Why you should care
Because John Zhang could help women with heritable diseases have healthy kids.
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When reproductive endocrinologist John Zhang introduced a new in vitro fertilization technique at a medical conference in China in 1997, the audience responded with snickers and modest applause. “[They] told me my head was in the clouds,” Zhang recalls.
Twenty years later, Zhang, 53, made headlines when his team announced the delivery of the world’s first “three-person” baby using a version of the procedure known as mitochondrial replacement therapy, similar to the method that he had discussed in 1997. The infant carries DNA not only from his mother and father but also from a female donor. The procedure spared the baby from inheriting a deadly neurological disorder from his mother, stemming from a genetic mutation in the cells’ “energy factories,” or mitochondria. One day, MRT could prevent a number of mitochondrial diseases, or treat infertility more broadly by boosting an egg’s chances of leading to a pregnancy.
But the technique also raises thorny ethical questions due to Zhang’s bypassing the oversight that typically regulates research on human subjects at American hospitals and universities. Since MRT isn’t approved in the United States, Zhang’s team carried out the procedure in Mexico. In addition, the safety of the procedure has been called into question, in part because MRT transfers some of the mother’s mutation-harboring mitochondria — mutation levels that could increase over time.
If proved safe and effective, MRT could prevent a host of incurable, often fatal diseases resulting from mutations in the DNA. Affecting 1 in 4,000 people in the U.S., mitochondrial diseases can cause impaired growth, seizures, deafness and other serious health problems. To understand how MRT works, Zhang says, think of a mother’s egg as a nucleus, or yolk — housing the vast majority of her DNA — surrounded by the egg white, which contains mitochondria. MRT plucks the yolk from the mother’s egg and transfers it to a donor egg whose yolk has been removed, leaving only the white. The result: an egg combining nuclear DNA from the birth mother and healthy mitochondrial DNA from the donor, to be fertilized with the father’s sperm.
Some scientists refer to Zhang as “a maverick,” says Martin Johnson, professor emeritus of reproductive sciences at the University of Cambridge, who co-authored the editorial accompanying Zhang’s paper. Zhang’s pioneering work on MRT has spurred other efforts to create “three-person” babies and, says Johnson, helped encourage the U.K. to approve MRT, the only country to do so.
If this technology is possible, we must perfect it and use it to save lives.
John Zhang, reproductive endocrinologist
Still wearing his doctor’s coat after rushing from the clinic, Zhang Skypes from his chic, all-white Manhattan office, not far from where he lives with his wife and three children. His responses would seem brusque, even boastful, if not for his impish smile and goofy dad humor. He grew up in Hangzhou, China, “a very pretty city that produces silk, tea and smart people,” he jokes. Seeing hopeful couples visit his mother’s fertility clinic year after year, Zhang felt called to the same profession. After graduating from Zhejiang University School of Medicine, he earned a Ph.D. in IVF from the University of Cambridge in 1991.
Shortly before starting a fellowship in reproductive endocrinology at New York University, Zhang gave his infamous talk in China. In the audience was embryologist Hui Liu, who was sufficiently impressed that he left the Chinese Academy of Sciences to collaborate with Zhang. At Sun Yat-sen University, they conducted the first human trial of pronuclear transfer, a form of MRT in which both the mother’s and donor’s eggs are fertilized with the father’s sperm before swapping out their nuclei. Although their client became pregnant, her twins didn’t live to term.
Meanwhile, Zhang was gearing up to open New Hope Fertility Center in Manhattan. After being ridiculed by the scientific community, he explains, “Nobody wanted to hire me, so I had to figure out how to make a living.” His charismatic personality appealed to patients, and it didn’t hurt that the clinic attracted celebrity clients who spread the word, says a New Hope spokesperson. (Last year, Forbes listed New Hope as the second-busiest clinic in the country.)
In 2011, a Jordanian couple sought Zhang’s help. They had given birth to two children, both of whom died of a syndrome that can cause nervous system abnormalities. Genetic testing revealed the mother carried the disease in her mitochondrial DNA. Pronuclear transfer would destroy two embryos, which went against the couple’s Muslim faith, so Zhang turned to another form of MRT, called spindle nuclear transfer, which bypasses the sticky ethics of discarding parts of fertilized eggs. After the procedure showed promising results in mice, Zhang and his team treated the couple, conducting the transfer in New York and implanting the embryo in Guadalajara. The couple gave birth to a son in April 2016.
Most mitochondrial researchers justify MRT as a means for women carrying mitochondrial diseases to deliver healthy children, writes Lisa Ikemoto, who teaches bioethics at the UC Davis School of Law, in an email to OZY. But using mitochondrial replacement to improve fertility rather than to prevent disease, “changes the issues,” she notes — there’s insufficient evidence that it’s the safest or most effective way to become a parent.
Ikemoto also worries that Zhang’s work might spur other U.S. scientists to conduct research that circumvents federal regulations. In December 2015, Congress passed a statute banning the Food and Drug Administration from considering applications for research on humans involving a human embryo with a heritable genetic modification. “It was basically done at the end of the year in the middle of the night,” with little public consultation, says Josephine Johnston, director of research at the Hastings Center, a bioethics research institute. “It’s an example of Congress trying to prevent a type of scientific research.”
Zhang welcomes the debate as “healthy,” but he’d rather identify MRT’s risks than avoid them altogether. “If this technology is possible, we must perfect it and use it to save lives,” he says. And he’s begun exploring the use of MRT for “egg rejuvenation” — improving egg quality in older women, for example — despite criticism from Ikemoto and others who think it’s too early to expand the technique’s use. “I always go against the stream,” Zhang says. Those waves have already rippled through the medical community; where they’ll break remains to be seen.