D. (Co-Chair), President, National Academy of Medicine JOHN SKEHEL, Ph.D. (Co-Chair), Former Vice-President and Biological Secretary, The Royal Society ARNAUD BERNAERT, MBA, Head of Shaping the Future of Health and Healthcare, World Economic Forum CARLOS HENRIQUE BRITO DE CRUZ, D.Sc., Scientific Director, São Paulo Research Foundation and Professor, University of Campinas SUZANNE CORY, Ph.D., Professor, Walter and Eliza Hall Institute of Medical Research and Past President, Australian Academy of Science FELIX DAPARE DAKORA, Ph.D., South African Research Chair in Agrochemurgy and Plant Symbioses, Tshwane University of Technology and President, African Academy of Sciences JEREMY FARRAR, Ph.D., Director, The Wellcome Trust JIM KIM, M.D., Ph.D., Vice Chairman and Partner, Global Infrastructure Partners MARCIA MCNUTT, Ph.D., President, National Academy of Sciences QI ZHOU, Ph.D., Professor and Deputy Secretary-General, Chinese Academy of Sciences VENKATRAMAN RAMAKRISHNAN, Ph.D., President, The Royal Society K. VIJAY RAGHAVAN, Ph.D., Principal Scientific Adviser, Government of India JANET ROSSANT, Ph.D., President and Scientific Director, The Gairdner Foundation and Professor, University of Toronto RAJIV SHAH, M.D., President, The Rockefeller Foundation IOB Staff ANNE-MARIE MAZZA, Senior Director, Committee on Science, Technology, and Law, NAM/NAS v

PREPUBLICATION COPY | UNCORRECTED PROOFS Special Acknowledgments We are immensely grateful for the dedication and talent brought to bear on the work of this Commission by our fellow commissioners, the exceptional staff members of the NAS and the Royal Society, the external reviewers and monitors, and the many scientists, clinicians, and people with inherited disorders who have generously lent their time and insight to this project. All have far exceeded what we ever could have asked of them. Finally, we thank the members of the International Oversight Board for this study, who ensured that our report underwent a rigorous process of information gathering and external review prior to publication. With gratitude and admiration, Kay E. Davies, D.Phil. (co-chair) Richard P. Lifton, M.D., Ph.D. (co-chair) vi

PREPUBLICATION COPY | UNCORRECTED PROOFS Foreword The appointment of this Commission and the beginning of its deliberations occurred at a time when the reported birth of the “CRISPR babies” in China was fresh in many minds. This event made clear the absence of broad international consensus regarding both the societal acceptability of particular applications of heritable human genome editing (HHGE) and the scientific evidence that would be needed to demonstrate that HHGE could be done safely. It was recognized that, without evidence of high efficiency and specificity to ensure that only the desired changes were introduced into the genome, there was continuing risk of ad hoc editing efforts that could cause significant harm to individuals. Moreover, given that heritable changes would be introduced that could be passed to subsequent generations, it was clear that careful consideration would need to be given to the specific applications of the editing technology. During the preparation of this report, pressing issues have intervened. With the emergence of the SARS-CoV2 coronavirus, the world’s attention has been focused on the health, economic and social consequences of the devastating Covid-19 pandemic, including the social inequalities of its impact in many countries. With intense protests that have taken place in many countries, the world’s attention has also been focused on calls for changes to address racial injustice and inequities. These twin upheavals have underscored that we live in an interconnected world, where what happens in one country touches all countries, and that science occurs in a societal context. Although of a very different nature, the potential use of HHGE is an issue that transcends individual countries, deserves wide-ranging global discussions, and entails important issues of equity. Genetic diseases can impose a major burden on families. For many prospective parents, viable options for having genetically-related unaffected children are already available; but for others, due to genetics or reduced fertility, current alternatives may never be successful. HHGE might, in the future, provide a reproductive option for such couples. At the same time, it is important to recognize that the idea of making intentional modifications to the human germline evokes to some the eugenics movements of the late 19th century and first half of the 20th century, which promoted now-discredited theories that led to the persecution of whole groups, based on race, religion, class, and ability. Should any nation decide to permit HHGE, it is vitally important that bias and discrimination be avoided. In addition, there must be constraints that prevent the use of HHGE for cases that are not medically justified interventions and not based on a rigorous understanding of genetics. Great caution must also be taken in the development of genetic technologies like HHGE, fundamentally because of the personal and social contexts and broader societal and ethical issues that surround their application. Proposed uses of these technologies must reflect the conditions and needs of diverse human populations around the world. They should be deployed in ways that prevent harm and ensure equitable access to their benefits. The technologies themselves and the rigorous oversight structures established to regulate their use should be developed in ways that respect the human rights and inherent dignity of all persons. The Commission is concerned that both the development and use of HHGE and allied assisted reproductive technologies (ARTs) must be properly regulated and overseen. In particular, it is important to avoid irresponsible practices in the use of HHGE. In making its recommendations, this Commission has taken into account the unfortunate fact that the practice of ART around the world too often lacks appropriate oversight. vii

