Human
Genome
Editing
SCIENCE, ETHICS, AND GOVERNANCE
Committee on Human Gene Editing:
Scientific, Medical, and Ethical Considerations
A Report of
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
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This activity was supported by Contract No. HHSP233201400020B/HHSP23337045 with the Defense Advanced Research Projects Agency, the Greenwall Foundation, Grant No. 15-108819-000-DIS with the John D. and Catherine T. MacArthur Foundation, Contract No. HHSP233201400020B/HHSP23337035 with the U.S. Food and Drug Administration of the U.S. Department of Health and Human Services, and the Wellcome Trust, with additional support from the National Academies of Sciences, Engineering, and Medicine’s Presidents’ Circle Fund and the National Academy of Sciences W.K. Kellogg Foundation Fund. 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: 978-0-309-45288-5
International Standard Book Number-10: 0-309-45288-0
Digital Object Identifier: https://doi.org/10.17226/24623
Library of Congress Control Number: 2017938606
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2017. Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/24623.
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COMMITTEE ON HUMAN GENE EDITING:
SCIENTIFIC, MEDICAL, AND ETHICAL CONSIDERATIONS
R. ALTA CHARO (Co-Chair), Sheldon B. Lubar Distinguished Chair and Warren P. Knowles Professor of Law and Bioethics, University of Wisconsin–Madison
RICHARD O. HYNES (Co-Chair), Investigator, Howard Hughes Medical Institute; Daniel K. Ludwig Professor for Cancer Research, Massachusetts Institute of Technology
DAVID W. BEIER, Managing Director, Bay City Capital
ELLEN WRIGHT CLAYTON, Craig Weaver Professor of Pediatrics, Professor of Law, Vanderbilt University
BARRY S. COLLER, David Rockefeller Professor of Medicine, Physician in Chief, and Head, Allen and Frances Adler Laboratory of Blood and Vascular Biology, The Rockefeller University
JOHN H. EVANS, Professor, University of California, San Diego
JUAN CARLOS IZPISUA BELMONTE, Professor, Gene Expression Laboratory, Salk Institute for Biological Studies
RUDOLF JAENISCH, Professor of Biology, Massachusetts Institute of Technology
JEFFREY KAHN, Andreas C. Dracopoulos Director, Johns Hopkins Berman Institute of Bioethics, Johns Hopkins University
EPHRAT LEVY-LAHAD, Director, Fuld Family Department of Medical Genetics, Shaare Zedek Medical Center; Faculty of Medicine, Hebrew University of Jerusalem
ROBIN LOVELL-BADGE, Senior Group Leader, Laboratory of Stem Cell Biology and Developmental Genetics, The Francis Crick Institute
GARY MARCHANT, Regents’ Professor of Law, Lincoln Professor of Emerging Technologies, Arizona State University
JENNIFER MERCHANT, Professor, Université de Paris II (Panthéon-Assas)
LUIGI NALDINI, Professor of Cell and Tissue Biology and of Gene and Cell Therapy, San Raffaele University, and Scientific Director of the San Raffaele Telethon Institute for Gene Therapy
DUANQING PEI, Professor and Director General of Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
MATTHEW PORTEUS, Associate Professor of Pediatrics, Stanford University School of Medicine
JANET ROSSANT, Senior Scientist and Chief of Research Emeritus, Hospital for Sick Children, University of Toronto
DIETRAM A. SCHEUFELE, John E. Ross Professor in Science Communication and Vilas Distinguished Achievement Professor, University of Wisconsin–Madison
ISMAIL SERAGELDIN, Founding Director, Bibliotheca Alexandrina
SHARON TERRY, President and CEO, Genetic Alliance
JONATHAN WEISSMAN, Professor, Department of Cellular and Molecular Pharmacology, University of California, San Francisco; Investigator, Howard Hughes Medical Institute
KEITH R. YAMAMOTO, Vice Chancellor for Science Policy and Strategy, Vice Dean for Research for the School of Medicine, Professor, University of California, San Francisco
Study Staff
KATHERINE W. BOWMAN, Study Director
MONICA L. GONZALEZ, Associate Program Officer
JOANNA R. ROBERTS, Senior Program Assistant
ANDREW M. POPE, Director, Board on Health Sciences Policy
FRANCES E. SHARPLES, Director, Board on Life Sciences
Consultants
RONA BRIERE, Editor
HELAINE RESNICK, Editor
Dedication
Dr. Ralph Cicerone (1943-2016) was President of the National Academy of Sciences in 2015 when, in partnership with the President of the National Academy of Medicine, he announced a human genome-editing initiative that would encompass science, ethics, and regulation. He noted that the National Academies of Sciences, Engineering, and Medicine have led the effort to develop responsible, comprehensive policies for many emerging and controversial areas of genetics and cell biology, such as human embryonic stem cell research, human cloning, and “gain-of-function” research. Most notable was its involvement in key events leading up to the 1975 Asilomar conference. But there are important differences between the Asilomar era and today, Dr. Cicerone said in an interview with Nature, because few researchers were pursuing recombinant DNA research in 1975. Modern genome-editing techniques are easy to use and widely accessible, leading him to conclude that the situation requires an approach that is “really more international than Asilomar ever had to be.”
Dr. Cicerone was as good as his word. In collaboration with science and medicine academies from China and the United Kingdom, an initiative was launched with an international summit. From this came a commitment to future summits and the formation of a study committee, with members hailing from or working in Canada, China, Egypt, France, Germany, Israel, Italy, Spain, the United Kingdom, and the United States. This report is the culmination of the work by that committee and is dedicated to this great leader of the National Academy of Sciences.
