John Zhang holding baby

Fertility specialist John Zhang holds the newborn baby (face blurred for privacy).

New Hope Fertility Center

Unanswered questions surround baby born to three parents

News broke today of what is believed to be the first baby created using a controversial genetic technique to avoid transmission of a potentially fatal genetic disease. Beyond stretching the boundaries of in vitro fertilization (IVF) procedures, the technique has gained notoriety because it leaves the baby with three genetic parents. The little boy was reportedly born 5 months ago, and a New York City fertility specialist performed the treatment in Mexico, where rules around human embryo manipulation are more lax than in the United States, which has declined to greenlight the experimental procedure.

Details remain sketchy. New Scientist, which broke the story, published a smiling photo of the fertility specialist, Dr. John Zhang of New Hope Fertility Center in New York City, holding the newborn, and told the family’s tale. The married parents had lost two older children to a mitochondrial disease, a rare class of conditions caused by defects in the DNA of mitochondria, the organelles that provide energy to cells. Babies inherit their mitochondrial DNA maternally, so if the mother carries a mutation in that DNA, a variety of life-threatening conditions can afflict the newborn.

Zhang reportedly used an approach called spindle nuclear transfer to create five human embryos. The method involves removing the nucleus—the bulk of a cell’s DNA—from one of the mother’s egg cells, and inserting that nucleus into a donor egg cell stripped of its own nucleus. The result is an egg with mitochondrial DNA from a healthy donor and nuclear DNA from the mother. Five donors eggs prepared this way were then fertilized with the husband’s sperm—but only one of the resulting embryos had a normal number of chromosomes. That embryo was transferred into the mother-to-be.

Zhang declined additional interviews today. (“Patients come first,” an employee in the clinic’s marketing department wrote to Science.) But many scientists were uneasy with how Zhang’s team reported the development and the fact that it took place in an environment of potentially minimal oversight.

In addition to the New Scientist piece, the only other information available was an abstract in an upcoming issue of Fertility and Sterility that details talks to be presented at the American Society for Reproductive Medicine meeting in October. The abstract, which said the baby was “doing well” at 3 months, reported that roughly 1% to 2% of the mother’s diseased mitochondrial DNA persisted in the baby’s cells that were tested. But the baby didn’t appear to have Leigh syndrome, the condition that had killed his two siblings.

The limited information in the abstract left many wanting more. “Right now it’s just, ‘We have done it.’ It’s a claim,” says Dieter Egli, a stem cell biologist at Columbia University. Unanswered questions included what type of ethics review the IVF procedure received (the abstract notes an Institutional Review Board approved the experiment, but did not specify whether it was in Mexico or elsewhere), what medical follow-up the child would receive, whether this was the first time the group had performed the technique, and whether previous efforts were unsuccessful and went unreported. “This and other important questions remain unanswered because this work has not been published and the rest of the scientific community has been unable to examine it in detail,” wrote Dusko Ilic, a reader in stem cell science at King’s College London, in a public comment for journalists. “It’s vital that that happens soon.”

Norbert Gleicher, a fertility specialist at the Center for Human Reproduction in New York City, says that the New York team’s decision to work in Mexico is to be expected, given the obstacles to trying such an experimental procedure—or even applying for approval to offer it—in the United States. Gleicher says he has sought a meeting with the U.S. Food and Drug Administration (FDA) to discuss mitochondrial DNA replacement for U.S. patients, including as a treatment for infertility. “We have not even been able to get an appointment,” he says.

The United Kingdom, as well as a U.S. National Academy of Sciences panel, has given its approval in theory to mitochondrial transfer to prevent disease. In the United States, however, Congress has blocked FDA from allowing any such experimental treatments.

The regulatory situation in the United States “kind of doesn’t make any sense,” Gleicher argues, “because what it results in is exactly what you have been witnessing”—essentially, an experiment that moves “to places with no supervision.” 

Egli agrees. “For me, the lesson here is that it’s very important that regulatory agencies like FDA move forward,” he said. “This could have been done in the United States by groups that have many years and decades of research [experience].”

Clinical embryologist Jacques Cohen of Reprogenetics in Livingston, New Jersey, who has advised Zhang’s team about regulatory issues, defends their decision to perform the procedure in Mexico because of the U.S. restrictions. “Just because this was done in Mexico doesn’t mean it was not done ethically,” says Cohen, who himself led controversial fertility experiments in the 1990s involving the transfer of cytoplasm, in which the resulting babies also had three genetic parents.

Zhang is not a newcomer to embryo modification techniques. In 2003, he revealed that he had done something similar in China, swapping a nucleus from one egg to another, though in that case the egg was already fertilized. The news was publicly reported, including in The New York Times, but a research paper describing it appeared only last month, in Reproductive BioMedicine Online. The 30-year-old woman did become pregnant, but her twins both died before birth.

In 2009, a group led by Shoukhrat Mitalipov of the Oregon Health & Science University in Portland revived the debate about mitochondrial replacement therapy by achieving success in macaque monkeys. Like others, Mitalipov suggested in a statement to Science that it was troubling that “desperate parents” were being forced to “countries with less oversight.” He attributed this to congressional action that is blocking FDA from allowing the mitochondrial replacement procedures to be attempted.

With reporting by Gretchen Vogel and Jocelyn Kaiser.