PREPUBLICATION COPY | UNCORRECTED PROOFS Matters of equitable access are of course also raised by other ARTs and by healthcare in general, but these issues deserve note here. There is no doubt that the economic costs of developing and using the technology will be substantial. Moreover, since there are already viable alternatives for prospective parents to have genetically-related, unaffected offspring in the vast majority of cases, the benefits will accrue to very few prospective parents. Nonetheless, it is possible that HHGE might someday become sufficiently safe, robust and efficient to be routinely applied in conjunction with ART to provide an improved option that would reduce the burden to women of repeated cycles of ovarian stimulation. Equitable access is the province of national jurisdictions, and the Commission recognizes the cost of development and the breadth of access to be issues that must be considered. The Commission was specifically tasked with defining a responsible pathway for clinical use of HHGE, should a decision be made by any nation to permit its use. In fulfilling this assignment, we have considered current understanding in the areas of human genetics, genome editing, reproductive technologies, and associated social and ethical issues. This report is the product of our deliberations. International Commission on the Clinical Use of Human Germline Genome Editing viii

PREPUBLICATION COPY | UNCORRECTED PROOFS Contents SUMMARY 1 1 INTRODUCTION AND ORIGINS OF THE REPORT 18 International Discussions of Heritable Human Genome Editing, 19 Clinical Use of Heritable Human Genome Editing Reported, 20 Formation of the International Commission and World Health Organization Expert Panel, 22 Mitochondrial Replacement Techniques: Modifying the Embryo, 23 A Translational Pathway for Heritable Human Genome Editing, 26 Study Focus and Approach, 30 Organization of the Report, 32 2 THE STATE OF THE SCIENCE 34 Monogenic Diseases: Genetics and Reproductive Options, 35 Genome Editing: Scientific Background for a Translational Pathway, 52 Future Issues in Assisted Reproduction: Implications of In Vitro Stem Cell-Mediated Gametogenesis, 74 Additional Components of Any Clinical Translational Pathway for Heritable Human Genome Editing, 79 Other Possible Uses of Heritable Human Genome Editing, 85 Conclusions and Recommendations, 89 3 POTENTIAL APPLICATIONS OF HERITABLE HUMAN GENOME EDITING 94 Defining Appropriate Uses of Heritable Human Genome Editing, 94 Criteria for Defining Responsible Translational Pathways for Initial Uses of Heritable Human Genome Editing, 96 Criteria for Possible Initial Uses of Heritable Human Genome Editing, 99 Categories of Uses of Heritable Human Genome Editing, 100 Circumstances for Which a Responsible Translational Pathway Could be Defined, 108 How Common are the Circumstances for the Initial Clinical Uses of Heritable Human Genome Editing?, 112 The Need for Continued Research, 119 Conclusions and Recommendations, 121 4 A TRANSLATIONAL PATHWAY TO LIMITED AND CONTROLLED CLINICAL APPLICATIONS OF HERITABLE HUMAN GENOME EDITING 123 ix

