Fig. 28.1
Maternal spindle transfer
Fig. 28.2
Pronuclear transfer
PNT is a similar process, but this time two embryos are initially created. A donor egg is first fertilised by the father or another donor’s sperm to create an embryo. Towards the end of meiosis, the nuclear DNA of the embryo, from the sperm and the egg, form pronuclei. These are removed and discarded leaving an enucleated embryo with normal mitochondria. A second embryo is created through the fertilisation of the mother’s egg by the father’s sperm. The pronuclei are again removed, but this time they are transferred into the enucleated embryo. This reconstructed embryo contains the nDNA of the mother and father together with healthy mitochondria from the donor egg. The enucleated embryo containing the abnormal mitochondria is discarded.
MST and PNT were the only techniques considered in the consultation process with the public, but recently, a third technique, polar body transfer, has been described in the literature [19]. At this point in time, the potential efficacy and safety of PBT is being monitored by an expert group appointed by the HFEA [20].
Engaging the Public
Given the above descriptions of mitochondrial disorders, their inheritance and potential treatments, it is evident that the issues on which the HFEA had to test public reaction were exceptionally complex and controversial; communicating and engaging effectively with the general public would be a demanding task. Following consultation with a small group of stakeholders about its composition and remit, an Oversight Group was appointed. Key elements of the terms of reference were to explore (a) the ethical aspects and issues involved in mitochondrial transfer and (b) the practical implications of allowing mitochondrial transfer within regulation [21]. Members of the Group, who were acting as individuals rather than formally representing an organisation, were drawn from a range of backgrounds: public dialogue/science communication, science/research, bioethics, patient interests, religious interests and welfare of the child. A notable feature of the body that was appointed was its inclusivity [22]; the Oversight Group included members who were in principle opposed to ARTs as well as those committed to alternative family structures.
The role of the Oversight Group was advisory; the HFEA carried responsibility for making decisions on the consultation process, materials and the report to the Department of Health. The Oversight Group and HFEA worked with providers with experience and expertise in public dialogue (Sciencewise-ERC, The Office for Public Management, Forster and Dialogue by Design), and academic social scientists were contracted to monitor the whole process and prepare a report at its completion [23].
In order to understand how people comprehend the ethical and regulatory issues involved in mitochondrial replacement, the difference between informed and uninformed views and the deliberative process people go through to form those views, five different methodologies were agreed (Table 28.1) [24]. Two of these involved members of the public who could not be said to be interested parties: a face-to-face poll of around 1,000 people who formed a random quota sample and three workshops each run over two separate days in three major cities (London, Newcastle and Cardiff) for people who had been recruited to reflect a range of ages, gender and ethnicity. Open consultation meetings were held in two cities (London and Manchester), at which a panel of speakers with differing expertise and perspectives introduced the issues, participants worked together in mixed groups and there was public debate. A focus group for those affected by mitochondrial disease met once to explore the issues. Additionally there was an online open consultation questionnaire consisting of seven questions, though participants were able to send in written copies or respond by e-mail. A variety of different means were used to raise awareness of the ‘open’ elements (the consultation meetings and the questionnaire), including the use of websites, Twitter, the press, e-mailing stakeholder groups and encouraging networking. Members of the Oversight Group helped shape the material (including video material and diagrams) and frame questions to best enable lay people to understand and respond to the scientific, regulatory and ethical dimensions involved in mitochondrial replacement.
