The Road to Mitochondrial Gene Transfer: Follow the Middle Lane

Embarking toward a new option

Mitochondrial DNA (mtDNA) disorders often result in severe diseases involving defects in cellular energy production.¹ In the absence of effective treatment, helping carriers of mtDNA mutations to bear healthy, genetically related children has been a key focus. To this end, the UK Parliament voted last February to permit a novel reproductive genetic technology to prevent the transmission of mitochondrial disease, also known as mitochondrial gene transfer (MGT).

MGT transfers the nuclear DNA of a woman's egg carrying an mtDNA mutation into a donor oocyte with healthy mitochondria. The transfer can be performed either before in vitro fertilization (by switching the nuclei of diseased and healthy oocytes) or after (by transferring the pronuclei of the affected woman's zygote).² Because children inherit all mitochondria from their mothers' eggs, such transfers would in theory prevent maternal transmission of mtDNA disease while preserving the genetic link between affected mothers and their offspring.

If successful, MGT could be a valuable addition to current reproductive options for carriers of mtDNA mutations in the United Kingdom and elsewhere. At present, the US Food and Drug Administration has requested that the Institute of Medicine (IOM) produce a consensus report regarding the ethical and policy issues related to MGT. In weighing whether to proceed down the road to MGT, might the United States benefit from the UK experience as a reliable course to follow?

Context matters

Last month, the ethical and policy considerations of MGT were discussed at the first IOM public workshop in Washington, DC (http://www.iom.edu/Activities/Research/MitoEthics/2015-MAR-31.aspx). A wide array of ethical and regulatory challenges were examined, among which were the moral significance of modification of the mitochondrial genome, questions of kinship and identity, and the science and ethics of first human use. Although we acknowledge that the United Kingdom has made pioneering steps toward MGT, we do not think that the regulatory lessons learned there can serve as an immediate road map for the US context. We observe at least three differences that make a copy-and-paste transposition of the UK decision impossible at this point.

First, in the United States there is no federal legislation that regulates assisted reproductive technology and no formal review system in place specifically for the creation and use of research embryos.³ By contrast, the UK Human Fertilization and Embryology Authority (HFEA) has strict oversight and will regulate the development and use of MGT by means of a licensing system.

Second, the Dickey-Wicker Amendment in the United States prohibits federal funding for any scientific research that would create and/or destroy human embryos in the process—activities that are necessary to study preclinically any assisted-reproduction techniques such as MGT. UK researchers, by contrast, can rely on their own government's funding support, rendering their drive to develop MGT relatively unencumbered both financially and politically.

Third, the United Kingdom is the first country to move MGT forward after extensive ethical and political debate. The US political and social landscape is different, and there is less experience to date in facilitating similarly widespread and deep social discourses over emerging biotechnologies such as MGT.

In short, the United States does not currently have the regulatory, funding, and deliberative framework in place to fully support MGT. Indeed, the United Kingdom is driving ahead with this new technology largely because it already has clearly marked lanes and traffic signals for the delivery of such scientific innovation to the clinic. Furthermore, citizens in the United Kingdom might be more open than those in the United States to the use of novel assisted-reproduction technologies—a quirky cultural convention that many Americans might equate with “driving on the wrong side of the road.” The IOM Committee will need to embrace and acknowledge these differences in its report.

Follow the middle lane

Needless to say, whether in the United Kingdom or the United States, first-in-human use of MGT will be replete with risks and uncertainties, because the needed evidence to reliably predict risk and benefit (i.e., testing in humans) is missing. The bold leap from bench to bedside needs sufficient preclinical evidence and careful, long-term, interdisciplinary research, including more ethics research. Although research ethics has made several efforts to better appreciate the risks and benefits of medical research, less work has been done to determine when an acceptable risk–benefit balance has been reached. One must find a balance here between taking appropriate precautions and not unnecessarily hampering innovation.⁴

We conclude by listing the three distinct precautionary lanes that the United States might take in pursuing MGT. Those favoring the left lane will regard risk and uncertainty as rooted merely in the (temporary) lack of scientific data. The go/no go decision here would be based on both further research and where one sets the threshold for having “sufficient” information about the risks. Those favoring the right lane are much more cautious. They are prepared to take the next exit to find alternative avenues to MGT for preventing mitochondrial disease. Right-lane drivers are inherently distrustful of new technologies, and distrustful of our ability to control or reverse the harms caused by them. In this case, the go/no go decision will be based on whether other approaches can be identified that are intrinsically less risky. Between the right and left lanes is the middle lane.

Finally, those favoring the middle lane view uncertainty as a persistent characteristic of all science, not merely a temporary condition. Thus, other social values and ethical considerations aside from one's faith in scientific and safety data will be necessary to inform the go/no go decision. We recommend that the United States follow the middle lane in pursuing MGT. A cautionary approach means that a wide variety of concerns should be taken seriously—wider than safety and efficacy alone—and that one should not to be so anxious about the way forward that progress itself becomes impossible.