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Expert reaction to study explaining technique behind first mitochondrial replacement therapy baby

Published in Reproductive Biomedicine Online, scientists have described the technique they used to create the first live birth after oocyte spindle transfer to prevent transmission of the mitochondrial disease, Leigh syndrome.

 

Dr David Clancy, Lecturer in the Department of Biomedical & Life Sciences, Lancaster University, said:

“We now have data, albeit incomplete, on a person resulting from a mitochondrial replacement technique. It might not be unreasonable to consider this as an experiment; an experiment which uses a child. A child who had no ability to consent.

“As expected, because the technique is imperfect, the child’s cells contain disease-associated mitochondria carried over from the mother’s egg, in variable amounts though not as high as in the mother’s cells. Mitochondria are vital cell components though in some tissues they are more critical than in others. Such tissues are heart, brain, liver and kidney, and because it is not ethical to do needle biopsies on those organs in children we do not have data on levels of disease-associated mitochondria in those tissues. We can only hope it is less than the 9.23% seen in a skin sample. Of course if the child begins to show disease symptoms, perhaps then it will be necessary to take needle biopsies of these organs.

“Even a moment’s consideration of the ethical issues completely overridden by this work should make us very concerned. Here in the UK I think it would be wise for the HFEA, having granted a licence for this procedure, to clearly outline criteria for failure and for halting the program.

“Finally, last year a birth was announced resulting from use of a similar technique in China, however we have not yet heard the results. Given that we are now using this technique on humans it would be useful to know that outcome.”

 

Prof. Sir Doug Turnbull, Director of the Wellcome Centre for Mitochondrial Research at Newcastle University, said:

“Mitochondrial donation is an important new IVF technique that provides more reproductive choice for women with mitochondrial DNA mutations.

“In the UK there is a clear regulatory framework and Newcastle has recently obtained a licence from the HFEA to allow mitochondrial donation for women at risk of having severely affected offspring.

“It is important that all reproductive options are explained to potential mothers and there is long-term follow up of children born, all of which are planned in the UK.”

 

Prof. Mary Herbert, Professor of Reproductive Biology, Newcastle Fertility Centre, part of Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University, said:

“This report of a healthy baby following spindle transfer is indeed encouraging.

“However, it is difficult to comment on the science as the details are sketchy and the authors have not published any underpinning research data. The regulatory and ethical backdrop also seems unclear.”

 

Prof. Peter Braude, Emeritus Professor of Obstetrics and Gynaecology, King’s College London, said:

Aside from the issues that have been raised about avoiding USA regulations by treatment in Mexico, and questions of adequacy of their consent procedures, this is an excellent proof of principle that MST can be applied to ameliorate the transmission serious mitochondrial DNA disease in a very deserving family which has been plagued with many members dying of Leigh Syndrome. Although the mtDNA carryover in some tissues may have been higher than one might have been expected, it is likely that it will remain below the threshold for manifestation of the disease with the MST thus providing an effective risk reduction strategy. The follow-up regime will help provide essential ‘first-in-man’ data for this promising technology”

 

Prof. Robin Lovell-Badge, Group Leader, The Francis Crick Institute, said:

“It is of course good news that the woman being treated was able to have an apparently healthy child with no signs of mitochondrial disease, but from the paper it seems that in many respects Zhang and colleagues were sailing very close to the wind and that luck played a large part in the outcome.

“Leaving aside all the issues of consent and legality, as outlined in the accompanying editorial and a recent article (https://academic.oup.com/jlb/article/3078927/Mitochondrial-replacement-techniques-and-Mexico-s), the details given, or often omitted, about the methods reveal further concerns. For example, to introduce the nuclear genome from the patient’s eggs into the enucleated donor eggs (with normal mitochondrial DNA) the Zhang team used electrofusion methods that were abandoned by other researchers because they gave a high frequency of abnormal embryos. We are told the electrofusion conditions used in this one set of attempts, but not how the authors arrived at these. Three out of the four embryos that developed to blastocyst stage were abnormal, but was this was because of the electrofusion methods or some other variable?  And what is the real reason why the authors rejected the more reliable, gentler methods used by others? The degree of carryover of abnormal mitochondria in the one normal embryo was considerably higher than that seen by other groups using the spindle transfer method (we do not even know the actual extent of carryover as Zhang et al did not determine the degree of heteroplasmy within the enucleated patient’s egg), and while probably OK, it is at a level that is of some concern.

