Sharpening the cutting edge: additional considerations for the UK debates on embryonic interventions for mitochondrial diseases
© The Author(s). 2017
Received: 19 August 2016
Accepted: 22 December 2016
Published: 13 January 2017
In October 2015 the UK enacted legislation to permit the clinical use of two cutting edge germline-altering, IVF-based embryonic techniques: pronuclear transfer and maternal spindle transfer (PNT and MST). The aim is to use these techniques to prevent the maternal transmission of serious mitochondrial diseases. Major claims have been made about the quality of the debates that preceded this legislation and the significance of those debates for UK decision-making on other biotechnologies, as well as for other countries considering similar legislation. In this article we conduct a systematic analysis of those UK debates and suggest that claims about their quality are over-stated. We identify, and analyse in detail, ten areas where greater clarity, depth and nuance would have produced sharper understandings of the contributions, limitations and wider social impacts of these mitochondrial interventions. We explore the implications of these additional considerations for (i) the protection of all parties involved, should the techniques transfer to clinical applications; (ii) the legitimacy of focussing on short-term gains for individuals over public health considerations, and (iii) the maintenance and improvement of public trust in medical biotechnologies. We conclude that a more measured evaluation of the content and quality of the UK debates is important and timely: such a critique provides a clearer understanding of the possible, but specific, contributions of these interventions, both in the UK and elsewhere; also, these additional insights can now inform the emerging processes of implementation, regulation and practice of mitochondrial interventions.
In October 2015 the UK became the first country to enact legislation, originally agreed by Parliament in February 2015, to permit the clinical use of embryos that have been constructed using genetic material from three people. The purpose of constructing such embryos is to allow women who carry certain types of incurable mitochondrial disease to attempt to have genetically related children who will, it is hoped, be free from such diseases. Following a decade of research, two IVF-based techniques have been developed: (i) pronuclear transfer (PNT) and (ii) maternal spindle transfer (MST), both often erroneously referred to as ‘mitochondrial donation’ (Haimes and Taylor 2015).1 In both techniques the intending parents’ DNA is transferred into an egg (containing healthy mitochondria) provided by another woman, from which the nuclear DNA has been removed. Both techniques therefore result in a ‘constructed’ embryo that contains DNA from three people: nuclear DNA from the intending mother, nuclear DNA from the intending father and mitochondrial DNA from the woman acting as the egg provider. Elsewhere we have described the resulting embryo as a ‘three-genome embryo’ in a challenge to the more commonly used phrase of ‘three parent babies’ (Haimes and Taylor 2015).
Major claims have been made about the quality of the UK debates leading up to the February 2015 decision and the significance of those debates for UK decision making on other biotechnologies, and for other countries considering whether to approve mitochondrial therapies. For example, the UK’s Government Chief Scientific Adviser, Sir Mark Walport, asserted that ‘approval in the United Kingdom of mitochondrial donation provides a blueprint for future decisions on modifying the genome’ (Hawkes 2015). In December 2015 Walport also said of the UK, ‘…we are good at the science, we’re very good at the regulation and we’re very good at the public discussion.’ (Knapton 2015).
However, in this article we suggest that these claims about the quality of the UK debates around mitochondrial interventions are somewhat over-stated. Through a systematic analysis of the published documents and statements that were produced by key participants in those debates we identify ten areas where greater clarity, depth and nuance would have produced a more rounded debate over the field of mitochondrial interventions. We suggest that a more careful consideration of these areas sharpens understandings of the contributions, and limitations, of mitochondrial interventions as well as of their wider socio-ethical impacts. Our analysis of the ways in which wider debates over mitochondrial interventions could be improved is very timely. In December 2016 the UK regulatory agency, the Human Fertilisation and Embryology Authority (HFEA) will decide whether to issue licences to clinics to allow them to pursue these clinical applications; also, other countries, such as the USA, are considering whether to approve such interventions. Our review of, and suggestions for improving, the UK deliberations, contribute to discussions over mitochondrial interventions in other jurisdictions; it also contributes to a growing literature on innovations and governance in biotechnologies more generally.
Mitochondrial interventions, hereafter referred to as PNT/MST to better reflect the actual techniques under scrutiny, have provoked much discussion because they involve changing the genetic inheritance of any children born, in novel, untried, irreversible ways that could never occur through ‘natural’ conception. Further, this genetic change will be perpetuated in future generations who are descended from any girls born using this approach, because it is a form of germline modification. As noted above, the use of these techniques is justified by the aim to prevent the maternal transmission of some types of mitochondrial disease. It is therefore pertinent to provide some contextualising information (see also Bredenoord and Braude 2011).
Mitochondria and mitochondrial diseases
Mitochondria are small structures (organelles), multiple copies of which are found in almost all human cells,2 including gametes; they are the sites at which the energy that sustains life is produced. Uniquely amongst organelles, mitochondria possess their own DNA (mt-DNA) which is distinct from the nuclear DNA that contains the majority of a person’s genetic material. The mitochondrial genome is composed of 37 genes, 13 of which code for proteins involved in energy production. It is estimated that there are around 21,000 genes in the nuclear DNA (Pennisi 2012).
Mitochondrial diseases, which result from a reduction in the capability of mitochondria to produce energy, are complex. There are many different mitochondrial diseases, which range in severity and age of onset, some of which are difficult to diagnose. Both sexes can suffer from mitochondrial diseases and the same disease can affect different individuals to varying degrees. Some mitochondrial diseases are caused by mutations in the mt-DNA, though not every mitochondrion may carry the pathogenic mutation; it is this variation in ‘mutation load’ that accounts for the variability in the way the mitochondrial diseases affect different individuals.
