Mitochondrial Replacement Techniques
ETHICAL, SOCIAL, AND POLICY CONSIDERATIONS
Committee on the Ethical and Social Policy Considerations of
Novel Techniques for Prevention of Maternal Transmission of
Mitochondrial DNA Diseases
Board on Health Sciences Policy
Institute of Medicine
Anne Claiborne, Rebecca English, and Jeffrey Kahn, Editors
THE NATIONAL ACADEMIES PRESS
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This activity was supported by Contract No. HHSP233201400020B/HHSP2337010 between the National Academy of Sciences and the U.S. Department of Health and Human Services, U.S. Food and Drug Administration. 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: 978-0-309-38870-2
International Standard Book Number-10: 0-309-38870-8
Library of Congress Control Number: 2016933603
Digital Object Identifier: 10.17226/21871
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2016. Mitochondrial replacement techniques: Ethical, social, and policy considerations. Washington, DC: The National Academies Press. doi: 10.17226/21871.
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COMMITTEE ON THE ETHICAL AND SOCIAL
POLICY CONSIDERATIONS OF NOVEL TECHNIQUES
FOR PREVENTION OF MATERNAL TRANSMISSION
OF MITOCHONDRIAL DNA DISEASES
JEFFREY P. KAHN (Chair), Robert Henry Levi and Ryda Hecht Levi Professor of Bioethics and Public Policy, Johns Hopkins Berman Institute of Bioethics
JEFFREY R. BOTKIN, Professor of Pediatrics and Chief of the Division of Medical Ethics and Humanities, University of Utah
DAVID C. CHAN, Professor of Biology, California Institute of Technology
R. ALTA CHARO, Warren P. Knowles Professor of Law and Bioethics, University of Wisconsin–Madison
JAMES CHILDRESS, University Professor, John Allen Hollingsworth Professor of Ethics, Professor of Religious Studies, Professor in Medical Education, and Director of the Institute for Practical Ethics and Public Life, University of Virginia
ALAN DECHERNEY, Branch Chief, Reproductive and Adult Endocrinology/Reproductive Biology and Medicine, National Institute of Child Health and Human Development, National Institutes of Health
MARNI J. FALK, Assistant Professor of Pediatrics, Perelman School of Medicine, University of Pennsylvania, and Director, Mitochondrial-Genetic Disease Clinic, The Children’s Hospital of Philadelphia
JONATHAN KIMMELMAN, Associate Professor in Biomedical Ethics and Social Studies of Medicine, McGill University
ANNA C. MASTROIANNI, Professor of Law, University of Washington
VAMSI K. MOOTHA, Professor of Systems Biology and Medicine, Harvard Medical School, and Investigator, Howard Hughes Medical Institute
LAURIE STRONGIN, Founder and Executive Director, Hope for Henry Foundation
KEITH A. WAILOO, Townsend Martin Professor of History and Public Affairs, Department of History and Woodrow Wilson School of Public and International Affairs, Princeton University
ANNE B. CLAIBORNE, Study Director
REBECCA A. ENGLISH, Program Officer
MORGAN L. BONAME, Associate Program Officer
MICHAEL J. BERRIOS, Senior Program Assistant
ELLEN K. KIMMEL, Senior Research Librarian
ANDREW M. POPE, Director, Board on Health Sciences Policy
RONA BRIERE, Briere Associates Inc.
ERIN HAMMERS FORSTAG, Science Writer
This report has been 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:
George J. Annas, Boston University
Francisco J. Ayala, University of California, Irvine
Cristy Balcells, MitoAction
Françoise Baylis, Dalhousie University
Courtney S. Campbell, Oregon State University
Bruce H. Cohen, Akron Children’s Hospital
Marcy Darnovsky, Center for Genetics and Society
Dieter Egli, Columbia University
Sara F. Goldkind, Research and Clinical Bioethics Consultant
Henry T. Greely, Stanford University
Ronald Haller, University of Texas Southwestern Medical Center
Michio Hirano, Columbia University
Eric Juengst, University of North Carolina at Chapel Hill
Michael Manganiello, HCM Strategists, LLC
Bonnie Steinbock, University at Albany
Laurie Zoloth, Northwestern University
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the report’s conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Enriqueta C. Bond, QE Philanthropic Advisors, and Ellen Wright Clayton, Vanderbilt University. 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.
The proposed investigation and potential clinical use of mitochondrial replacement techniques (MRT) raises a novel collection of ethical, social, and policy issues. At the request of the U.S. Food and Drug Administration (FDA), the National Academies of Sciences, Engineering, and Medicine convened a committee with diverse interdisciplinary expertise and a range of backgrounds to examine and analyze these issues, make recommendations regarding whether and how to go forward with MRT, and elaborate principles for initial clinical investigations involving these novel techniques for avoiding some types of inherited mitochondrial DNA (mtDNA) diseases.
