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When his wife was pregnant with their first child, physicist Stephen Quake, PhD, had an unsettling experience that would change the course of his work. His wife was undergoing amniocentesis, in which the doctor inserted a needle into her abdomen to obtain fluid to identify possible genetic abnormalities like Down syndrome. The test can put both the life of the mother and the baby at risk.
“It was the kind of experience that shook us a bit, as it does many people,” says Quake, the Lee Otterson Professor of Bioengineering and Applied Physics. “So I began to appreciate that there were important problems in prenatal health that needed to be solved.”
The issue was on his mind when he came to Stanford in 2005. He felt intrigued by an old observation that the free-floating DNA of a fetus can be found in the mother’s bloodstream. He wondered whether the phenomenon could be put to practical use in a clinical test. It so happened that Yair Blumenfeld, MD, then a fellow in maternal-fetal medicine at Stanford, was interested in the same question.
Blumenfeld helped recruit a group of pregnant women at Packard Children’s who agreed to donate their blood for study. Using advanced gene-sequencing methods developed in Quake’s lab, the researchers accurately detected nine cases of Down syndrome among the women in the 14th week of pregnancy.
The results were published in 2008, opening the floodgates to a new non-invasive blood test, which has now been used by millions of pregnant women worldwide. It has virtually replaced amniocentesis, says David Stevenson, MD, Harold K. Faber Professor of Pediatrics, senior associate dean of maternal and child health, and professor, by courtesy, of obstetrics and gynecology.
“It has led to a complete transformation of the way obstetricians practice in this country—and around the world,” Stevenson says. “And it all started here at Stanford.”
Quake began collaborating with Stevenson on another intractable problem in pregnancy—prematurity—which is the leading cause of death worldwide among children under age 5. Quake’s own daughter had been born a month premature, a fragile infant in the 5th percentile of weight. Though she is now a thriving 17-year-old, he knew there had to be a way to predict which mothers might deliver early and prevent needless infant deaths and complications.
Fortunately, one of his Stanford colleagues, visiting professor Mads Melbye, MD, had assembled a group of 31 pregnant Danish women willing to have their blood taken every week. Using these samples, researchers were able to monitor the RNA in the women’s blood, eavesdropping on the molecular messages being generated over the course of the pregnancy by the mother, baby, and placenta.
“We could watch the whole program of human development happening,” Quake says. “It was amazing.”
From this data, they identified nine genes produced by the placenta that can predict the age of the fetus in the third trimester. These estimates were comparable to those based on ultrasound; however, the new technology has several advantages, Quake says.
“Ultrasound only works early in pregnancy,” he says. “If you happen to miss that window, there are not a lot of other choices. Now we can offer another choice, and we can do it in a way that we think will be cheaper and easier to use in the developing world because It doesn’t involve expensive equipment.”
He and his collaborators also worked with two groups of pregnant women at the University of Pennsylvania and the University of Alabama who were at risk of having preterm deliveries because of their past histories. The researchers twice sampled the women’s blood and identified seven genes from the mother and the placenta that could predict which pregnancies were likely to end early.
The results, published in 2018, could lead to the first prematurity test. It would give women the chance to prepare, say, by getting care from a high-risk obstetrician and being near a hospital when their delivery time comes, Quake says.
He and Melbye and Stanford Genetics Chair Michael Snyder, MD, have since formed a startup that is planning a large trial of the prematurity test, which could reach the market in two to three years. He says collaboration was key to the success of the seven-year project.
“No one could have done it by themselves, and by working together, we were able to accomplish something significant,” Quake says.
Watch Stephen Quake’s keynote at the Childx conference: supportLPCH.org/Quake.
Much of the funding for this work came from philanthropy, including the March of Dimes Prematurity Research Center at Stanford; the Bill and Melinda Gates Foundation; and the Chan Zuckerberg Biohub, of which Quake is co-president.
This article originally appeared in the Spring 2019 issue of Packard Children’s News.