Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations (2016)

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Do Ethical, Social, and Policy Considerations Preclude MRT?

The unique combination of characteristics of mitochondrial replacement techniques (MRT) 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,¹ a novel intervention never before approved by U.S. federal regulatory authorities.² Second, if MRT were carried out to conceive female offspring, the resulting mitochondrial DNA (mtDNA) modifications would be heritable (i.e., could be passed down through generations) in female offspring due to the matrilineal nature of the inheritance of mtDNA, and the effects of those modifications (whether beneficial or deleterious) could

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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—nuclear DNA (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.

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, the U.S. Food and Drug Administration (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.

persist for generations. Third, the effects of the genetic modification performed on oocytes or zygotes, once carried out, would not, at this time, be reversible.³ 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. This chapter explores the most prominent ethical, social, and policy issues raised by these characteristics of MRT and presents the committee’s analysis of whether these issues preclude its introduction into first-in-human clinical investigations.

The chapter first examines the parental motivation to access MRT. It then turns to the central ethical, social, and policy issues related to genetic modification of germ cells and the germline; this section addresses the latter three of the four issues enumerated above: the genetic modification would be heritable, irreversible, and would affect every cell type of the resulting individual. Next is a discussion of unintended downstream implications of MRT. The chapter continues with a discussion of two other major ethical, social, and policy issues related to MRT: (1) the DNA contribution of two women of different maternal lineage (the intended mother, who would provide the nuclear DNA [nDNA], and the individual providing an oocyte or zygote, who would provide the nonpathogenic mtDNA), and (2) the creation, manipulation, and possible destruction of human gametes and embryos in MRT that would be involved in MRT research or clinical application. Following the analysis of these issues, the chapter concludes with a discussion of key differences between nDNA and mtDNA as related to the foundational question of whether it is ethically permissible for clinical investigations of MRT to proceed.

The title of this chapter—“Do Ethical, Social, and Policy Considerations Preclude MRT?”—comes from the committee’s charge (see Box 1-1 in Chapter 1), which raises the core question regarding the ethics of moving forward with MRT:

The evaluation and analysis of ethical, social, and policy issues in this chapter reflect the committee’s attempt to answer this foundational question. The committee’s analysis included discussion of whether the ap-

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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.

propriate 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.

For the committee’s analysis, this meant recognizing the importance of research for advancing medicine, in light of the ethical, social, and policy concerns raised by this technology, including respect for the interests of women who carry a risk of passing on serious disease, tempered by consideration of the risks and uncertainties of a first-in-human application of MRT. The latter include uncertainties regarding the likelihood and severity of both known and unknown risks to future children, the likelihood and consequences of intergenerational effects, and the downstream implications of introducing a new reproductive technology with a unique combination of characteristics. The following sections examine these issues in turn, presenting the committee’s conclusions regarding each, as well as an overall conclusion regarding the full range of issues taken together.

DEMAND FOR MRT

MRT, if proven to be effective, would represent the only reproductive option for mitigating the risk of maternal transmission of pathogenic mtDNA to children that would also preserve the nuclear genetic relationship between the prospective mother and child. Without the prospect of MRT, families face the choice of risking mtDNA disease in offspring born as a result of unassisted sexual reproduction⁴ or selecting reproductive options

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⁴ The probability of maternal transmission of mtDNA disease is highly variable and depends on a number of factors, including mutation type and heteroplasmy level in the intended mother. Furthermore, such factors as postnatal bottleneck and penetrance might affect the tissue distribution of mtDNA mutations and clinical manifestation in offspring born as a result of MRT. As a general principle, the higher the heteroplasmy level in the intended mother, the higher is the probability of clinically manifest mtDNA disease in offspring. (See the detailed discussion in Chapter 2.) The recurrence risk for offspring of females carrying pathogenic mtDNA mutations is estimated to be 1-4 percent if the female is asymptomatic and up to 50 percent if the female is symptomatic (Falk, 2010).

that would result in a child lacking a nuclear genetic relationship with the prospective mother. The motivation of prospective parents to pursue MRT thus is likely to fall into two overlapping categories: (1) the value to parents of bearing offspring with an nDNA connection to both parents whose risk of developing mtDNA disease would be significantly reduced, if not eliminated; and (2) eradication of mtDNA disease from future maternal descendants.

Genetic Relatedness as a Social and Emotional Value

Parents considering MRT would do so out of a desire to have children who have a nuclear genetic connection to both prospective parents (otherwise they would pursue other, less resource-intensive and more proven interventions, such as oocyte or embryo donation).⁵ Although it may constitute, at least in part, a socially constructed value that differs across societies (Sault, 1996), nuclear genetic relatedness is a deeply held, significant value for some people, for a variety of reasons. Having a child genetically related to both prospective parents may be part of one’s conception of traditional family formation. Physical and physiological resemblance of the child to both parents—and to their siblings and kinship network—could also be psychologically and socially meaningful. Indeed, some research has shown that this resemblance can be a powerful basis for kinship bonds across generations that can often “cement” parent-child relations (Heijkoop et al., 2009; Loomans, 2013; Plomin et al., 1997).

Nuclear genetic relatedness is not, however, a universal desire, and different women and families vary in how they understand genetic kinship and in the priority they place on genetic relatedness. In a study of women who were known or at-risk carriers of pathogenic mtDNA mutations, for example, 52 percent viewed having genetically related offspring as “very important,” 43 percent as “somewhat important,” and 5 percent as “not important” (Engelstad et al., submitted). Generally, social trends in the use of assisted reproductive technology (ART) support the argument that many prospective parents see value in having genetically related children, although many who pursue ART place greater importance on having children regardless of their genetic relation (Kirkman, 2008; Ravin et al., 1997; Thornton et al., 1994; van den Akker, 2000). For example, the advent and uptake of such techniques as those based on oocyte and sperm donation has seen users of ART accept some loss of genetic kinship when using a third party to aid in family formation.

Sociological evidence also suggests significant demographic variations. Studies of in vitro fertilization (IVF), for example, highlight that, because

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⁵ In some cases, the sperm may be provided by a man who is not the prospective father, in which case it is the prospective mother that desires the genetic connection.

of variations in insurance coverage, time demands, and costs of treatment, the benefits of the technology accrue most commonly to those with health insurance covering the costs, those with the financial ability to pay for fertility services themselves, and those with the flexibility to schedule the time-intensive procedures (Bell, 2009). Indeed, the relative importance placed on genetic relatedness may be influenced by whether a prospective parent perceives it as being an attainable goal (Bell, 2009; Thornton et al., 1994).

