Top 10 myths about 3-person IVF mitochondrial transfer

It’s been somewhat of a helter-skelter time for the new technology often referred to as 3-person IVF or mitochondrial transfer as the UK considers whether to legalize this experimental technology for use in humans.

I believe that this technology is not ready now for use in humans and for more background on why as well as other opinions you can see articles here.

The admirable goal of this experimental 3-person IVF approach is to prevent transmission of mitochondrial diseases from mother to child, but it raises many complicated scientific and ethical questions. Like advocates of the use of this technology in humans, I too want to see new options for people with mitochondrial diseases to be able to have healthy families, but unfortunately this technology although well-intentioned could int reality end up doing far more harm than good, especially if implemented too soon.

The two main methods proposed for this technology are outlined in images from the UK HFEA.

3-person IVF

Unfortunately in the fray, some myths have popped up that we now often see quoted in newspaper articles as facts.

Here are what I believe are the top myths or inaccuracies that have arisen and the facts that counter them.

Myth: This technology would cure mitochondrial diseases. Fact: The technology, even if proven successful and that’s a big ‘if’, would prevent some children from being born with mitochondrial diseases. It would not treat or cure them.

Myth: This technology has been conclusively proven safe in animals and would definitely produce healthy babies. Fact: Animal studies are mixed as to whether this approach is safe. Some that are limited in scope are encouraging, while others have raised serious warnings. More studies, particularly in primates, would be needed for a conclusive determination. As this technology is highly experimental it is unknown if the human babies produced would be healthy. In fact, it might put them at risk.

Myth: This technology would only be used for treating mitochondrial disease. Fact: One of the leading advocates of this technology in the US, Dr. Shoukhrat Mitalipov, has already asked the US FDA to approve this technology for treating infertility as well. Therefore, in addition to mitochondrial diseases this technology could well be used for infertility as well as for other purposes that even today’s backers might find not so clear-cut from a bioethical perspective.

Myth: This technology involves transfer of mitochondria. Fact: This technology does not involve moving mitochondria. Instead it involves moving entire nuclei or so-called “spindles” that are groupings of chromosomes, from one human egg or embryo to another.

Myth: This technology does not lead to human genetic modification. Fact: This technology conclusively does create genetically modified human embryos and hence it would produce human beings that are GMOs. Mitochondria have a genome including genes. Plants that only have a single added gene are definitively called GMO.

Myth: Mitochondria are just like little batteries that can be swapped out. Fact: Mitochondria are vital for energy production in cells, but there’s a whole lot more that they do as well. There is strong evidence that the mitochondrial genome, for example, “talks to” the nuclear genome, and has pervasive effects on cellular and organismal functioning. Therefore the notions that mitochondria are simply like replaceable batteries or that mitochondrial transfer would be just like transfusing blood into an anemic patient are misleading at best.

Myth: This technology would remove all diseased mitochondrial DNA. Fact: This technique is not perfect and it is essentially certain that at least some small amount of diseased mitochondria would remain. The consequences of the resulting heteroplasmy are reason for concern and it is possible that the diseased mitochondria might preferentially replicate, increasing their relative numbers.

Myth: Women with mitochondrial diseases have no other options for creating healthy families. Fact: There are several other options. One option is to utilize pre-implantation genetic diagnosis (PGD), which has proven potential to lead to healthy offspring and is an option for most women with mitochondrial diseases. PGD technology is only going to continue to improve as well, potentially expanding options further. Another possible option is to utilize an egg donor to be fertilized by the partner’s sperm, with the downside being that the mother to be would not be genetically related to the child produced. A third option is adoption.

Myth: This is not a new technology. Fact: While some unauthorized fertility experiments were conducted in the 1990s (eventually prohibited by the FDA) that have some resemblance to 3-person technology, they were different in important ways. For example, the technology used in the 1990s involved cytoplasm transfer between eggs rather than the more extreme intervention of nuclear or DNA transfer (as now proposed in the UK) and it did not involve mitochondrial disease. It is important to point out that even so the experiments in the 1990s led to some negative outcomes including chromosomal damage and developmental disorders.

Myth: IVF was a risky technique originally and was successful for the UK and the world so 3-person technology will do the same. Fact: While 3-person technology does involve IVF, it is a much more severe medical intervention and far riskier both to the children to be created and the country that allows the work. The pioneering work that the UK did on IVF was noble and successful, but the situation with 3-person technology is not quite analogous. The lesson from the success of IVF is not that 3-person technology will similarly prove to be safe, effective or bring honor to the UK. On all three accounts that optimistic perspective could be flat-out wrong.

11 thoughts on “Top 10 myths about 3-person IVF mitochondrial transfer


  1. Hi Paul,
    With regard to Myth 1, I’m just trying to figure out what fraction of mitochodrial afflictions might be prevented should 3-parent IVF prove safe and effective.

    Being an ignoramous, I had to go to wikipedia. There I found:
    “Mitochondrial diseases are sometimes (about 15% of the time) caused by mutations in the mitochondrial DNA that affect mitochondrial function. Other causes of mitochondrial disease are mutations in genes of the nuclear DNA, whose gene products are imported into the Mitochondria (Mitochondrial proteins) as well as acquired mitochondrial conditions.”

    So — please correct me if I am wrong — it seems that, at best, the 3-parent IVF can only reduce the number of afflicted people by 15%?


  2. Hello Paul

    I don’t think there are perfect techniques, but, I don’t think this should be a blockage to progress.

    Embryo manipulation required for IVF itself might have several consequences itself. For instance in ICSI it is extremely difficult to control for the amount of media or foreign bodies that go into the egg. We are still discovering the effects different medias have in epigenetics and overall gene expression in the early development, but, we have been incubating and generating embryos in vitro for over 30 years, well, some of these embryos have generated embryos of their own and so far so good.

