Reproductive technologies that marry DNA from three individuals will receive a trial in the court of public opinion this week. Such technologies may hold promise for averting certain genetically inherited diseases passed down via mutations to mitochondria, the cell’s battery pack.
Scientists have already had successes with this type of reproductive approach in monkeys and in human embryos, and are now eager to launch human clinical trials. First, however, they must get the green light from the U.S. Food and Drug Administration, which will convene a public hearing before an advisory committee on February 25.
The technology, called oocyte modification (but sometimes nicknamed “three-parent IVF”), involves scooping out potentially mutated mitochondrial DNA (mtDNA) from a woman’s egg and replacing it with the mtDNA of an unaffected donor woman. The process is designed to prevent the transmission of some debilitating inherited mitochondrial diseases, which can result in vision loss, seizures and other maladies. Such inherited diseases, often unfortunately known by acronyms for complex medical names that include LHON, for Leber's Hereditary Optic Neuropathy, along with MELAS, MERRF and NARP, occur in about one in every 5,000 live births and are incurable.
Once the mtDNA has been swapped out, the egg could be fertilized in the lab by the father’s sperm and the embryo would be implanted back into mom where pregnancy would proceed. The resulting child would be the genetic offspring of the intended mother but would carry healthy mitochondrial genes from the donor.
Although the mitochondrial genome is quite small, the genes themselves are avid reproducers, so that an individual cell contains hundreds or thousands of copies of its DNA. The mutation rate of mtDNA is much higher than that of nuclear DNA and such miscodes can cause severe damage to any part of the body.
Scientists already have evidence for the promise of this type of oocyte modification. Shoukhrat Mitalipov of the Oregon Health & Science University and his colleagues created human embryos in this way, although they did not implant those embryos to make babies. Their findings were published in October 2012 in Nature. Other work from that same team also found that in monkeys the process could lead to the birth of healthy offspring that remained free of complications into adulthood. (Scientific American is part of Nature Publishing Group).
A human clinical trial would be the next frontier, and Mitalipov says he has already proposed conducting one to the FDA, although its details remain confidential. At a two-day hearing starting today the FDA advisory committee will broadly discuss the state of oocyte modification science and what clinical trials should look like for procedures designed to modify human eggs.
But wading into this type of approach is also fraught with ethical issues. Marcy Darnovsky, executive director of the Center for Genetics and Society, fears that this reproductive approach could soon lead to tampering with other traits, such as intelligence or sports ability. “Life is full of slippery slopes and we need brakes,” she says. “This is described as saving lives but it is not aimed at people who are sick,” she adds. The FDA advisory committee does not plan to consider ethical issues at this meeting. Instead it will focus on the scientific aspects of future clinical trial considerations, including long-term risk of carryover of abnormal mtDNA, the potential benefits and harm to mothers and future children, and the need for multigenerational follow-up in any trials (because female children could pass on mitochondrial disease to future offspring). “Our job will be purely to air the issue and bring it out into the open,” says Evan Snyder, chair of the committee and director of the Stem Cell and Regenerative Biology Program at Sanford–Burnham Medical Research Institute in La Jolla, Calif. “We’re not going to come out at the end of the meeting and say we are advocating for clinical trials or any particular technique. This is educational,” he says.
Without oocyte manipulation, the main current approach to try to circumvent mutations involves a process called preimplantation genetic diagnosis, which hinges on closely examining embryo cells early on. But it can be a poor predictor of mtDNA mutations. “The problem is the mutation load in one cell is not predictive of what is in the other cells,“ Mitalipov says. Although one cell could look relatively mutation free, the others may still have higher mutation loads because the mutation was not eliminated and the cells are often not uniform.
The U.K. is also grappling with these questions as they consider how to proceed with therapeutic applications of oocyte modification. Its Parliament is expected to take up the question this year. The London-based Nuffield Council on Bioethics did consider the ethical ramifications of this approach and concluded that if it proved safe and effective, and as long as proper information and support were offered, it would be ethical for families to use these techniques as treatment to block transmission of inherited mitochondrial disease.
Meanwhile researchers are also interested in exploring how—or if—oocyte modification approaches could help some women overcome infertility issues. There is no current scientific consensus regarding whether the quality and quantity of mtDNA impacts fertility, but some researchers wonder if a strong link exists between the two. The theory is that perhaps accumulation of mutations throughout a woman’s lifetime could contribute to the age-related fertility decline. “I don’t think it’s conclusive that this is mitochondria at work and not something else. I think the science has some way to go to make the link between fertility and mitochondrial function,” says Dieter Egli, a senior research fellow at the New York Stem Cell Foundation, adding it would need to be tried in mice or monkeys before moving into human trials.
When it comes to the more established research for oocyte modification and genetic inheritance, “We’re focusing on if the field is ready for clinical trials to alleviate this real horrible human suffering,” Snyder says.