Mitochondrial-DNA is inherited only through the female line, as all the mitochondria in a developing embryo are derived from those originally present in the egg. Complex and incompletely understood patterns of replication of mitochondria in the developing embryo mean that it is rarely possible to predict accurately the severity of mitochondrial diseases. Nonetheless, if a woman has a disease-causing mt-DNA mutation, she will inevitably pass that mutation on to all her children. It is maternally transmitted mt-DNA disease, as opposed to mitochondria diseases from de novo mutations, that clinician-scientists3 hope to eradicate from families through the use of PNT/MST.
… introducing new powers which allow for Regulations to be passed by Parliament that will allow techniques that alter the DNA of an egg or embryo to be used in assisted conception, to prevent the transmission of serious mitochondrial disease (HFEA 2013, 9).
In May 2010 the HFEA reviewed developments in the science and, in collaboration with the Newcastle clinician-scientists, made a request to the Government to invoke the provision for such Regulations to be debated. This led to debates in Parliament and the subsequent change in the law, in February 2015. This change was then enacted on October 29th 2015.
Sharpening the UK debates on the clinical applications of PNT and MST
Other ways to have a baby.
One of the most prominent gaps in the UK debates of mitochondrial interventions was the absence of consideration of other reproductive possibilities available to affected women, accompanied by a failure to weigh, systematically, the costs and benefits of each option against the others. Instead the new science of mitochondrial intervention was the starting point for deliberation and was presented in some quarters as the only desirable way in which women with faulty mitochondria could have healthy babies. The alternatives of ‘traditional’ full egg donation,6 surrogacy with egg donation, or adoption, were rarely discussed, let alone given detailed or informed consideration. For example, even an organisation as well versed in assisted conception as the HFEA made no reference, in its advice to Government resulting from its public consultation, to these other ways that affected women could have a healthy child. This suggests that these alternatives were not prominent in their deliberations or in the consultation processes (HFEA 2013).
Mitochondrial DNA diseases are transmitted maternally, and for families carrying these mutations, a major, and justifiable, desire is to have unaffected children. For some women, pre-implantation or prenatal diagnosis may be helpful [4,5], but for other women, these techniques will not result in disease free offspring and the only options available are either oocyte donation or mitochondrial replacement at the oocyte or zygote stage. The need for this technique for these families is well established, as are the experimental methods that are required for mitochondrial replacement [6–8] (2014, 1, emphasis added).
Valorising ‘genetic connections’.
Ellison: … The techniques provided for by these regulations offer the only hope for some women who carry the disease to have healthy, genetically related children who will not suffer from the devastating and often fatal consequences of serious mitochondrial disease (Hansard, 2015a: Col 160).
My Lords, the purpose of the regulations is to enable women to have their own genetic children, free of terrible disease caused by disorders in their mitochondrial DNA (Hansard, 2015b: Col 1569).
Such opening statements set the terms for these debates and thereby limited the opportunity to debate alternative approaches, by establishing the view that genetic relatedness was a key consideration driving the development of the techniques.
this new technique to be given the go-ahead, so my daughter will have healthy mitochondria and can have children who will not die when they are teenagers, as her brother Adam did (2014, 19).
A Daily Mail article reported that ‘Women carrying damaged mitochondria can also miscarry repeatedly and often face the heartbreaking choice of whether it would be best to remain childless’ (Macrae 2014). Neither of these pieces (typical of the many published) mention the alternative routes that affected women could take to become mothers of healthy children, again reinforcing the assumed importance of the genetic connection sustained by PNT/MST. The Macrae article also raised the notion of ‘choice’ which was common in many contributions to these discussions. When questioned on the possibility of using non-PNT/MST methods to conceive, an affected woman interviewed on a BBC national news programme on the day of the House of Commons debate, said that the mitochondrial techniques would give her, and women like her, ‘choice’. She did not expand on that though the insinuation within the context of the discussion was that this is the choice to have a genetically related baby; this was not pursued by the interviewer, as if ‘choice’ in and of itself was an unquestioned value.
‘Choice’ is a word that has, arguably, become near-ubiquitous in UK political discourse. It has an air of simplicity in meaning, ingrained in casual use and yet the word is value-ridden. The term ‘choice’ in the context of health care and beyond has become an extension of expressing (or choosing) preferences. To have choice implies that there is the opportunity for an individual to have what they want, when they want it; demand if you will (2013, 148).
This emergence of the language of choice and consumerism in the discourse around health care provision in the early 2000s coincided with the long period of development of PNT/MST (Fotaki, 2010, 898). Nonetheless, in the context of the radio interview and other discussions around mitochondrial interventions, the notion of ‘choice’ was used to close down consideration of existing alternatives and to promote the new interventions, by those who were advocates for the science and by those who prioritised genetic relatedness between parents and children. Genuine discussion of choice in conception and reproduction (and more generally) would clearly have been an important aspect to add to these debates, given that families in twenty-first century UK are composed of individuals with a diverse range of genetic relationships, or none at all.
As fundamental as the question, ‘what alternatives are available?’ is the question, ‘how safe is the proposed new intervention?’ Questions of the safety of PNT/MST were addressed by a Safety Review Panel (hereafter, the Panel) convened by the HFEA, to ‘review the latest evidence of safety and efficacy’ (HFEA 2014, 9).
