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Science Alert: Experts Respond

UPDATED: World’s first ‘three-parent’ baby – Expert Reaction

Posted in Science Alert: Experts Respond on September 28th, 2016.

News broke overnight that a baby born in April was the result of a new technique using DNA from three people.

dna strandThe Jordanian parents contacted researchers at New York’s New Hope Fertility Center after discovering the mother had a rare mitochondrial disease – Leigh syndrome – which she had passed on to two children, both of whom died from the disease.

The method used – which took donor mitochondrial DNA and combined it with the mother’s nuclear DNA and the father’s sperm – is not approved in the United States, so the researchers went to Mexico.

The New Scientist broke the news, which has not been published or peer-reviewed. The researchers will present their work at a reproductive medicine conference in October.

The SMC gathered expert reaction to the announcement, feel free to use these comments in your reporting. Further details are on scimex.org.

Dr Mike King, lecturer, Bioethics Centre, University of Otago, comments:

“This is an impressive example of the power of reproductive medicine to benefit future parents and children at risk from severe mitochondrial disease. The care taken by the team to use a technique that was compatible with the ethical stance of the couple should also be applauded and is a good example of patient-centred medicine, in this respect. The weight of evidence suggests that the technique is not unsafe, but there are still concerns about possible risks arising from

“The weight of evidence suggests that the technique is not unsafe, but there are still concerns about possible risks arising from combination of donor mitochondrial DNA with the genomes of the parents, and with any remaining mitochondrial DNA with the mutation. Consequently, close monitoring of the child’s health will be crucial, not only for the child himself, but also to inform future use of the procedure. It should be hoped that the parents had adequate opportunity to consider all such information before consenting to the procedure.

“In New Zealand, the procedure is currently not permitted by guidelines issued by our Advisory Committee on Assisted Reproductive Technology (ACART), and may constitute genetic modification under the Human Assisted Reproductive Technology (HART) Act 2004, which would render the implantation of the resulting embryo prohibited by the Act. If the procedure is to be offered in New Zealand, this would require further consideration by ACART to develop guidelines for the procedure, and may require advice from ACART to the Minister of Health from ACART, and legislative change. It is also likely to require research to be conducted on viable embryos in New Zealand, which is currently not permitted.

“This lack of permission persists despite advice to the Minister of Health from ACART in 2007 that some viable embryo research be permitted in New Zealand, partly in order to ensure safety of reproductive procedures (Jones, 2014). It is important that permitted procedures are both ethical and safe, and it is also important that ethics and the law doesn’t unduly delay the availability of beneficial procedures for those who need them.”

 

Dr Lynsey Cree, senior lecturer, Department of Obstetrics and Gynaecology, University of Auckland, comments:

“It is extremely difficult to comment on this as the details provided in the conference abstract are brief. Whilst this may represent a really exciting advancement for patients with mitochondrial disease, this study has not been subjected to the rigorous scientific peer review process required for publication in a scientific journal. This has sadly meant that several questions remain unanswered.

“Interestingly 3 of the 4 embryos biopsied had abnormal numbers of chromosomes, which could either be due to chance or the manipulation process itself. Another important consideration is whether this is the team’s first attempt or whether all previous attempts have failed and therefore have not been reported.

“While this is a promising advancement it is vital that the ethical implications are considered and the techniques are appropriately regulated. Moving forwards it is also important to follow-up children born using these techniques to ensure that they remain healthy.

“Current New Zealand legislation prevents research on viable human embryos. Unfortunately, this means we cannot perform the necessary validation to be able to offer these techniques to New Zealand patients with these diseases.”

Our colleagues at the UK and Australian Science Media Centres also gathered the following comments.

Dr Ainsley Newson, Associate Professor of Bioethics, University of Sydney, comments:

“This couple’s decision to use mitochondrial replacement – after four miscarriages and the deaths of two children – is unlikely to have been taken lightly. They have also chosen to use maternal spindle transfer (MST) as it may lead to less embryo destruction than other forms of mitochondrial replacement.

“Ethical aspects of this technique, such as the cost of the technology and the value of having a genetically related child need to be weighed against the value for this couple. But, the manner of this particular case is disquieting. The treatment location seems to have been chosen due to there not being any regulations in place. This is in stark contrast to the UK, where specific regulation was developed after a lengthy process of scientific, legal and public engagement. There has also been less research into MST than other approaches, raising safety aspects.

