Last week, a Greek woman with a history of multiple in vitro fertilization failures gave birth to a healthy baby with DNA from three biological parents. It was the first successful birth in a clinical trial of a controversial fertility treatment known as mitochondrial replacement therapy, which combines genetic material from the intended mother and father plus a female donor.

In the U.S., the procedure is effectively banned because of a congressional amendment passed in 2015 that’s been renewed every year since. But now, a group of scientists, patient advocates, and bioethicists want to see the prohibition lifted. The technique, they say, could help certain women who are carriers of serious genetic diseases have healthy, biologically related children.

In the first of a series of meetings meant to draft policy recommendations to Congress, stakeholders will meet Wednesday at Harvard Law School to discuss how to move forward in the U.S.

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I. Glenn Cohen, one of the organizers of the event and faculty director of the school’s Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics, said a public discussion is needed in the wake of revelations late last year that a scientist in China used the gene editing tool CRISPR to modify twin girls as embryos. He worries that mitochondrial replacement therapy has “been swallowed up in the eddy of debates around germline gene editing,” which he sees as a separate and distinct technology.

He said there are several ways to try to make mitochondrial replacement therapy legal in the U.S. Congress could change the language of the amendment, which has to be voted on each year, or the Food and Drug Administration could change the way it interprets it.

Another path would be through litigation. “Parents who want to use this could bring a challenge to the interpretation to this language or possibly even a constitutional challenge to their interference of their rights related to procreation,” Cohen told STAT, though a lawsuit would likely take several years to be resolved. He’s hopeful that Congress or the FDA could change the ban sooner.

Meanwhile, clinics in Ukraine and the U.K., in addition to Greece, are already using the technology, and more babies are likely to be born using the technique. But mitochondrial replacement therapy remains controversial in the U.S. because it’s considered a form of genetic modification, and changes made to eggs, and sperm and embryos — known as germline modification — can be passed on to future generations. There are also safety concerns about its long-term effects on the child, ethical questions about informed consent, and religious objections.

In Greece, the procedure was used for infertility, but the push in the U.S. centers around its potential for avoiding mitochondrial diseases in babies, which occur in about 1,000 to 4,000 births in the U.S. per year. These diseases are inherited from the mother’s DNA, so mitochondrial replacement therapy involves taking the nucleus of the mother’s egg and swapping it into a donor egg that has had its nucleus removed. The donor egg contains healthy mitochondria, the energy-making structures of the cell, which float around in the jelly-like cytoplasm outside the nucleus. The egg is fertilized with sperm either before or after this transfer, and the rest of the IVF process is the same.

Three-parent embryo explainer graphic
How maternal spindle transfer works: 1. The patient’s egg (blue) has faulty mitochondria (gray). The nucleus from this egg is extracted and placed into a donor egg (orange) that has healthy mitochondrial DNA. The donor egg has had its own nucleus removed. 2. The newly created cell is fertilized by sperm and transferred into the patient’s womb. 3. The baby has healthy mitochondria and has DNA from three different people. Hyacinth Empinado/STAT

The procedure is also known as “three-parent IVF” because the resulting baby ends up with a portion of DNA — albeit a tiny amount — from the donor.

For couples like Lori and Neil Martin of Houston, the health of their children is a more important consideration. Their 9-year-old son has Leigh syndrome, a severe neurological disorder that is caused by mutated mitochondrial DNA. He was diagnosed at age 2 when his parents realized he wasn’t gaining weight or learning to walk.

Lori feels lucky that her son is still alive; most children born with Leigh syndrome die from respiratory failure before their fourth birthday. She and her husband didn’t want to take any chances when having another child.

“We quickly decided that having another baby with my genetics was not a good choice for our family,” she said. “There was a high likelihood that that baby would have Leigh syndrome and it could be more severe.”

So they sought out an egg donor to have their second child. If she’d have had the chance, Lori said, she would have used mitochondrial replacement therapy.

Philip Yeske, the science and alliance officer for the United Mitochondrial Disease Foundation, who will be attending Wednesday’s event, said he’s heard from affected families that mitochondrial replacement therapy is an option they want access to.

“In our mind, this is an extension of in vitro fertilization. That, too, had its challenges with being accepted from a societal point of view,” he said. “At the end of the day, this is really about providing a reproductive option to a relatively small group of women that carry this pathogenic variant.”

The organization estimates that about a dozen U.S. women a year would be interested and eligible for the procedure. There are no routine prenatal or newborn screening tests for mitochondrial disease, so right now, women carriers are typically found only when their child receives a diagnosis. Yeske said only a small number of these women are likely to want to use mitochondrial replacement therapy to have another child.

There has been only one reported birth of a baby following the use of the technique to avoid mitochondrial disease. That was in April 2016, after a U.S.-based fertility doctor, John Zhang, traveled to Mexico to transfer the resulting embryo into a woman’s uterus. The woman, a carrier of Leigh syndrome, and her husband had lost previous children to the disease.