From a medical or scientific point of view all novel treatments pose essentially the same question: when is a treatment safe to offer? Research can never answer every question before a new treatment is offered, nor can it be expected to guarantee safety or efficacy when applied for the first time in the clinic. It can only serve to reduce the risk and to highlight areas that need close attention. … the panel concluded both in 2011 and 2013 that the evidence available at those times did not suggest that the techniques are unsafe. The direction of travel remains the same, and the panel therefore come to the same conclusion in this report (HFEA 2014, 5, emphasis added).
Clearly the argument that it cannot be fully known whether new treatments are safe until they are tried in human beings is correct but it is questionable whether the appropriate comparator was addressed by the Panel. Medicines or medical devices that do not behave as safely as expected might well affect the first individuals to receive them, but PNT/MST are interventions of a different order, with the potential to affect the whole human species, rather than a series of individuals, because they change the germline. Given that there are existing alternative ways for affected women to try to conceive, it can be argued that a stronger indication of safety should have been required for the introduction of the new techniques.
a contradiction to claim [as some proponents do: see section (vi) below] that mtDNA is not important for an individual's characteristics … while at the same time acknowledging that changes in the mitochondrial genetic code are important for an individual's risk of disease (2014).
St John (2014) identified the need to avoid any transfer of damaged mitochondria from the affected woman’s egg, and the practical difficulty of doing so, describing animal experiments that have shown the persistence of damaged mitochondria. He also raised concerns about epigenetic effects and mismatching of nuclear and mitochondrial DNA.
People have extreme beliefs about whether it is right for humans to tamper with embryos in any way at all. Sometimes the values discussion gets conflated with the science discussion. We shouldn't pretend we're having an argument about science when we're having an argument about values. People need to say [why] they really object and not duck why they object by pretending there is something wrong with the science (Knapton 2015).
I want to speak against the Government motion… Human mitochondrial disease is a dreadful condition and, as a caring society, we must do all we can to address it… in an ethical manner and with proper regard for safety. I believe that the regulations we are considering today fail on both counts—ethics and safety—and that they are inextricably interlinked. Let me be straightforward: I do oppose these proposals in principle. However, that should not prevent my concerns regarding their safety from being given a fair hearing (Hansard 2015a: col 168).
The public dialogue and consultation work we undertook was focused on gathering and understanding public views on the social and ethical issues associated with mitochondria replacement. We wanted to explore their views independent of any questions of safety and efficacy. In practice, however, people’s views on these issues tended to be linked to questions of safety; this was a strong theme through all the responses. Sometimes, safety concerns become a proxy for concerns about ethical and social issues, which are often hard to express. On other occasions, support for mitochondria replacement dipped when the scientific evidence was less clear (HFEA 2013, para 6.8, emphasis added).
Clearly, issues about the safety of any intervention cannot be neatly distinguished from socio-ethical concerns, not least because it can never be morally correct to offer interventions that are known to be unsafe, except under exceptional circumstances and where no alternatives exist. On the more general point, there is also not as clear a divide between science and values as some contributors suggested: as we have seen above, PNT/MST are partly being offered in the first place because of the largely unstated valorisation in the scientific literature of genetic ties between parents and children. The vast literature from Science and Technology Studies identifies the numerous ways in which ‘science’, far from being an external source of objective knowledge, is inextricably shaped by, and shapes, wider social values, institutions and processes (e.g. Jasanoff 2004).
It is worth noting that papers published since the 2015 UK legislation indicate that earlier concerns about the safety of PNT/MST are justified. Callaway (2016) reports that work carried out by Egli’s group in New York (Yamada et al. 2016) found, as Knoepfler feared, that small amounts of the intending mother’s damaged mt-DNA might be carried over and ‘outcompete healthy mitochondria in a child’s cells and potentially cause the disease [that] the therapy was designed to avoid’. Further evidence of this phenomenon was reported in Nature in November 2016 (Kang et al. 2016; Cook 2016b). Egli argued that this problem would ‘defeat the purpose of doing mitochondrial replacement’ and recommended that the procedure not be used in the meantime, arguing ‘I don’t think it would be a wise decision to go forward with this uncertainty’ (quoted in Callaway, 2016).
The focus on children and severe forms of disease.
A facet of the discussion that made such a political decision possible was the clear focus on babies and children, and on the most severe forms of mitochondrial diseases, by the mass media and patient advocacy groups. This is rather misleading since many mitochondrial diseases only manifest themselves in adults and have varying degrees of severity (NCoB 2012, Dimond 2015). It would have been more transparent (and the calculations of the numbers of affected persons would be higher) if the case in favour of allowing these techniques had reflected the full range of affected persons.
It could be argued that the devastating conditions that affect babies and young children are predominantly the conditions that the proposed techniques will be used to prevent. However, the women who are the targeted beneficiaries of PNT/MST have mitochondrial disease themselves and yet have a quality of life that has enabled them to get to the point of wanting to start a family; this is an indication that the impact of mitochondrial diseases is much more variable than presented in the debates. Therefore the focus on babies and children was a missed opportunity to raise awareness of the full range of mitochondrial diseases, and their manifestations, and of the differing experiences of living with such conditions.
The potential for raising unrealistic expectations.
In Newcastle, Turnbull is working on ways to eliminate the risk of disease by replacing the mother's faulty mitochondria wholesale with those from a healthy donor (2012).
