Open letter to UK Parliament: avoid historic mistake on rushing 3-parent technology

Dear UK Parliament and Science and Technology Committee,

I am writing to you about your deliberations on “mitochondrial donation” (also known as 3-parent technology) intended for the purpose of preventing heritable mitochondrial disorders. I am concerned about the Department of Health’s recent draft regulations that would allow 3-parent experiments to go forward and the possibility that the UK Parliament may vote to allow it.

This experimental technology has a noble goal, but in my opinion there are too many unanswered questions and risks that remain to allow it to proceed at this time. In fact, I believe that moving forward with it would most likely be a tragic mistake for the UK.

Who am I and why do I oppose this technology?

I am a stem cell and developmental biology researcher who is an Associate Professor at UC Davis School of Medicine. Here I speak for myself and not my institution. I have no personal or professional stake in whether this 3-parent technology proceeds or not. In fact, if anything my publicly opposing this technology poses possible downsides to me because some colleagues in my field are strong advocates of the technology. My lab conducts embryonic and induced pluripotent stem cell research in addition to our cancer studies and I’m a supporter of IVF as a means for infertile couples to have children. Therefore, I am not some kind of radical extremist or luddite, but rather a concerned scientist with what I feel are rather logical, common sense concerns about mitochondrial transfer technology and the heritable human genetic modification that it always would produce.

While a recent FDA hearing by an advisory Committee here in the US took what I view as an appropriately cautious approach to 3-parent technology, I am concerned that the UK may soon approve this technology without first seeing evidence that the potential risks and problems have been addressed successfully in concrete ways. I would respectfully ask, “what’s the rush?”

The FDA hearing articulated numerous unresolved concerns and the FDA Committee Chair, Dr. Evan Snyder, concluded “I think there was a sense of the committee that at this particular point in time, there was probably not enough data either in animals or in vitro to conclusively move on to human trials.” [1]

Of course the UK could take a different path than the US and the rest of the world. And it is certainly attractive to be an innovator in the biomedical field. But is it really in the interests of the UK to go out on this particularly high-risk limb all alone? Have the problematic issues raised at the US FDA hearing including by concerned scientists been addressed by the UK or elsewhere? The evidence strongly indicates the answer is “no” to these questions. The UK and the specific leaders making this decision, should they rush forward on this, could well find themselves on the wrong side of history on this one with horrible consequences.

What are the concerns?

There are numerous serious risks associated with this technology. These include most notably the possibility that developmentally disabled or deceased babies will be produced. As an objective scientist, I believe the odds of this happening are at least equal to the chance that this technology will succeed in preventing mitochondrial disorders. In fact, there are precedents that would suggest that negative outcomes are reasonably likely.

In the 1990s, fertility clinics in the US, China, and elsewhere performed human reproductive procedures similar to what is being proposed now [2-6]. While the goal in those experiments was to simply create babies for infertile couples and not specifically to deal with mitochondrial disorders, the technologies employed are largely alike. In fact, these 1990s procedures were far simpler and less invasive (they only involved transfer of some oocyte cytoplasm) than what is being proposed now with mitochondrial therapies where an entire nucleus or set of chromatin is moved from one cell to another, where an entire nucleus has also been removed.

The end result from these human reproductive experiments in the 1990s was a mixture of outcomes including not only seemingly healthy children (thank goodness), but also miscarriages, a child with severe developmental disability, and chromosomal aberrations. These are very real, concerning possible outcomes for the proposed human mitochondrial transfer technology today and in the future should it be allowed to proceed.

Animal studies have yielded variable outcomes including some concerning results. Although today’s mitochondrial transfer technology may be relatively improved, there is no clear evidence that these kinds of potential negative outcomes in humans could most often be avoided with new technology.

Scientists around the world have identified several more specific risky elements to the proposed experiments including, but not limited to:

• epigenetic harm caused by nuclear transfer, etc. (as I myself discussed)
• mito-nuclear mismatch (Reinhardt, et al.)
• impact of mitochondria on traits i.e. not just metabolic function (Dowling, also New Scientist here and here)
• preferential replication of even tiny amounts of carryover mutated mtDNA (Burgstaller, et al.)

What are the alternatives? Preimplantation genetic diagnosis (PGD) is a powerful technology that can help many (although admittedly not all) families dealing with this situation in an effective manner.

Proponents of 3-parent technology have adopted several, nonscientific, non-medically-based tactics to attempt to minimize concerns about it such as those I articulated above.

For example, the proponents claim incorrectly that “mitochondrial donation” is not human genetic modification. It is in fact genetic modification. Notably, the first team to ever make this kind of technology work unambiguously stated in their paper [7] that it was genetic modification:

“This report is the first case of human germline genetic modification resulting in normal healthy children.”

The proponents of 3-parent technology also incorrectly claim that the concerns about it or risks associated with it are just hypothetical, although in reality the concerns based on past experiences discussed earlier are quite concrete and real.

Proponents also might be overly optimistic about the chances that the technology will frequently prevent mitochondrial disorders in humans.

A scientific reality often passed over in this discussion is that while mitochondria have been studied for decades, the field of studying the mitochondrial genome is in its infancy and is far too new to support a major human intervention that involves the mitochondrial genome. The interactions between the mitochondrial genome and the nuclear genome are also only poorly understood today. It would be rash and premature to proceed with human mitochondrial transfer now given how primitive our knowledge is in this area at this time.

Even if hypothetically this technology might help avoid some people from having mitochondrial disorders (and that’s a big if), the bottom line is that there is an equal or arguably greater chance that it will tragically produce very ill or deceased babies.

Overall, the UK would most likely be making an historic mistake by allowing 3-parent technology to proceed in the near future. Please wait on this critical decision for the additional information needed to make a wise choice in the long run.

Sincerely,

Paul Knoepfler, Ph.D.

References

• 1. http://www.npr.org/blogs/health/2014/02/26/283022514/scientists-question-safety-of-genetically-altering-human-eggs
• 2. http://www.nytimes.com/2001/05/05/health/05DNA.html?module=Search&mabReward=relbias%3Ar%2C%7B%221%22%3A%22RI%3A11%22%7D 
• 3. http://www.bbc.com/news/magazine-28986843
• 4. http://www.nature.com/news/reproductive-medicine-the-power-of-three-1.15253?WT.mc_id=TWT_NatureNews
• 5. http://www.nature.com/news/2003/031014/full/news031013-4.html
• 6. http://www.sciencedirect.com/science/article/pii/S0015028203019538
• 7. http://humrep.oxfordjournals.org/content/16/3/513.full.pdf