July 10, 2020

The Niche

Knoepfler lab stem cell blog

UK should freeze mitochondrial replacement as Egli paper ID’s serious problem

An important new Cell Stem Cell paper from Dieter Egli’s lab points to an inherent, serious problem with so-called 3-person IVF or mitochondrial replacement technology that warrants putting an immediate hold on all efforts to use it in humans. I have pasted the graphical abstract from the paper below.

Egli genetic drift paper
Graphical Abstract, Cell Stem Cell

For years a few of us scientists and policy groups have argued strongly that this experimental technology is far too risky to try in humans for reproductive efforts in the near future. There were simply not enough data to support the reasonable expectation that the technique would be safe and effective to use to create new children. I felt so strongly I wrote an open letter to the UK Parliament suggesting that they not proceed and this led to a bit of a kerfuffle.

The UK leadership approved the clinical use of 3-person IVF, which was a bold, but highly risky decision.  I believe the UK is now going to have to step back and authorities there should now freeze all clinical efforts at 3-person IVF/mitochondrial transfer for the time being because of seriousness of this new paper’s findings.

What concerns me specifically?

One of the big potential issues about 3-person IVF raised by those of us who earlier argued for more time and more data before pulling that regulatory approval trigger to proceed with use in humans is that the nuclear transfer from the mom-to-be’s egg into the donor’s enucleated egg would bring some diseased mitochondria with it and those faulty mitochondria could amplify. The new paper from Egli’s lab proves that this kind of thing can happen. It suggests that in some cases this troublesome phenomenon is likely to occur after 3-person IVF and in my view this is likely to lead to health consequences for the future offspring.

While preventing mitochondrial disease is a noble goal and in theory mitochondrial replacement might work as a fix, if a technique could itself directly cause serious health problems or death then that is too big a risk. Isn’t it? There has been so much pro rhetoric on how mitochondrial replacement therapy is “definitely ready” that sometimes one must focus on the data.

For more on this new paper I recommend an article by Ewen Callaway at Nature News, one by Tina Saey at Science News and a piece over at Science by Kelly Servick.

Servick points to some central issues and unknowns raised by the new paper:

“Having all one population of mitochondria or the other didn’t seem to make a cell more competitive or healthy, Egli notes, so the competition seems to play out within cells, not between them. What gives some mitochondrial DNA copies the advantage in this microscopic battle isn’t clear. And the battle may play out very differently in a developing embryo carrying mutant DNA than it did in these dishes of repeatedly cultured cell lines with only healthy DNA, experts warn.”

There seems to be no ready solution to this “drift” problem after mitochondrial replacement  other than improving the nuclear transfer-type technology (another version is called spindle transfer) to the point where there are effectively no diseased mitochondria that slip through in the beginning. However that may not be something that can be readily achieved. Further, this is a catch-22 kind of situation since if researchers proceed with making 3-person IVF babies in real world experiments then they probably will not know how effectively they got rid of the diseased mitochondria until too late when there is already a baby in the picture.

Perhaps not surprisingly, one of the UK scientists pursuing 3-person IVF is quoted in Callaway’s piece at least indirectly taking issue with Egli’s paper at least relative to her own work:

“Mary Herbert, a reproductive biologist at the University of Newcastle, UK, who is part of a team pursuing mitochondrial replacement, says that mitochondria behave very differently in embryonic stem cells compared to normal human development. Levels of mutant mitochondria can fluctuate wildly in stem cells. “They are peculiar cells, and they seem to be a law unto themselves,” she says, calling the biological relevance of the latest report “questionable”. She thinks that data from embryos cultured for nearly two weeks in the laboratory will provide more useful information than Egli’s stem cell studies.”

Hmm, I’m not so sure anyone can really know that mitochondria would behave better in embryos versus stem cells. They could actually behave less well for all we know.

Also from the same Callaway piece are some cautionary words related to how the UK agency HFEA is proceeding:

“An HFEA spokesperson says that the agency is waiting for further experiments on the safety and efficacy of mitochondrial replacement (including data from Herbert’s team) before approving what could be the world’s first mitochondrial replacement in humans.”

My take home message overall is that this paper is a big deal and it points to how little is really known about what happens after nuclear transfer, in particular to mitochondria. 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.

I hope that HFEA will soberly review the Egli data and all other relevant data. Note that the U.S. FDA has not approved 3-person IVF and the National Academy of Sciences (NAS) here in the U.S. recently issued a prudent and much more precautionary report on this technology as compared to the current UK policy. Some have incorrectly interpreted the US NAS report as giving recommending that the FDA approve 3-person IVF, but in fact the NAS committee listed some strict mandatory criteria before such efforts should proceed.

Kudos to the Egli lab for this paper (which by the way has a lot more other interesting data too than I have covered here in this initial post) and other important publications they have had recently that rigorously address what really happens with human nuclear transfer technologies. Also, you may want to check out my earlier interview with Dieter Egli here.

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