A new report in Science offers a valuable pointer to “theory and experimental findings that appear to have been overlooked in the scientific and public forums” on controversial mitochondrial replacement (MR) techniques, which the media often refers to as “three-parent IVF.”
MR would combine the mitochondria of a healthy woman’s egg and the nucleus from the egg of a woman affected by a severe form of mitochondrial disease; this constructed egg would be used to try to create a healthy child. MR techniques are currently being considered for clinical trial in the United Kingdom and the United States.
The Science paper, written by evolutionary biologists Klaus Reinhardt, Damian K. Dowling, and Edward H. Morrow, provides a critical look at the scientific evidence behind MR and concludes “that it is premature to move this technology into the clinic.”
Reinhardt et al. explain why disruptions to the interaction between the nucleus and mitochondria could be problematic.
Energy production critically hinges on extensive cross-talk between genes dispersed across the nucleus and the mitochondria. Because phenotypes with less-than-ideal cross-talk are disfavored by natural selection, coordinated mitochondrial-nuclear interactions become highly specific over evolutionary time. If MR disrupts such specific, highly coordinated mito-nuclear allelic interactions, adverse health outcomes might occur.
They also problematize the notion that nuclear DNA is unaffected by this procedure.
Studies on model organisms, ranging from mice to fruit flies, indicate that MR can profoundly change the expression profiles of nuclear genes and affect a range of important traits such as individual development, cognitive behavior, and key health parameters. These studies also suggest that males of reproductive age are particularly sensitive to MR-induced effects.
The authors point out an important limitation to the only primate study carried out thus far, noting that the macaques born following MR need to be studied through to sexual maturity (they are only three years old currently) since, “the results from mice and invertebrates suggest that many deleterious effects of MR would not be revealed until adulthood.”
Their paper does not stress the fact that only one MR technique – maternal spindle transfer – has met with any success in primates. The other MR technique being considered in the UK – pronuclear transfer, which has been the focus of researchers at Newcastle University – did not work when researchers at Oregon Health and Science University (OHSU) tried it with macaques. When faced with that development, the Human Fertilisation and Embryology Authority (HFEA), which had previously required primate testing for pronuclear transfer, quietly dropped the requirement (page 21) earlier this year.
As the UK Parliament prepares regulations to allow this technology to move to clinical trial, and the US FDA gears up for a public meeting to consider these techniques, it is critical that these complications inform the discussion.
The Science paper states that these points “deserve careful consideration prior to any change in legislation,” but also that using this technique to allow women suffering from mitochondrial diseases to have a healthy child “is clearly an exciting prospect.” Despite giving the technology this allowance, the paper has stirred up some controversy and defensive responses.
In an article in The Conversation, Director of the Centre for Genetic Diseases at Monash University Justin St John said, “The authors of the Science piece mention that the research they are highlighting hasn’t been included in the public debate. It’s important to note that it has not been overlooked by the scientists working on the technology or the agencies involved.”
However, the press statement issued by the HFEA in response to the Science article admits that its panel did not analyze the four Drosophila studies Reinhardt et al. cited, despite the issue of interaction between nuclear and mitochondrial DNA being what HFEA termed “one of the key considerations in assessing the safety and efficacy of mitochondria replacement.”
Furthermore, scientists working on MR can’t agree (at least previously, and publicly) on the best way to handle these safety concerns. Each of the two major research groups involved has voiced its ideas about why the other group’s method won’t work. When the researchers at OHSU found that human eggs were more difficult to work with than monkey eggs (with a majority of the embryos created from the constructed eggs showing abnormalities), one of the lead researchers at Newcastle said,
The unfertilized egg has the complex task of remaining poised in readiness to halve its DNA content upon sperm entry. Given the biological complexities associated with maintaining this state, we have always held the view that manipulation of the egg at this stage would be rather precarious.
The Newcastle group has focused on a technique that transfers cellular material between embryos rather than between eggs. However, when the Oregon researchers tried that technique in macaques, they abandoned it after finding that “embryos fail early and no pregnancies [were] established.”
In a Nature paper on a third MR technique, nuclear genome transfer, researchers from Columbia University and the New York Stem Cell Foundation suggest reasons why both the methods used in Newcastle and in Oregon could create problems.
In fact, at least five articles have explored the potentially dire safety consequences of mitochondrial replacement:
- “Nuclear transfer to prevent mitochondrial DNA diseases,” The Lancet, Joanna Poulton Ph.D, Professor of Mitochondrial Genetics at the University of Oxford, et al.
- “The British Embryo Authority and the Chamber of Eugenics,” Huffington Post, Stuart Newman Ph.D, Professor of Cell Biology and Anatomy at New York Medical College
- “My concerns about Nature paper on Genome Transfer for mitochondrial disease,” Knoepfler Lab Stem Cell Blog, Paul Knoepfler Ph.D, Associate Professor, Department of Cell Biology and Human Anatomy at UC Davis
- “Human Genetics Alert Submission to HFEA update on safety of MST/PNT,” David King Ph.D, Director of Human Genetics Alert
- “Mitochondrial Replacement, Evolution, and the Clinic,” Science, Klaus Reinhardt Ph.D, Visiting Scientist, University of Sheffield, et al.
There have also been many critical commentaries about the social, ethical, political, and philosophical concerns. Some important examples include:
- “A slippery slope to human germline modification,” Nature, Marcy Darnovsky Ph.D, Executive Director of the Center for Genetics and Society
- “Brave New Cells?” Project Syndicate, Donna Dickenson Ph.D, Emeritus Professor of Medical Ethics and Humanities at the University of London
- “The ethics of creating children with three genetic parents,” Reproductive BioMedicine Online, Francoise Baylis Ph.D, Dalhousie University's Canada Research Chair in Bioethics and Philosophy
- “On Designer Babies,” Tufts Medicine, Sheldon Krimsky Ph.D, Professor of Humanities and Social Sciences at Tufts University and an adjunct professor of public health and community medicine
- “Three person IVF,” Practical Ethics, Paula Boddington Ph.D, Lecturer in Philosophy at the University of Oxford
Most of the responses to the scientific, social and ethical critiques of MR, like the defensive response to the Science paper, have not been inspiring. The question is why critical opinions, coming from well-respected scientists, scholars, and advocates, are being dismissed and mislabeled?
I can’t help but wonder if the answer lies in Henry Gee’s recent article in The Guardian called, “Science: the religion that must not be questioned.”
Previously on Biopolitical Times: