Summary¹

Mitochondrial replacement techniques (MRT) are designed to prevent the transmission of mitochondrial DNA (mtDNA) diseases from mother to child. These diseases vary in presentation and severity, but common symptoms include developmental delays, seizures, weakness and fatigue, muscle weakness, vision loss, and heart problems, leading to morbidity and in some cases premature death. The goal of MRT is to prevent the transmission of these serious diseases by creating an embryo with nuclear DNA (nDNA) from the intended mother and mtDNA from a woman with nonpathogenic mtDNA through modification of either an oocyte (egg) or zygote (fertilized oocyte). While MRT, if effective, could satisfy the desire of women seeking to have a genetically related child without the risk of passing on mtDNA disease, the techniques raise ethical, social, and policy issues.

The U.S. Food and Drug Administration (FDA) would regulate MRT under its authority to regulate “human cells or tissues that are intended for implantation . . . into a human” (21 CFR 1271). Under guidance issued by FDA, any clinical use of MRT would require an Investigational New Drug (IND) application. If approved, an IND allows clinical investigations in humans to begin. FDA’s Cellular, Tissue and Gene Therapies Advisory Committee met in February 2014 to discuss MRT. At this time, the FDA committee received public comments that reflected concern about certain ethical, social, and policy issues surrounding MRT. Because these issues

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¹ This summary does not include references. Citations for the discussion presented in the summary appear in the subsequent report chapters.

were beyond the purview of the FDA committee, FDA requested that the National Academies of Sciences, Engineering, and Medicine convene a consensus committee to consider the ethical, social, and policy issues raised and develop recommendations to inform the agency’s consideration of MRT-related INDs.

This report presents the results of the committee’s deliberations. In accordance with the statement of task provided by FDA, the committee addressed the foundational question of whether it is ethically permissible for clinical investigations of MRT to proceed.

The committee concludes that the most germane ethical, social, and policy issues 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.

STUDY CHARGE AND APPROACH

To address its charge (see Box S-1), the committee held both open and closed meeting sessions and a public workshop. The committee also solicited public comments to gather expert and public opinion on such issues as the ethics of heritable genetic modification (i.e., germline modification), patient perspectives, the role of religion, and how to conduct an ethically acceptable investigation of MRT.

The committee’s analysis included discussion of whether the appropriate approach should be (1) to begin from a permissive perspective that would support going forward unless restrictions are justified, or (2) to begin from a restrictive or precautionary perspective that would support restrictions on going forward until risks have been sufficiently managed or controlled, or prohibit going forward at all based on fundamental ethical, social, and policy concerns. The committee used an approach that recognizes important aspects of liberal democratic theory, which acknowledges the acceptability of individual interests and desires and the autonomy of

parental decision making in a society capable of deliberation, transparency, and the rule of law, along with an optimism about scientific knowledge. The committee applied this approach with a healthy skepticism as to whether foundational concerns about some of the ethical, social, and policy issues raised by MRT could be addressed at all.

ETHICAL, SOCIAL, AND POLICY CONCERNS SURROUNDING MRT

While recognizing that review of the safety and efficacy of MRT would ultimately be FDA’s purview, the committee worked to learn about the latest science on mitochondrial genetics and MRT to inform its ethical analysis. The committee examined the scientific context in which MRT is proposed, and concluded that the field of mitochondrial genetics is characterized by complexities that make predicting the behavior of mtDNA difficult and uncertain. A thorough understanding of the state of the science related to the unknowns of mtDNA genetics and MRT is important for informing the benefit and risk assessment entailed in potential regulatory decisions regarding if, when, and how to proceed with MRT in first-in-human clinical investigations.

In addition to the developing scientific context underlying MRT, the techniques have a unique combination of characteristics that raises a novel collection of ethical, social, and policy issues. First, MRT would create embryos that if transferred would result in offspring with genetic material from two women of different maternal lineage,² a novel intervention never before approved by U.S. federal regulatory authorities.³ Second, if MRT were carried out to conceive female offspring, the resulting mtDNA modifications would be heritable (i.e., could be passed down through generations) in female offspring due to the matrilineal nature of the inheritance

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² 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 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.

