UK Researchers Now Say Three-Person Embryo Technique Doesn’t Work; Propose New Method

Cross-posted with Biopolitical Times on June 8th, 2016.

In February 2015, the UK decided to create a controversial exception to its law against any form of human germline modification to allow the creation of “three-person embryos” to prevent the transmission of some mitochondrial disease. Then and now, unresolved scientific concerns remained, and many people have been waiting to see whether the science will indeed come through.

Adding to anxiety to see these data is the enormous global attention on a different technology proposed for human genetic modification: the gene editing technique CRISPR, and current controversy over varied attempts to try it on human embryos.

However, there is only one central place where the mitochondrial research is being carried out in the UK – the Wellcome Trust Centre for Mitochondrial Research at Newcastle University. But despite opening its doors in 2012 and encouraging excitement about the importance of  this research, none of the specific research requested by the Human Fertilisation and Embryology Authority (HFEA) had been published until now.

Today, that changed. Well-known Newcastle researchers including Mary Herbert and Douglass Turnbull have just published an update to their six-year-old Nature paper, which originally described how their preferred form of mitochondrial replacement – pronuclear transfer (PNT) – “has the potential to prevent the transmission of mtDNA disease in humans.”

Shockingly, their new paper reports that the proof-of-concept studies upon which everyone had been basing their enthusiasm “were not well tolerated by normally fertilized zygotes.”

In other words, the scientific basis for the controversial UK law and HFEA policy change turns out to have been unfounded. It did not work.

The researchers were able to develop an alternative method however, which may still justify the technique as a potential method to reduce the transmission of mitochondrial disease from mother to child. Their new paper (behind a paywall) is optimistically titled, “Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease.”

Initial media coverage has run with this alternative ePNT and downplayed the additional concerns raised by the new research

Three-person babies IVF technique ‘safe’ [BBC]
UK scientists find new 3-parent IVF technique safe in lab tests[Reuters]
‘Three-parent baby’ success could see trials in two years [New Scientist]

This overly positive characterization is perhaps understandable given the small but eager group of patients who wish to use this technology to decrease the chances of passing on mitochondrial disease to their offspring.

Yet as of this writing, only The Telegraph is giving weight to the range of unknowns still at play:

‘Three parent baby’ technique could still pass on mutated DNA, study shows

A more cynical headline for this news may be:

Scientists effectively distract press and public from the dangers inherent to the controversial technique they promised wasn’t unsafe by introducing a new technique promised not to be unsafe.

The new paper describes the alternative method as early PNT or ePNT because the researchers found it works better to transplant the pronuclei from one embryo into another immediately after meiosis rather than right before the first mitotic division. In 79% of the resulting embryos, less than 2% of the unhealthy mitochondria of the first embryo had transferred over to the new embryo, which might be enough to help a child avoid symptoms of mitochondrial disease. On the other hand, it might not. In decidedly less confident language than has often been used up to this point, the researchers conclude, “PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.”

Part of the reason for this caution is because of a Cell Stem Cell paper published just days earlier by US researchers including Dieter Egli called “Genetic Drift Can Compromise Mitochondrial Replacement by Nuclear Transfer in Human Oocytes.” This paper highlights their findings that even small amounts of carryover mitochondria can cause “genetic drift,” which can “lead to the restoration of the original donor mitochondrial genotype” and undercut any positive outcome from the technique. They suggest “although vertical inheritance of mtDNA is not required, it is critical to ensure inheritance of a single maternal mtDNA lineage.”

This paper led to Nature saying “Three-person embryos may fail to vanquish mutant mitochondria,” and stem cell scientist Paul Knoepfler declaring, “The data in it also in my view strongly make the case for now there should be no human clinical efforts using 3-person IVF for the foreseeable future.” Knoepfler also contributed a helpful headline to the coverage today: New Herbert lab Nature paper reinforces mitochondrial replacement Achilles heel.

As in 2010 when Turnbull and Herbert first published research using PNT in nonviable embryos, the conclusions from these recent data is still “we’re working on it” not “this is safe.” Such data support previous warnings from scientists, and the fact that we are still unsure about the extent of the role of mitochondria in the overall functioning of our bodies.

So, what’s the moral of the story? Perhaps that humility is the best path forward if we are ever to seriously contemplate bringing new lives into the world this way. And maybe also that policymakers should not be so easily won over by over-zealous promises of science not yet confirmed.

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