Table 28.1
Strands in the design of the consultation
Participants | Selection method | Knowledge level of consultation issues | Number of participants | |
|---|---|---|---|---|
Deliberative public workshops | Members of the public | Recruited to a quota sample | Low at start of the workshops, much higher by the end | Approximately 30 participants at each workshop |
Public representative survey | Members of the public | Random quota sample | Most people likely to have had low knowledge of the consultation issues | 979 participants |
Open consultation meetings | Interested stakeholders and members of the public | Self-selected sample through open invitation | Interested and knowledgeable about the consultation issues, but levels of knowledge were likely to be variable | 53 participants [London meeting] and 39 participants [Manchester meeting] |
Patient focus group | People directly or indirectly affected by mitochondrial disease | Invited to attend through patient contacts and patient groups | Interested and knowledgeable about the consultation issues, but levels of knowledge were variable | 7 participants [including 1 telephone interview] |
Open consultation questionnaire | Interested stakeholder and members of the public | Self-selected sample | Varied—relevant information was available via the consultation website which respondents were encouraged but not obliged to consult | 1,836 participants responded to the consultation |
Gathering and Interpreting the Data
Given the breadth of approaches, differing formats and the numbers involved, analysis of the responses was complex and difficult to make quantitative. The data was primarily analysed in a qualitative way, presenting comments in discussion while assessing the predominance of views. Where a questionnaire had been used, it was possible to give a semi-quantitative ‘score’, but the methodology was not designed or expected to deliver this kind of measurement. The online material was subject to a sorting algorithm which enabled the flagging and grouping of particular comments, but, again, this was necessarily a ‘soft’ quantitation. The consultation was not aimed at finding absolute percentages; rather it was concerned with ‘taking the temperature’ and identifying key issues in relation to the ethics and practical implications of mitochondrial replacement.
Six headings were used to sort and group the data. The data from each methodology, or ‘strand’, was presented by the Oversight Group to the members of the HFEA’s governing board in a series of substantial reports and conclusions [25–29]. These were appended to the main report and advice which went from the HFEA governing board to the Department of Health [24, 30]. Given the extensive nature of the reports, including the summarised data, what follows here is necessarily highly abbreviated.
1.
Permissibility of new techniques
The public representative survey showed a number of trends [26] with strong support for medical research, the care and treatment of those with genetic disease, good awareness of IVF treatment and clear support for genetic testing during IVF and for genetic testing to avoid children being born with serious disease. However, the proportion of people declaring they were unsure was significantly raised by questions relating to genetic testing as was the (smaller) number actively opposed. Answers to a specific question about treating mitochondrial disease by altering the genetic make-up of an egg or embryo reflected this latter type of response with 56 % positive, 33 % unsure and 10 % negative. It should also be noted that some three quarters of participants had not heard of mitochondrial disease and that 50 % believed that medical research had unforeseen negative side effects, with only 15 % dissenting.
In the deliberative workshops [25], the first part was aimed at explaining the science behind mitochondrial replacement, while the second part explored ethical, social and regulatory dimensions. In general there was a positive response to the techniques though anxieties around ‘playing God’, ‘aborting disabled people’, ‘designer babies’ and the ‘slippery slope’ were expressed. When compared with currently available treatments such as egg donation (or adoption), overall participants favoured the new techniques as giving parents the opportunity to have a child that is genetically ‘their own’. They also came down on the side of giving parents personal and individual choice.
During the workshops concerns were raised around safety and efficacy and whether maternal spindle transfer was ethically preferable because it did not involve the creation and destruction of another embryo. These concerns also emerged during the open consultation meetings [28] and from the open consultation questionnaire [27]. Strong views were expressed by stakeholders at the London meeting representing a tension regarding the moral status of the embryo versus the right of affected parents to receive this treatment. In Manchester, where there were many science and law students, there was generally openness to the techniques, and in London, too, there was also a majority in support. The patient focus group advocated permitting both procedures, though questions about safety were raised and to what extent the first children born after this treatment would be ‘an experiment’ [29].
The impact of stakeholder positions surfaced in the open consultation questionnaire [27]. There was a distinction between those who identified as ‘students’ or those with a ‘family member or friend affected by mitochondrial disease’ when compared to those who identified as ‘other’; while the former were more often supportive, the latter were predominantly opposed. 275 responses were received, in different formats, which did not directly answer the questions posed and used similar wording in expressing opposition to both techniques.
With the exception of the open consultation questionnaire, where a small majority of responses were against the techniques, the general conclusion was of support [24]. However, their safety was frequently raised as a concern, and there was a preference expressed for MST over PNT by those concerned with the use of embryos. It was also evident that a significant proportion of those new to the subject wanted further information before making their mind up.