PREPUBLICATION COPY | UNCORRECTED PROOFS Context for any Heritable Human Genome Editing Translational Pathway, 125 Basic Research Foundation to Establish Safe and Effective Genome Editing Methodologies, 126 Preclinical Evidence to Support a Proposed Use, 129 Decision Points and Required Approvals, 137 Clinical Evaluation of the Proposed Use, 139 Heritable Human Genome Editing Using In Vitro Stem Cell-Derived Gametes: What a Potential Translational Pathway Would Entail, 142 Conclusions and Recommendations, 145 5 NATIONAL AND INTERNATIONAL GOVERNANCE OF HERITABLE HUMAN GENOME EDITING 148 A Responsible Governance System for Heritable Human Genome Editing, 148 Heritable Editing in the Context of Current Regulatory Systems, 150 Requirements for National Oversight Systems for Heritable Human Genome Editing, 157 The Need for a System of Global Coordination and Collaboration, 159 Conclusions and Recommendations, 168 REFERENCES 171 APPENDIXES A Information Sources and Methods 188 B Commissioner Biographies 193 C Glossary 200 D Acronyms and Abbreviations 209 ACKNOWLEDGMENT OF REVIEWERS 211 x

PREPUBLICATION COPY | UNCORRECTED PROOFS Boxes and Figures BOXES S-1 Report Recommendations, 2 1-1 Terminology used in this Report, 18 1-2 The Pathway Toward the Regulated Use of Mitochondrial Replacement Techniques in the United Kingdom, 25 1-3 Statement of Task, 31 2-1 In Vitro Fertilization, 45 2-2 Preimplantation Genetic Testing, 46 2-3 DNA Sequencing, 58 4-1 Essential Elements of a Responsible Translational Pathway Toward Initial Clinical Uses of HHGE, 125 5-1 Societal Considerations to Inform Future Discussions about HHGE, 149 5-2 Experience Conducting Independent Assessments of Safety and Efficacy of Mitochondrial Replacement Techniques, 155 5-3 Adherence to Human Rights and to Bioethical Principles, 158 FIGURES S-1 The main elements of a clinical translational pathway for a proposed use of HHGE to enable parents to have a genetically-related child without a serious monogenic disease, 11 1-1 Methods for mitochondrial replacement therapy include maternal spindle transfer (A) and pronuclear transfer (B), 24 1-2 General elements that form a translational pathway for HHGE, 27 2-1 Genetic disorders encoded on the non-sex chromosomes (the autosomes) have dominant or recessive inheritance, 41 2-2 Circumstances in which parents would not be able to produce an embryo unaffected by a genetic disease, 42 2-3 Preimplantation genetic testing, 45 2-4 Formation of the first polar body (PB1) and second polar body (PBD) during oocyte meiosis, 50 2-5 The CRISPR/Cas9 genome editing system, 54 xi

PREPUBLICATION COPY | UNCORRECTED PROOFS 2-6 A cell uses two main mechanisms to repair a double-strand break at the targeted site, 57 2-7 Cytosine base editors consist of a base-modifying catalytic subunit fused to the Cas9 nickase, and a gRNA, 60 2-8 Mosaic embryos, 69 2-9 1) Treating somatic cells from a patient with transcription factors/growth factors can reprogram the cells to become induced pluripotent stem cells. 2) Alternatively, human embryonic stem cells can be derived from embryos following nuclear transfer into enucleated oocytes (ntESCs), 79 4-1 A clinical translational pathway for a specific proposed use of HHGE, 124 5-1 An International Scientific Advisory Panel (ISAP) would provide regular, independent assessments along the clinical translational pathway, as envisioned in Chapter 4, toward HHGE for certain circumstances of serious monogenic diseases, 164 5-2 International discussions would be required to determine whether it would be possible to cross significant thresholds and describe translational pathways for potential uses of HHGE, 167 xii

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Heritable human genome editing - making changes to the genetic material of eggs, sperm, or any cells that lead to their development, including the cells of early embryos, and establishing a pregnancy - raises not only scientific and medical considerations but also a host of ethical, moral, and societal issues. Human embryos whose genomes have been edited should not be used to create a pregnancy until it is established that precise genomic changes can be made reliably and without introducing undesired changes - criteria that have not yet been met, says Heritable Human Genome Editing.

From an international commission of the U.S. National Academy of Medicine, U.S. National Academy of Sciences, and the U.K.'s Royal Society, the report considers potential benefits, harms, and uncertainties associated with genome editing technologies and defines a translational pathway from rigorous preclinical research to initial clinical uses, should a country decide to permit such uses. The report specifies stringent preclinical and clinical requirements for establishing safety and efficacy, and for undertaking long-term monitoring of outcomes. Extensive national and international dialogue is needed before any country decides whether to permit clinical use of this technology, according to the report, which identifies essential elements of national and international scientific governance and oversight.

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