Future Tense

“Three-Parent IVF” Might Open the Door to Human Genome Editing

Mitochondrial donation is a promising technology for carriers of some diseases, but it needs to be thoughtfully regulated.

An adult holds a baby in their arms.
Wes Hicks/Unsplash

On Oct. 19, a team of researchers from Greece and Spain made a remarkable announcement: They had started six pregnancies using a new genetic technology, mitochondrial donation. This was not the first time the technology had been used, but it is the first clinical trial approved by a government. In this case, Greek regulators approved the trial back in 2016 for assisted reproduction. Now the team has reported that four live births have resulted from the trial, with at least one more pregnancy ongoing. While that number may seem small, he outcome is notable. Of the 25 women enrolled in the trial, all of whom had struggled to become pregnant even after several IVF attempts, almost one-quarter could successfully conceive with mitochondrial donation. This technology is promising—but now is the time to start considering when and why it should be used.

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Mitochondria,the small organelles that produce energy for our cells, are critically important for the proper growth and functioning of our bodies. When they fail to do their job, cells are starved of energy, which can have devastating effects. Mitochondrial diseases are not uncommon: One in every 5,000 adults suffers from some form of disease, which is caused by problems in the mitochondrial genetic code. Mitochondria are inherited from our mothers, so women with with so-called “defective” mitochondrial genes pass that faulty mtDNA on to their biological children. Those with no or mild symptoms—who might not even know they carry unhealthy mitochondria—can unexpectedly have a child with a more severe mitochondrial disease, or be unable to carry a baby to term at all. Yet screening of mtDNA is not common, and generally only occurs after a woman with defective mtDNA has multiple failed pregnancies. Even if a pregnancy is successful, the child may suffer from one or many forms of mitochondrial disease, which can lead to serious disability; early deaths are not uncommon in these children. Symptoms can affect almost any part of the body, ranging from muscle weakness (including the heart), hearing difficulties, impaired vision and/or impaired neurological functioning.

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Since the 1990s, researchers have been attempting to develop new treatments for women with faulty mtDNA to allow for these women to have healthy and disease-free babies. Enter mitochondrial donation. Clinical advances in the past six to seven years, by clinical pioneers including John Zhang and Doug Turnbull, have now allowed this to become a reality. Affected women now have the opportunity to give birth, for the first time, to their own biological, mitochondrial disease–free, children. But this is a controversial procedure because although it does not involve editing an embryo’s nuclear DNA, it does result in heritable changes to an embryo’s genetic material. That is, the changes won’t be expressed just in the baby but in any children that a female baby may grow up to have.

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Several methods of mitochondrial donation exist, but they all work to create an embryo that receives mitochondria from a third person—a donor woman. The procedure is sometimes called “three-parent IVF” because while the genes in the nuclei of the embryo’s cells will come from the two parents, mitochondria themselves carry tiny pieces of DNA (called mtDNA) that make up about 0.1 percent of our genes, so the resulting embryo will have DNA from three people.

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Mitochondrial donation to prevent devastating illness in children is already controversial—so much so that the technique is not permitted in the United States—because the embryo is purposefully “modified to include a heritable genetic modification,” and is therefore viewed by some—especially when peformed on a female embryo—as a form of germline editing. Groups ranging from fertility specialists to religious and patient communities have begun to express their concerns over its regulation.

In addition to the questions about safety and efficacy, these groups have raised many questions about the social and ethical issues relating to the technique’s use. These range from asking what rights, if any, the donor woman should have in relation to the child, to questions of how that child may perceive themselves given they have DNA from three people, to issues around inintended consequences—which could not be reversed—for future generations.

Using mitochondrial donation to treat infertility, as in the new Spanish-Greek trial, could be even more contested, because while this technology is the only way a carrier of faulty mtDNA could have a biological child, women with fertility issues have a number of options, such as surrogacy. And because applying mitochondrial donation to treat infertility is bending our rationale for using an advanced genetic technology to prevent genetic diseases, this path could even move us closer to editing nuclear DNA for the purposes of preventing metabolic disorders—an even more controversial technique that has already been used to produce children by a team in China, with at least one other scientist in Russia having expressed an interest in going down that path.

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In 2015, the United Kingdom became the first country to expressly legalize mitochondrial donation—but only for preventing heritable diseases. The U.K. law allows clinics to offer mitochondrial donation only after receiving a license from the government. Only one clinic in the U.K. has received a license, and no births have yet been reported. Births have been reported, though, in Mexico and Ukraine—countries that have not gone through a similarly robust regulatory review process as the U.K. and do not have legislative regimes that explicitly allow for the technique.

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However, as evidenced by the Spanish-Greek trial, the exact same mitochondrial donation techniques can be successfully used to assist women with fertility challenges to start a pregnancy. Mitochondrial function is essential for embryo development, and by employing this technique the team believed that they could create higher quality oocytes, which would then, in term, increase the likelihood of a clinical pregnancy. Despite their success, the evidence supporting this is still fairly thin due to ethical concerns—including potential risk to children— resulting in very few trials focused on infertility having actually been conducted. The European Society of Human Reproduction and Embryology, for example, issued a statement in 2019 strongly discouraging using the technology to treat infertility. They argue that there is a lack of robust data proving efficacy and safety and stress that the technique should be used with “extreme caution.”

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Whether mitochondrial donation could be used for any reason in the U.S. is still up in the air. Since 2015, Congress has forbidden the FDA from even reviewing applications to make heritable genetic changes in human embryos—a rule that likely was targeting human genome editing with methods like CRISPR, but also applies to mitochondrial donation. This is despite an expert committee from the National Academies of Sciences, Engineering, and Medicine having concluded in 2016 that the treatment was ethical, provided it was properly regulated.

Should the U.S. permit the FDA to review mitochondrial donation applications, which Congress considered doing in 2019 and may be more feasible under a Biden administration, there does not appear to be a policy in place that would limit clinical use to preventing heritable disease. In contrast to the situation in the U.K., access to IVF and similar methods in the U.S. occurs under a convoluted mix of federal and state rules. The limited federal policy in the U.S. on how embryos are used in IVF—and how they might be used in mitochondrial donation—could mean that approving the technology would allow for its use in treating infertility.

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Ultimately, October’s clinical trial results have created a new precedent in mitochondrial donation by normalizing its use to treat infertility. While this announcement could provide new hope for families struggling with fertility issues, it should also be a reason to stop and think through how powerful new genetic technologies are being used—technologies that can make heritable genetic changes to embryos. Access to mitochondrial donation for infertility treatment in one country could, through medical tourism, mean access to anyone with enough means. And, if the rationale for using mitochondrial donation to make heritable changes in embryos can be bent—and shifted from metabolic disorders in mtDNA to nuclear DNA—why couldn’t the very strict conditions proposed for using human germline editing with tools like CRISPR also be distorted in the future?

Let’s be clear: The infertility clinical trial was conducted with all the appropriate oversight and approvals from the Greek government. But, at least for now, allowing mitochondrial donation to be used for anything other than preventing heritable diseases might not be the right call given the lack of robust data on efficacy and the very different risk/benefit ratio for those women without faulty mtDNA. It could have consequences beyond any one family, country, or reproductive technology.

This research for this article was funded in part through Diana Bowman’s Andrew Carnegie fellowship.

Future Tense is a partnership of Slate, New America, and Arizona State University that examines emerging technologies, public policy, and society.

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