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Mitochondrial replacement techniques: US-style

15 February 2016
By Dr Peter Mills
Assistant Director, Nuffield Council on Bioethics
Appeared in BioNews 839

On 3 February the US National Academies of Sciences, Engineering, and Medicine published a report on the ethical, social and policy considerations relating to mitochondrial replacement techniques (MRTs - a somewhat misleading description but one the authors defend in the report) (1). The report was written by a committee convened to advise the US Food and Drug Administration (FDA). This line of accountability may be significant.

The committee's report reflects many of the conclusions of the Nuffield Council on Bioethics' 2012 report Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review and subsequently embodied in UK legislation and Human Fertilisation and Embryology Authority (HFEA) licensing guidance (2, 3). At its centre is the concern to minimise any risk to a child who may be born as a result of the procedure. It recommends, accordingly, that the safety and efficacy of the procedure should be established through preclinical research, and that it should be resorted to only in cases in which there is an undisputed risk of transmitting a severe mitochondrial disease.

As in the UK, the report recommends that the treatments should only take place in specialist centres, that patients should be given appropriate information and support, and that there should be long term follow-up of any children born. It is also welcome that the report takes the position that MRTs do not constitute a treatment for disease but an expansion of the reproductive options available to those who know themselves to be at risk of passing on a severe, inherited mitochondrial disorder. Neither of these is an unimportant thing but they are not the same thing (though there is much more to be said about this).

The recommendation that has inevitably attracted most attention, however, is that only male embryos should be transferred, an approach that was considered but rejected in the UK. There are two distinct lines of argument supporting this position, though the report equivocates between them.

One is that introducing the procedure first in male offspring allows its effects to be observed without the risk of any adverse outcomes being passed on to future generations (because mitochondria are inherited from the mother, through the egg). The report states clearly that this embodies a 'cautious' approach and constitutes permissible 'sex selection for medical purposes'. Another line of argument is that by stipulating that only male embryos are transferred, the supposedly more contentious prospect of germline modification is avoided. Again, this is clearly acknowledged in the report, which, like the earlier Nuffield report, calls for further public debate on this question.*

In the UK, in contrast, it was concluded that MRTs should not be used at all until preclinical research had shown that they were sufficiently safe and would not pose a significant risk to any offspring or their descendants. Where the US has a gradient, the UK has a threshold. Why?

MRTs are not obviously the sort of thing that lend themselves to investigation on the model of a conventional clinical trial. When MRTs are introduced they must be introduced as part of a treatment service; there will be no adjustment of the 'dose', no control groups; the treatment cannot be withdrawn if adverse effects are observed; and the consent conditions are both more complex (the invasive assisted conception procedure and the use of embryos in MRT require different and distinct kinds of consent) and lack sufficiency.

The US report, however, is framed – by the charge to the committee – as advice on 'the conduct of clinical investigations' of MRTs. One reason for this is the FDA's prior assertion of regulatory competence over the use of the products of MRT as 'human cells or tissues that are intended for implantation … into a human' (4) and, according to its own guidance, the requirement for an Investigational New Drug application to be made. But while, in this way, the FDA's risk-based regulatory mechanism may gain purchase on MRTs, it is not obviously a good fit for the purpose. Whereas in the UK we have a dedicated regulatory system that can respond to the multiple clinical, moral and social dimensions of assisted conception, no such system exists in the US. This is an important difference if, as the US report underlines, MRTs are about reproductive options and not about treating illness, and if, given rapid advances in genome editing, it is becoming increasingly difficult to hide behind safety concerns to avoid complex moral questions about germline modification.

There is an interesting coda on the question of transferring male embryos. Were a centre in the UK licensed to carry out this procedure – as one soon surely will be – the couple in question would be unable to elect to have only male embryos transferred, whatever their personal views about germline modification. (Such a preference would not be medically indicated – the procedure having been judged sufficiently safe by the regulators – and sex selection is not permitted in the UK for non-medical reasons). The UK has already accepted the permissibility of germline modifications; which germline modifications should be permitted must therefore be a matter of urgent and public debate.

*This question has been taken up in the current debates around genome editing, including a current Nuffield Council project: http://nuffieldbioethics.org/project/genome-editing/

SOURCES & REFERENCES
1) National Academies of Sciences, Engineering, and Medicine (2016) 'Mitochondrial replacement techniques: Ethical, social, and policy considerations'
Washington, DC: The National Academies Press |  3 February 2016
2) Nuffield Council on Bioethics (2012) 'Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review'
Nuffield Council on Bioethics |  21 May 2018
3) The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations (S.I 2015 No. 572) and HFEA Code of Practice (8th Edition), part 33 ('Mitochondrial donation').
|  21 May 2018
4) Title 21 Code of Federal Regulations (CFR), Part 1271.
| 
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