Mitalipov says funding restrictions mean he cannot take the research on in humans. “We hope the UK takes it further. We have a way to prevent transmission of these diseases in children. It has to be tested or we will never know if it works,” he says (Sample 2012).
The lack of clarity about the range of conditions that will be valid targets for attempts to prevent transmission from mother to child is evident; the overall impression is that all mitochondrial diseases will be prevented.
We have within our reach the possibility of eradicating mitochondrial disease from families who have been blighted by it for generations: families who have endured a disease for which there is no cure, who have suffered daily battles with painfully debilitating symptoms, and who have sadly lost their children prematurely (Hansard 2015a: Column 164).
Gillan: Can [you] confirm that mitochondrial disease from the nuclear DNA will remain in our population even after this treatment is licenced?
Berger: […] it is not something I have been made aware of, and it certainly has not come up in any of the discussions or debates that I have attended (Hansard 2015a: Column 168).
The conflation of ‘mitochondrial disease’ with specific serious mitochondrial diseases caused by mt-DNA mutations, plus the lack of clarity that ensues from the conflation of ‘preventing transmission’ with the numbers of children estimated to be affected by all mitochondrial diseases, results in the inflation of hope and expectation for the proposed interventions; not least expectations about the public health impact of permitting PNT/MST.
The paradox of small numbers…or the insignificance of significant genes.
It is important to remember that mitochondrial DNA represents less than 0.054% of the total DNA, and is not part of the nuclear DNA, which determines our personal characteristics and traits such as personality, hair and eye colour. (Davies 2015).
The baby would have <0.1% of their total DNA from a 3rd person and this would be the mitochondrial DNA (mtDNA) in the donated mitochondria which enables normal energy production.
The overwhelming majority of the DNA, 99.9% (all the nuclear DNA that determines human characteristics) would only come from the mother and father (Lily Foundation 2015).
The Parliamentary Under-Secretary of State for the Department of Health, when opening the Lords debate, said ‘the DNA from the donor egg amounts to less than 1% of the resulting embryo’s genes’ and that ‘One important point to emphasise here is that none of the nuclear DNA, which determines our personal characteristics and traits, is altered by mitochondrial donation.’ (Hansard 2015b: Col 1569). Other examples abound. This is not the place to enter into argument with the claim that nuclear DNA ‘determines’ personality, other than to note that the presence or absence of mitochondrial disease is likely to have a profound impact on an individual’s personality (NCoB 2012; Baylis 2013; Haimes and Taylor 2015). More important to note for our analysis here is the way in which claims about the tiny portions of donated mt-DNA are configured. The implication of this repeated refrain is that, because the numbers being discussed are so small, the genetic material to which they refer is unimportant and insufficient to provoke concern. And yet, without these tiny amounts of mt-DNA, an affected woman would have no hope of bearing a healthy, genetically-related child – which of course is the whole point of these discussions in the first place. Minimising the contribution of the mitochondrial genome in numerical terms means that the proponents of the techniques were making paradoxical claims: saying these interventions and therefore these genes are both crucial (to prevent transmission of mitochondrial diseases) but are also essentially insignificant because they are only few in number. The insinuation is that opposing an intervention which involves such a small amount of genetic material could be nothing but unreasonable.
The number of affected individuals and families.
Just as numerical calculations were deployed to minimise and deflect concerns about the proposed interventions, they were also deployed to strengthen the case in favour of these interventions, albeit in confusing and inconsistent ways.
[m]utations in mitochondrial DNA (mtDNA) are a common cause of genetic disease. Pathogenic mutations in mtDNA are detected in approximately 1 in 250 live births and at least 1 in 10,000 adults in the UK are affected by mtDNA disease (Craven et al. 2010, 82).
Using publicly available information, we can use these figures to estimate that around 5280 adults in the UK are affected by mt-DNA diseases.11 However, until 2015, the number of families to be treated through PNT/MST per year was often cited in debates as ‘around 10’ (for example (BBC 2013), Sample (2013)) though it is unclear from whence this figure originated. Just before the 2015 House of Commons debate, the Newcastle Group estimated that the ‘average number of births per year among women at risk for transmitting mtDNA disease’ was 152, from a population of 2473 affected women in the UK suggesting that in the future about 150 births per year could potentially benefit ‘if all women opted for the procedure’ (Gorman et al. 2015, 886-7). Again, using publicly available figures and an alternative approach to estimating the number of women who might be able to benefit from PNT/MST, it is possible to estimate that the number of children born each year who may be affected by serious mitochondrial disease is between 112 and 148.12 (See also Herbrand 2016).
Regulatory oversight and capacity.
Each application will be decided on a case by case basis and in accordance with the latest scientific advice. An HFEA committee will determine whether individual patients and families have a particular risk of an abnormality in their mitochondrial DNA; and whether there is a significant risk that a child born with that abnormality will have, or will develop, a serious physical or mental disability, a serious illness or another serious medical condition (HFEA 2015).
While 10 cases per year might be manageable, the question of how the HFEA would deal with up to 150 cases per year was not part of the wider discussions. When asked a question13 about the possibility of 150 cases coming forward per year, the Chair of the HFEA echoed the claim that only around 10 applications were expected per year and that the Authority had the resources to cope with that number. No acknowledgement was made that the higher figure might be possible. It is a moot point as to what impact the higher numbers had on the views of Parliamentarians, but clearly the higher figures could be deployed to make the case that PNT/MST interventions are much needed, while the lower number was deployed to reassure all parties that regulatory oversight could and would be provided. Whatever the baseline figures, the work for the HFEA may be increased given the recent recommendation from the Newcastle Group that PNT should only be used in conjunction with embryo screening (Hyslop et al. 2016).
