Clinical translation of mitochondrial replacement therapy in Canada: a qualitative study of stakeholders’ attitudes

Mitochondria are dubbed power plants of the cell. They provide our cells with the energy that is required for their normal functioning. Mitochondrial DNA (mtDNA) contains 37 genes. These genes encode core components of the mitochondrial respiratory complexes (Russell et al. 2020). Pathogenic mutations in mtDNA lead to rare, debilitating, and progressive disorders that can be fatal in childhood, typically striking organs requiring the highest energy demands. Currently, there is no known cure for mitochondrial diseases and for the vast majority of patients, therapy is limited to symptomatic relief (NASEM 2016; Ng and Turnbull 2020).

Mitochondrial DNA deficiencies have considerable genetic and clinical heterogeneity, which provides a real challenge for any estimates of prevalence. It is estimated that 1 in 4300 people are affected by primary mitochondrial diseases (Gorman et al. 2015). Due to the challenges in predicting the degree of mtDNA mutation load, the risk of disease manifestation in future children is difficult to evaluate with predictive tests, such as preimplantation genetic diagnosis (Shoubridge and Wai 2007; Wai et al. 2008; Lee et al. 2012).

Mitochondrial replacement therapy (MRT), also known as nuclear genome transfer and mitochondrial donation, is a new type of in vitro fertilization (IVF) that aims to prevent the transmission of mitochondrial diseases to future generations. As mtDNA is passed down from the maternal line, MRT replaces a mother’s mutated mtDNA with mitochondria from a healthy egg donor. The most prominent methods of MRT include Pronuclear Transfer (PNT) and Maternal Spindle Transfer (MST) (NASEM 2016; NHMRC 2020a). PNT requires the fertilization of a healthy donated egg and the intending mother’s oocyte with the intending father’s sperm. Both sets of fertilized oocytes are allowed to develop until the early zygote stage. The pronuclei of zygotes formed by the donated oocytes are then removed, discarded, and replaced by the intending parents’ pronuclei. In MST, on the other hand, the transfer of parental nuclear DNA (nDNA) occurs before fertilization. This method involves removing and discarding the metaphase II spindle from the donor oocyte. The chromosome spindle complex of the intending mother will then be transferred to the enucleated healthy donor oocyte followed by fertilization with the intending father’s sperm (Craven et al. 2010; Kang et al. 2016). The distinctive benefit of MRT is considered to be fulfilling the desire of having healthy, biologically related children. Since there are alternatives to having (biological) children such as egg and embryo donations as well as adoption, MRT is often regarded as less of a priority worthy of societal resources (Rulli 2016; Baylis 2017).

According to the 2004 Assisted Human Reproduction Act (AHRA), MRT is considered a criminal offense in Canada. The Act prohibits any practice that introduces heritable changes into the germline. This is applicable for both research and clinical contexts. Article (5)(1)(f) of the AHRA states that, “no person shall knowingly alter the genome of a cell of a human being or in vitro embryo such that the alteration is capable of being transmitted to descendants” (AHRA 2004: Sec 5 (Prohibitions)). A person who violates this prohibition is punished by a fine of up to $500 000 and (or) imprisonment for up to 10 years (AHRA 2004: Sec 60 (Offences)).

Currently, the United Kingdom (UK) is the first and only country to regulate the clinical applications of PNT and MST (Rhys-Evans 2020). In the UK, IVF and embryo research are regulated by the Human Fertilisation and Embryology Authority (HFEA), a regulatory agency that enforces the Human Fertilisation and Embryology Act, 1990. Prior to 2008, under Section 3ZA of the Act, permitted eggs and embryos must not have had their “nuclear or mitochondrial DNA altered” (HFEA 1990: Sec (3ZA)). In 2015, both the Upper and Lower Houses of the UK Parliament voted to pass the Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 (Castro 2016). Following the UK’s lead, Australia appears to be on a similar path toward considering MRT’s clinical implementation. Australia’s 2006 Prohibition of Human Cloning for Reproduction and Regulation of Human Embryo Research Amendment Act prohibits introducing heritable changes into the germline (Australian Government 2006). In June 2018, the Senate Community Affairs Reference Committee, a group of members of the Australian Parliament, drafted recommendations in support of the technique (Community Affairs References Committee 2018). In January 2019, the government responded to the Senate Report indicating that MRT will be of great interest to the Australian community (Australian Government 2019). On 5 June 2020, the National Health and Medical Research Council (NHMRC) released two reports to inform the MRT debate in Australia (NHMRC 2020a, 2020b). The NHMRC reports were sent to the Federal Health Minister in March 2020. Now, Australia expects advice concerning the timing of draft legislation to be introduced in Parliament (Mito Foundation 2021).

