Derived from bacteria, mitochondria are our cells’ energy-producing powerhouses. Now, a Massachusetts company is convinced that these microscopic cylinders are also key to conceiving a baby, and it has persuaded several groups of physicians outside the United States to test that controversial premise in women with fertility problems. More than 10 women are pregnant via the firm’s proprietary in vitro fertilization (IVF) method, which adds a bolus of a woman’s own mitochondria to her mature egg.
Meanwhile, the U.S. Food and Drug Administration (FDA) has erected roadblocks in front of a fertility specialist and a stem cell biologist who want to clinically test the mitochondrial hypothesis in the United States. The duo would like to harness a different IVF strategy: swapping out a woman’s mitochondria by transferring chromosomes from her egg into an egg from another woman. The technique, called mitochondrial replacement therapy (MRT), was just legalized in the United Kingdom to prevent rare genetic diseases. But even before that, the two researchers applied for permission to use it in women who are struggling to conceive. FDA said it needs far more data before allowing the work to proceed.
A central question for both IVF strategies is whether faulty or aging mitochondria actually drive infertility, and whether correcting that problem restores eggs to health. OvaScience, the Cambridge-based biotech firm, says the results it presented at a meeting in San Francisco last week answer that. In one small cohort of women with fertility issues, the company achieved a pregnancy rate of 35%. “We are so excited,” says Michelle Dipp, OvaScience’s CEO.
That enthusiasm is far from universal. John Eppig, a reproductive biologist at Jackson Laboratory in Bar Harbor, Maine, says he is “highly troubled” that the company has already made the leap to human pregnancies. No published animal studies with a control group have been done to test whether this approach can improve fertility—let alone whether it is safe for offspring, Eppig says. “What are the consequences” of adding mitochondria to an egg cell? he asks. “We really don’t know.”
MRT, the technique legalized in the United Kingdom, is in some respects even more of a lightning rod, because the resulting baby, with mitochondrial DNA from a donor and the rest of its DNA from mom and dad, would have three genetic parents. It has prompted intense debate on both sides of the Atlantic. The United Kingdom approved MRT in February, but not for infertility: It’s permitted only to prevent babies from inheriting potentially fatal mutations harbored by the DNA in their mother’s mitochondria. (Most DNA is in the nucleus, but each mitochondrion also has some.) In the United States, there are no laws prohibiting MRT, but FDA hasn’t given anyone a green light to try it. Last year, the agency asked the Institute of Medicine to weigh the pros and cons of MRT. The institute’s second meeting starts tomorrow, and it’s expected to issue a report in 2016.
FDA has flexed its muscles in this arena before. In 2001, it stopped physicians from squirting cytoplasm, which contains mitochondria, from a healthy woman’s egg into the egg of a woman who had been unable to conceive. But before FDA stepped in, 17 babies were born, most healthy, but not all. Now teenagers, they are often cited as proof of mitochondria’s value in fertility. “All we’re doing is copying that exact same concept,” Dipp says, albeit with a woman’s own mitochondria. “Adding mitochondria improves IVF success rates.”
Yet one of the physicians who led the cytoplasmic transfer effort nearly 20 years ago contends it’s impossible to draw such a clean conclusion. This was “a pilot experiment, not a randomized study,” says Jacques Cohen, a clinical embryologist at Reprogenetics, a company in Livingston, New Jersey. Cohen and his colleagues were certainly encouraged that several women who had failed many in vitro fertilization cycles were able to have a baby. But, he points out, the numbers were small, there was no control group, and cytoplasm contains a lot of factors beyond mitochondria that could explain any success the method had.
Evidence that faulty mitochondria impede fertility remains preliminary, agrees Jennifer Kawwass, a reproductive endocrinologist at Emory University in Atlanta, who has studied the safety of IVF. More important, she says: “We also don’t know the degree to which fixing it improves anything.”
Stem cell biologist Ali Brivanlou of Rockefeller University in New York City, one of the investigators who asked FDA to permit MRT in infertile woman, says human tests are the best way to resolve the issue. At this point, he adds, “one can make the argument that it is almost unethical not to provide care” to women who would welcome it. The pushback against MRT is emotional, not science-based, adds fertility specialist Norbert Gleicher of the Center for Human Reproduction six blocks away, who is working with Brivanlou and would treat any women involved. The technique has produced seemingly healthy offspring in monkeys. Furthermore, Gleicher notes, “we manipulate eggs and embryos in many other procedures.”
FDA is wary, however. The agency wrote that MRT “has not been sufficiently established … to support a first-in-human study,” according to communications provided by a lawyer assisting Gleicher and Brivanlou. FDA didn’t completely shut the door, requesting additional lab studies of human eggs and animal studies to demonstrate safety and effectiveness. It also said that any clinical test of MRT would need stringent cell-processing guidelines, strict enrollment criteria, and, ideally, a control group. The agency recommended following babies into adulthood and tracking their own offspring, if possible. Brivanlou and Gleicher say that many of the demands are too costly for them or any fertility center. (FDA declined to speak with Science about the case.)
Dipp says OvaScience believes it doesn’t need FDA’s blessing to try its treatment, called Augment, in the United States, although the firm is in a “low-level ongoing dialogue” with the agency. It’s already offering Augment in Canada, Turkey, and Dubai. Physicians isolate “immature” eggs from a small piece of tissue removed from the lining of a woman’s ovaries. They extract mitochondria from the cells, and deliver them to the IVF clinic, where they’re injected, along with sperm, into a woman’s mature eggs. The resulting embryo is transferred into the woman as in traditional IVF.
“The Augment procedure shows real promise,” said Robert Casper of the Toronto Centre for Advanced Reproductive Technology in Canada, during a conference call last week at which OvaScience discussed its results. Out of 26 women treated at Casper’s clinic, 17 had embryos fertilized and transferred. In nine, a pregnancy took hold. All of these women were 40 and under, all had failed between one and three IVF cycles, and they often had poor-quality eggs or embryos. “This population would probably have a pregnancy rate less than 10%" if they had another IVF procedure, Casper said. At the San Francisco meeting, doctors from Turkey also reported one ongoing pregnancy with Augment.
But Glenn Schattman, a fertility specialist at Weill Cornell Medical College in New York City, says OvaScience’s results are “not that impressive.” Many of his patients have failed two IVF cycles at another clinic before they reach him, yet many get pregnant. Schattman considers a control group essential. Cohen agrees that OvaScience’s technology warrants a randomized trial, though he acknowledges it’s difficult to control all the variables in IVF, such as age.
But the company has no such plans. “The fertility [industry] just doesn’t do trials,” Dipp says. As for MRT, Gleicher is considering offering that option outside the United States. Kawwass notes that infertile couples themselves may demand it. “Once an intervention has any hope,” she says, “they want the intervention.”