³ U.S. federal regulatory authorities have never approved a cell-based product that involves genetic material from two women of different maternal lineage, 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.

of mtDNA, and the effects of those modifications (whether beneficial or deleterious) could persist indefinitely. Third, the effects of the genetic modification performed on oocytes or zygotes, once carried out, would not, at this time, be reversible.⁴ Fourth, the genetic modification would affect every cell type in 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 the unique combination of characteristics of MRT, the committee examined 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. The committee also considered ethical, social, and policy concerns related to genetic modification of germ cells and the germline; unintended downstream social implications of MRT; the implications of MRT for identity, kinship, and ancestry; and the creation, manipulation, and possible destruction of human gametes and embryos that would be involved in MRT research or clinical application. The committee addressed as well the key differences between nDNA and mtDNA as they relate to the foundational question of whether it is ethically permissible for clinical investigations of MRT to proceed.

Availability of Alternatives

At present, prospective mothers⁵ at risk for transmitting mtDNA disease to their offspring must choose among reproductive options that allow for varying degrees of nuclear genetic connection between the child and the prospective parents with variable risk of transmitting mtDNA disease. These options include unassisted sexual reproduction, preimplantation genetic diagnosis (PGD), oocyte or embryo donation, adoption, or childlessness. Unassisted sexual reproduction and PGD both would preserve the genetic relationship to prospective parents but are not viable options for reliably preventing transmission of mtDNA disease. In the case of oocyte

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⁴ 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.

⁵ This report uses the term “prospective parents” (including prospective mother or father) to mean those people who are interested in accessing MRT and would be clinically suited for MRT to prevent transmission of mtDNA disease. The report uses the term “intended parents” (including intended mother and father) to refer to the people who have entered the process of undergoing MRT, should clinical investigations be approved. The intended mother is the contributor of nDNA to the MRT oocyte or zygote and is the intended social mother; the intended father, if applicable, may or may not contribute sperm for the MRT oocyte or zygote, but is the intended social father.

donation, children have no genetic relationship to the prospective mother; in the case of embryo donation or adoption, children have no genetic relationship with either of the prospective parents.

Parental Desire to Pursue MRT

Although prospective offspring born as a result of MRT would lack an mtDNA connection with prospective mothers, MRT could satisfy a deeply held desire on the part of these mothers to have a child who bears an nDNA connection to them. MRT would not treat an existing person for a disease, illness, or condition, so its pursuit does not address a medical need per se. While pursuit of reproductive goals and desires deserves to be respected within the bounds of options made available through research and clinical settings, the responsibilities of professionals and the oversight process necessarily also include the protection of the health and well-being of a child created through use of these techniques. In the committee’s judgment, the desire of prospective parents to have children who are at significantly reduced risk of manifesting serious mtDNA disease and with whom they have an nDNA connection is justifiable, and clinical research on the use of MRT could be permitted within limits. These limits would be focused on protecting the health and well-being of the children who would be born as a result of MRT.

Genetic Modification of Germ Cells and the Germline

For the purposes of this report, “genetic modification” means changes to the genetic material within a cell. In the case of MRT, the genetic modification is the combination of mtDNA from one woman with the nDNA of another woman of different maternal lineage within an oocyte or zygote. While there is no direct modification or editing of the mtDNA sequence itself,⁶ this novel combination would not occur in unassisted sexual reproduction or in other assisted reproductive technologies. “Germline modification” is defined by the statement of task provided by FDA to this committee as “human inheritable genetic modification.”⁷ Using these definitions, the committee finds that MRT results in the genetic modification of germ cells, but that it constitutes heritable genetic modification (germline modification) only if used to produce female offspring because mtDNA is solely mater-

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⁶ While there is not direct gene editing of the nucleotide sequence of mtDNA through MRT, the overall frequencies of mtDNA alleles within the population are altered.

⁷ The committee has adopted the shorter synonym “heritable” (instead of “inheritable”) in this report.

nally inherited, and therefore MRT to produce male offspring would not constitute heritable genetic modification (germline modification).

