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Powerhouse. Mitochondria in a lung cell.

Louisa Howard/Wikimedia Commons

New Controversy Over Experimental IVF Method

A critique of potential in vitro fertilization (IVF) strategies to prevent babies from developing a common class of genetic diseases is sparking controversy. In today’s issue of Science, three evolutionary biologists argue that the ethical and scientific debates over an experimental IVF approach called mitochondrial replacement have underplayed some potential risks of the technique. While the trio support further development of the therapy, they say that more animal studies might be needed before clinical trials should proceed. But supporters of the technique—and a key IVF regulatory body in the United Kingdom—say that the concerns have already been taken into account and are minor compared with the symptoms the technique would prevent.

Mitochondria are organelles that provide cells with energy. Replacing these powerhouses in egg cells has been proposed for women who carry mutations in their mitochondrial DNA (mtDNA) but still want to have a baby themselves. (Mitochondria carry their own DNA, which is inherited almost exclusively through the mother; although sperm have mitochondria, they degrade after fertilization of an egg.) Mutations in mtDNA can cause mitochondrial diseases, with a range of symptoms affecting the eyes, heart, brain, and other organs. Some cases are mild; others are fatal.

Researchers have been working to develop ways that women who carry mtDNA mutations could have biological children without passing on the defect. Several methods are under development, but they all involve replacing the faulty mitochondria from a patient’s egg with those from a healthy donor. The techniques raise ethical concerns, because they involve altering the inheritable DNA of an embryo—“Three-parent babies” is often part of the headline that accompanies stories about the concept. In the United Kingdom, several ethical and scientific review panels have given the techniques a cautious endorsement, however, and the government has said that it wants to allow the technique. It is expected to release proposed regulations in the coming months, and the U.K. Parliament could vote on a final version next year. 

A number of animal studies have shown that the technique can produce live offspring, and a study last year showed that it can produce normal-looking human embryos, at least through the blastocyst stage, about 5 days after fertilization. Some supporters of the technique have compared it to changing the battery in a camera.

Klaus Reinhardt, an evolutionary ecologist at the University of Tübingen in Germany, and his co-authors contend that that analogy is too simple. They say animal studies suggest that the interactions between mtDNA and nuclear DNA are extensive, and minor changes in either one can affect mitochondrial function. Introducing donor mtDNA could lead to subtle problems in offspring that haven’t yet been studied in the only primate model for mitochondrial replacement: macaques. In mice and fruit flies, Reinhardt says, problems from swapping mitochondria show up disproportionately in males and often affect fertility. The published macaque studies on mitochondrial replacement follow the new offspring for 3 years, but males don’t reach adulthood until 4 years of age, Reinhardt notes.

The U.K. Human Fertilisation and Embryology Authority (HFEA), which would be in charge of regulating the technique if it were allowed in the United Kingdom, says that its expert panel did take those concerns into account. The panel “carefully considered the interaction between nuclear and mitochondrial DNA and concluded that the evidence did not show cause for concern,” the agency says in a statement released today. The agency is talking with panel members to consider the issue of whether the macaques in the study were followed long enough, a spokesperson says.

Developmental geneticist Robin Lovell-Badge of the MRC National Institute for Medical Research in London, who co-chaired the HFEA scientific review panel, says he doesn’t know of any evidence that interactions between mitochondrial and nuclear DNA could cause severe health problems in humans. If the therapy might lead to minor effects, “it is important that the family knows this risk,” he writes to ScienceInsider in an e-mail.  However, he adds, “I suspect they would still choose [mitochondrial replacement] rather than have a very sick child.”

Reinhardt says he agrees. “We are sure that HFEA will decide [whether to allow the therapy] on a case-by-case basis and will have safeguards. But couples that have mild mitochondrial disease might choose to wait 2 years until the macaques are a bit more mature.”