The popular press has recently covered the topic of adopted children’s desire to connect with their parents, and the challenges they face in doing so (Neville, 2015; Pine, 2015). Studies of adolescents and adults born as a result of oocyte or sperm donation—in which half of the individual’s genetic information is derived from the individual providing the oocyte or sperm—have suggested that some individuals experience confusion surrounding their identity upon disclosure of the nature of their conception due to the genetic contribution of someone not acting as their parent (Hewitt, 2002; Mahlstedt et al., 2010; Turner and Coyle, 2000).

The use of ART has allowed people to become parents through a variety of innovative methods that blur the conventional meanings of kinship, family, and genetic relatedness. In this sense, MRT is not particularly novel. The notion of genetic relatedness, however, is complicated in the case of MRT, primarily because a child born as a result of these techniques would be both genetically related, via nDNA, and genetically unrelated, via mtDNA, to the intended mother—a novel phenomenon in human reproduction. The potential ethical, social, and policy implications of the contribution of DNA from a third party are discussed later in this chapter.

Inability of Current Alternatives to Achieve All Goals

For prospective parents who might consider using MRT, mitigating the risk of mtDNA disease in their children and future generations while retaining a nuclear genetic connection to their children currently represents an otherwise unachievable combination. At present, prospective mothers who are 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: unassisted sexual reproduction, preimplantation genetic diagnosis (PGD), oocyte or embryo donation, adoption, or childlessness.

Unassisted Sexual Reproduction

Unassisted sexual reproduction would provide for a full nuclear genetic contribution from both prospective parents. For women who are heteroplasmic for pathogenic mtDNA mutations, however, it would present a variable, unknown risk of transmitting mtDNA disease, owing to the complexities of mtDNA genetics. For women who are homoplasmic for pathogenic mtDNA mutations, the risk of transmitting mtDNA disease would be 100 percent (although penetrance of the disease across the offspring’s lifetime could depend on a variety of factors).⁶

Preimplantation Genetic Diagnosis

PGD would preserve the nuclear genetic connection between the child and both prospective parents. For some women at risk of transmitting pathogenic mtDNA mutations, however, it is not a viable option for reliably preventing transmission of mtDNA disease (see the discussion of PGD in Chapter 2).⁷

Oocyte and Embryo Donation

Oocyte donation with fertilization by the intended father or a sperm provider represents a reproductive option for prospective parents that could reliably prevent transmission of pathogenic mtDNA from the prospective mother. However, it would not permit a nuclear genetic connection to the prospective mother while retaining the genetic connection to the prospective father. In the case of embryo donation, the transmission of mtDNA diseases from the prospective mother would be prevented, but the resulting child would not have a nuclear genetic connection to either the prospective mother or prospective father. Moreover, while in clinical best practice all

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⁶ This concept is exemplified by one of the common mtDNA homoplasmic mutations that can cause blindness—Leber’s hereditary optic neuropathy—which exhibits increased penetrance in carriers who smoke or consume alcohol.

⁷ As previously described, PGD may not be a reliable method for preventing transmission of mtDNA disease in women who are at known risk of transmitting such disease because of limitations related to complexities of mitochondrial genetics. With the advent of increasingly sensitive and accurate sequencing technologies, however, PGD is expected to be a reliable technique for determining the efficacy of MRT prior to embryo transfer.

efforts are made to obtain as much information as possible on the health history and status of gamete or embryo providers, including genetic risk factors, there is always a chance that the provider could carry unknown health risks that could be transmitted to the offspring.

Adoption

An additional option for preventing transmission of mtDNA disease is adoption, although this option would not result in any genetic connection between offspring and prospective parents. Like oocyte donation, adoption presents issues to be weighed by prospective parents. For instance, a range of well-known features of the adoption process are of potential consequence for the prospective parents and offspring, including the uncertain time frame for completion of the process; the potential for birth parents to claim or reclaim parental rights or custody; limited information about health risks; concern about the ability to create a cohesive family unit; preferences for (and the often limited number of) children who are young, healthy, and with a racial/ethnic and religious background similar to that of the adoptive family; and the potential for long-term psychosocial complications for the adopted child (Collishaw et al., 1998; Smyer et al., 1998). It is important to note, however, that, while challenges to adoption exist, the benefits to adopted children, adoptive families, and society can be significant.

Childlessness

If none of the above reproductive options are appealing to prospective parents for preventing transmission of pathogenic mtDNA mutations, the remaining option is to forgo having children or additional children. This option would guarantee the prevention of maternal transmission of mtDNA disease to offspring and future generations but at the cost of the parents having no (additional) offspring, nDNA-related or otherwise.

In sum, each of the above options would achieve some of the desirable attributes of MRT as a reproductive technique, but none would achieve all of them.

Procreative Liberty and Parental Desire to Pursue MRT

Procreative liberty is generally taken to mean the right of prospective parents to decide whether and when to have children, without unjustifiable restraints or restrictions (which would be a negative right). In some contexts, this definition has been expanded to include other choices related to reproduction, including the method by which one reproduces (i.e., unassisted sexual reproduction or ART). A more contentious aspect of reproductive rights is whether there is a positive right of prospective parents to avail themselves of social resources in accessing scientific advances in reproductive technologies, including entitlement to any available ART. Some have suggested that the regulatory and financial investments required for the development, evaluation, and delivery of the techniques amounts to a claim on collective resources that necessarily entails the recognition of a positive right in relation to MRT (Baylis, 2013; Bredenoord et al., 2008; Robertson, 1988).

While collective resources must be brought to bear to create and maintain the infrastructure and processes necessary to ensure oversight and safe use of goods and services—whether they be drugs, medical devices, cleaning supplies, or toys—the use of such infrastructure and processes does not invoke or suggest a positive right to claim provision of those things or services, nor is it the result of anything like a conscious trade-off between the use of resources for one purpose versus another. The pursuit of research in the United States triggers regulatory oversight, and while some may see this as a sort of claim on collective resources, the same argument could be made about a multitude of examples for which a system of evaluation and regulation exist, up to and including the resources needed to ensure good medical care for women who conceive through unassisted sexual reproduction. Therefore, if FDA were to approve MRT, its availability to a few does not create the recognition of such a positive right, any more than it would be in the case of the pursuit of any area of research, submission of licensure applications to regulatory bodies, or delivery of regulated services.

However, every reproductive choice—be it the birth of a child through unassisted sexual reproduction or the use of ARTs such as gamete donation, embryo donation, and gestational carriers—involves risk and has the potential for considerable health and social implications. MRT provides a potential opportunity to avoid a predicted health risk but with the uncertain potential to incur unknown developmental risks to the future child and unknown risks to future generations associated with the techniques.