It is particularly important to acknowledge that clinics in jurisdictions where reproductive laws may be less strict or nonexistent have been moving forward with clinical applications of MRT, notably in Ukraine and Greece (BioTexCom 2021; Darwin Life Nadiya 2021; Institute of Life 2021). While the primary aim of MRT is to prevent mitochondrial diseases from being passed on to future generations, the technique could also be used in other nontherapeutic contexts, such as “treating infertility” and lesbian motherhood where maintaining genetic ties to both mothers may be preferred (Darwin Life Nadiya 2021; Cavaliere and Palacios-González 2018). The claim that MRT may represent a new era in assisted reproduction technology as a means of solving issues of infertility is on the basis that the mitochondria in eggs are the cause of some cases of infertility. However, there is no available evidence linking mitochondria with infertility in the general population (Cecchino et al. 2018; NHMRC 2020a).

Concerns regarding reproductive tourism and the use of MRT, further highlight the importance of addressing key issues in the MRT policy discussions. Public opinion is a requirement that supports the development and implementation of policies, programs, and services designed to meet the needs and expectations of relevant stakeholders and the general public. Aside from establishing MRT’s safety and efficacy, it is important to sufficiently address the implications of different germline-altering interventions. To this extent, factors such as definitions, level of evidence, risk assessments, and communication of accurate and relevant information to the public are key to establishing a favorable risk/benefit assessment. As such, we sought out to explore the attitudes of various stakeholders toward the clinical translation of MRT in Canadian clinics using a qualitative study.

The concept of MRT research appeared to be widely supported by the participants. Experts, key stakeholders, and the public had different and sometimes skeptical views on the foreseeable clinical translation of MRT in Canada. Nonetheless, there was consensus on the need to undertake an evidence-based review of the current AHRA ban on MRT and the importance of recognizing reproductive autonomy in the MRT debate. There was also consensus amongst participants on the lack of support for mitochondrial disease patients in the current Canadian health care system. This suggests that Canada has much room to improve upon in regard to their training of experts and the funding of research for mitochondrial diseases.

The general consensus was that failing to address the AHRA ban on the research and safe clinical practice of new reproductive technologies, such as MRT, could fall short of providing society with the access to breakthrough scientific innovations. This will then prompt Canadians to seek MRT in jurisdictions with no established regulations, further exposing them to the associated risks and shortcomings of unregulated practices around the world. The potential dangers of medical tourism could further put a strain on the Canadian health care system.

MRT is often categorized and thus regulated as germline genetic modification. Although there is no general consensus in the research community on the status of MRT so far, there have been attempts at separating the technique from the field of germline genetic modification. The supposed normative significance of distinguishing MRT from impermissible germline modifying techniques are proposed to be that (i) with MRT, there is no direct modification or editing of the nDNA or the mtDNA sequence, (ii) mitochondria are responsible for solely the production of cellular energy and only accounts for <0.1% of the genome, and (iii) mtDNA is only transferred through the maternal line so male offspring do not transmit any changes (Gómez-Tatay et al. 2017).