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Reviewers
This 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 institution in making its published report as sound as possible and to ensure that the report meets institutional standards for 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 wish to thank the following individuals for their review of this report:
Eli Adashi, Brown University
George Annas, Boston University
Dana Carroll, University of Utah
Michael Dahlstrom, Iowa State University
Hank Greely, Stanford University
J. Benjamin Hurlbut, Arizona State University
Maria Jasin, Memorial Sloan Kettering Cancer Center
James Lawford-Davies, Hempsons Law Firm, United Kingdom
Andrew Maynard, Arizona State University
Krishanu Saha, University of Wisconsin–Madison
Fyodor Urnov, Altius Institute
Keith Wailoo, Princeton University
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Harvey Fineberg (Moore Foundation) and Jonathan Moreno (University of Pennsylvania). They were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.
Preface
Genome editing—a suite of methods for creating changes in DNA more accurately and flexibly than previous approaches—was hailed as the 2011 Method of the Year by Nature Methods, and the CRISPR/Cas9 system of genome editing was named the 2015 Breakthrough of the Year by Science. The technology has excited interest across the globe because of the insights it may offer into fundamental biological processes and the advances it may bring to human health. But with these advances come many questions, about the technical aspects of achieving desired results while avoiding unwanted effects, and about a range of uses that may include not only healing the sick, but also preventing disease in this and future generations, or even altering traits unrelated to health needs. Now is the time to consider these questions. Clinical trials using edited human somatic cells are already underway, and more are anticipated. To help direct the use of genome editing toward broadly promoting human well being, it is important to examine the scientific, ethical, and social issues it raises, and assess the capacity of governance systems to ensure the technologies’ responsible development and use. Doing so also entails articulating the larger principles that should underlie such systems.
These were not easy tasks, but we are profoundly grateful to the committee members who joined us in tackling our charge. They willingly and thoughtfully brought their diverse perspectives to bear on our discussions, and we thank them for their commitment to this study and for devoting so much of their time and energy over the past year. It has been a pleasure and a privilege to work with them. The report was also informed by many presentations and discussions with speakers whose contributions provided a
wealth of information and insight. We thank them for sharing their research and viewpoints with us. Finally, on behalf of the committee, we would like to thank the staff of the National Academies of Sciences, Engineering, and Medicine for working alongside us throughout the study—their ideas and support were crucial to bringing the project to fruition—and thank the sponsors of the study, who had an expansive vision for its potential.
R. Alta Charo and Richard O. Hynes, Co-Chairs
Committee on Human Gene Editing: Scientific,
Medical, and Ethical Considerations
Contents
2 OVERSIGHT OF HUMAN GENOME EDITING AND OVERARCHING PRINCIPLES FOR GOVERNANCE
Principles for Governance of Human Genome Editing
Regulation of Gene Therapy in the United States
Conclusions and Recommendation
3 BASIC RESEARCH USING GENOME EDITING
The Basic Tools of Genome Editing
Rapid Advances in Genome-Editing Technology
Basic Laboratory Research to Advance Understanding of Human Cells and Tissues
Basic Laboratory Research to Advance Understanding of Mammalian Reproduction and Development
Advantages of Genome Editing Over Traditional Gene Therapy and Earlier Approaches
Homologous and Nonhomologous Repair Methods Used for Nuclease-Based Genome Editing
Potential Human Applications of Somatic Cell Genome Editing
Ethical and Regulatory Issues Posed by Somatic Cell Genome Editing
Conclusions and Recommendations
Potential Applications and Alternatives
Scientific and Technical Issues
Ethics and Regulation of Editing the Germline to Correct Disease-Causing Traits
Conclusions and Recommendation
Human Genetic Variation and Defining “Normal” and “Natural”
Understanding Public Attitudes Toward Enhancement
Drawing Lines: Therapy Versus Enhancement
Heritable Genome Editing and Enhancement
Conclusions and Recommendations
Public Engagement: Broad Concepts
Lessons Learned from Public Engagement Activities
Conclusions and Recommendations
8 SUMMARY OF PRINCIPLES AND RECOMMENDATIONS
Overarching Principles for Governance of Human Genome Editing
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Boxes, Figures, and Tables
BOXES
S-1 Principles for the Governance of Human Genome Editing
S-2 Oversight and Use of Human Gene Editing: Summary of Recommendations
1-2 Related Studies of the NAS and the NAM
1-3 Excerpts from Selected Calls Around the World for Continued Study and Public Discussion
2-1 Overarching Principles for Research on and Clinical Applications of Human Gene Editing
2-2 Example of an Alternative Governance Regime
3-2 Differences Between Mouse and Human Development
5-1 Mitochondrial Replacement Techniques
FIGURES
A-2 Schematic of targetable nucleases discussed in this appendix
A-3 Schematic of Cas9 and different Cas9 variants
A-4 Strategies for globally detecting off-target cutting events
A-5 Schematic of a CRISPR/Cas9 genome-editing system using a variant of the Cas9 nuclease
A-6 The generation of transgenic mice with randomly inserted transgenes
A-8 The generation of gene-edited mice by CRISPR/Cas9 targeting in the zygote (one-step process)
B-1 Countries take varying approaches to the regulation of human heritable germline modifications
TABLES
2-1 Summary of U.S. Regulatory Pathway for a Medical Product Created Using Genome Editing
3-1 Reasons for Laboratory Studies of Human Embryos
4-1 Examples of Potential Therapeutic Applications of Somatic Cell Genome Editing
7-1 Attributes of Public Engagement: Selected Examples
7-2 Public Engagement in Denmark: Consensus Conferences
A-1 General Approaches to Delivering Genome-Editing Components
B-1 Three General Approaches to International Regulatory Convergence