FDA urged to approve ‘three-parent embryos,’ a new frontier in reproduction

The United States should permit scientists to implant embryos with DNA from three genetic parents into women with certain diseases who otherwise wouldn’t be able to conceive a healthy child, an expert panel said Wednesday.

The technique could open a new frontier in reproductive medicine and upend the fundamental truth of sexual reproduction, which merges DNA from one father and one mother to create a baby. The new procedure, which federal regulators are reviewing, would create an embryo with genetic material from two women and one man.

It’s still in the experimental phase and will not be available in fertility clinics for some time. The expert panel is recommending that it be approved only for clinical trials to help women who carry certain grave genetic diseases bear children who are biologically related to them, yet free of the disease. Such work is already permitted in the United Kingdom.

But the prospect of three-parent embryos raises thorny ethical, medical, and sociological questions, so the US Food and Drug Administration has not yet approved the technique to impregnate women in this country. The FDA commissioned the expert panel — which included doctors, lawyers, bioethicists, and historians — to study those questions and offer advice.

“The committee concludes that it is ethically permissible to conduct clinical investigations” of the therapy, so long as it’s used only to help women with those genetic disorders reproduce, the experts wrote in a 164-page report, issued by the Institute of Medicine, a nonprofit that advises the government on science policy.

The FDA still has to decide whether it will approve clinical trials of the technique. That may not come for quite a while: The omnibus spending bill that Congress passed at the end of last year prohibits funding for “the creation of a human embryo or embryos for research purposes.” An FDA spokesperson said that ban applies to this type of research, so the agency will not even consider applications until the next fiscal year begins in October.

But the expert report was significant enough on its own that the White House requested a briefing on Tuesday. The White House Office of Science and Technology Policy declined to comment on the briefing.

The science of three-parent embryos

To supporters, three-parent embryos are an elegant solution to a devastating problem: a class of diseases caused by dysfunctional mitochondria — the tiny organelles inside most human cells. The mitochondria, often called the powerhouse of the cell, produce nearly all the energy the body needs. Mutations that disrupt them cause a number of incurable and often fatal diseases.

Mitochondrial diseases are passed down in women’s eggs. But the faulty mitochondria reside in the periphery of the egg, outside the nucleus that contains most of the DNA. That quirk of geography opens the door to this new reproductive therapy.

Here’s one way to make it work: Scientists remove the nucleus from an egg of the mother-to-be. They then insert it into a donor egg, extracted from a woman who has perfectly healthy mitochondria. (First, they have to strip that healthy egg of its nucleus.)

The egg now contains DNA from both women — but, crucially, it does not contain dysfunctional mitochondria. It’s fertilized, adding the father’s DNA, and then implanted into the mother-to-be, who will (if all goes well) become pregnant.

The mitochondrial DNA contributed by the healthy egg donor amounts to less than 1 percent of all the genetic material in the embryo.

The expert panel’s report is “a significant step forward toward real clinical application of these techniques,” said Philip Yeske, science and alliance officer at the United Mitochondrial Disease Foundation, a patient advocacy group.

That could be good news for women like Lori Martin of Houston.

Martin’s 6-year-old son has Leigh syndrome, a deadly mitochondrial disease. Two years ago, she had a second child, a daughter, through an egg donor; her husband’s sperm fertilized the egg and she carried the pregnancy. Martin said she would have used this new technique instead, if it were available, because it would have allowed her to pass her genetic material on to her daughter without transmitting the disease.

“It’s kind of a cool feeling to be able to see you’ve given something to your child other than mutated mitochondria,” she said.

Weighing potential risks

The US government has tread carefully because of the novelty of mixing genetic material from three individuals, as opposed to the natural two. Among the many questions the procedure raises: How valuable are the benefits relative to the costs? How would the addition of a third genetic parent impact the identity of the child? Could there be a danger in mixing two women’s DNA in a single egg?

That last question remains under investigation.

In sexual reproduction, the egg cell contains nuclear DNA and mitochondrial DNA from the same person. The two might communicate in some way to keep both of them functioning properly. Some scientists are concerned that a foreign set of mitochondrial DNA might not speak the same language as the mother’s nuclear DNA, creating problems down the road when they are mixed.

Mice with mismatched nuclear and mitochondrial DNA got exhausted more quickly while running on treadmills, for example. Another research team showed that mismatched mitochondria were associated with differences in learning speeds and exploratory behavior, but it wasn’t clear why or how.

Other negative consequences might take a long time to manifest, so it’s possible that animals or children conceived through this technique could look healthy at birth but have problems later in life.

Recognizing that the technique is still novel, the expert panel recommended that the FDA impose several conditions on research in humans.

Among them: that only male embryos be implanted. Males do not pass mitochondria to their offspring, so if the offspring from this experiment somehow happened to carry the faulty genetic material from their mothers, they couldn’t transmit it to a new generation.

The panel also recommended that the technique only be used to prevent the transmission of mitochondrial disease. They did not recommend research into other uses of mitochondrial replacement therapy, such as helping older women to become pregnant.

Experimenting first in monkeys

It’s unclear when the FDA will make its decision. But it does have an application on file to use the technique in humans.

Shoukhrat Mitalipov, a biologist at Oregon Health & Science University, has bred six macaques using a type of mitochondrial replacement therapy. Mitalipov said that they are healthy, and that he plans to breed them and assess the health of their offspring. He also applied mitochondrial replacement therapy in human eggs, successfully creating embryos, as reported in a 2013 paper in the journal Nature. But he did not implant them.

Mitalipov has asked the FDA for approval to take this next step. In response, the FDA convened first an advisory committee, then asked the Institute of Medicine to form the expert panel.

Now that the panel has given its conditional approval, Mitalipov said his application should proceed. He said he is ready to start recruiting women into a clinical trial.

This story has been updated with comments from the FDA.