Mitochondrial Replacement Techniques, the Mexican Case

cesar-palacios-gonzalezBy César Palacios-Gonzalez 

Earlier this week New Scientist broke the news that the first baby born after Maternal Spindle Transfer is already five months old, and even more, he seems to be doing well. Even when John Zhang’s team has achieved a world first, I agree with Dr. Alison Murdoch in that: “The translation of mitochondrial donation to a clinical procedure is not a race but a goal to be achieved with caution to ensure both safety and reproducibility”.

At the moment there is very little information regarding how all this went down, science wise, and for sure this instalment of the Scientific Congress of the American Society for Reproductive Medicine is going to be a really interesting one (I wonder if there will be any bioethicists around). A particularly salient feature of this news is that John Zhang’s team did not carry out the procedure in the US, but they went to México because, as Zhang is quoted saying, “there are no rules” in Mexico. I found such a quote really troubling, even if it was taken out of context, because amendments concerning assisted reproduction to the Mexican National Health Law are being discussed at the moment. As someone who works in the ethics of mitochondrial replacement techniques, and that was born and raised in Mexico, this whole story particularly worried me. The timing of the news could not have been worse for all those people in Mexico trying to get a scientifically informed and liberal amendment to the current National Health Law (yesterday I talked to some very distraught colleagues based in Mexico). It is surprising that this fact about the Mexican regulatory landscape was not taken into account by the New Scientist feature, and it is even more surprising that no news article or think piece has talked about it yet. Now, the amendment that at the moment seems to have the best chance of being approved is not only really conservative and discriminatory, as I have said here, but it is so poorly written that it interferes with other scientific areas. For example, it completely halts chimera research and human embryo research. The NIH moratorium on chimera research pales in comparison with this amendment. It truly seems as if it had been forged in the Vatican.

It is true that Zhang’s team did not break any laws, but it I think that, for practical purposes, there is an important difference between carrying out experimental techniques in places without regulations that are moving towards having them, and carrying them out in places with intentionally lax regulations. Why? Because making such a ‘stunt’ in a place where regulations are being discussed, and where there is no public debate regarding the technique employed, can have an adverse effect in assisted reproduction as a whole. For example, the technique used by Zhang’s team has already been wrongly portrayed in the media and this has fuelled anti-ARTs sentiment. You would be appalled by the inaccuracies and mistakes in Mexican news reporting on this issue (although it must be said that there have also been inaccuracies and mistakes in how it has been reported in the US and UK). It is as if the whole Dolly the sheep PR meltdown did not teach us anything. For the time being, Mexico fits in the category of “country moving towards having ARTs regulation”, and in a couple of days I will be able to tell you if there will be no more ‘three person babies’ in Mexico for a considerable time.

Finally, I also think that it is problematic that there has been an erasure of the woman who donated the egg from most, if not all, the news and think pieces. While it has been said once and again that the intending mother egg’s maternal spindle was rehoused in a healthy enucleated egg, nothing has been said about the donor. It is appalling to see that there has been no mention of just how important she was for this procedure to occur. In addition to this, we do not know if she donated the egg in Mexico, or if the donation took place in the US. Even when Zhang’s team has stated that they had IRB approval, it is important to remember that there are serious ethical questions that arise from egg donation that need to be answered (which I suppose will be answered at the conference?). Specially when all this is carried out in place where there are no specific regulations in place.

César Palacios-Gonzalez is a Research Associate at the Centre of Medical Law and Ethics, The Dickson Poon School of Law, King’s College London.

You can find more on the ethics of mitochondrial replacement techniques here: https://www.reproductivedonation.com

First 3-person IVF baby born via “rogue” experiment at Mexico clinic?

Today we got the first report of a baby being born via so-called “3-person IVF”, sometimes called 3-parent IVF, in which the DNA of three people contribute to an offspring.

Before discussing this further I have to emphasize that we need proof that this is indeed really a 3-person IVF baby via genetic testing. Until that data is released publicly we should all be cautious on this news. Apparently the clinic plans to present such data later.