As a form of genetic modification of germ cells, MRT raises concerns about interference with nature, “playing God,” eugenics, and the potential impact on persons with disabilities. Some contend that international treaties or country-specific laws against germline modification would be violated by MRT. In the committee’s judgment, although a number of ethical, social, and policy concerns have been raised about human genetic modification, whether heritable or not, through the use of MRT, these concerns warrant significant caution and the imposition of restrictions rather than a blanket prohibition on the use of MRT to prevent transmission of serious mtDNA disease.

Unintended Downstream Social Implications of MRT

As a result of the regulatory context and the social and market forces that drive the uptake of innovative reproductive technologies in the United States, concerns exist about the expanded use of MRT should it be approved by FDA, including its use for scientifically unproven or potential enhancement purposes. For instance, female idiopathic or age-related infertility is a likely candidate for expanded use of MRT, one that would significantly enlarge the pool of possible patients. The committee does not suggest an absolute limit on any eventual applicability of MRT to other conditions or diseases, but rather believes FDA and relevant professional societies need to take a cautious approach, with deliberate attention to ethical, social, and policy issues, in considering any uses of MRT beyond the primary indication of preventing transmission of serious mtDNA disease. To this end, the committee concluded that federal regulations would be needed and principled professional society guidelines interpreting the regulations would be helpful to limit the use of MRT to the prevention of transmission of serious, life-threatening mtDNA diseases and to prevent slippage into applications that raise other serious and unresolved ethical issues.

Identity, Ancestry, and Kinship

MRT would result in a novel combination of, and interaction between, mtDNA and nDNA different from that which would otherwise be the case, with potential implications for identity, kinship, and ancestry. In the committee’s view, an mtDNA provider’s genetic contribution would connect her to the resulting child through the sharing of an aspect of their lineage or ancestry. The novel combination of mtDNA and nDNA that would result from MRT blurs traditional notions of relatedness in ways that may undermine intergenerational connections and lineage as measured by mtDNA. In

the committee’s view, however, the contribution of genetic material from two women of different maternal lineage does not form a basis for prohibiting initial investigation of MRT; rather, it is a matter for reflection by families considering undertaking MRT and for societal discussions related to conceptions of identity, kinship, and ancestry.

Important Distinctions Between Modification of mtDNA and nDNA

In light of the relative and important, albeit different, scientific, medical, and social contributions of mtDNA and nDNA to health, well-being, and conceptions of identity, as well as the unique combination of characteristics of MRT as an approach, a central question for the committee was whether the sort of heritable genetic change resulting from MRT raises ethical, social, and policy issues comparable to those raised by heritable modification of the nuclear genome. In the committee’s judgment, there are 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:

• 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. The replacement of whole, intact, and naturally occurring mitochondrial genomes represents a qualitatively different form of heritable genetic change from that resulting from any approach for modifying nDNA, which would likely involve editing rather than en bloc replacement of chromosomes—the closest parallel to MRT.
• 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.
• While some forms of energetic “enhancement” (such as selecting for mtDNA to increase aerobic capacity) might hypothetically be possible through MRT, they appear to be far fewer and more speculative relative to what might be possible in modifications of nDNA.

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. In the committee’s judgment, the significant and important distinctions between modification of mtDNA to prevent transmission of

mtDNA disease through MRT and modification of nDNA (1) have implications for the ethical, social, and policy issues associated with MRT and (2) could allow justification of MRT independent of decisions about heritable genetic modification of nDNA.

While significant ethical, social, and policy considerations are associated with MRT, the most germane of these issues can be avoided through limitations on the use of MRT or are blunted by meaningful differences between the heritable genetic modification introduced by MRT and heritable genetic modification of nDNA. Therefore, the committee concludes that it is ethically permissible to conduct clinical investigations of MRT. To ensure that clinical investigations of MRT were performed ethically, however, certain conditions and principles would need to govern the conduct of clinical investigations and potential future implementation of MRT.

INITIAL INVESTIGATIONS AND GOVERNANCE OF MRT RESEARCH IN HUMANS

Having addressed the foundational question of whether it is ethically permissible for clinical investigations of MRT to proceed, the committee considered the conditions and principles necessary to guide clinical investigations and oversight of MRT.

