Response to open letter on mitochondrial transfer

The following is a response to the open letter to the UK Parliament by Dr Paul Knoepfler (see BioNews 781).

Dear Professor Knoepfler,

We read your open letter to the UK Parliament and the Science and Technology Committee with interest and concern. We are two scientists, like you, with particular interests in genetics, stem cell and developmental biology and preimplantation genetic diagnosis (PGD), who were appointed amongst others to form a Panel of independent advisors to the HFEA and the UK Government on the subject of mitochondrial donation.

You will no doubt be aware of the three main reports in the public domain, and the recent addendum to the third one, that have been published by this Panel. Those reports are detailed examinations of the current available evidence on the possible use of mitochondrial donation procedures, and their safety and efficacy for severe mitochondrial disease. Unlike the FDA we did not consider the use of cytoplasmic transfer proposed for protracted infertility, nor did we consider the ethics, a task undertaken here by the Nuffield Council on Bioethics.

Whilst we take no role in lobbying Parliament, we believe it behoves us to defend the findings as presented in our reports, and the advice that our Panel unanimously agreed should be put forward. In this regard we would like to take the opportunity to correct some of the misunderstanding about the processes in the UK, and to bring to your readers' attention some of the information we considered in forming our opinions.

First, it is important to appreciate that the regulatory process in the UK by the HFEA is different from that in the USA as demonstrated in the FDA hearing. In contrast to the USA where there is no federal regulation of IVF technology, in the UK we have specific legislation that deals with the use of gametes and human embryos in vitro wherein, after thorough debate during the 2008 amendments to this legislation, specific provision was made that could allow in prescribed circumstances, processes to be applied to an egg or embryo designed to prevent the transmission of serious mitochondrial disease. This clause would come into force if allowed by Parliamentary regulations, which are soon to be the subject of the vote you comment upon in your blog.

However, even if passed, these Parliamentary regulations would not allow any trial to take place in the UK until the regulator (the HFEA) felt that there was sufficient safety and efficacy information to do so; this is in contrast to the FDA's Cellular Tissue and Gene Therapies Advisory committee hearing which addressed deliberations on permitting a clinical trial. Thus these Parliamentary regulations are in essence 'enabling legislation' which would simply take the UK onto the same footing as the current situation in the USA, where safety and efficacy data determine whether clinical application should be allowed. We are therefore not rushing ahead of the USA, and the same issues that concern you and the FDA committee are those that exercised us in our deliberations.

Second, the main difference with the UK approach so far is that rather than spending a day and a half of public presentation and debate to include genetic disease, infertility and ethics, we have spent over three and a half years examining in detail published and also as yet unpublished evidence, interviewing those involved with basic and clinical mitochondrial science (including Evan Snyder whom you quote), and holding round table discussions with those 'at the coal face' of mitochondrial replacement techniques; we allowed opponents of the technology the opportunity to present their cases in person and included them in our discussions.

We have thoroughly examined the 'more specific risky elements to the proposed experiments' as suggested by Burgstaller, Dowling, Reinhardt, Morrow and others, and have produced detailed comment in our 2014 report, and have published a rebuttal of the New Scientist article warning about three-parent IVF that you quote. In our 2014 report, we suggested that, where practical, the use of haplotype matching could overcome some concerns, and have taken a view in balancing the theoretical risk of harm against the inevitable inheritance of a serious genetic mutation whose effects and expression are variable and unpredictable, including death, or lifelong disability and the inevitability of transmission along the female line.

We are also concerned in the mistaken general belief that PGD is a panacea for couples with mitochondrial DNA (mtDNA) mutations — although you yourself acknowledge it is not suitable for all. Although it can help those with mitochondrial disorders of nuclear origin, for those with mtDNA mutations, there are some who have such high levels of heteroplasmy (or homoplasmy) that the likelihood of finding an embryo for transfer with an acceptable mutation level is very low if not impossible. Moreover, it is clear that in many cases of PGD for mtDNA disorders, embryos selected for replacement have a significant heteroplasmy for the mutant gene, much in excess of that being expected for mitochondrial replacement. In these cases, all the concerns being levelled at the risks of carryover of mutant DNA apply here too, but are not mentioned in the arguments put forward against mitochondrial replacement.

We are of the view, and have expressed such to the Select Committee, that most concerns about mitochondrial replacement are based on expecting a near zero tolerance for risk, especially where alternatives might exist. For couples with mtDNA mutations, there are no alternatives that allow the couple to have genetically related children free of mitochondrial disease. No medical first-in-man technique is ever without risk, whether this be heart or kidney transplants, or the first IVF or the first embryo biopsy for PGD. The risk of treatment must be balanced against the certainty of adverse outcome without.

Yours,

Peter Braude PhD FRCOG FMedSci

Robin Lovell-Badge PhD FMedSci FRS

This letter was first published on the Knoepfler Lab Stem Cell Blog: http://www.ipscell.com/2014/11 /response-from-drs-braude-lovell-badge-to-my-letter-on-mitochondrial-transfer3-parent-technology/