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/