Assuming it is a 3-person IVF baby, which seems most likely, I discuss the key issues below.

For the 3-person IVF baby, it is hoped to be free of mitochondrial disease (the whole point of doing the procedure), but there are serious risks here. The doctor doing this experiment was John Zhang of New York University and New Hope Fertility Center, but he did it in Mexico.

john-zhang-with-3-person-ivf-baby

John Zhang holds the baby; New Scientist picture

I’m deeply concerned by this news.

The fact that Zhang went to a place where he reportedly himself said, “there are no rules”, to do this illustrates that this 3-person IVF procedure was not given proper regulatory and ethical oversight. It feels more like it was done in secret.

Marcy Darnovsky, Executive Director of The Center for Genetics and Society referred to this kind of thing as “rogue experimentation” in a press release. In a sense she’s right about this, in particular because the world’s experts are really still trying to sort out the core issues surrounding this kind of technology. It is an understatement to say this was jumping the gun. 3-person IVF is not permitted in the US due to safety concerns.

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Stem cell predictions top 20 list for 2016

Stem Cell PredictionsWhat will the new year have in store for stem cells?

2016 promises to have many striking stem cell developments. Below are my top 20 stem cell predictions for what is to come this year in no particular order. Share your stem cell tea leaves in the comments please.

  1. Another stem cell biotech acquisition by pharma (recall Ocata (almost now finally sold) & CDI in 2015).
  2. Charging patients for clinical trial participation, particularly in Japan due to the new policy and here in the US related to predatory clinics, remains a hot topic
  3. Stem cell clinics and doping in sports flares up more
  4. Organoids continue to excite
  5. Bioheart and some other small stem cell companies struggle
  6. Stem cell stocks overall have a bad year
  7. Stem cell clinics ever more aggressively use celeb clients for PR and marketing Why? It is powerful, effective, and essentially free advertising
  8. More news on human-animal chimeras
  9. FDA continues its slow-go approach to action on stem cell clinics/unapproved stem cell products
  10. Pressure from industry and some academics on FDA to not regulate adipose products as drugs and/or to not enforce some other draft guidances including at the upcoming public hearing on the draft guidances
  11. FDA receives increasing public criticism for “slowness” on approving new stem cell therapies including from beyond the stem cell clinic industry
  12. One or more lawsuits against a stem cell clinic
  13. A new stem cell scandal pops up related to publication issues
  14. Some hiccups on mitochondrial transfer/3-person IVF in the UK or China
  15. The trend last year of increasingly blurred lines between legit research entities such as universities and dubious stem cell enterprises continues. This is worrisome.
  16. Stem cell-derived human germ cells stay in the headlines. This has exciting potential for providing new windows into human development and tackling infertility, but also raises thorny issues such as human genetic modification
  17. ViaCyte has some big news
  18. High-profile developments on veterinary use of stem cells
  19. Animal cloning, particularly in China, continues to proliferate
  20. More rumblings on possible human reproductive cloning attempts

Disclaimer: This post is not meant as financial advice. Consult an expert before making financial decisions.

Views on Izpisua Belmonte Cell Paper on Gene Editing for Mitochondrial Disease

mtDNA edit paper abstractJuan Carlos Izpisua Belmonte’s group published a Cell paper today on using gene editing to reverse mutations associated with human mitochondrial disease.

The paper is Reddy, et al. and is entitled, “Selective Elimination of Mitochondrial Mutations in the Germline by Genome Editing”.

The authors report success using TALEN-based gene editing or mitochondrial-direct restriction enzyme (mito-ApaLI) to reduce the burden of mutant mitochondrial DNA (mtDNA).

Their work was done primarily in mice, but also using chimeras made with murine oocytes fused with human cells bearing mitochondrial mutations.