The egg providers.
As we have detailed elsewhere (Haimes and Taylor 2015) the discussion of the egg providers (for both research and treatment), and the terminology used to describe them in the debates, was problematic. Little, if anything, was said about the role and contributions made by these women. Indeed it appears that their role was deliberately minimised: for example, the NCoB argued they should not ‘be given the same status in all aspects of regulation as a reproductive egg or embryo donor’ (2012, para 5.3) and the HFEA ‘Advice to Government’ reduced their status to that of mere ‘tissue donors’ (2013, para 1.13). The commitment of time, energy and generosity required from the egg providers and the invasiveness of the procedure through which the eggs are produced and collected for use in research or treatment were all but ignored. (For further discussion see Baylis 2013, Haimes 2013, Haimes and Taylor 2013).
Viscount Ridley (Con): … Finally, is it rushed? Far from being hurried, it has been under development for more than 30 years, under debate for 15 and under scrutiny for five. There is nothing slippery about this slope. There has been no rush. Now, however, that we have reached this stage there jolly well should be some reasonable haste on behalf of the women whose reproductive life is running out and who desperately want their own child, people such as Claire Wright, who is now 40 and who had to watch her son Jacob lose his smile on the way to a cruel death. Yes, there is understandable urgency. We would have to have very good reasons to argue that the ethical thing to do is to prolong her suffering and that of others like her. I cannot see those reasons (Hansard 2015b: Col 1588).
Bruce (Congleton) (Con): … Sir John Tooke, president of the Academy of Medical Sciences has said: “Introducing regulations now will ensure that there is no avoidable delay in these treatments reaching affected families once there is sufficient evidence of safety and efficacy.” In other words, Parliament should vote blind and sign off legislation permitting these procedures before the recommended experiments—some of them critical, regarding safety—have been completed (Hansard 2014: Col 94).
While an acknowledged opponent of embryo research in general, Bruce here is expressing concerns that Parliament would (and did) vote on the legislation with incomplete understanding of the safety of PNT/MST and therefore with an incomplete understanding of the possible long-term consequences for the affected women and any offspring they may have through using these techniques.
The group is seeking to establish the fertility status of the Macaques by entering them into a breeding programme and more focussed studies looking at physiological impact will be conducted. There remains one female Macaque who is 2–3 years old… that has not yet reached sexual maturity (HFEA, 2014, paragraph 3.3.3).
This means that it would only have been two to three years before the health of any offspring from the female Macaque could be established and therefore any long term negative consequences detected. Some Parliamentarians, such as Bruce above, clearly thought that waiting until these (and other) safety experiments had been completed would have been prudent. Therefore, within the terms of existing and imminent knowledge within the field, it could be argued that there was an over-hasty move to legislation.
Much contemporary medical ethics focuses on the values considered to be crucial in protecting the individual. Such values are important, but other values, more visible in public health practice and related to societies, populations and communities, are just as important (Dawson, 2015, p109).
Similarly, Petrini and Ricciardi (2015) describe the need for ‘the balancing of individual rights and collective interests, which are often in conflict’ (2015, 270). It could be argued that legalising PNT/MST operates in an inverse manner to public health measures such as vaccination, which requires that parents take a risk with their child for the benefit of the population (Wood-Harper 2005) since the former entails taking a risk with the future of the population, through the unknown and irreversible consequences of modifying the germline, in favour of the immediate, hoped-for benefits to individual families.15
In summary, we have identified ten areas in which the UK discussions of PNT/MST initiatives would have benefitted from greater clarity, depth and nuance; in each area we have highlighted information and knowledge that could have been more prominent and contributed to a more fully rounded debate. Through this analysis we have sharpened awareness of the wider social implications of this cutting-edge science, by contextualising these developments and drawing more centrally into consideration questions concerning, amongst other things: the reproductive choices available; the kinship relationships created; the relationship between safety and ethics; the characterisations of the assumed beneficiaries; the ambitions and limitations of the proposed interventions, and the challenges for regulatory capacity. These contributions are important since, while the UK legislation has already been changed, details of implementation, regulation and practice have not yet settled into place; alerting the field to the need to consider these areas, and the challenges they represent, is a timely and useful task. While some of these topics constitute a critique of the UK debates, others support the claims of those eager to translate the science into clinical applications as fully as possible; the point of this analysis is not simply to pick holes in existing debates but to assist in ensuring that the full range of deliberations is as strong and clear as possible. Together, the examination of these areas enhances our understandings of the contributions that mitochondrial interventions can make and enhances our understandings of how this new science can best be developed to benefit those who want and need it most; it also assists the achievement of a more measured evaluation of the wider social and ethical impacts of these developments.
