Mitochondrial Replacement Techniques Ethical, Social, and Policy Considerations (2016) / Chapter Skim
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3 Do Ethical, Social, and Policy Considerations Preclude MRT?
3 Do Ethical, Social, and Policy Considerations Preclude MRT?
Pages 79-112
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From page 79... ...
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.
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From page 80... ...
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?
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From page 81... ...
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 4 The probability of maternal transmission of mtDNA disease is highly variable and de pends 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.
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From page 82... ...
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)
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From page 83... ...
Finding: 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. 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.
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From page 84... ...
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.
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From page 85... ...
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)
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From page 86... ...
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.
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From page 87... ...
Conclusion: 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.
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From page 88... ...
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)
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From page 89... ...
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.
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From page 90... ...
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.
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From page 91... ...
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)
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From page 92... ...
. Another closely related concern about genetic modification of germ cells via MRT is the potential impact on persons with disabilities.
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From page 93... ...
Second, MRT involves the introduction of genetic modifications that could be passed on to future generations, as discussed in the next section.
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From page 94... ...
. 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)
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From page 95... ...
.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. Conclusion: Although a variety 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 prohi bition on the use of MRT to prevent transmission of serious mtDNA disease.
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From page 96... ...
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.
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From page 97... ...
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.
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From page 98... ...
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.
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From page 99... ...
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. Conclusion: Federal regulation would be needed and principled pro fessional society guidelines that interpret 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.
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From page 100... ...
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.
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From page 101... ...
. 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.
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From page 102... ...
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)
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From page 103... ...
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)
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From page 104... ...
. 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)
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From page 105... ...
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.
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From page 106... ...
However, the responsible use of human embryos in research on and clinical use of MRT would give women at risk of transmitting mtDNA diseases the opportunity to have genetically related children who would be at significantly reduced risk of having these diseases. Useful ethical frameworks have already been developed that could inform appropriate bounding of embryo manipulation in the conduct of pre clinical and clinical investigations of MRT.
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From page 107... ...
Finding: There are significant and important distinctions between modi fication 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 chromo somes -- the closest parallel to MRT.
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From page 108... ...
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.
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From page 109... ...
2003. Designing our descendants: The promises and perils of genetic modifications.
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From page 110... ...
1994. Report of the Human Embryo Research Panel (Vol.
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From page 111... ...
1983. Report of the Royal College of Obstetricians and Gynaecologists Ethics Committee on in vitro fer tilisation and embryo replacement.
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From page 112... ...
2013. Mitochondria replacement in cases of serious diseases -- ethical aspects 2013:2 (Summary of the original report "Mitokon driebyte vid allvarlig sjukdom -- etiska aspekter, 2013:2)
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