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 or 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.
Hi Paul,
Thanks for the clarification. There is a lot for the nonspecialist to learn. The Cytochalasin B data sheet blew my mind. (I guess that Dame Davies must take the position that “one mans poison is another womans spice of life”.)
I accept the fact that everyone has their bias but I fear that the political process is poorly suited to arriving at an informed-biased opinion. My reading of the situation is that the real responsibility for prudent action is being handed off to HFEA.
Your comment about (unknown) epigenetic changes is pertinent in several ways. Whatever it is that constitutes a person must have something to do with epigenetics, not just genetics. With this thought in mind, I now propose that 3-Person IVF be renamed 3Modified-Persons IVF… Imagine, offspring that are as akin to the soup in the test tube as they are to their putative parents. (I feel a movie script coming on.)
Paul,
You are clearly correct here. The Davies’ dismissive tone and logically inconsistent reply are a clear red flag.
Hi Junko,
I looked at your abstract (couldn’t get hold of the paper). It seems that the 3P-IVF methods that Dame Davies promotes can indeed cause heteroplasmy. If I understand you correctly, this would be because the genetic material is not cleanly transferred from one cell to the other???
In her letter
https://www.ipscell.com/wp-content/uploads/2015/02/Sally-Davies-Letter.pdf
Dame Davies seems to suggest that heteroplasmy is not a problem for humans. My understanding (as a layperson) is that Dame Davis is of the opinion that our species is “outbred” and therefore has the ability to deal with the full range of genetic variation that would result from imperfect transfer of genetic material from one human cell to another???
Is my understanding of the matter even close to reallity?
If I am right, Dame Davies is saying heteroplasmy happens but claims that it won’t matter for humans. If one was to drill down into the issue: would it be correct to say that evidence for/against this claim would be most fundamental to the entire debate that Paul is having?
Hey Brian,
Heteroplasmy is just one concern.
In that regard, Davies’ assertion that humans being outbred makes heteroplasmy not a problem is really just a hypothesis. I suppose the 3-person IVF experiments that will now proceed in the UK will test this theory, but if she and other proponents are wrong, it could be a disaster.
Junko raised two other concerns with (1) the use of Sendai virus or electroporation for fusion and (2) the drug cytochalasin B.
Cytochalasin B is a really potent drug with various toxicities including potential for reproductive harm (https://www.caymanchem.com/msdss/11328m.pdf).
These factors together with enucleation (very harsh on oocytes) and nuclear or spindle transfer taken together clearly damage cells and it seems there’s risk of chromosomal damage.
Given the ability of the oocyte cytoplasm in SCNT to reprogram somatic nuclei, it seems certain that transfer of the nucleus/DNA of one woman’s oocyte to the enucleated oocyte of another woman will cause some degree of epigenetic changes after transfer. This could be hugely important, but it’s pretty much a black box at this point.
Paul
I agree that more extensive data from additional animal studies is needed.
I have one publication regarding nuclear transfer procedures and I would just like to share my points-of-view regarding the possible approval of the procedures related to mitochondrial transfer in the U.K. In my view, it is too early for the approval due to the following reasons:
First of all, both procedures, spindle transfer and 2PN transfer, require the medium containing “cytochalasin B” to avoid lysis of the cytoplasm when they are enucleated. However, there is no data to show that the usage of cytochalasin B is safe. Furthermore both procedures need to use electrical fusion or Sendai virus to fuse enucleated spindle or 2PN, which could be a very harmful procedure.
As long as I feel that there is a better option (mentioned in my publication http://www.sciencedirect.com/science/article/pii/S1472648313005774, but still a work in progress) aside from the currently dicey procedures, they could do further research on the procedure, instead of jumping the gun and hastily implementing a potentially dangerous method that could lead to abnormal babies.
As a scientist in the same field, I share the same passion and tenacity as that of other scientists in pursuing this method and assist patients who suffer from mitochondrial diseases who would like to have healthier babies. However, I feel that we have to be more prudent, have more foresight and avoid hasty decisions, until we have confirmed results that they are safe treatments for humans.
Great points, Junko.
Paul, please keep right on being the voice of reason here!! I agree– it would be so amazing if this technology works out, but there are indeed red flags here, and not only in a strictly scientific sense. And I think I’ll leave it there… but we need to keep hearing skeptical voices on this issue.
Thanks, Cathy. Sometimes being the contrarian one is very difficult, but this issue is a big one.
Hi Paul,
I recall one of your readers pointing out that cats would be a better animal model than non-human primates. So perhaps Dame Davies is correct about the use of non-human primates being pointless and therefore “unethical” — whilst, by the same token, further experiments on other types of animals (eg cats) might be “useful” and perhaps “ethical”.
Disclosure of ethical bias: I’m a dog guy.