This more moderate, and modest, assessment is necessary since the existing UK debates on mitochondrial interventions, including their influence on the legislative process, raise questions about the governance of this, and associated areas of biotechnology, in at least three related areas. (i) The protection of women, offspring and patients. The protection of research participants and of patients is one of the key roles of any governance system in biomedical sciences. In research involving assisted reproduction, the protection of any persons born and that of the providers of gametes or embryos must also be considered. However, in the case of the clinical applications of PNT/MST we have demonstrated that the regulations passed in Parliament, and which will be implemented by the HFEA, were influenced by, and so repeated, the weaknesses prevalent in the wider discussions. For example, the ‘strategy of persuasion’ (Haimes 2014) adopted by proponents of the techniques acted to reduce the egg provider to just a ‘tissue donor’ (HFEA 2013). This results in her being considered in law in a more instrumental way than other women who provide eggs for treatment in other circumstances, insofar as she is seen merely in terms of her provision of healthy mitochondria rather than in terms of her own agency in acting in such altruistic ways or for her wider contributions to the field as a whole (see section (ix) above and Haimes and Taylor 2015). Similarly, the protection of any people born as a result of PNT/MST should also require that the techniques used in their conception be as safe as possible, in accordance with agreed clinical standards (see section (iii) above). However, in confidently dismissing opponents’ questioning of safety as being rooted in questions of values, some proponents of the interventions (Jack 2016) closed down the possibility of open discussion that is a requirement of good systems of governance. This raises questions about the effective protection of the offspring and the women who bear them (Crouch 2016). There is no doubt that the clinician-scientists involved in developing PNT/MST have the best interests of their patients at heart and are concerned for the safety and wellbeing of all involved. However, the manner in which safety concerns, raised in good faith, were dismissed by some supporters of PNT/MST interventions is not what might be expected in a high quality discussion.
…a sustained and default assemblage of conditioned and habitual regulatory behaviours and impulses that adversely limit potentially more critical and reflexive regulatory deliberation (Brown and Benyon-Jones 2012, 224).
…reflex regulation is characterised by a focus on promissory risk and an emphasis on avoiding the loss of opportunity over that of avoiding other hazards and dangers. … This resonates closely with what we have called the ‘technocratic reflex’, i.e. policy culture’s enduring deference to scientific stakeholders’ definitions of risk in spite of a widely purported policy ‘turn’ towards greater inclusivity in deliberation concerning technoscientific futures (2012, 237).
In the case of PNT/MST we have seen both the emphasis on pressing ahead with legislation to enable the clinician-scientists to offer treatment quickly to affected women, accompanied by the effective (even if unintentional) silencing of criticisms of the science. We have highlighted the absence of informed discussion of the risks to wider society and the focus instead on the risks to individuals from not being offered treatment, despite the supposedly ‘open’ approach to policymaking and governance espoused by Government (HM Government 2013).
One means of achieving the better regulation envisaged by Brown and Benyon-Jones could result from the adoption of the principle of ‘Responsible Research and Innovation’ (RRI) (Stilgoe et al. 2013). This approach to the conduct of science has recently been gaining importance, particularly at European level (EU 2016). Stilgoe et al. identify how, despite recent approaches that include consultation or engagement with a range of stakeholders, in a bid to identify wider concerns about the purposes of and motivation for research, current governance arrangements for science are still focussed on the narrower, formalised means of risk assessment (2013, 1569).
In an effort to develop a framework for ‘responsible research’ Stilgoe et al. avoid the approach taken by others (e.g. von Schomberg 2011) who see RRI as a means of pursuing particular values and desired outcomes, and instead focus on the processes of governance that encompass ‘the distinctive social and ethical stakes’ in technological developments (quoted in Stilgoe et al. 2013, 1577). It is just this sort of focus on the wider societal interests in PNT/MST that our ten areas add to the UK debates and any subsequent regulation processes.
[s]cientists have developed ground-breaking new procedures which could stop these diseases being passed on, bringing hope to many families seeking to prevent their future children inheriting them. It’s only right that we look to introduce this life-saving treatment as soon as we can (Department of Health 2013).
(iii) The risk to public trust. We have raised concerns about the protection of those who may be involved in research and clinical applications of PNT/MST and about the legitimacy of the rapid legislative process by which clinical applications have been enabled. Such concerns have implications for the trust that wider publics might or might not have in biosciences. By pressing ahead without a more detailed and more nuanced discussion that could have involved more diverse publics, more thoroughly, the proponents of PNT/MST risk jeopardising the trust in medical scientists currently held by those publics (Castell et al. 2014, Marris 2015). As Brown and Benyon-Jones showed, the promise of areas such as human-animal hybrid embryos for research and medicine has been left unfulfilled, as indeed is the case for much that was expected of human embryonic stem cell research. Should the proposed clinical application of PNT/MST be less than hoped for, or worse still, cause harm, then wider publics are even more likely to come to distrust both the therapeutic promise of other new technologies and those who make such promises.
The modern biosciences require governance frameworks that are capable of simultaneously managing risk, coping with uncertainty, combating ambivalence, and building trust, all the while encouraging the delivery of those instrumental outputs that we value/demand (better health, new technologies, commercial reward). This multi-dimensional task makes the design and delivery of good governance frameworks … extremely difficult (Harmon et al. 2013, 31).
In Harmon et al’s view, which mirrors those of Stilgoe et al. (2013) and Brown and Benyon-Jones (2012), approaches to the governance of bioscience have tended to be inadequate. One reason for such inadequacy is that a key element of good governance is an assessment of the risk, in the wider, socially-defined, understandings of that term, posed by a particular technology or process. Harmon et al’s review of the work in this field leads them to conclude that the scientific understanding of the risks of biosciences are incomplete and ‘risk articulations are tentative and sound assessments are not yet within our grasp’ (2013, 26). In such a situation, legislators face a dilemma: should the law be used to prohibit certain technologies, or promote them, given that risks are largely unknown? A precautionary approach may be taken, but Harmon et al. consider this to be a contributing factor to the ambivalence around bioscience observed in wider publics.