“While research on some forms of mitochondrial replacement in Australia may be possible under licence, the format of our cloning laws means that performing MST in either a research or clinical setting would be illegal. Given advances in this area, Australia needs to look at how its laws can keep pace with fast-moving technologies like this one.”

Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London, comments:

“Without much ado it appears the first mitochondrial donation baby was born three months ago. This was an ice-breaker. The baby is reportedly healthy; hopefully, this will tame the more zealous critics, accelerate the field, and we will witness soon a birth of the first mitochondrial donation baby in the UK.

“But some questions remain.  By performing the treatment in Mexico, the team were not subject to the same stringent regulation as some other countries would insist on.  We have no way of knowing how skilful or prepared they were, and this may have been a risky thing to do.  On the other hand, we have what appears to be a healthy baby.  Because it was successful, fewer questions will be raised but it is important that we still ask them.

“Was this the first time ever they performed the technique or there were other attempts and they are reporting this one because it was successful?  This and other important questions remain unanswered because this work has not been published and the rest of the scientific community has been unable to examine it in detail.  It’s vital that that happens soon.

“So it appears to be a good end result.  But it risks encouraging others to follow the example, as we saw with ‘stem cell tourism’.  That could be dangerous as understandably impatient people pursue treatment in the very places where regulation is the least strict.”

Prof Doug Turnbull, Professor of Neurology, Newcastle University, comments:

“Mitochondrial donation is a technique that offers hope to mothers who carry mitochondrial DNA mutations. There have been extensive discussions in the UK to ensure that families with mitochondrial disease get the best possible advice about their reproductive options and that any new IVF based technique is appropriately regulated and funded. This abstract gives very little information about the technique used, the follow up of the child or the ethical approval process.”

Prof Justin St John, Professor and Director of the Centre for Genetic Diseases, Monash University, comments:

“It is very hard to comment as this is just a meeting abstract where all the important relevant information is not available.

“As this technology is controversial and a world first, I think the investigators should have submitted a manuscript for full peer review instead of announcing these outcomes in this manner. The review process would have ensured complete validation of the data and provided a tested platform from which to conduct a debate about the degree of achievement. As it now stands, there will be much conjecture. For example, there will be much discussion about whether sufficient tissues in the offspring were analyzed to draw reasonable conclusions about the low level of mtDNA mutation transmitted.

“Furthermore, as part of the peer review process, the genetic testing results would have undergone rigorous assessment and further analysis could have been requested to ensure no doubt existed. Until we know these outcomes, it is very difficult to comment.

“Nevertheless, if all the validations are sound, this represents a first for the treatment of some very serious disorders. However, extensive monitoring will be required as there has been limited testing of this technology in appropriate animal models.”

Dr David J Clancy, Lecturer, Lancaster University, comments:

“It is quite confronting to have the actual procedure reported for the first time in a human. It throws the range of ethical and practical issues into immediate and sharp relief.

“With MRT, the choice is between IVF by donor embryo vs. MRT to allow the mother to have a genetically related child. That is the benefit the procedure provides. In this case the procedure itself sounds little different to what would likely happen in the UK, except possibly the patient might have been offered IVF by donor embryo earlier, so might not have had the affected children who subsequently died. But we do not know the order in which her pregnancies and live births occurred, we do not know how the patient was recruited and we do not know the importance she attached to bearing a child who is related to her genetically.

“From the brief report it is not clear what the levels of disease mtDNA are in the various tissues of the offspring, although the average is relatively low, nor is it clear whether the +/-0.92% is standard deviation, standard error or a confidence interval, although we assume standard deviation.  This is important because we know that the procedure is not perfect, generally transmitting disease mtDNA at low levels as is the case here, and we now know that tissue-specific expansion of mutated mtDNA during development can occur (Naue, 2015) and so could cause disease if levels are high enough. Also, in MRT experiments in macaque monkeys, expansion of original maternal mtDNA from low levels in embryos to significantly higher levels in eggs has been documented, which would allow disease to again be transmitted, so we must expect the possibility in humans.

“It is therefore perhaps good that the baby is a boy, as was recommended by the US panel who considered but recommended against MRT, since a female child with the mutant mtDNA levels reported in this male baby could transmit the mutation upon becoming pregnant herself.

“While we should remain vigilant about this technique as new information and research accumulates, let us hope this child grows up and has a long healthy life.”

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