As a general matter, parents have broad discretion to make decisions about the care, custody, and control of their children, including putting their children at some risk in the conduct of everyday family life. With regard to procreative liberty, the U.S. societal experience with the use of ART to treat infertility has revealed great tolerance for parental decisions to impart unknown risks to future children in the pursuit of relatively novel reproductive technologies. In those cases, the desire to conceive and bear children (whether genetically related or not) rather than to adopt or remain childless has effectively been given priority over concerns about risks to children born as a result of the novel technologies. To the extent that social concerns have arisen, they have not been identified or addressed through restrictions imposed by the U.S. legal and regulatory system, though this may be a function of the limits of regulation rather than a conscious decision. For example, the system has allowed the development and initial investigations and eventual clinical use of IVF, intracytoplasmic sperm injection (ICSI), and PGD with minimal FDA oversight (although regulation of medical practice at the state level does serve to regulate IVF), all of which may expose the future child to some risk. MRT would satisfy a strongly felt desire to bear genetically related offspring, coupled with the reduced risk of passing on mtDNA disease (Klitzman et al., 2015). MRT would not treat an existing person for a disease, illness, or condition, so its pursuit does not address a medical need per se. But satisfying a desire to bear genetically related offspring through use of MRT requires clinical interventions provided by professionals using manipulated materials, and thus is within the regulatory authority of FDA.

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. Upholding these responsibilities requires limits on initial investigations and potential eventual use(s) of MRT. The committee believes that MRT could move forward within such limits, through means noted later in the report.

GENETIC MODIFICATION OF GERM CELLS AND THE GERMLINE

Numerous ethical, social, and policy issues arise when one is considering techniques, such as MRT, that involve genetic modification of human germ cells or gametes. Although the term “genetic modification” could be used to encompass a variety of techniques, including gene editing, here the committee uses the term to mean changes to the genetic material within a cell. The type of genetic modification associated with MRT is the combination of mtDNA from one woman with nDNA from another woman of different maternal lineage within an oocyte or zygote. While there is no direct modification or editing of the mtDNA sequence itself,⁸ the novel combination of mtDNA from one woman and nDNA from another would not occur in unassisted sexual reproduction or in other ARTs. Thus, the committee considers MRT to be “genetic modification” of the oocyte or zygote.

The statement of task provided by FDA to this committee defines “germline modification” as “human inheritable genetic modification.”⁹ Some have defined these terms differently. During deliberation over MRT, for example, the United Kingdom used a working definition of “genetic modification” as “the germline modification of nuclear DNA (in the chromosomes) that can be passed on to future generations.”¹⁰ This committee, in contrast, views “genetic modification” and “germline modification” as two separate concepts, the first being “changes to the genetic material within a cell” and the latter “human inheritable genetic modification.” Using these definitions, the committee finds that MRT involves genetic modification, but that it constitutes heritable genetic modification (germline modification) only if used to produce female offspring because mtDNA is solely maternally inherited, and therefore any changes to mtDNA in male offspring would not be inherited by their descendants.

A clear line has been drawn in U.S. policy on genetic modification in humans between somatic cell genetic modification, which is not heritable, and germline modification.¹¹ Recent advances in MRT research have reignited ethical debates over long-standing prohibitions on heritable genetic modification, and require clarification of the meaning and use of these terms.

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⁸ 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.

⁹ The committee has adopted the shorter synonym “heritable” (instead of “inheritable”) in this report.

¹⁰ See https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/332881/Consultation_response.pdf (accessed January 15, 2016).

¹¹ See overview of the germline modification policy context in Chapter 2.

The following sections review issues associated with genetic modification of human germ cells and heritable changes to future generations (“crossing the germline”).

Genetic Modification of Human Germ Cells

Discussions about human genetic modification often distinguish between somatic and germ cell modification. The ethical, social, and policy issues involved differ, largely because modifications to germ cells may be heritable if and when individuals whose oocytes or sperm have been modified choose to reproduce, and whatever modifications have been introduced into the germline have effects potentially in perpetuity. By contrast, genetic modifications to somatic cells do not survive beyond the life of the affected individual. Some people oppose human genetic modification in general, whether at the germ or somatic cell level, and indeed some of the arguments presented here may be relevant to both. Taking this into account, this section provides a broad overview of issues raised by the fact that MRT results in human genetic modification at the level of both germ and somatic cells, including safety concerns, concerns surrounding interference with nature and “playing God,” and concerns surrounding eugenics and attitudes toward disability.

Safety Concerns

A primary concern in considering the ethics of genetic modification is the safety of any proposed techniques. This committee’s task was not to review the preclinical evidence for MRT to determine the safety of the techniques, but to address the foundational ethical question of whether it is ethically permissible for clinical investigations of MRT to proceed. Because safety considerations are central to the ethics of MRT, a major premise of the committee’s deliberations was the understanding that FDA would perform a stringent analysis of the preclinical evidence for MRT to determine whether the safety of the techniques is adequate to support clinical investigations (see also the section in Chapter 4 on assessing benefits and risks).

Concerns Surrounding Interference with Nature and “Playing God”

One objection to human genetic modification is that it constitutes an inappropriate interference with nature. For some people, this objection relates to a call for limitations on the degree of control humans exercise over their biological makeup. For others, this concern focuses on risk and is based on a belief that the natural, unaltered human genetic state is to be protected for fear of poorly understood consequences of changes in the fundamental nature of humans. Similar concerns are echoed in debates over genetically engineered foods and vaccines, with “natural” forms being preferred in part because they are perceived as safer. While respect for the “natural” genetic blueprint of humans is understandable, it is unclear how to characterize such a state of nature as safer or superior given that it is the source of a large burden of human genetic disease (Cotton, 2007; McKusick, 2007; Stenson et al., 2009); thus, “unaltered” nature can be far from an ideal default. Humans have long strived to improve on their natural state for themselves as well as for their children through a variety of activities (pursuing treatments for illness and disease; seeking advantages in education; and even enhancing desirable traits, such as boosting immunity through vaccination).

In the committee’s view, the need to understand the consequences of a new genetic technology is crucial, and argues for careful and incremental advances—much as has been the case in other instances, most notably gene transfer research in humans. The desire to protect what is “natural” about human genetic composition solely because it is perceived to be better is not, in this committee’s judgment, a basis for maintaining a “natural” state in which individuals suffer severe, debilitating diseases.

Concerns about interventions in nature are often expressed in public debates in the language of “playing God.” For instance, the committee received public comments suggesting that the use of MRT would equate to “playing God.”¹² In general, this metaphor is frequently invoked, with little or no connection to specific religious traditions and beliefs, in order to dismiss some reproductive and genetic technologies—or some uses of those technologies—as illegitimate. Warnings against “playing God” decry human pride, arrogance, and the like. Those who “play God” are accused of hubris, overreaching, and defiance of limits, while those who refrain from “playing God” are deemed to have proper humility in recognition of human finitude and fallibility. Whether these characterizations of the vices and virtues of different interventions in nature are defensible depends

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¹² One public comment submitted to the committee states, “This ‘creation’ attempt is nothing other than playing God, arrogantly assuming that we flawed humans can improve ourselves. That perfection could ever be created by the imperfect. This will never work, will assuredly backfire and many will suffer.”

on whether the “natural” state should be maintained or may be modified. However, the phrase “playing God” is not always negative; it may be more neutral or even positive. Humans can even be “collaborators,” “partners,” or “created co-creators” with God or “agents” of God. Overall, the metaphor “playing God” itself is too vague and indeterminate to guide such judgments without additional premises and arguments.