2.
Changing the germline
If permitted, mitochondrial replacement transfer would modify the germline and pass donor mtDNA down the maternal line to succeeding generations—one of the major ethical dimensions raised by the proposed treatment. In the deliberative workshops, participants were introduced to this and provided with up-to-date information on the uncertainties and risks of altering the germline [25]. An ‘ethics’ questionnaire used in the workshops revealed that over 60 % of participants had no real concerns about changing the germline and that their views on this remained similar both before and after hearing about the ethical dimensions. These were largely informed by the significance participants gave to parents in making choices.
The place and responsibility parents have in making decisions for their children emerged in both of the open meetings [28]. In response to an argument from a member of the platform panel that it was morally unacceptable to alter the germline and that a child might have difficulties with the way they were brought into being, a member of the audience in London and one in Manchester spoke of how they would communicate their decision to any children born by mitochondrial replacement. Both emphasised their desire to do what they considered was best for their child, even if it might not be something with which the child agreed. This captured the view of almost everyone in Manchester and the majority in London. With respect to changing the germline itself, there were three general types of response: (1) that it would not be altered significantly because variation in mtDNA is limited and this could be minimised further by using a sequence (haplogroup) similar to the mother’s; (2) that germline modification would pose serious risks, both to individuals and societies; and (3) that it would ‘change the germline for the better’ and reduce the incidence of mitochondrial disease. Those who took part in the patient focus group had limited concerns around altering the germline and again stressed parental decision-making. One participant expressed the view that an affected child might resent their parents for not taking an option which could have alleviated their pain and suffering.
A concern which emerged in the open questionnaire [27] was the way in which society might regard those who chose not to make use of these techniques: would there be pressure on parents to use them, or discrimination against them, or a generalised knock-on effect against disabled people? Alternatively, would those who chose to use them be treated differently, at least until the procedures moved from being new? Given that ‘scientific understanding of genetics is far from comprehensive’, concern was also expressed by some respondents about consequences from changing the germline which could be hard to predict and be severe and far-reaching.
The predominant ethical concern expressed by respondents was that these techniques would make altering the germline acceptable and, in the words of some, open the door to eugenics and cloning. All of the above emerged from a question on the possible social and ethical implications of changing the germline. Of the 1,115 respondents, those who were more positive about the techniques argued that the benefits outweighed the risks, that there were no implications or that the only implication was decreasing the incidence of an awful disease.
3.
Implications for identity
The implications of having DNA from three people on identity raised more concern than germline alteration among participants in the representative survey [26]; 40 % were undecided and 15 % took a more negative view. Participants in the deliberative workshops, largely unfamiliar with the concepts beforehand, likewise responded with caution at first [25]. The use by presenters of analogies such as tissue donation, gamete donation or adoption helped participants to review their anxieties, and overall they moved to being less concerned about identity issues.
The impact of sensationalist reporting was raised in open meetings [28] and the patient focus group [29]. Variously described as ‘emotive’, ‘misleading’ and ‘confusing’, attention was drawn to the potential impact this might have on a child’s sense of identity. The differences between the contribution of mitochondrial and nuclear DNA to a person’s make-up were regularly emphasised, with the latter regarded as by far the most significant. At the open meetings, in contrast to claims that mitochondrial replacement created ‘an artificially constructed identity’, the conclusion of the 2012 Nuffield enquiry that these techniques did not raise any ethical issues for identity was referenced [13]. The point was also made that identity issues from mitochondrial replacement might be less than for adopted children or those conceived by donor eggs.
The concerns of contributors to the open questionnaire were linked to whether the donor of mtDNA was viewed as a ‘third parent’ [27]. If mitochondrial donation were equated to donor gamete-conceived children, the social and ethical implications would be comparable; if equated to blood or bone marrow donation, there would be no significant implications. However, the point was made by a few respondents that mitochondrial donation could not be fully equated with any other analogy, and the importance to a sense of identity of parents explaining how they came into being was expressed by many.
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