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A mitochondrion.

A mitochondrion.

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For boys only? Panel endorses mitochondrial therapy, but says start with male embryos

An experimental assisted reproduction technique that could allow some families to avoid having children with certain types of heritable disease should be allowed to go forward in the United States, provided it proceeds slowly and cautiously. That is the conclusion of a report released today from a panel organized by the U.S. National Academies of Sciences, Engineering, and Medicine (NAS), which assesses the ethics questions surrounding the controversial technique called mitochondrial DNA replacement therapy. (Some of the panel also summarizes the deliberations in a Policy Forum in Science.)

More controversially, however, the panel recommended that only altered male embryos should be used to attempt a pregnancy, to limit the possible risks to future generations. (Males can’t pass along the mitochondrial DNA that is altered in the procedure.)

Mitochondria are organelles that supply cells with energy. They carry their own DNA, coding for 37 genes, which is passed down from mother to child through the mitochondria in the egg cytoplasm. (Sperm have mitochondria, but they are thought to degrade shortly after fertilization.) Mutations in mitochondrial genes cause a range of disorders, some mild and others life-threatening. They tend to affect tissues and organs that need lots of energy, including brain, eyes, and muscle. Often the diseases are progressive, and there are few treatments available.

Scientists have developed ways to transfer the genetic material from an egg with faulty mitochondria into a healthy egg, either before or just after fertilization. Such techniques, called mitochondrial DNA replacement therapy (MRT), could in theory allow women who are carriers of mitochondrial disease to have genetically related children. (Current options include adoption or using an egg donor.)

The embryo resulting from MRT carries DNA from three people: nuclear DNA from the couple undergoing treatment and mitochondrial DNA from the healthy egg donor. The prospect of such “three-parent embryos,” along with the fact that any offspring would pass their mitochondrial genes on to their own children, has made the technique controversial. So the U.S. Food and Drug Administration (FDA) asked for the review as part of its deliberations about whether to allow researchers in the United  States to use the technique.

MRT’s potential benefits outweigh the problems, the NAS committee says, provided that work proceeds slowly. That means only the women who are considered very likely to pass on severe forms of mitochondrial disease should be candidates for the first clinical attempts.

In addition, to avoid the possibility that babies born via MRT would pass unforeseen problems along to their own children, the panel also recommended that only male embryos be used to start a pregnancy.

“This is the first time it will happen in humans. We don’t know how it will work,” says Jeffrey Kahn, a bioethicist at the Berman Institute of Bioethics at Johns Hopkins University in Baltimore, Maryland, who chaired the panel. “We thought it only prudent to make sure it will only affect the individual born and not future generations.”

That restriction would add an extra burden for couples interested in MRT, says Sarah Norcross, director of the Progress Educational Trust in London, an advocacy group that focuses on issues surrounding infertility and genetic conditions. Male embryos might not be the healthiest embryos that result from the already complicated procedure, she says, and in some cases it could mean that women would have to undergo extra egg collection procedures.

Kahn notes that the recommendation is temporary, however. Once early research shows that the technique can be safe, and more animal data are available on possible effects in later generations, regulators could consider loosening that restriction.

Long-term thinking

The committee strongly recommends that any studies be designed so that results from multiple studies can be combined to learn as much as possible about the safety of the techniques. They also recommend that any children born via MRT be followed by researchers over the long term, so any physical or even psychological effects could be better understood. That requires permission from the parents at first, but would later require permission from the children themselves once they are old enough. That’s a challenge, Kahn says. “You can’t give consent for people who have not yet been conceived.”

The panel also encourages FDA to consider carefully how they can prevent other possible uses of the technique. Some researchers have proposed using MRT to treat age-related infertility, for example, but that is not ethically justified, the committee says.

That’s a potential problem, says Marcy Darnovsky, executive director of the Center for Genetics and Society, and advocacy group in Berkeley, California, that has opposed approval of MRT. “It’s important to realize that if the FDA were to approve these techniques, it would have few mechanisms for preventing what would essentially be ‘off-label uses,’” Darnovsky says in a statement. “One U.S. proponent of these techniques has already made it publicly clear that he would like to expand their use widely to fertility clinics. Their use could easily spin out of control.”

After years of scientific and ethical debate, the United Kingdom passed a law last year that would allow fertility clinics there to offer the technique—but on a case-by-case basis and closely overseen by that country’s Human Fertilisation and Embryology Authority (HFEA), which regulates assisted reproduction and embryo research. No clinics have yet received approval to use the technique there.

The United States does not have an equivalent to HFEA, but FDA has said that anyone who wants to use the technique needs to apply to the agency for permission, because MRT is a form of gene therapy. In 2014, it started a process to assess the scientific and ethical questions surrounding the technique. The NAS report will help shape FDA’s decision on regulations and guidelines for such applications. 

But don’t expect any such experiments to proceed quickly in the United States. Federal legislation passed in December limits the agency’s ability to grant permission for any mitochondrial replacement therapy efforts for fiscal year 2016. Because of the legislation, a FDA spokesperson noted in an email, “the agency will not receive or review INDs [Investigational New Drug applications] for human subject research utilizing genetic modification of embryos for the prevention of transmission of mitochondrial disease in FY 2016 and human subject research using these technologies cannot be conducted in compliance with the Federal Food, Drug, and Cosmetic Act and FDA’s implementing regulations.”

*Update, 4 February, 5:55 p.m.: This story has been updated to include comments from the FDA and the link to Science’s policy forum.