Mitochondrial Replacement Techniques: Ethical, Social and Policy Considerations

Françoise BaylisMitochondrial Replacement Techniques: Ethical, Social and Policy ConsiderationsThe Royal Society of Canada is pleased to announce the publication of a new Expert Panel report from its sister academy, the National Academies in the United States. The full report can be accessed online.

Dr. Françoise Baylis, FRSC, has kindly provided a Canadian perspective on this report and its relevance to Canada and Canadians. Dr. Baylis is a Professor and Canada Research Chair, Bioethics and Philosophy at Dalhousie University. Her research aims to move the limits of mainstream bioethics and develop more effective ways to understand and tackle public policy challenges in Canada and abroad. Dr. Baylis was an external reviewer for this report and provided comments on an earlier draft.

Mitochondrial Replacement Techniques: Ethical, Social and Policy Considerations - A Canadian Perspective

On February 3, 2016, the United States National Academies of Sciences, Engineering, and Medicine released its long awaited report, “Mitochondrial Replacement Techniques: Ethical, Social and Policy Considerations”.  The committee included among its members, Jonathan Kimmelman, Associate Professor in Biomedical Ethics at McGill University. The technology that is the focus of this report involves the transfer of nuclear DNA from an unfertilized or a fertilized egg with dysfunctional mitochondrial DNA (mtDNA) into a fertilized or unfertilized egg that has healthy mtDNA and has had its nuclear DNA (nDNA) removed. 

While some refer to this technology as “germline gene replacement”, “nuclear genome transfer techniques” and “nuclear genome transplantation”, others would prefer not to draw attention to the downstream ethical and social issues related to germline genetic modification and human cloning. For this reason, they have a marked preference for one or other of the following increasingly popular euphemisms: “mitochondrial replacement techniques”, mitochondrial manipulation”, and “mitochondrial donation”.   To be clear, the terms “nuclear genome transfer” and “mitochondrial replacement” describe one and the same techne.  

Call it what you will, there are two central ethically contentious issues associated with this technology: (i) the fact that children born of this technology will have three genetic parents, insofar as they will have genetic material for a male sperm provider and two female egg providers; and (ii) the possibility that this genetic modification will be passed on to subsequent generations should female children born of this technology reproduce.

Many are concerned about the ethics of creating humans that could not exist but for human manipulations (i.e., for which there is no wild type).  Meanwhile, neither the U.S. report nor recent legislation in the United Kingdom evidence particular concern for the fact that children born of this technology would be created using genetic material from two women – nDNA from the intending parent and mtDNA from a second woman whose role is that of egg provider.  

As regards the prospect of germline modification, both the U.S. report and the U.K. legislation address this, but here an important difference emerges. In October 2015, the U.K. became the first country in the world with regulations explicitly permitting mitochondrial donation so that women at risk of having children with serious mitochondrial disease could have healthy, genetically-related children.  In sharp contrast, in February 2016, the U.S. National Academies of Sciences, Engineering, and Medicine adopted a more cautious approach, concluding that research in this area could only proceed under a number of very specific conditions.  

While the authors of the U.S. report, like the U.K. legislator and the U.K. Human Fertilisation and Embryology Authority were similarly motivated to “satisfy the desire of women to have a genetically related child without incurring the risk of passing on mtDNA disease,” the U.S. report recommends limiting research to the intrauterine transfer of genetically modified male embryos, so as to avoid heritable genetic modification.  Mitochondria are maternally inherited; males do not pass on their mitochondria to their children.  In sharp contrast, in the UK there is no such limit. The option of sex selection of embryos was considered, but rejected. 

This difference is significant as it signals an unwillingness on the part of the U.S. to risk potentially harmful and irreversible, intergenerational effects (assuming that harmful consequences would relate to the mitochondria).  What is unclear with the U.S. approach is whether the “excess” female embryos should routinely be destroyed, used for other research purposes, or stored indefinitely for some future reproductive or research use. 

Additional conditions for initial clinical investigations outlined in the U.S. report include:

  • limiting clinical investigations to women who are at risk of passing on a serious mitochondrial disease to her offspring, where the mitochondrial DNA’s mutation is known to cause disease, and clinical presentation of the disease is predicted to be severe by causing early death or substantial impairment in the child. 
  • initial safety is established and risks to all parties directly involved in the proposed clinical investigations are minimized, although minimizing risk to future children should be of highest priority;
  • the likelihood of efficacy is established by preclinical research using in vitro modeling, animal testing, and testing on human embryos as necessary;
  • if the intended mother at risk of transmitting mitochondrial disease also desires to carry the pregnancy, it is determined by professional opinion that she is able to complete a pregnancy without significant risk of serious adverse consequences to her health or the health of the fetus;
  • clinical investigations are limited to investigators and centers with demonstrated expertise in and skill with the relevant techniques; and
  • FDA has reviewed the science surrounding matching the mitochondrial DNA subtype of the egg provider with that of the intended mother and if compelling, has considered such matching as a means of mitigating the possible risk of incompatibility that could arise from combining the egg provider’s mitochondrial DNA with the nuclear DNA of the intended mother.

In addition, to these concrete limits, the report proposes a number of guiding principles for the oversight of research involving mitochondrial replacement techniques. These include “transparency, public engagement, partnership, maximizing data quality, circumscribed use, and long-term follow-up.” In my view, these principles are generally sound, but incomplete in their failure to include a principle of “care and concern for egg providers” who assume the risk of potential harm for no potential benefit (other than perhaps financial compensation which, for some, exposes them to the harms of either commodification or exploitation).

So what does all of this mean for Canada?  On my reading of the Assisted Human Reproduction Act (2004) nuclear genome transfer technology (a.k.a., mitochondrial replacement techniques) is prohibited, even if embryo transfer is limited to male embryos. The relevant prohibition states:

5.(1) No person shall knowingly

(f) alter the genome of a cell of a human being or an in vitro embryo such that the alteration is capable of being transmitted to descendants. 

Could this prohibition be amended?  Perhaps, but it is difficult to imagine that nuclear genome transfer research would garner sufficient support in Canada to warrant legislative change.  In part, this is because there isn’t an obvious population benefit owing to the limited prevalence of disease amenable to this type of intervention.  To quote Phil Yeske, the science and alliance officer for the United Mitochondrial Disease Foundation, at most mitochondrial replacement techniques could ultimately benefit “a slice of a slice of a slice of the affected community.”  To explain, recent research by Gráinne Gorman and colleagues suggests that the maximum potential benefit of this technology is 152 healthy births per year in the U.K. (a country of close to 65 million) and 778 healthy births per year in the U.S. (a country of close to 320 million) – and this presumes that all eligible women at risk of having children with serious mitochondrial diseases would choose to reproduce using human nuclear genome transfer, which is a false presumption. Canada has a population of 35 million.  

It is hard to imagine nuclear genome transfer research being a priority in Canada, unless one advances the argument that this research might yield insights relevant to other (more common) genetic diseases.  To date, however, no one has been singing from this songbook. Meanwhile, it is important to note that therapeutic options for the treatment of persons with mitochondrial disease may be in the offing.