International Commission on the
Clinical Use of Human Germline Genome Editing
A Consensus Study Report of
THE NATIONAL ACADEMIES PRESS
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 United Kingdom, 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: 978-0-309-67113-2
International Standard Book Number-10: 0-309-67113-2
Digital Object Identifier: https://doi.org/10.17226/25665
Library of Congress Control Number: 2020949045
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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. https://doi.org/10.17226/25665.
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.
A. RAHMAN A. JAMAL, M.D., Ph.D., Professor of Paediatric Oncology and Haematology, 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, J.D., 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 the Massachusetts Institute of Technology 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
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 January 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)
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
STEVE OLSON, Writer
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, M.B.A., Head of Shaping the Future of Health and Healthcare, World Economic Forum
CARLOS HENRIQUE de BRITO 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
K. VIJAY RAGHAVAN, Ph.D., Principal Scientific Adviser, Government of India
VENKATRAMAN RAMAKRISHNAN, Ph.D., President, The Royal Society
JANET ROSSANT, Ph.D., President and Scientific Director, The Gairdner Foundation and Professor, University of Toronto
RAJIV SHAH, M.D., President, The Rockefeller Foundation
QI ZHOU, Ph.D., Professor and Deputy Secretary-General, Chinese Academy of Sciences
ANNE-MARIE MAZZA, Senior Director, Committee on Science, Technology, and Law, NAM/NAS
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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)
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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-CoV-2 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.
Matters of equitable access are of course also raised by other ARTs and by health care 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
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Boxes and Figures
2-9 (1) Treating somatic cells from a patient with transcription factors/growth factors can reprogram the cells to become iPSCs. (2) Alternatively, human embryonic stem cells can be derived from embryos following nuclear transfer into enucleated oocytes (ntESCs)