If one turns from free-standing uses of the metaphor “playing God” to the views of particular religious traditions—for instance, the Abrahamic traditions (Judaism, Christianity, and Islam), Hinduism, and Buddhism—the literature indicates widespread concern about making heritable genetic modifications, along with widely divergent views within and across these traditions on the acceptability of exercising specific reproductive and genetic choices (see, e.g., Chapman and Frankel, 2003; Dorff and Zoloth, 2015; Evans, 2010; Lustig et al., 2008; Pfleiderer et al., 2010). It is beyond the scope of FDA’s charge to the committee to delve deeply into these religious views, although it is important to recognize the depth and diversity of views among many in American society and the role of those views in their understanding of the acceptability and appropriate uses of technologies such as MRT. Because religious traditions are diverse and sometimes lead to diverging perceptions of genetic modification, selectively applying a particular religious tradition’s framework to the ethical, social, and policy analysis of MRT was not an appropriate or useful grounding for the committee’s analysis.¹³

Concerns Surrounding Eugenics and Attitudes Toward Disability

Some people are concerned that genetic modification of germ cells via MRT could represent a form of eugenics. The ambitions for eugenics, as well as means and policies for achieving these ambitions, have varied widely in different eras and settings. In one form, negative eugenics, governments have used hereditary knowledge and coercive policies such as sterilization in an effort to prevent transmission and propagation of traits believed to be hereditary. In another form, positive eugenics, governments and other groups have used hereditary knowledge to promote “better babies,” “fitter families,” and “race betterment.”

Both negative and positive eugenics were practiced across the globe, including in the United States, in the early 20th century as a means of im-

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¹³ The committee also notes a useful initiative of the American Association for the Advancement of Science (AAAS) to convene a working group of scientists, ethicists, theologians, and policy analysts to develop a report considering the ethical, religious, and social implications of human inheritable genetic modifications (AAAS, 2000). The AAAS project also involved the development of a book of essays describing the pros and cons, and what is at stake, when society considers human heritable genetic modifications (Chapman and Frankel, 2003).

proving the gene pool of the human population (Adams, 1990; Allen, 2002; Kevles, 1985; Larson, 1995; Lombardo, 2003; Paul, 1995; Reilly, 1991; Schoen, 2005). Many commentators today, however, while recognizing that current genetic interventions aimed at preventing or treating serious disease or promoting offspring free of serious disease (sometimes referred to as the new eugenics) are not comparable to the negative eugenics of earlier eras, emphasize that the distinction between eugenics and recent genetic interventions depends on whether the latter are carried out in contexts where proper safeguards are in place, such as respect for and legal protection of patient and reproductive autonomy. For many observers, both social vigilance and better science are needed to ensure that old eugenic ideals promoting so-called biological fitness and devaluing the “unfit” do not reappear (Kevles, 1992; Lindee, 2005; Rapp, 2000).

Another closely related concern about genetic modification of germ cells via MRT is the potential impact on persons with disabilities. If MRT were approved in the United States, women at risk of transmitting mtDNA disease might feel pressure to use the techniques. The very existence of the techniques, coupled with any resulting pressure on families to use them, might also reinforce or result in expression of the already strong social and cultural norms that marginalize persons with disabilities.

Individuals identified with the disability rights movement have criticized prenatal genetic testing for disabilities for a number of reasons. They have suggested that this form of genetic testing (1) reinforces social discrimination against people with disabilities, (2) leads to rejection of an otherwise wanted child because parents believe the child’s disability will diminish their parental experience, and (3) reflects decisions made by parents based on the misconception that a child with disabilities would not fulfill what most people seek in childrearing (Asch, 1989). On the other hand, some have suggested that individual women and families seek such testing or medical interventions not to cause negative perceptions of those with disabilities but to meet their own familial goals and to avoid imposing potential, avoidable suffering on a future child. It is also noted that many people with disabilities may still be harmed by the apparent perceptions created by prenatal genetic testing, despite the intentions of individual women and families (Parens and Asch, 1999).

In Sweden, the National Council of Medical Ethics has cited similar concerns about the effect of MRT on discrimination against people with disabilities and on society at large. In weighing the ethical and social implications of MRT, a minority of the council’s members suggested that MRT is not ethically permissible, even if proven safe, in part because in the long run, it “could be a threat to the humanistic view of the individual and human dignity. . . . If this technique is permitted, we would thus risk a development towards a society that discriminates, a society that places demands

on citizens to reject and make the right choices, a society that becomes more technified and where what we consider makes us human is lost” (Swedish National Council on Medical Ethics, 2013).

Similarly, the United Nations Educational, Scientific and Cultural Organization (UNESCO) stated that “the human genome underlies the fundamental unity of all members of the human family, as well as the recognition of their inherent dignity and diversity. In a symbolic sense, it is the heritage of humanity” (UNESCO, 2005). One might thus contend that genetic modifications of future individuals are ethically unacceptable because they alter a fundamental aspect of human existence in ways that are passed on to successive generations. Along these lines, some have proposed a Genetic Bill of Rights, indicating that “all people have the right to have been conceived, gestated, and born without genetic manipulation” (Board of the Council for Responsible Genetics, 2000). Of course, reproductive technologies have an impact on genetic makeup in various ways, as do epigenetic effects of the in utero environment and experiences and exposures after a child is born. Together, these observations suggest calling the human genome “the heritage of humanity” is a vague and aspirational basis for crafting policy related to the use of MRT. Therefore, the committee is not persuaded that MRT should be prohibited based on arguments that the genome represents an inviolable “heritage of humanity” or that there is an inviolable right to be born without the aid of MRT.

The process of MRT would lead to the creation of an individual, the primary intervention occurring at the stage of an oocyte for maternal spindle transfer (MST) or a fertilized oocyte (zygote) for pronuclear transfer (PNT). Some commentators have expressed concern that because a future child cannot make an informed decision about being born as a result of MRT, nor can any descendants of that future child, the techniques are unethical (Darnovsky, 2015). Every other ART shares the similar feature that future children who are the product of such a technology cannot consent to its use in their conception, nor does any child conceived through sexual reproduction have the ability to consent to its own “natural” conception. For these reasons, the committee does not find the lack of child consent to be an insuperable ethical objection to using MRT. However, MRT represents an important new development in two respects. First, the issues around developing a potential research protocol for MRT are novel with respect to applying federal regulations (including informed consent); consent is discussed in detail in Chapter 4. Second, MRT involves the introduction of genetic modifications that could be passed on to future generations, as discussed in the next section.