    If we think about PGD, we are either removing a polar body (very invasive), blastomeres (so early development amputation at a stage that chemical gradients are crucial) or messing with the trophectoderm. If this is not extreme by itself, we should keep in mind that all of this is done in an environment far from close to what is observed in vivo.

    MitosRNAS are recent and are pretty exciting, but, again, compared to all the manipulation embryos suffer by the point that they are ready to have the genomic transfer.

    I agree that we need more studies, but, I consider this a welcomed progress.

    Primates are actually a horrible model for humans when it comes to reproductive research (I mean, it was much harder to achieve IVF and stem cell derivation in primates than in ourselves, it seems like cats are a bit more like us from a gamete point of view curiously).

    We have been using stem cells for therapy for many many years (that bone marrow) and we had no idea of what were doing back in the day.

    Also, there are already plenty of GMO humans around, people taking glybera (even considering the low rates of insertions), people that were part of the trial for the F9 insertion 3 years ago, the 50 something patients from the B-cell chronic lymphocytic leukemia trial.

    We will get there.


  3. @Brian

    It might seem like a very low number, but, if you consider how much money and care is needed for the few children born with congenital mitochondrial disease, and how much hardship is associated with the care of these children the value of eradicating the disease might be huge.

    One might argue that we are now moving to the realm of eugenics (I mean we kinda are there already with PGD) this is the type of step I would be ok to take.

    There are diseases that might have solutions down the line with the improvement of gene therapy techniques but we might also be increasing the numbers of these diseases in the gene pool by just treating them later in life.


  4. @Brian
    I thought the % of mitochondrial diseases caused by mitochondrial DNA mutations was higher than that, but there are definitely mitochondrial diseases caused by mutations in nuclear DNA as well.
    Paul


  5. @tadpole,
    Thanks for your comments and sharing that info. It’s surprising that primates wouldn’t be a good reproductive model for humans. It’s important to point out that the mitochondrial transfer is different than the gene therapy examples because the genetic modifications would be heritable.


  6. @admin

    Yes they are heritable, but they could also contribute to abolish these diseases.

    What would be your opinion if these same children were just treated with genetic therapy?

    Or, if for the people that have the disease we generated ipscells, sorted out the populations that were defective, and differentiated these selected cells for gametes?

    Would this be acceptable?


  7. @tadpole
    Thanks for your insight. Good to hear that the (nominally) 85% are not being forgotten. Re eugenics, it seems like the time has come to do something about a few truly bad genes but I wouldn’t be able to recognize a good gene if I tripped over it.


  8. @Brian

    The particular case of mitochondrial diseases makes them a good initial target for these kinda of “therapies”.

    They are exclusively transmitted by the mothers (since human sperm does not give a mitochondrial contribution to the embryo) and it will fill a gap over something PGD cannot access.

    There are several methods to determine the transmission of mitochondrial diseases that go from gene expression levels to fish, but, unfortunately, interblastomeric differences make it very hard to have a good diagnostic.

    Often, the blastomere that is biopsied gives a great result, only to find after birth, that the rest of them might not have been as good.

    I have only seen two cases of mitochondrial disease on my undergrad research work and it was quite devastating. I would love to see these diseases solved.

    I can’t help but feel like there are some parallels between the fear to go ahead with this technology and the new anti vaccine movement.

    Yes, this is an unready technology in the sense that we are not sure of what are the consequences to the children born out of them, but, the alternative is so grim that I can understand why people want it addressed fast.


  9. I should just add that I am actually thrilled that this is such a discussed issue.

    It is very selfish of me, but I am sure this will bring the interest over the mitochondria in stem cells and reproductive sciences to new hights,and maybe this way, more researchers will be open to projects on mitochondrial function and bioenergetics.

    A lot of doors closed the past 6 years on projects on this subject, maybe this will now change!


  10. Hi Paul,

    I too, like Brian, would like to know the actual number of children this would impact. The number presented to the UK’s Parliament seems to agree with the figures given in an article, “Mitochondrial Disease: A Practical Approach for Primary Care Physicians.” However, within that article, the authors note two items I haven’t seen discussed in the secular news.

    One, they say, “allowing for incomplete ascertainment, a lifetime risk of developing mitochondrial disease of 1 in 5000 live births is a more probable estimate.”

    The second item to note is the authors say, “Although primary mitochondrial disease by definition has a genetic etiology, the genetic abnormality may be found in either mtDNa or nDNA…However, nDNA mutations account for the majority of mitochondrial disease that presents in infants and children.”

    This article was published in 2007. Do nDNA mutations still account for the majority of mitochondrial diseases seen in infants and children. If so, why did Parliament vote on a procedure that is said to address only mtDNA defects?


  11. Hi Paul,

    Another thought/question. Let’s say “if” this procedure did prove to be a safe and an ethical option for parents with a known specific mtDNA defect, and they could go on to have a child born free of that mitochondrial disease that’s been associated with said defect, those so-called mito-disease free individuals are still at risk of developing a mito disease in their lifetime.

    Has anyone weighed in on the vulnerability each of us has in developing a mitochondrial based disease due to drug-induced toxicity, which can result in either mitochondrial dysfunction or mutations? Yet even with this knowledge, mitochondrial toxicity testing is still not required by the U.S. FDA for drug approval.

    IF this procedure does come to prove to help those few at birth, there is no guarantee their mitochondria won’t be harmed down the road. Sort of reminds you of that amusement park game of banging the weasels on the head with a hammer, only to have another one pop up just as you think you’ve knocked them all back down their holes.

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