Centrality of Minimizing Risk to the Future Child

In discussing the benefits and risks of MRT, a weighing and balancing that would ultimately be the responsibility of FDA, the committee observed that proponents of MRT sometimes describe use of the techniques as either a preventive measure or a therapy for children with mtDNA disease. Because in vitro fertilization (IVF) techniques are required as part of the MRT process to create an embryo, MRT would not treat a preexisting person or prevent a likely medical condition in an already existing individual. Drawing on this observation, the committee finds that MRT has at least two potential benefits: (1) the subjective benefit accruing to prospective parents of having a child related to the prospective mother by nDNA (but not mtDNA), and thereby at reduced risk of manifesting mtDNA disease; and (2) the population level benefit in the reduction in the number of children who would be born with serious mtDNA disease as a result of access to this reproductive technology. The committee notes that neither of these potential benefits would accrue to the children who would be born as a result of MRT, heightening the need for and importance of an emphasis on minimizing risk to future children because risk would accrue to the child, while benefit would accrue to others. In contrast with the typical case in biomedical research where some individuals are asked

to consent to bear risks voluntarily to enable potential benefits that would be enjoyed largely or exclusively by others, in the case of MRT consent cannot play a role in ensuring understanding of and agreement with these conditions because the child is brought into existence as a result of the research in question. Therefore, the committee concludes 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 MRT clinical investigations.

Conditions for Clinical Investigations

The committee’s recommendations for conditions for potential initial investigations of MRT focus on taking a cautious approach. Among the most potentially contentious of these conditions is that initial investigations be limited to transferring male embryos for gestation, a condition based on the need to take a cautious approach to any pursuit of MRT. Because of the scientific uncertainties associated with these novel techniques and because MRT in female embryos would result in heritable genetic modification, the committee believes that a cautious approach to MRT in the U.S. research context is required, including a restriction to male embryos in initial clinical investigations. Sex selection for medical reasons is generally accepted; for instance, PGD was initially introduced to enable selection of female embryos to avoid X-linked disorders. While there is ethical debate about the acceptability of sex selection, the restriction recommended by the committee is predicated not on selection of one sex over another, but on the need to proceed slowly and to prevent potential adverse and uncertain consequences of MRT from being passed on to future generations. In addition, preclinical research to study intergenerational effects of MRT could continue while at the same time allowing families to use MRT to have male children with a significantly reduced risk of mtDNA disease. Other conditions noted in Recommendation 1 below also address risk minimization and the safety of MRT in the setting of a potential initial clinical investigation.

• Initial safety is established, and risks to all parties directly involved in the proposed clinical investigations are minimized. Because attempts to minimize risk and burden for one of the parties could interact with risk for another, minimizing risk to future children should be of highest priority.

• Likelihood of efficacy is established by preclinical research using in vitro modeling, animal testing, and testing on human embryos as necessary.
• Clinical investigations are limited to women who otherwise are at risk of transmitting a serious mitochondrial DNA (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.
• If the intended mother at risk of transmitting mtDNA disease is also the woman who will carry the pregnancy, professional opinion informed by the available evidence determines that she would be able to complete a pregnancy without significant risk of serious adverse consequences to her health or the health of the fetus.
• Intrauterine transfer for gestation is limited to male embryos.
• Clinical investigations are limited to investigators and centers with demonstrated expertise in and skill with relevant techniques.
• FDA has reviewed mtDNA haplogroup matching and if compelling, considered it as a means of mitigating the possible risk of mtDNA-nuclear DNA (nDNA) incompatibilities.

Manipulation of Embryos

MRT would involve the creation, manipulation, and possible destruction of embryos not only in the preclinical research phase but also during clinical investigations and perhaps in clinical use. The creation, manipulation, and destruction of embryos for research purposes has long been controversial in the United States. While the creation of human embryos for research is not prohibited under federal law in the United States (although some states are more restrictive), neither FDA nor any other agency of the U.S. Department of Health and Human Services can financially support such research where embryos are destroyed, discarded, or subjected to risks with no prospect of medical benefit for the embryo. And even an agency request that data from such research be submitted in support of an IND to start first-in-human clinical investigations could well be controversial.