Heritable Changes to Future Generations: “Crossing the Germline”

Ethical, social, and policy issues raised by MRT may vary depending on whether it works as intended. If MRT were proven to be successful, children born as a result of the techniques, and in the case of females their future offspring, would be spared from serious, life-threatening mtDNA diseases that they would otherwise have been at high risk of both inheriting and transmitting. If MRT were proven to be unsuccessful or caused significant adverse consequences, any missteps in the genetic modification and the associated health outcomes would be transmitted irreversibly to future generations via any female offspring. For some people, however, even successful interventions that result in a heritable genetic modification are unacceptable because it is impossible to say with certainty that the interventions would be safe and have the intended results into the infinitely foreseeable future (Bonnicksen, 1998). Some people might be comfortable with genetically modifying a single embryo in the interest of avoiding a life-threatening disease but would deem such modifications unacceptable if the effects became heritable and thereby unbounded in duration in terms of the number of future individuals affected (Bacchetta and Richter, 1996). Concerns about the risk of heritable change and the effects on future generations are valid and important, and both restrictions on the application of MRT and the collection of information about its effects would be crucial aspects of acceptable policies that would have to be in place for MRT investigations to proceed (see the discussion in Chapter 2 of the policy context surrounding heritable genetic modification).

Creating a heritable genetic change in humans also could, over a long time frame, skew evolutionary processes by introducing deleterious, irreversible genetic effects that would be detrimental to the human species. Some people argue that the human gene pool is a resource shared among the world’s people—similar to air or water—and should not be purposefully changed without the consent of all humans (Suzuki and Knudtson, 1990). However, population genetics amply demonstrates that the scale of use of MRT required to have such an evolutionary effect would be enormous—and unlikely to occur.

As discussed in Chapter 2, while the exact prevalence of mtDNA diseases is unknown, estimated ranges indicate that these diseases are collectively rare. The limitation of MRT to women at risk of transmitting severe mtDNA disease, in combination with the likelihood that not all women potentially eligible for MRT would be interested in the techniques, indicate that the number who would potentially pursue MRT is likely quite small. One study estimates that the average number of children born each year to

women at risk of transmitting mtDNA disease in the United States could be 778 (Gorman et al., 2015).¹⁴ Given the small number of individuals at risk for severe mtDNA disease who might qualify for and also decide to use MRT should it become available, MRT would be unlikely to have significant effects on evolutionary processes.

UNINTENDED DOWNSTREAM SOCIAL IMPLICATIONS OF MRT

Most of the issues discussed below are premised on speculation about a broad application of MRT that goes beyond pathogenic mtDNA diseases and the circumscribed conditions and applications detailed in this report. However, some of these issues and their implications apply to both circumscribed and broad applications of MRT.

Equitable Access

If MRT were approved, regulation and uptake of and access to the technologies could interact with important social values concerning equity in access to medical treatments. The ability to diagnose mtDNA diseases has improved in recent years, but recognition of potential symptoms and the knowledge and ability to seek appropriate care from a team of specialists are still most likely among individuals with higher levels of health literacy, access to health insurance, and the financial means to pay for services not covered by insurance. Indeed, it has been documented that women of low socioeconomic status are marginalized in reproductive policies and view themselves largely as outsiders with respect to the array of reproductive technologies available at IVF clinics in the United States (Bell, 2009). Given the likelihood that MRT would be available only in one or two U.S. centers, access could be further limited to women who could afford the cost of the procedure and an extended stay away from their job and home life. And if mtDNA haplogroup matching were implemented in the context of human investigations or clinical use, the scarcity of oocyte providers with particular haplogroups also could result in inequitable access to MRT.

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¹⁴ This text has been updated since this report’s initial release.

This reality is a microcosm of the overall U.S. health care system, in which many cutting-edge technologies are more readily available to individuals of high socioeconomic status. Yet the likelihood that MRT for the prevention of maternal transmission of mtDNA disease would first be available to individuals of high socioeconomic status is not a reason to abandon the development of these techniques. Because women of low socioeconomic status have traditionally been excluded from reproductive technologies, it would be important for the multidisciplinary teams that would conduct potential human clinical investigations on MRT and eventually apply it in patient populations to pay particular attention to the challenge of reaching individuals in their community who might benefit from these techniques. Such efforts could entail working to identify family members of current mtDNA disease patients who might also be at risk of or suffering from these diseases, and could be carried out in conjunction with partnerships with mitochondrial disease advocacy groups, MRT researchers, and clinicians.

Expanded Applications of MRT and Enhancement

Once MRT had been approved, FDA could find it challenging to control applications of the techniques because the agency’s authority is greater during the research stage than during the postapproval marketing stage, when off-label uses are permitted (see the discussion of the policy context in Chapter 2). Because the U.S. system regulates the products used in medicine, not medical practice, the greater regulatory oversight and control of use that exist in some other countries, such as the United Kingdom, are not exercised here. In theory, and based on observations of past practice, MRT has the potential to be applied beyond any approved use.

Indeed, a chief concern surrounding MRT is the potential for its application for purposes beyond preventing the transmission of serious mtDNA diseases. One area of expanded application that raises particular concern for the public is “enhancement.” For instance, several genetic studies have identified statistical associations between mtDNA haplogroups (fixed sets of variants that make up population-defining haplotypes; see Chapter 2) and such traits as exercise performance and aerobic capacity. Most of these studies to date remain controversial because of the small sample sizes, issues of population stratification, and the lack of robust experimental systems in which to demonstrate causality. Traits such as athleticism and aerobic capacity are classically highly polygenic (influenced by more than one gene), so contributions to these traits from mtDNA are expected to be small. Yet while at present it is very challenging to identify mtDNA variants that would confer on offspring a marked improvement in physical performance or aerobic capacity, the expanded use of MRT for such “energetic” enhancement purposes is a theoretical possibility.

A long and significant debate in the ethics literature is focused on the distinctions among prevention, treatment, and enhancement. Efforts to establish a clear definitional boundary between treatment and enhancement confront examples that defy simple classification, such as vaccination to enhance an individual’s immunity against infectious disease. For MRT, similar gray areas might include its use to avoid a common mtDNA variant that confers a small statistical risk for developing a disease with limited morbidity, or a rare mtDNA mutation whose pathogenicity for a severe disease remains controversial. Another might be the possible use of MRT for some forms of female age-related or idiopathic infertility; the experiments with cytoplasmic injection of the 1990s suggest there might be some interest in this application. At the far and hypothetical end of this spectrum, and at present lacking an evidentiary base, would be enhancement applications such as seeking oocyte providers whose mtDNA might convey some advantage—for example, the capacity for greater aerobic capacity or physical performance. For individuals with serious mtDNA disease who had already decided to use MRT, an attempt to identify a “best” mtDNA provider, regardless of how unrealistic, could occupy a gray area with respect to such enhancement of the future child. This possibility appears remote, however, given the limited expectation of such benefit and the significant additional time, effort, and potential expense that would be entailed beyond those already associated with MRT.