Many authors have suggested that biotechnology governance frameworks would benefit by involving publics in their development, which, it is argued, would also lead to increased trust in biosciences (e.g. Harmon et al. 2013, 27). Public consultations are mechanisms frequently employed to involve publics in the legislative process; this was, as we have shown, an approach taken in the legalisation of PNT/MST therapies. However, the timing of the HFEA consultation in 2012 (let alone its conduct) can be seen as a concern, since, as Harmon et al. note, one-off, ‘snapshot’ consultations are inadequate for capturing the nuances of opinion about rapidly developing fields such as PNT/MST; they recommend ongoing dialogues between publics and policymakers instead (2013,28). These authors see a positive role for public engagement when done thoughtfully and robustly, providing policy-makers with ongoing evidence, assessment of risks and understanding of values that could inform governance frameworks over time. However, this was not aimed for, let alone achieved, in the case of PNT/MST.
Other jurisdictions might appreciate the usefulness of a more fully rounded debate. As Bredenoord and Hyun (2015) argue, when discussing whether the USA should follow the UK’s lead in permitting MST/PNT, ‘The bold leap from bench to bedside needs sufficient preclinical evidence and careful, long-term interdisciplinary research, including more ethics research’ (2015, 976). They recommend that the USA should take a more cautious path and argue, ‘A cautionary approach means that a wide variety of concerns should be taken seriously – wider than safety and efficacy alone’; the need is to find a balance between ‘taking appropriate precautions and not unnecessarily hampering innovation’ (2015,976). The US National Academies of Science, Engineering and Medicine report on mitochondrial disease (National Academies of Sciences, Engineering, and Medicine 2016) describes these interventions as raising ‘a novel collection of ethical, social and policy issues’ (2016, xiii). The starting point for their deliberations was ‘parental motivation’ for using these techniques in light of ‘alternative approaches to creating families’ and the ‘primary value’ to be considered when balancing risks and benefits of further clinical investigations was ‘minimizing the risk of harm to the child born as a result’ (2016, xv). They concluded that it is ethically permissible to conduct clinical investigations of these interventions but with two major restrictions: that investigation should be limited to women at risk of transmitting a serious mitochondrial disease and that only male embryos are transferred for gestation, ‘to avoid introducing heritable genetic modification during initial clinical investigations’. (2016, xv). While this second restriction raises its own ethical challenges in creating ‘experimental offspring’ (Taylor and Haimes 2012, NCoB 2012, 80), the USA is clearly taking more time to reach a decision and appears unlikely to follow the same path as the UK.
As we have shown, many important areas were neglected in the UK debates and the claims about the quality of those debates are over-stated. It is impossible to say what the outcome of the debates would have been had these more nuanced discussions been included. What we can suggest is that by leading the argument in the way that they did, focussing on the emotive and profoundly distressing effects of mitochondrial disease on babies, children and their families, and by failing to address a range of other issues in detail, the proponents of the technology leave themselves open to challenge in the future should the techniques fail to have as powerful an impact on mitochondrial diseases as some parties to the debates clearly expect them to have, or prove to be unsafe, or lead to other (perhaps more commercial and exploitative16) uses being approved.
The analysis presented here provokes the question of where the UK stands on the global stage in relation to mitochondrial interventions. Clearly the scientific endeavour in the UK is at the cutting edge of progress in this field. However, given that the UK legislation is the first example of the permissibility of genetic modification of human beings, and given the more cautious approach recommended for, and being taken by, the USA and Australia (de Lacey 2016), it could be argued that the UK is precariously out on a regulatory limb,17 until the many aspects discussed in this article are more clearly understood.
As we have explained elsewhere, the terms ‘mitochondrial donation’ and ‘mitochondria donor’ are ‘misleading as they imply a direction of travel for the mitochondria that is in fact the opposite of what will actually occur. In the therapeutic application of PNT, an egg from the intending mother will be fertilised using sperm from the intending father. At the same time, an egg provided by a volunteer will be fertilised by the intending father’s sperm and that fertilised egg will be enucleated. The intending parents’ nuclear DNA, in the form of two pronuclei from their own fertilised egg, will then be transplanted into the enucleated egg which then acts as a ‘host’ to the transplanted nuclear DNA. MST will similarly involve the transfer of the intending mother’s nuclear DNA into an enucleated egg from the egg provider; that egg will then be fertilised by the intending father’s sperm. In other words, the egg provider’s mitochondria, whether in research or treatment contexts, are not moved anywhere. Therefore, rather than phrases such as ‘mitochondria donation/transfer/replacement’, a more accurate term would be ‘nuclear DNA hosting’, for both PNT and MST.’ (Haimes and Taylor 2015, 364-5).
Throughout this paper we discuss mitochondria as related to human life processes and health, though of course mitochondria are present in the cells of all multicellular organisms.
We use this term to emphasise that those leading the research on PNT/MST also tend to have clinical roles in diagnosing and caring for people affected by mitochondrial disease.
The authors are employed at the same university as that to which the clinician-scientists engaged in mitochondrial research and the recruitment of egg providers are affiliated, and our study was funded by the same organisation (Wellcome Trust) that funds the scientific research. However, our study was independent. We were assisted by a Project Advisory Group comprised of senior academics from other universities to ensure analytical objectivity.