As data accrued from all sources on the benefits and risks of MRT, these data would need to inform the assessment of benefits and risks for potentially less beneficial or riskier investigations. A cautious, staged approach would need to be taken in the design of both initial and subsequent investigations, for example, in determining eligibility for prospective mothers, numbers of participants, and pacing of investigations.

• The health and well-being of any future children born as a result of clinical investigation protocols of MRT should have priority in the balancing of benefits and risks with respect to the design of investigations, eligibility of prospective mothers, numbers of participants, and pacing of investigations.
• Study designs of clinical investigation protocols of MRT should be standardized to the extent possible so as to minimize the number of variables and enable valid comparisons and pooling of outcomes across groups.
• Data from research or clinical practices outside FDA jurisdiction should be incorporated into FDA’s analysis to enhance the quality of the assessment of benefits and risks.
• Clinical investigations should collect long-term information regarding psychological and social effects on children born as a result of MRT, including their perceptions about their identity, ancestry, and kinship.

The question of whether and when to expand MRT research to include transfer of female embryos for gestation is complex and depends on factors that are presently uncertain and unknowable. In addition to sharing characteristics of MRT with male embryos, MRT involving female embryos would introduce intergenerational effects, whether they be positive or negative. The committee’s view is that sufficiently robust evidence of the safety and efficacy of MRT in males would be necessary before introducing the additional risks associated with the potential intergenerational effects that would accompany transferring female MRT embryos, regardless of how long it took to collect this evidence. Sufficiently compelling evidence that would reach the level of confidence envisioned by the committee would include information from experience with numerous male children followed at least during their early childhood years, as well as evidence from animal models that showed no adverse intergenerational effects when MRT was used to produce female offspring.

If and when sufficiently compelling evidence of safety and efficacy from experience with male MRT offspring and preclinical data on intergenerational effects were obtained, moving to transferring female embryos would remain a controversial step in that it would entail heritable genetic modification. A productive public discussion and process has been initiated to establish a shared framework with respect to whether heritable genetic modification is acceptable and if so, under what circumstances and for what purposes. The committee believes that its analysis can aid this ongoing discussion and that any decision about moving forward with MRT with female embryos should be informed by this discussion, and should be consistent with the established shared framework in effect at that time concerning the acceptability of techniques that result in heritable genetic modification of human embryos.

• 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.

Informed and voluntary consent of those deemed research participants in MRT clinical investigations would be required pursuant to federal guidelines and applicable state laws and institutional practices. In addition, it would be important for MRT researchers and institutions, in consultation with local review committees or a central institutional review board, to consider current guidance and emerging best practices in determining appropriate compensation for gamete providers, taking into account the demands placed on a gamete provider by an MRT research protocol.

• For individuals who provide gametes, consent processes should reflect
  • the range of MRT procedures contemplated for preclinical and/or clinical investigations and the general ethical, social, and policy considerations surrounding MRT;
  • the management of incidental findings, should they arise;
  • appropriate compensation, with sensitivity to socioeconomic status;
  • the prospect of future contact between individuals who provided their gametes and children born as a result of MRT; and
  • the management of residual eggs and embryos.

• For intended parents, consent processes should reflect
  • information on the MRT research protocol, with focus on the implications for the health and well-being of resulting children;
  • alternative ways of becoming parents that can avoid maternal transmission of mitochondrial DNA (mtDNA) disease;
  • the management of and potential restrictions on access to embryos created through MRT (e.g., if initial investigations are limited to male embryos);
  • preimplantation and prenatal genetic diagnostic tests that would be incorporated into clinical investigation protocols;
  • the importance of long-term follow-up and how it would be part of the experience of any child born as a result of MRT; and
  • the challenges of maintaining patient privacy given intense media interest in MRT.

• For children born as a result of MRT, consent processes should reflect assent (and eventual consent) for monitoring and research procedures to be performed after birth, up to and including seeking informed consent from the children upon their reaching the legal age of consent.

MRT would require special considerations across the trajectory of regulation and oversight—from preclinical studies to authorization of an IND, potential approval for clinical use, and postmarketing surveillance. These considerations could be addressed through the following guiding principles for oversight.

• 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 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.

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