Three weeks ago, the Institute of Medicine released its FDA-requested report “Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations.” The report may be read online, or a prepublication pdf copy may be downloaded for free, at this link.
In view is the so-called “3-parent babies” technology, intended to treat inherited diseases of the mitochondria, components (called “organelles”) of a cell that are responsible for producing the energy needed for life. These diseases are rare, but devastating when they occur. There are actually genes in our mitochondria—37, to be exact, compared with 20-30,000 in the nuclei of our cells. Those 20-30,000 are the genes that “make you you,” as they say. The 37 in the mitochondria are ones we don’t notice unless they are messed up—kind of like you view your car’s engine on most days, I bet. Mitochondrial diseases are inherited from mom, not dad, because sperm lose their mitochondria when they are formed.
To fashion treatment, there are two main options. One is to take an affected fertilized egg, remove its nucleus, and insert said nucleus into a second, normal fertilized egg that has had its nucleus removed. The result is a new fertilized egg—the earliest stage of an embryo—that has the genetic material from the diseased mom, but healthy mitochondria from the normal fertilized egg—that is, embryo—which has been “donated” for the purpose. Both of the original embryos are destroyed in the process; the new one is at least mostly new. The second approach, considered less promising, is to try to do this process between two eggs before fertilization: one normal (donated) and one diseased (which has the genes from the mom, for her intended baby—healthy, it is hoped). The nucleus (and its genes) are removed from the diseased mom’s egg and placed into the donor egg, which has had its nucleus removed. The resulting new egg is then fertilized, implanted into mom’s uterus, and from there one hopes things proceed smoothly. This has been done successfully in animals, and the resulting offspring at least appear normal. (Longer-term results, including outcomes for subsequent animal generations, are still to be determined.) Whether it all would work in people remains to be seen, not just at birth or in childhood, but throughout the offspring’s life and potentially extending into subsequent generations. We don’t know how they will do, and we wouldn’t for some time now.
The IOM committee addressed whether, and under what conditions, it is ethically permissible to try this to give an affected mom a chance at healthy offspring. The report is detailed and thorough. I cannot cover its recommendations, or the ethical issues, in a single blog post. Other contributors and I have written about this on this blog during the last two years.
If one holds that human lives warrant protection from the point of fertilization, then the pronuclear transfer between embryos, at least, is out of bounds. If one, like the committee, does not hold that, then emphasis is placed on the many other ethical concerns. Some of the key points of the IOM report are:
- · Regarding the ethics of “donated” healthy embryos, they would require that these be “excess” embryos from IVF, initially intended for procreation. In other words, embryos may be intentionally destroyed as part of the treatment, but not specifically created for the purpose.
o For preclinical research (no intent to birth a baby), “nonviable” human embryos should be used “when possible.” When not possible, as few embryos as possible should be used and only when required for “developing science to minimize risks to children.”
§ This sounds to me a lot like how we approach animal welfare concerns in biomedical research.
- · Inheriting DNA from two women will “introduce complexities that might affect the child’s experiences of identity, kinship, or ancestry.” How problematic this really is, is debatable. But it is “a matter for reflection” by involved families and a matter for “societal discussions.” This is “not sufficient to justify prohibiting” attempts to birth babies in this setting.
- · MRT (mitochondrial reproductive technique) is NOT the same as gene editing, because in the latter, specific genes are altered, while in the former, whole mitochondria are replaced.
- · MRT will cause genetic changes that can be passed down to future generations of female offspring. Because men do not pass mitochondrial disease down, MRT should be used to birth only boys, at least at first.
o FDA could consider extending clinical applications to include transfer of female embryos if outcomes in males were clearly favorable, research in animals showed evidence of safety for multiple generations (number not specified), and such extension is “consistent with the outcomes of other deliberations” about heritable genetic changes.
- · MRT does not seem to be a meaningful example of “enhancement,” because of the relatively limited genetic information in mitochondria.
- · Attempts to apply MRT to situations other than mitochondrial disease (some have proposed it as a broader treatment for infertility) raise other “serious and unresolved ethical issues” and should be not be permitted, at least for now. Regulations and guidelines should be developed to limit this “slippage.”
- · It is assumed that FDA will regulate MRT, presumably much as it currently regulates cell-based therapies. Substantial supporting research is expected, as are standardization of techniques and clinical study designs. Health and well-being of any children born should be paramount, and these children should be followed “long-term” to collect information about their medical, psychological, and social well-being. Consent (initially, assent) for such follow-up should be obtained from the children themselves.
MRT proponents fear that the IOM report is academic at best. It is said (I can’t find detailed information) that in last year’s FDA appropriation, Congress included language prohibiting FDA from spending money on approving any attempt to use MRT in the clinic. One critic said this language is self-defeating; FDA has to spend resources to determine whether to review or block applications for clinical research. And President Obama’s 2017 budget apparently deletes this provision.
And Congress also mandated—at least for now—that FDA convene a separate review of MRT applications by a panel of religious leaders. Some bioethicists, I have read, object to that. After all, the IOM Committee had a religious representative. One. And they thought about the issues carefully. No doubt they did—but that is to be part and parcel of a full societal discussion of an epochal development?
So, maybe not full-speed ahead, as in the U.K., but half-speed. And that’s too fast for some of us.
Note: another brief summary on this topic, accessible here, is in this week’s New England Journal of Medicine.