In Chapter 4, where the committee presents its recommendations, Recommendation 1 outlines the conditions under which the committee believes FDA should consider approving clinical investigations of MRT. One of these conditions is that FDA review the scientific evidence on the utility of haplogroup matching and if compelling, consider it as a means of mitigating the risk of mtDNA-nDNA mismatch. The committee believes this would likely be a primary criterion for the selection of oocyte providers for MRT, which could in practice preclude the option of selecting a haplotype for enhancement purposes. At the most basic level, as long as the underlying motive for prospective parents pursuing MRT remained having a child unaffected by mtDNA disease, there is no reason to believe that enhancement would be seriously considered by those parents. Nonetheless, this sort of scenario has led to discussions about treating children as “products” to be designed according to parental desires, similar to the discussions that once took place with sperm donation, oocyte donation, IVF, and PGD. Thus, clinicians, investigators, regulators, and policy makers will need to be cognizant of these hypothetical concerns as the field evolves.

Further complicating these discussions is the distinction between curing a disease and circumventing it through preventive measures. MRT would not reduce the risk of a mother’s mtDNA mutation developing into disease, nor would it cure a mother’s preexisting mtDNA disease; rather, it would

be used to prevent that disease in her offspring. Circumvention or prevention does not in itself transform a medical intervention into an enhancement, although as noted above, prevention can in some cases occupy a gray area in this regard. But this goal of MRT does speak to the availability of alternatives, such as oocyte donation and adoption, that provide some of the benefits of reproduction via MRT, although not the nDNA connection that comes with use of these techniques. This point is relevant in deciding whether the risks of such an intervention are reasonable in relation to its possible benefits.

In the committee’s view, the differences between mtDNA and nDNA, discussed in more detail below, and the fact that, as opposed to gene editing, MRT procedures lack the precision and flexibility to target particular phenotypes helps circumscribe MRT’s applications and places some natural limitations on the potential for its misuse. Thus, it may not be necessary or useful to draw strict lines among prevention, treatment, and enhancement for purposes of developing an ethical boundary for MRT. As discussed in the remainder of this report, including Recommendation 6 in Chapter 4, the use of MRT would need to be appropriately controlled in the U.S. market to limit off-label applications beyond its intended use. If postmarket controls were not implemented and enforced, off-label use could allow physicians to perform MRT for a wider range of purposes than those for which it had been tested and approved (see also Chapter 2 for discussion of the policy context for MRT).

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 (Connor, 2015). As noted above, experience with IVF in the 1980s and 1990s demonstrated that a technique developed to circumvent a specific problem (in that case, blocked fallopian tubes) can, under some circumstances, be expanded to much broader patient populations than originally intended. While IVF was not itself the subject of FDA regulation at that time, this experience demonstrates the potential expansion of indications for MRT, whether in the form of off-label use or research aimed at obtaining an additional, approved indication.

In addition to concerns that MRT could be used off-label in embryos not at risk for mtDNA disease, the developing science around the role of mitochondria and mtDNA in other chronic conditions may signal additional potential applications for MRT (see Chapter 2). As the science in this area develops, potential applications of MRT could include a wider array of diseases (such as diabetes and cancer) in which it is suspected that mtDNA may play a lesser but still significant role. Any effort to expand MRT to such “suspected or secondary mtDNA diseases” would need to be undertaken only after careful professional consideration and regulatory deliberation.

In sum, special attention needs to be paid to any potential expansion of MRT as a means of treating idiopathic or age-related infertility or preventing transmission of mtDNA that might be linked to diseases or conditions with tangential connections to mtDNA. 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.

DNA CONTRIBUTION OF TWO WOMEN

This section focuses on how MRT would introduce genetic material from two women of different maternal lineage—the intended mother’s nDNA and mtDNA from the woman providing an oocyte or zygote. In so doing, 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.

Identity

As some other reviews have suggested, introducing the mtDNA of a second woman could cause the child born as a result of MRT to have a confused or conflicted self-perception (see Nuffield Council on Bioethics, 2012, pp. 70-72). Such effects on self-perception could arise as a function of the desire for knowledge about the meaning of the oocyte provider’s mtDNA for the child’s identity or for information about the identity of the oocyte provider. Some popular media characterizations go so far as to suggest that children born as a result of MRT would have two mothers (Tingley, 2014), capturing the concern that the replacement of a population of mtDNA could mean that the child’s identity was determined by contributions from two different women, giving the child some shared identity with both. Some scholars also defend the claim that MRT would result in three genetic parents on the basis that the issue of relevance is the “presence or absence of identifiable genetic material from someone other than the two individuals identified as genetic parents” (Baylis, 2013).

A desire for knowledge about the evolutionary origin of the oocyte pro-

vider’s mtDNA or to know the identity of the provider, although legitimate and potentially of interest to some children born as a result of MRT, could be mitigated or fully addressed, for example, through systems for documenting, tracking, and possibly facilitating receipt of information from the oocyte provider. With respect to the concern that children born as a result of MRT could experience confusion about whether their identity had been fundamentally altered as compared with what would have been the case without mtDNA from an oocyte provider, this is a metaphysical issue that will not be solved through empirical study. In Chapter 4, the committee discusses its conclusion that MRT would result in a new child who would not have existed but for the conduct of the technique. If children born as a result of MRT accepted this formulation, their understanding of their existence should be no different from that of children born as a result of other ART procedures. Indeed, every child who is the result of unassisted sexual reproduction after a period of contraception is a different child from the one who would have been born had the intended parents not sought to prevent earlier pregnancies. Offspring who did not accept this formulation would likely perceive that MRT had prevented a likely condition of having mtDNA disease, and thus that they had personally benefited medically from the procedure, not that their identity had been altered in any confusing manner.

In the committee’s view, experience with MRT births and the collection of information about MRT offspring would be necessary before factors relevant to conceptions of identity could be applied to assessments of the benefits and risks of MRT over time. There is no direct precedent on which to base conclusions about whether the unusual configuration of genomes of a child born as a result of MRT would yield a confused or conflicted self-perception of sufficient concern to render proceeding with MRT investigations unacceptable. Systematic studies in children born after cytoplasm transfer in the late 1990s have not yet been reported. However, there are some analogies that could be informative with regard to the influence of donated genetic material on identity formation in recipient individuals. Studies of adolescents and adults born as a result of oocyte or sperm provision—in which half of the individual’s genetic information is derived from a gamete provider—have suggested that some individuals experience confusion surrounding their identity upon disclosure of the nature of their conception due to the genetic contribution of someone not acting as their parent (Hewitt, 2002; Mahlstedt et al., 2010; Turner and Coyle, 2000). However, it has been found that timely and appropriate disclosure of the conditions of the child’s conception, as well as access to identifying information about the gamete provider, is critical to healthy identity formation, the development of positive self-conception, and psy-

chological development (Hewitt, 2002; Kirkman, 2003; Mahlstedt et al., 2010; Turner and Coyle, 2000).

Organ or tissue donation shares with MRT the transfer of biologic (and hence genetic) material from a provider to alleviate disease manifestation in the recipient. In this area, retrospective studies have found conflicting results with regard to the influence of the provided material on the recipient’s perceived self-identity: while some recipients view provided tissue merely as part of a “machine” and thus do not perceive a significant impact on their identity (Sanner, 2001, 2003; Sharp, 1995), others believe their identity was altered or at least affected by the receipt of someone else’s biologic/genetic material, in some cases even perceiving that they have taken on the mental, physical, or social traits of the provider (Sanner, 2001, 2003; Sharp, 1995).

The experiences of individuals born from oocyte or sperm providers, as well as recipients of organ or tissue donation, are interesting but provide limited insight into the potential identity-related issues facing any children born as a result of MRT. Children born from third-party nDNA providers (oocytes or sperm) are often deeply curious about whether they share similar characteristics (physical or behavioral) with their genetic mother or father because, from a social perspective, these traits are carried in nDNA. By contrast, mtDNA is not typically associated with the complex behavioral and physical traits attributed to nDNA, and therefore it is less clear how or whether obstacles to healthy identity formation would arise as a result of MRT. In the committee’s view, MRT, if safe and effective, could have a significantly positive impact on individuals born as a result of the techniques primarily because of the physical health benefits realized. In addition, family and social support for any child born as a result of MRT would likely play an important role in facilitating healthy, positive self-perception that would acknowledge the novel genetic combination that contributed to the child’s existence.

Kinship

Regardless of whether the sense of self and perception of his or her identity of a child born as a result of MRT were affected, it appears likely that the child, and his or her family, could have different perceptions of the relevance of the unusual combination of genetic relatedness resulting from MRT. For example, questions could arise about whether MRT had altered kinship and if so, whether it had done so to an extent that was troubling with respect to its impact on the child. The concept of kinship is fluid, and families in U.S. society have many different combinations of genetic, birth, and social parents. Whether adopted or born as a result of the use of provider gametes or gestational carriers, some children find it important to seek

information about their biological origins, and the same could be the case for children whose mtDNA came from an oocyte provider.

Ancestry

An interesting aspect of MRT is that, although it is valued specifically for its potential ability to preserve a genetic connection between the resulting child and his or her mother, in the process it would alter the child’s mtDNA, which is a primary means of ascertaining one’s maternal ancestry. Recent decades have seen a growing popular interest in what genetic analysis can reveal about an individual’s ancestral origins. Genetic ancestry has become linked to important social and political debates over citizenship, social group boundaries, race, immigration policy, and exclusion. Much of the focus of interest in genetic ancestry revolves around analyzing mtDNA due to its matrilineal inheritance. If women with mtDNA disease used MRT for conception, their sons and daughters (as well as all future offspring with the new maternal mtDNA) would carry the mtDNA of the provider, not of the mother whose nDNA they had inherited. It is not possible to predict how mtDNA ancestry will develop in the future or how genetic ancestry information would be used.

An mtDNA provider’s 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.

MANIPULATION OF EMBRYOS

MRT necessarily would involve the manipulation of human gametes and embryos, a topic of significant ethical, social, and policy debate. These manipulations might include fertilization via ICSI, biopsy of embryonic cells for testing, and removal of genetic material from one oocyte or zygote and its transfer to another oocyte or zygote. In addition to manipulation, MRT

would involve the creation and possible destruction of embryos, both in the research phase and in clinical use. The ethical, social, and policy concerns surrounding the creation and destruction of embryos are long-standing, and not unique to MRT. For example, IVF involves the creation of embryos and usually results in a number of unused embryos that are destroyed, frozen and stored for potential future use, or donated to others for their use in reproduction or for research; embryonic stem cell research requires the destruction of embryos for derivation of the stem cells.

The manipulation, creation, and destruction of embryos are opposed by a range of groups, and federal funding for research involving these processes is severely restricted (the Dickey-Wicker amendment prohibits federal funding from the U.S. Department of Health and Human Services [HHS] for embryo research that destroys, discards, or offers no prospect of medical benefit to the embryo (45 CFR § 46.204(d); see also Chapter 2). Other technologies that involve creation or manipulation of embryos, such as IVF and PGD, were developed outside of the federal regulatory scheme, so the examination and potential regulation of the manipulation, creation, and destruction of gametes and embryos for the purpose of clinical investigation and as part of an IND are novel.

The “moral status” of the embryo is central to the debate over the manipulation, creation, and destruction of embryos. Some scholars argue and many others believe that morally significant life begins at conception, that legally significant personhood should begin at conception, and that human embryos are indeed human beings (Noonan, 1970). A report by the UK Department of Health & Social Security’s Committee of Inquiry into Human Fertilisation and Embryology (1984, p. 61) (“The Warnock Report”) observes that in this view, “the human embryo is seen as having the same status as a child or an adult, by virtue of its potential for human life.” In a more recent publication, George and Lee (2009, p. 301) argue that “the embryo has the same nature—in other words, it is the same kind of entity—from fertilization onward; there is only a difference in degree of maturation, not in kind.” This argument generally relies on the notion that an embryo has “all of the internal information needed … and the active disposition to develop itself to the mature stage of a human organism” (George and Lee, 2009, p. 301). Some who argue for the equal moral status of the embryo evoke religious views; for example, the Catholic Church holds that the embryo “must be treated from conception as a person” (Catholic Church, 2003, para. 2274).

Others contend that the moral status of an embryo is not equivalent to that of a person, arguing that this status is conveyed at some later point in development. Sandel (2004, p. 208) states that “the fact that every person began life as an embryo does not prove that embryos are persons,” and notes that “although every oak tree was once an acorn, it does not follow

that acorns are oak trees.” Among proponents of this view, ideas on the point at which personhood begins vary, ranging from the beginning of sentience, to the onset of brain activity, to the development of cognitive abilities such as reasoning (Department of Health Education and Welfare Ethics Advisory Board, 1979; NIH Human Embryo Research Panel, 1994). Others do not speculate on the point at which an embryo becomes a person, but contend that it is at least sometime after successful implantation. The British Royal College of Obstetricians and Gynaecologists, noting that around 60 percent of embryos are spontaneously aborted within the first days and weeks after fertilization, observes, “It is morally unconvincing to claim absolute inviolability for an organism with which nature itself is so prodigal” (Royal College of Obstetricians and Gynaecologists Ethics Committee, 1983, p. 13).

A third view falls somewhere between the two described above, denying full moral status to the embryo but nonetheless according it a “measure of respect” (Department of Health & Social Security (United Kingdom), 1984, p. 62). According to this view, the embryo is not a “full human being,” but neither is it “a mere thing, open to any use we desire” (Sandel, 2004, p. 208). The moral status of an embryo increases as it accrues qualities that make it more similar to a person, such as genetic uniqueness, the potential for full development, sentience, brain activity, a degree of cognitive ability, human form, and the capacity for survival outside the womb (NIH Human Embryo Research Panel, 1994). A preimplantation embryo possesses some of these qualities—genetic uniqueness and potential for full development—so by this view it deserves a measure of respect that is not due to the sperm or the oocyte. This third view holds that the absence of all other qualities, however, “makes it unreasonable to think of personhood as beginning here and places limits on the degree of respect accorded” (NIH Human Embryo Research Panel, 1994, p. 39).

The creation, manipulation, and possible destruction of embryos would occur both in the preclinical research phase of MRT and in clinical investigations or clinical use of MRT. Because MRT is still in development, preclinical research could involve the creation and destruction of many embryos in efforts to improve the techniques to the point at which clinical investigations could safely proceed. Any preclinical data required by regulators for consideration in advance of first-in-human investigations could increase the numbers of embryos created, many of which would likely not be transferred for implantation. The creation of embryos solely for research purposes is controversial. Those opposed argue that fertilization is the first step in bringing a human being into existence, and that creation of embryos for research purposes is “inherently disrespectful of human life” and open to significant abuses (NIH Human Embryo Research Panel, 1994, p. 42). Even those who do not accord full moral status to an embryo might be

wary of creating embryos for research. The National Institutes of Health’s (NIH’s) Human Embryo Research Panel concluded that the embryo “does not have the same moral status as an infant or child” but recommended minimizing the creation of embryos by allowing such research only when “the research by its very nature cannot otherwise be validly conducted,” or when it is necessary for the validity of a study that is “potentially of outstanding scientific and therapeutic value” (NIH Human Embryo Research Panel, 1994, pp. x, 44, and 45).

In addition to the research phase, embryos might be created and destroyed in clinical research on or the regular clinical use of MRT. Even at its most efficient and successful, PNT would require the destruction of one zygote because it would involve the transfer of nDNA from one zygote to another, resulting in the destruction of the first zygote. On the other hand, the efficient and successful performance of MST would in theory involve only the destruction of one unfertilized oocyte in the usual course of the procedure. In recent preclinical research on MST, however, an unexpected number of MST embryos developed abnormally (Tachibana et al., 2013); therefore, the procedure could require the creation of many extra embryos to produce a sufficient number viable for intrauterine transfer. For those who consider embryos to have moral status, destruction of a potentially viable embryo in the regular practice of MRT—not just in the research phase—might be unacceptable. It is possible that some research could be conducted on poor-quality embryos that were nonviable, although this possibility could depend on the specific preclinical research conducted or on clinical diagnostic needs (Baylis, 1990; Gavrilov et al., 2009).

Finally, clinical use of MRT would likely produce unused embryos, much as has been the case with IVF. Although there are no official numbers, a conservative estimate indicates that more than a million embryos, most of them excess from IVF, remain in storage across the United States (Lomax and Trounson, 2013),¹⁵ with many more being stored around the world. Families that created the embryos face the choice of what to do with them; options include freezing and storage for potential future transfer, destruction, donation to research, or donation to another individual or couple for their reproductive purposes. The surplus of embryos created by MRT, although on a much smaller scale relative to IVF, could result in effects similar to those seen in IVF: emotional reactions and financial concerns due to fees required for storing embryos. Clinical phases of MRT also could introduce emotional hardship in that very few MRT embryos might be produced for each woman. A male-only restriction on clinical investigation, as proposed

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¹⁵ In response, Snow et al. (2015) argue that there were significant methodological inaccuracies in the calculation of this estimate and suggest that the number of stored embryos is actually significantly higher.

by the committee in Chapter 4, could impose an additional emotional burden by further limiting the number of usable embryos.

CONCLUDING DISCUSSION

There is no question about the importance of mtDNA to the health and development of humans. Any focus on the difference in size of mtDNA and nDNA, as well as the substantially larger number of genes encoded by nDNA, masks the critical contributions of mtDNA to health and normal function. Quantification of the relative amount of DNA or number of genes in the two genomes is likely to distract from the fact that relatively small changes in mtDNA lead to devastating health effects for affected individuals, and it is this fact that motivates the development and proposed use of MRT. It also is clear that genetic ancestry is closely linked to mtDNA. In fact, mtDNA is crucial for tracking and charting notions of ancestry.

The potential use of MRT entails a unique combination of characteristics not seen in other proposed techniques for preventing inherited disease. In contrast with inherited nDNA diseases, there currently are no adequate alternatives for achieving the goals of prospective parents who face a high risk of transmitting mtDNA disease, which are to have a child who shares an nDNA connection with them and who is at significantly reduced risk of developing mtDNA disease. For most nDNA disorders with Mendelian inheritance, PGD offers an effective means of embryo selection to avoid transfer of an affected embryo. This is not a highly reliable option for mtDNA disease for reasons articulated in Chapter 2. In addition, MRT would offer a heretofore unavailable approach for replacing pathogenic mtDNA prior to transfer.

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.

• 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.

The ethical, social, and policy issues associated with MRT need to be considered in light of the interests of women desiring to prevent transmission of mtDNA disease while preserving an nDNA connection with their future offspring. In the committee’s judgment, none of these ethical, social, and policy considerations individually or in combination warrant a prohi-

bition on proceeding with initial investigations of MRT in humans. In the case of each area examined for this consensus study, the ethical, social, and policy considerations fall into one or more of three categories: (1) considerations similar to those experienced and successfully addressed in the use of other forms of assisted reproduction, (2) those that could be addressed in policy or practice, and (3) those that do not rise to the level of a prohibitive concern. Any pursuit of the reproductive interests of individuals can be limited by interests in protecting the health and well-being of children, both those who would be born as a result of MRT and any future generations, and the need for precautions regarding possible deleterious effects of heritable genetic modifications. By limiting initial MRT research to cases in which there could be no intergenerational effects, the first uses of MRT could be assessed for safety in a highly circumscribed context. Only through such a slow, cautious approach can the appropriate balance be struck between women’s pursuit of their reproductive interests and the protection of the health and well-being of children.

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