We do not claim to have conducted a full blown ‘media analysis’ as our aim is to identify themes cutting across the different contributions to the UK debates rather than to analyse how one particular type of contribution (the ‘mass media’) shaped the overall debates. Newspaper and other media articles were identified via the systematic collation of all reporting (favourable or otherwise) of the work on mitochondrial disease interventions by Newcastle University-based clinician-scientists carried out by the University’s Press Office between May 2010 and September 2016, augmented by our own online searches.
Of course from the egg provider’s point of view all such measures entail giving a whole egg; however the distinction we draw here is between ‘traditional’ egg provision that contributes 50% of the genetic material to any resultant offspring, the donated egg completely replacing the intending mother’s egg, compared to egg provision in PNT/MST which will result in a smaller amount of genetic material being contributed and combined with both the intending parents’ DNA.
While it is always difficult to prove the absence of any feature, further evidence of the lack of consideration of alternative routes to reproduction can be found in utterances such as that from the lead scientist, Professor Turnbull, on greeting the news in December 2016 that approval might be given for the go ahead of clinical applications for PNT/MST: ‘This gives women who have mitochondrial DNA mutations reproductive choice, and I am delighted for them.'. The implication here is that they did not have any choices prior to this. See also section (ii) ‘Valorising ‘genetic connections” in this article.
The references given in the text ‘[6-8]’ are to scientific papers describing the experimental methods; no evidence is offered for the claim that the need for ‘this technique … is well established’.
It is of course possible to refer to ‘adult children’ in everyday speech but that qualifying adjective was also absent in these discussions, which further underlines the view that the prevailing tendency was to see the person conceived only in their infant status.
It is not clear precisely how these various parties were calculating their figures, given the variations between 0.1% and 0.01%, but they were all very clear that the figures were very small.
The ONS report that there are 52,798,300 adults in UK (ONS, http://www.ons.gov.uk/ons/rel/pop-estimate/population-estimates-for-uk--england-and-wales--scotland-and-northern-ireland/2013/sty-population-estimates.html). Using the figure given by Craven et al. of 1 in 10,000 affected individuals implies that around 5280 adults in the UK are affected. As mitochondrial diseases affect both sexes equally, this figure is in line with the estimate of 2473 affected women reported by Gorman et al. (2015).
The HFEA report that ‘Around 1 in 6500 children [are] thought to be born with a serious mitochondrial disorder due to faults in mitochondrial DNA’ (HFEA 2014). The Office of National Statistics report that in 2012 there were 729,674 live births in England and Wales. This suggests an incidence of 729,674/6500 = 112 affected children born per year. However, Sanderson et al. (2006) report the incidence of mitochondrial disorders as 1 in 4929. Thus, England and Wales would expect to see 729,674/4929 = 148 new cases of mitochondrial diseases in children per year.
The question was asked by one of the authors, KT, at the same December 2015 conference in which Walport made the remarks quoted earlier.
The airbrushing of the egg providers’ role also poses threats to their own health since no consideration was given in the UK debates to the health screening of potential providers nor to the handling of any incidental findings or adverse information relevant to the providers’ health arising from that screening (Applebaum et al. 2014; Haimes and Taylor 2015).
Tangential to the concerns about over-rapid legislation were concerns expressed about ‘slippery slopes’. Opponents of PNT/MST often raised concerns that the legalisation of these techniques would lead to other forms of genetic modification of embryos (see for example McKie 2014). These claims were contested by the proponents of PNT/MST (see for example McKie 2014, Lily Foundation 2015) who argued that altering nuclear DNA would remain illegal and that PNT/MST were solely for the purpose of removing these mitochondrial diseases from the germline of the offspring of affected women. However, soon after the House of Commons vote, the afore-mentioned researcher, Mitalipov, was quoted as saying that he hoped to be able to use the MST technique to enable older infertile women have genetically related children (Farmer 2015). Similarly, Walport’s claims, cited earlier, that approval of ‘mitochondrial donation’ provides a blueprint for future decisions on modifying the genome, is further evidence for those who fear that the slope beckons.
See the discussion of Mitalipov in footnote 15 above.
With reference to Walport’s claim that the UK legislation provides a blue print for future decisions on modifying the genome, it is sobering to note that in the world of architecture, blueprints are not the finished product that popular usage of the term implies. The technology to make blueprints always resulted in the finished product being slightly smaller than the original drawing as the medium on which the blueprint was made shrank as it dried (Liebing, 1999). Blueprints carried a warning (as do their modern, digital, equivalents) reminding architects and engineers not to take measurements directly from them, but to look elsewhere for the necessary details to construct a stable, safe and long-lasting structure.
The authors would like to thank: two anonymous reviewers for their very helpful comments; the participants at the 13th World Congress of the International Association of Bioethics Symposium ‘UK mitochondrial legislation: cutting edge or out on a limb?’, and the Wellcome Trust for funding (award number WT102609).
EH conceived the study and secured funding. Both authors contributed to the research and development process that resulted in this article, and to the writing of the manuscript. Both authors read and approved the final manuscript.
EH is Emeritus Professor of Sociology, PEALS (Policy, Ethics and Life Sciences) Research Centre, Newcastle University. KT is a Research Associate in PEALS (Policy, Ethics and Life Sciences) Research Centre, Newcastle University.
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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