This report presents the consensus conclusions and recommendations of this diverse group of experts, each of whom brought her or his expertise and perspectives. As in the case of other ethics-related Academies studies, the subject did not lend itself to the typical approach of collection of data, but instead relied largely on conceptual considerations and analysis, as well as reference to existing practices and policies. The resulting recommendations reflect the committee’s assessment of the ethical, social, and policy issues at the core of MRT and its articulation of the conditions and principles that should govern any clinical investigations of these techniques. The committee’s deliberations were informed by information provided by FDA, input from a range of stakeholders, and presentations by invited experts at a public workshop. The recommendations that resulted from these deliberations are intended to be general enough to be applied as the science related to MRT evolves, but with enough specificity to address questions related to undertaking the first human investigations of these techniques.
This report would not have been possible without the dedicated, diligent, and skilled work of the Academies staff: Anne Claiborne, Rebecca English, Morgan Boname, and Michael Berrios. Erin Hammers Forstag also provided invaluable support to the committee. The committee gratefully acknowledges their truly tireless efforts. Lastly, thanks to my committee colleagues for their careful review of information; their thoughtful consideration of the many arguments and perspectives presented; and most of all their unflagging patience as we considered, and often reconsidered, our recommendations for addressing the ethical, social, and policy issues and challenges posed by human investigations of MRT. It was truly a privilege to work with them all.
Jeffrey P. Kahn, Chair
Committee on the Ethical and Social Policy Considerations of
Novel Techniques for Prevention of Maternal Transmission
of Mitochondrial DNA Diseases
At the request of the U.S. Food and Drug Administration (FDA), the National Academies of Sciences, Engineering, and Medicine assembled an ad hoc committee tasked with developing a consensus report regarding ethical, social, and policy considerations related to mitochondrial replacement techniques (MRT), which entail modification of human oocytes and zygotes to prevent the transmission of mitochondrial DNA (mtDNA) diseases from mother to child. These diseases vary in presentation and severity, but lead to morbidity and in some cases premature death. MRT would be used to prevent the transmission of mtDNA diseases by creating an embryo with nuclear DNA (nDNA) from the intended mother and nonpathogenic mtDNA provided by a woman, using techniques that would modify either an oocyte (egg) or zygote (fertilized oocyte).
MRT, if effective, could satisfy the desire of women to have a genetically related child with a significantly reduced risk of passing on mtDNA disease. The techniques, however, have a unique combination of characteristics that raises a novel collection of ethical, social, and policy issues. These include that MRT would (1) create embryos that if transferred would result in offspring with genetic material from two women of different maternal lineage,1 a novel intervention never approved by U.S. federal
1 Every individual has genetic material from many individuals and ancestors. For instance, due to the matrilineal nature of the inheritance of mtDNA, each individual has genetic material from their mother, grandmother, great-grandmother, etc. Therefore, MRT is unique in that it would involve combining the genetic material of two women of different maternal lineage—nDNA from the intended mother who carries a pathogenic mtDNA mutation and mtDNA provided by a woman without pathogenic mutations in her mtDNA. In the instance
regulatory authorities2; (2) constitute modifications in the mitochondrial genome that could be heritable (i.e., could be passed down through future generations) if MRT were carried out to conceive female offspring, due to the matrilineal inheritance of mtDNA, and the effects of those modifications (whether beneficial or deleterious) could persist indefinitely; (3) entail genetic modification of which any resulting effects would not, at this time, be reversible3; and (4) constitute a genetic modification that would affect every cell type of the resulting individual, thus affecting the total organism rather than being confined to a specific organ system. In considering the ethical, social, and policy issues raised by this unique combination of characteristics, the committee examined (1) parental motivation to access MRT to produce genetically related children, taking into consideration the adequacy and availability of alternative approaches to creating families for women with a known risk of transmitting pathogenic mtDNA; (2) ethical, social, and policy concerns related to genetic modification of germ cells and the germline; (3) downstream social implications of MRT such as expanded clinical applications and potential enhancement; (4) implications of MRT for identity, kinship, and ancestry; and (5) the creation, manipulation, and possible destruction of human gametes and embryos that would be involved in MRT research or clinical application.
The committee identified significant and important distinctions between modification of mtDNA and nDNA that matter for an analysis of the ethical, social, and policy issues of genetic modification of germ cells and the germline. Among them, MRT is different from any technology that could be applied to the nuclear genome in that it would entail replacement of pathogenic mtDNA with unaffected mtDNA, as opposed to targeted genomic editing of either mtDNA or nDNA. Also, while mtDNA plays a central role in genetic ancestry, traits that are carried in nDNA are those that in the public understanding constitute the core of genetic relatedness in terms of physical and behavioral characteristics as well as most forms of disease. Moreover, while some forms of “energetic enhancement” (such as selecting for mtDNA to increase aerobic capacity) might hypothetically
where some level of mtDNA from the intended mother is carried over to the embryo created by MRT, this embryo would also contain mtDNA from two women of different maternal lineage.
2 U.S. federal regulatory authorities have never approved a cell-based product that involves genetic material from two women of different maternal lineages, as would MRT. In the case of unapproved cytoplasm transfer in the late 1990s/early 2000s, FDA halted the application of these techniques and asserted the agency’s jurisdiction in reviewing and approving any clinical applications of the techniques. To the committee’s knowledge, there was no application to FDA to pursue cytoplasm transfer techniques, and therefore, MRT represents a unique opportunity for U.S. regulatory review.
3 Only in highly hypothetical future technologies would genetic modifications introduced by MRT be reversible. The committee refers to the irreversibility of MRT in this report as it reflects the current state of science and the ethical analysis that accompanies MRT today.
be possible through MRT, they appear to be far fewer and more speculative relative to what might be possible in modifications of nDNA. In the committee’s judgment, none of these distinctions are meant to imply that mtDNA is unimportant from the perspective of health, genetic relatedness, or potential energetic enhancement, but that its modification is meaningfully different from that of nDNA.
The committee concludes that the most germane ethical, social, and policy considerations associated with MRT could be avoided through limitations on the use of MRT or are blunted by meaningful differences between the heritable genetic modification of nDNA and that introduced by MRT. Therefore, the committee concludes that it is ethically permissible to conduct clinical investigations of MRT, subject to certain conditions and principles laid out in this report.
The committee’s recommendations regarding potential clinical investigations and regulatory oversight of MRT include that minimizing the risk of harm to the child born as a result of MRT is the primary value to be considered in assessing the ethics of the balance of benefits and risks in clinical investigations of MRT.
Accordingly, the committee recommends that any initial MRT clinical investigations focus on minimizing the future child’s exposure to risk while ascertaining the safety and efficacy of the techniques. The recommended restrictions and conditions for initial clinical investigations include
- limiting clinical investigations to women who are otherwise at risk of transmitting a serious mtDNA disease, where the mutation’s pathogenicity is undisputed, and the clinical presentation of the disease is predicted to be severe, as characterized by early mortality or substantial impairment of basic function; and
- transferring only male embryos for gestation to avoid introducing heritable genetic modification during initial clinical investigations.
Following successful initial investigations of MRT in males, the committee recommends that FDA could consider extending MRT research to include the transfer of female embryos if clear evidence of safety and efficacy from male cohorts, using identical MRT procedures, were available, regardless of how long it took to collect this evidence; preclinical research in animals had shown evidence of intergenerational safety and efficacy; and FDA’s decisions were consistent with the outcomes of public and scientific deliberations to establish a shared framework concerning the acceptability of and moral limits on heritable genetic modification.
For any initial and subsequent investigations of MRT, FDA, research institutions, investigators, and institutional review boards should also pay close attention to best practices for consent in research and special atten-
tion to communicating the novel aspects of MRT research to potential participants.
The committee recommends adherence to the following principles for oversight of MRT investigations and, if applicable, future clinical use:
- Transparency: Regulatory authorities should maximize timely public sharing of information concerning the MRT activities and decisions within their jurisdiction. FDA should encourage sponsors to commit to depositing of protocols and deidentified results in public databases.
- Public engagement: Regulatory authorities should incorporate ongoing exploration of the views of relevant stakeholders into the overall plan for review and possible marketing of MRT and should support opportunities for public meetings to gather these views.
- Partnership: FDA should collaborate with other regulatory authorities within and outside the United States to improve the quality of the data available for the assessment of benefits and risks.
- Maximizing data quality: FDA should require that sponsors have adequate resources, use appropriate designs, and plan studies that enable cross-referencing and pooling of data for assessments of benefits and risks.
- Circumscribed use: FDA should use the means at its disposal to limit the use of MRT to the indications, individuals, and settings for which it is approved, and should engage the public in a fresh ethical analysis of any decision to broaden the use of MRT.
- Long-term follow-up: FDA should require that sponsors design, fund, and commit to long-term monitoring of children born as a result of MRT, with a plan for periodic review of the long-term follow-up data.