The concern with crossing the germline barrier, as MRT purportedly does, is that it will open the floodgates and allow other germline interventions to take place. In this regard, existing prohibitions on MRT in countries like Canada that legislate research and clinical applications of assisted reproductive technology tend to generally prevent people from altering the DNA of the gametes and embryos intended to be used to create a pregnancy (Singapore Statutes Online 2005; Australian Government 2006; Ministry/Agency: Ministry of Health and Social Affairs 2006). These prohibitions are mainly in place to prevent so-called “designer babies” that would be made to have specific desirable genetic traits. The AHRA defines genome as “the totality of the deoxyribonucleic acid sequence of a particular cell” (AHRA 2004: Sec 2 (Interpretation and Application)), which includes mtDNA. Thus, establishing consensus on the status of MRT seems to be one of the primary steps toward discussing the clinical translation of MRT in Canada.

In identifying the challenges of clinical implementation of MRT, the obvious question addresses the legitimacy of using this technique to fulfill the desire of having and raising healthy, biologically related children. It has been argued that the interest in having genetically related children is broad and strong and that MRT extends the reproductive freedom of women (Ishii and Palacios-González 2017; Schaefer and Labude 2017). However, since the technology is neither a cure nor a therapeutic intervention for those with mitochondrial diseases, the value of MRT rests solely in having healthy, biologically related children. In this sense, the desire to use MRT may not appear to be a priority worth allocating societal resources toward, because alternatives exist, such as egg and embryo donation, as well as adoption (Rulli 2016; Baylis 2017). A majority of patients (seven out of eight) did not consider the alternatives to MRT viable options. Respect for individuals’ autonomy, as a fundamental bioethical principle, guides the process of reproductive rights, which needs to be considered and addressed in greater detail in assessing the risks and benefits of MRT.

As with most qualitative research, we cannot assert that our findings are universal. Except for those from the general public, our participants belong to categories of individuals who are already likely to have a positive bias toward the clinical implementation of MRT. As bioethicists’ perspectives are already reflected in the literature to a great extent (Baylis 2013, 2017, 2018), we sought to talk to Canadians who had not been heard in the MRT debate. A greater variety of health technology evaluation expert perspectives (e.g., economists) could also further help enrich this debate.

As we aimed to talk to stakeholders and experts across Canada, we relied on phone interviews 70% of the time, which may have served as a limitation in the study design as we were unable to assess body language and nonverbal cues. We were also not able to collect data in all provinces and territories. However, due to the nature of mitochondrial expertise in Canada (an already scarce commodity), there is not a very large pool of experts to choose from. This affects the number of individuals who have a suspicion of or an established diagnosis of mitochondrial diseases, which was the patient inclusion criteria in our study. Also, we were not able to collect data on Indigenous peoples affected by mitochondrial diseases. There is a glaring inequality in accessibility and availability of health services between Indigenous communities and the rest of Canada due to socioeconomic status and geographical location as well as discrimination and stereotyping. How the Indigenous community perceive the emerging reproductive technology needs to be considered and addressed in greater detail in considering the clinical translation of MRT in Canada.

Because clinics in jurisdictions where laws are less strict or nonexistent are moving forward with clinical applications of MRT, efforts must be made to consider what the clinical translation of this technology would look like from a scientific, ethical, and policy perspective for Canada. This study takes the first step in focusing on the Canadian perspective on MRT and invites the possibility of future work to further the discussion. Additional work is needed to engage the greater public in exploring the need for a revised AHRA in regard to furthering research in the field of new reproductive technologies. Deliberative engagements will allow for discussions of both the potential and uncertainty of MRT providing a critical reflection on the strengths and weaknesses of current governmental strategies. Advocating for the needs of mitochondrial disease patients is a necessary next step to spread awareness in the community about the lack of a Canadian rare disease care system. This could further help policymakers outline elements to be considered in a robust national MRT strategy.

F.N. would like to thank the Canadian Institutes of Health Research (CIHR) for their funding through the Doctoral Research Award titled “Promoting Responsible Governance of Mitochondrial Replacement Therapy in Canada” (reference number 157936). The authors also thank the Quebec Cell, Tissue and Gene Therapy Network–ThéCell (a thematic network supported by the Fonds de recherche du Québec–Santé) for their funding, Ms. Julie Hagan for her help with the IRB submission, and the anonymous participants who took the time to be interviewed for this study.