The other births announced as a result of mitochondrial replacement therapy, from clinics in Greece and Ukraine, have been for infertility. Some embryologists have hypothesized that the mitochondria, and more generally, the cytoplasm outside the nucleus, affect egg quality and thus, replacing faulty mitochondria could boost pregnancy success.

In 2015, Rep. Robert Aderholt, a Republican from Alabama, introduced an amendment to the 2016 appropriations bill forbidding the FDA from considering clinical trial applications “in which a human embryo is intentionally created or modified to include a heritable genetic modification.”

The amendment spurred no debate before the appropriations bill passed in December 2015. (Aderholt did not respond to a request for comment.) Two months later, the National Academies of Science, Engineering and Medicine issued a report that said it would be ethically permissible to use mitochondrial replacement therapy in women at high risk of transmitting a severe mitochondrial genetic disease that could lead to a child’s substantial impairment or early death.

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The U.K. became the first country to approve the technique in February 2015, but only on a case-by-case basis for carriers of mitochondrial disease. The U.K.’s Human Fertilisation and Embryology Authority, which oversees fertility treatment and research, said it has so far received and considered 15 applications for the use of mitochondrial replacement therapy, of which 14 have been approved. To date, no pregnancies have been reported in the U.K. as a result of the procedure.

At the time the rider went into effect, Shoukhrat Mitalipov, who directs the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University, had been working with the FDA to begin a clinical trial for mitochondrial replacement therapy. “We don’t think this is modification. It’s not something that’s synthetic. It’s just taking a donor genome from somebody and replacing it with one that already exists. It’s natural,” Mitalipov said in a recent interview in his office in Portland.

But the FDA has taken the position that the technique cannot legally proceed because it involves a heritable genetic modification, which is what is barred by the rider. The FDA could decide, however, to allow the technique to create male embryos only, a recommendation that the National Academies report made. Since men are not believed to impart mitochondrial DNA to their children, the changes would not be heritable.

Zhang, the doctor who used mitochondrial replacement therapy to help a Jordanian couple have a child free of Leigh syndrome in 2016, is confident that Congress will change its mind on the procedure.

“More countries legalizing and using nuclear transfer technology means that other governments will loosen their restrictions, and it adds a level of credibility to the science so people know that it’s not false,” he said in a statement to STAT. “Like any science, if the technology proves good for mankind, every government eventually will support it.”

Cohen and others worry about the possibility for medical tourism for mitochondrial replacement therapy in countries where the procedure is not well-regulated. He said it’s important that patients and donors understand what’s involved with the procedure and give informed consent.

Americans already seem willing to go outside the U.S. to get the procedure. Valery Zukin, director of the Nadiya Clinic in Ukraine, which is doing mitochondrial replacement for infertility, said he has several U.S. patients looking to get pregnant. His staff has delivered seven babies as a result of the technique, and there are currently three ongoing pregnancies, though none in U.S. patients yet, he said. The clinic has received approval from the government in Ukraine for the procedure but is not registered in any database as a clinical trial.

Nuno Costa-Borges, director of Embryotools, a Spanish company collaborating with the Greek team, said the Athens clinic, the Institute of Life, has been contacted by U.S. parents hoping to use the technique.

Dr. Paula Amato, a physician and embryologist in Mitalipov’s lab, said in a recent interview that, because of the regulatory environment in the U.S., the group is planning to do a clinical trial for mitochondrial replacement therapy in Asia. She declined to give further details, saying the study is still in the planning stages.

“Believe me, we’d much rather do those trials here,” she said.

Many opposed to moving forward with using the technique for avoiding mitochondrial disease say there’s not enough evidence yet to show that it is safe. One potential side effect is that some mitochondrial DNA from the mother could carry over, replicate, and cause disease to reemerge. Clinical trials would need to follow children for a long period of time, possibly until age 18.

Others argue that mitochondrial replacement is not a true “therapy” because it does not treat a person. Some maintain that the term “mitochondrial replacement” is itself misleading because what’s being transferred is the nucleus. The technique is in fact similar to the one used to clone Dolly the sheep. In animal cloning, a mature somatic cell, such as a skin cell, is taken from an animal and transferred into an egg that has had its nucleus removed.

“It is a type of cloning,” said David Prentice, vice president and research director of the Virginia-based Charlotte Lozier Institute, an anti-abortion group that has advised members of Congress about mitochondrial replacement therapy. “It’s a nuclear genome transfer that’s being done.”

But many families dealing with mitochondrial disease don’t see it that way.

“I think personhood does start at the embryo level,” said Lori Martin. “When you know you’re bringing a person into the world who has a disease that could be fixed before they’re born, I don’t know why we wouldn’t try to help that person.”

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