Each year, around 4,000 babies are born with inherited mitochondrial diseases in the United States. Problems can include blindness, epilepsy, movement disorders, liver failure, necrotizing brain lesions, and other serious maladies.The Food and Drug Administration (FDA) is now considering whether to allow mitochondria replacement to be used in humans to prevent these diseases.
The FDA's Cellular, Tissue, and Gene Therapies Advisory Committee met on Feb. 25 and 26 to "discuss oocyte modification in assisted reproduction for the prevention of transmission of mitochondrial disease or treatment of infertility." The conversation was focused on scientific issues associated with the technology and whether it could safely be used in humans.
Mitochondria are organelles that act as energy-producing cellular power plants. Mitochondria have their own DNA, and mitochondrial DNA is passed on only by mothers. Like nuclear DNA, mitochondrial DNA can harbor mutations. Some mitochondrial mutations can be very bad news. According to testimony given to the FDA committee by Dr. Salvatore DiMauro of Columbia University, there are around 700 mutations that can cause "a Pandora's box of diseases." There are no cures for any of these disorders, and a female carrier of a disease-causing mitochondria mutation will pass on mutant mitochondria to all of her offspring. This means a woman with a mitochondrial disease has a high likelihood of passing on this disease to a biological child (although sometimes a child will be unaffected if they receive predominantly unmutated mitochrondria from their mother).
Choices currently are limited for women harboring deleterious mitochondrial mutations. Generally speaking, their options are to pass on the affected mitochondria to their own embryos or to opt for in vitro fertilization with a donated egg. Dr. Shoukhrat Mitalipov at Oregon Health and Science University thinks these women could have another option—to have a child with the mother's (and genetic father's) nuclear DNA but with a donor woman's mitochondrial DNA (thus creating an embryo with three genetic parents). In this technique, the nuclear DNA is removed from a donor egg containing normal mitochondria. The nuclear DNA from the mother is then injected into the donor egg, which is later fertilized with the father's sperm. The result is an embryo with nuclear DNA from the mother and father and mitochondrial DNA from the donor. Mitalipov has successfully used this technique in monkeys and would like to move on to human clinical trials.
The FDA has explicitly banned the creation of three-parent embryos since 2001. However, there actually are some humans who have three genetic parents. In the late 1990s, Science reports, "a fertility clinic in New Jersey treated the unfertilized eggs of infertile women by injecting them with cell cytoplasm from eggs from fertile donors." Because the injection included mitochondria from the donor, the offspring had a mix of mitochondria from the mother and the donor. At least 12 births resulted from this procedure, and some had genetic problems. It is unknown whether these problems resulted from the injected cytoplasm, however, because the New Jersey clinic treatments were not part of a controlled trial.
Using the new mitochondria-replacement technique in humans is controversial—hence the FDA forum. Most paramount is a concern that this technique has not been adequately tested in animals. Although Mitalipov has produced seven healthy monkey offspring this way, the lon- term consequences of changing the germline by replacing mitochondria are unknown.
Because nuclear and mitochondrial DNA often work in concert with one another, there is a possibility of a problematic mismatch between the two. According to Klaus Reinhardt and colleagues, "Studies on model organisms, ranging from mice to fruit flies, indicate that MR [mitochondrial replacement] 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."
Another question is whether this technology could—or should—be used as a potential treatment for infertility, given that faulty mitochondria or egg cytoplasm—elements that are exchanged when mitochondrial DNA is replaced—might be responsible for the decline in women's fertility after 30.
This all leads us to the slippery slope argument that has gotten the most press after the FDA hearing: Will this technique open the way to "designer babies" that are genetically modified to make offspring more attractive, intelligent or athletic (rather than purely disease-free)?
While the FDA committee was charged only with considering the scientific issues associated with mitochondria replacement, it will be interesting to see how public sentiment plays into the agency's decision to allow or prevent this technology from being used in humans. The United Kingdom also is considering allowing the technique and has opened up its draft of new regulations to public comment. According to Reuters, the FDA considering a public discussion on the technology as well.
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