“And in the end they only had one normal looking embryo that could be transferred into the patient. They were lucky that this was indeed normal and that it gave rise to a pregnancy. And they were lucky that the proportion of abnormal mitochondrial DNA remained relatively low in most tissues. The authors also argue that their policy was to transfer only male embryos because any females born would pass on mitochondria from the donor to their offspring. They can’t argue that this was following US guidelines, which they then flouted in other ways. But they only had one normal looking embryo and again they were lucky it was male. And what if it had been female, would they really not have transferred this?”

 

Prof. Darren Griffin, Professor of Genetics, University of Kent, said:

“This is an unusual publication in many ways.  First, the key selling point, that a child has been born by this procedure was announced in the lay press some months ago.  Often journals refuse to publish if something has already been reported in the press. To the best of my understanding the “point” of this particular manuscript is to publish the details of how it was done, rather than simply announcing the result.

“Second, there is a 3 page editorial criticising the work, pointing out its shortcomings but nonetheless ending with a positive message. The editorial is detailed in its criticism.  Without repeating the details, suffice to say that the issues that it raises are bound to be repeated. One could argue that the editors have been clever in being proactive in getting the criticisms in first.

“Finally it is one of those rare cases where both the scientific and legal details needed to be in place near simultaneously to make the treatment possible. The bigger picture however is that diseases such as Leigh Syndrome are severely debilitating for the affected children and devastating for the families involved. Having the ability to give hope to these families is incredibly important and no doubt the first of many treatments of its kind.”

 

Prof. Adam Balen, Chair of the British Fertility Society, says:

“The British Fertility Society welcomes new advances in the field of reproductive medicine, however, new technologies should be introduced with appropriate peer-reviewed publications. This particular case came to light through the media last year before the technological aspects were published. We very much welcome the full scientific details to enable the field of reproductive medicine to progress, and to help eliminate these genetic diseases, which can have devastating impact on families.

“In the UK, the treatment of mitochondrial disease was carefully considered after many years of scientific research and public consultation, approved by  the UK Government in 2015. The first license was awarded by the HFEA this month to the Newcastle Fertility Centre at Life which has pioneered these novel therapies.”

 

* ‘Live birth derived from oocyte spindle transfer to prevent mitochondrial disease’ by John Zhang et al. published in Reproductive BioMedicine Online on Monday 3rd April 2017. 

 

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/mitochondrial-dna/

 

 

Declared interests

Dr Dave Clancy: No conflict of interests to declare.

Prof Doug Turnbull: Prof Doug Turnbull receives funding from the Wellcome Trust for research into mitochondrial donation techniques and other research into mitochondrial disease. His other research is supported by MRC, BBSRC and NHIR.

Prof. Mary Herbert: M.Herbert is employed by Newcastle University as Professor of Reproductive Medicine based at Newcastle Fertility and Wellcome Trust Centre for Mitochondrial Research

Prof. Peter Braude: “Was a member of the HFEA expert panel considering the scientific methods to avoid mitochondrial disease, and formerly director of the Centre for Preimplantation Genetic Diagnosis at Guy’s Hospital.”

Prof. Robin Lovell-Badge: Robin Lovell-Badge is employed by the Francis Crick Institute where he works on some aspects of early mouse development and makes use of ES cells, but he has no conflicts of interest with respect to the study reported here.

Prof Darren Griffin: Prof Griffin is a Board Member of the Preimplantation Genetic Diagnosis International Society.

None others received.

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