Dear UK Parliament and Science
and Technology Committee,
I am writing to you about your
deliberations on 'mitochondrial donation' (also known as three-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 three-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
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 three-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
While a recent FDA hearing by an
advisory committee here in the US took what I view as an appropriately cautious
approach to three-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.'
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 to these questions is 'no'. 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
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 [1-5]. 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
Proponents of three-parent
technology have adopted several, nonscientific, non-medically-based tactics to
attempt to minimise 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 that it was genetic
modification: 'This report is the first case of human germline
genetic modification resulting in normal healthy children.'
The proponents of three-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
Overall, the UK would most
likely be making an historic mistake by allowing three-parent technology to
proceed in the near future. Please wait on this critical decision for the
additional information needed to make wise choice in the long run.
Paul Knoepfler, Ph.D.
This letter was first published on the Knoepfler Lab Stem Cell Blog: http://www.ipscell.com/2014/11/open-letter-to-uk-parliament-avoid-historic-mistake-on-rushing-human-genetic-modification/