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Mitochondrial Manipulation

As we approach the 5^th decade of the use of in vitro fertilization technology for the treatment of infertility as well as the 4^th decade of the use of this technology for the prevention of serious genetic diseases in offspring, we continue to face new scientific frontiers fraught with ethical challenges. One of the latest issues under serious discussion is whether or not we should attempt to manipulate intra-cellular DNA in human eggs.

Gene therapy, that is, manipulating nuclear

Unfortunately, there are conditions associated with mitochondrial DNA defects that can cause serious and disabling human diseases including heart failure, dementia and blindness. Mitochondrial diseases are usually associated with muscle disorders, as mitochondria provide the energy muscles need. Sometimes, the mitochondrial mutations are less severe and may just result in mild cognitive problems. These mitochondrial diseases can affect as many as 1 in 15,000 individuals, but because they can be fatal to a fetus or to a child, they may be even more common. If a woman carries this defect in her mitochondria, she will pass it on to all her children if she is able to reproduce.

In February of this year, a special advisory panel of the FDA, the Cellular, Tissue, and Gene Therapies Advisory Committee met in Washington, D.C. in an open public forum to discuss whether they would advise, allow and approve animal and human research into mitochondrial manipulation of human eggs. The goal would be to allow women that carry severe mitochondrial DNA mutations to have their eggs receive donor egg-derived mitochondrial infusions. To further diminish the contribution of mitochondria from the affected mother’s cell, the nucleus of her egg can be placed into a donor egg that has had its nucleus removed, thus removing almost all of the affected mitochondria.

This research is of interest to us in who work in the field of IVF not only for the prevention of mitochondrial DNA disease, but also for the wider implications of creating eggs that have mitochondrial DNA from two individuals. Furthermore, there is the possibility that mitochondrial DNA replacement may one day be used to treat poor quality human eggs, which is a common cause of infertility. In the late 1990s and early 2000s, some researchers were beginning to attempt these mitochondrial DNA replacements as part of IVF infertility research on human eggs to see if the resulting embryo quality would be improved. Although based on a limited number of observations, the researchers felt that these manipulations allowed a greater number of poor quality eggs to progress to blastocyst (Day 5) stage embryos. They never attempted to transfer the blastocysts to a patient, as far as we know. At that time, the FDA felt that this was a potentially dangerous manipulation of human DNA and disruption of the natural maternal mitochondrial DNA inheritance pattern, and thus forbid further manipulations. All research in this area in this country was halted.

Recently, the British Human Fertilisation and Embryology Authority, which governs all IVF research and treatment in the UK, formally allowed and even encouraged research to be undertaken in this area. However, concerns have been raised concerning the “mis-match” of nuclear and mitochondrial DNA that will arise in these embryos and individuals. Studies in animal models have shown that mitochondrial DNA affects the expression of nuclear genes and vice-versa. It has been suggested that mitochondrial DNA and nuclear DNA have evolved together in any particular family line and that mitochondrial DNA replacement may disrupt this natural evolutionary process. Indeed, some studies in invertebrates and in mice have shown alterations in some metabolic processes and (in mice) in learning and performance when these replacements have occurred. Also, fertility in these cross-matched offspring may be compromised.

This strongly suggests that thorough research in animals should be performed before clinical studies proceed in humans. Having said that, women that carry mutations that may cause severe diseases in their offspring may be ready and willing to participate in human research and ethically, this may be appropriate with adequate controls and follow-up.

The FDA Committee held its meetings on this and was open for public comment until May 6. It will probably be several weeks before they issue their directive. I’m fairly certain that the FDA, if they do ever allow human studies to proceed, will require that these children be followed up for many years, perhaps into adulthood. For all the reasons detailed above, it will probably - and appropriately - be a long time before this technology is used on the wider infertility population with poor quality eggs.

1. http://www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics/cellulartissueandgenetherapiesadvisorycommittee/default.htm- Transcripts available for public meeting.
2. “Mitochondrial Replacement, Evolution and the Clinic.” Reinhardt, K., Dowling, D., Morrow, E. Science vol. 341. Sept 20, 2013. p1345-6.
3. “Mitochondrial myopathies: Clinical features and diagnosis. Genge, A, Massie, R. On UpToDate (http://www.uptodate.com/contents/mitochondrial-myopathies).
4. “Ethics of modifying the mitochondrial genome.” Bredenoord, A, Dondorp, W. Pennings, G., De Wert, G. J Med Ethics 2011;37 p.97-100 .
5. HFEA, HFEA launches public consultation. Medical Frontiers: Debating mitochondria replacement; www.hfea.gov.uk/7517.html

- Carolyn Givens, M.D.

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