They sum up their work in this way:

“Using mitochondria-targeted nucleases, mtDNA mutations are specifically eliminated in the germline to prevent their transgenerational transmission. This strategy represents a potential therapeutic avenue for treating human mitochondrial disease.”

The graphical abstract is above.

I am of two minds about this paper.

On the one hand, I think technically it is intriguing that they could take a gene editing approach to mitochondrial mutations, but on the other hand the notion that this approach could be safely and effectively used clinically in a human context in the germline as a way to prevent mitochondrial disease is somewhat concerning. This also resonates more strongly because of yesterday’s report out of China of gene editing using CRISPR of human embryos.

There is a growing trend of scientists heading the direction of human genetic modification.

Could it be safe?

What would be the ethical considerations?

Focusing first on the technical side of this new paper, the data look convincing to me after a quick read. One model was heteroplasmic mice (NZB/BALB) that contain two distinct mtDNA mutation types. In this model they were able via gene editing-based targeting one of the two mutation types (BALB) to introduce “heteroplasmic shift” demonstrating reduced abundance of the mutation. They have published this kind of work in the past on somatic cells and others have shown the same so I suppose that makes this work a bit less novel.Reddy, et al. Figure 6B

They did most of the work with mito-ApaLI targeting a unique cutting site in BALB. The gene edited one-cell embryo was also able to produce healthy mice (Figs. 3-4), but one caveat there is that it wasn’t clear to me from the paper and a quick Google search whether the NZB/BALB heteroplasmic mice normally have any phenotype due to the mitochondrial mutations or not. I suppose at least the gene editing did not seem to affect normal development.

The other model system here (Fig. 6) was the fusion of mouse oocytes with human cells (see Fig. 6B) containing mtDNA mutations. Using mito-TALEN technology they could again observe a heteroplasmic shift in this context as well. Depending on the human mtDNA mutation that was target, the efficiency of the gene editing to remove the mutant form ranged from a modest just over two-fold (NARP) to an impressive near complete elimination (LHOND).

What about potential off-target effects?

They reported that CGH (Figure S3C) and exomic sequencing (I believe this was not shown) did not indicate significant off-target effects. I would have liked to have seen more data on this however. It’s difficult to imagine no off-target effects were created and if true that’d be great, but it seems like they should have shown more data on this.

Shifting now to the bigger picture, what about possible clinical application of this technology in humans?

The authors are fairly gung-ho about the translational potential of their approach in humans, especially relative to so-called “3-person IVF” or “mitochondrial transfer” technology, recently approved for human use in the UK, but not permitted in the US:

“Mitochondrial replacement techniques involve a series of complex technical manipulations of nuclear genome between patient and donor oocytes that will result in the generation of embryos carrying genetic material from three different origins. For these reasons, mitochondrial replacement techniques have raised some biological, medical, and ethical concerns (Hayden, 2013; Reinhardt et al., 2013). Despite their great potential, more studies are still required to show that these techniques are safe in human oocytes. The approach presented here relies on a single injection of mRNA into patient oocytes, which is technically simpler and less traumatic to the oocyte compared to mitochondrial replacement techniques (Craven et al., 2010; Paull et al., 2013; Tachibana et al., 2013; Wang et al., 2014). Importantly, it does not require healthy donor oocytes, thus avoiding ethical issues related to the presence of donor mtDNA.”

The idea that a gene editing approach to mitochondrial disease in humans could be superior to the so-called “3-person IVF” or “mitochondrial transfer” approach to mitochondrial disease is kind of provocative. The Scientist provides a quote suggestive of a possible tension between gene editing and “mitochondrial replacement” approaches to mitochondrial disease prevention:

“While mitochondrial replacement advocate Doug Turnbull of Newcastle University, U.K., praised this latest advance in an e-mail as “elegant and exciting,” he cautioned that the technique “may be of limited value for those women whose oocytes have either large amounts of mutated mitochondrial DNA or all mutated mitochondrial DNA.”

Some dispute the notion that alteration of the mitochondrial genome is a “genetic modification”, but frankly I think that kind of argument is more political that scientific. I don’t buy it. We would be talking about genetically modified human beings whether with 3-person IVF or the gene editing approach described in this new paper.

For many families facing mitochondrial disease and wanting to have a genetically related baby, a better and far safer approach is preimplantation genetic diagnosis (PGD), although admittedly that is not an option for 100% of families.

It is also notable that multiple groups and I myself on this blog have called for restrictions on clinical application of gene editing technology in humans.

Clearly there is a lot more to learn. Great care should be exercised in discussion of potential human clinical applications of human germline modifications from this kind of research.

From Nature News, it seems that despite ethical concerns, researchers want to forge ahead into human embryos and ultimately the clinic with gene editing:

“Nevertheless, Ocampo and Izpisua Belmonte say that they are in the process of acquiring discarded human eggs and embryos from a fertility clinic in California, and waiting for approval from an ethics board. They plan to develop a line of stem cells from these modified cells, but say that they will not implant embryos into mothers or allow them to grow.”

Are we really ready?

Red flags in Sally Davies letter on 3-person IVF mitochondrial transfer

There’s been some back and forth between me and some members of the UK Parliament and others in the UK on the issue of mitochondrial transfer 3-person IVF technology.

Some of this has involved the UK equivalent of the Surgeon General, Professor Dame Sally Davies, who at one point apparently called my views “bunk”. I wrote back to her via Lord Alton articulating my concerns and respectfully responding to the bunk allegation.

I am not opposed in principle to mitochondrial transfer technology, but rather from an impartial scientific and factual perspective it is clear to me that far more data from additional animal studies is needed. At some point with any experimental biotechnology intended for human use scientists and doctors have to take the plunge and try it in humans, but my view is that the animal data supporting mitochondrial transfer is incomplete at best.

Now I just recently indirectly received a letter from Davies, which seemed intended to rebut my concerns. I found some things about the letter to be surprising and in some cases to be red flags.

With all due respect, Davies seems to have a dismissive attitude toward those who disagree with her on the urgency for human mitochondrial transfer to proceed as soon as possible. This is evident in a newspaper article she wrote and also in this letter. You can see it without having to read between the lines in her word choices to describe the press and opponents of the immediate approval of the technology: ‘overly simplistic’, ‘sensationalist’, ‘unsophisticated’.

The most surprising element of her letter in reply to my concerns was her argument against a need for additional animal research and data.

It seems she and other proponents of this technology moving forward immediately have a tendency to pick and choose whether to value animal data depending on whether it supports their case or not. In this passage, they are fans of animal data, which they view as fairly definitive:

“The view of the Expert Panel was that experiments involving Pro-nuclear Transfer (PNT) and Maternal Spindle Transfer (MST) in animals (mice, macaques, and some other animals) have not given any cause for concern.”

So on the one hand she and others advocating immediate approval of this technology have asserted that mitochondrial transfer would be safe for humans based essentially entirely on animal studies including the non-human primate work of Mitalipov.

On the other hand, she goes on to argue that additional work of that kind would be bad:

“The use of non-human primate experiments was deemed by the Expert Panel, in its 2013 and 2014 reports, to no longer be necessary given the differences between non-human primate and human eggs / early embryos. Performing such unnecessary animal experiments would indeed be unethical given that non-human primates were not considered a good model for the human in this context.”

It sure seems like a self-contradictory argument, right?

I find the use of the word ‘unethical’ to be strikingly strong.

It is notable that in the past, if memory serves, the Expert Panel did feel that more data was needed (and that data is still not available), but it’s not clear what changed their minds.

Remarkably, then in a nutshell what she seems to be saying is that the only ethical thing to do since animal models are imperfect–except of course the specific past ones that we feel supported safety–is to experiment on humans and do it now.

That is more ethical?

This all sounds a lot more like politics than biomedical science. I say, let’s focus on the data and not the politics, but I’m not holding my breath.