Biophysicist Stephen Quake understands as well as anyone the anxiety prompted by prenatal testing such as amniocentesis, which requires the insertion of a needle into a mother’s uterus. The risk is statistically slight but haunting: as much as a 1 percent chance of miscarriage.
“I’ve got two kids, and my wife in both pregnancies had invasive tests done,” says Quake, a professor of bioengineering. “And it was really nerve-racking, so I knew that. I was sensitized to it being a pretty significant issue in a lot of people’s lives.”
In October, a Quake-led team of Stanford researchers published headline-making findings on the development of a blood test that could be an alternative to invasive procedures while accurately detecting Down syndrome and other congenital disorders involving an abnormal number of chromosomes. The hope is that it will be commercially available relatively quickly.
“I think two to three years, that’s my guess,” says Quake, ’91, MS ’91, who supervised the project while working at Stanford facilities as an investigator for the nonprofit Howard Hughes Medical Institute. The institute spends almost $700 million annually on biomedical research, becoming for periods of time the employer for investigators at more than five dozen universities, medical schools and other sites.
Quake, whose MS is in mathematics and PhD in physics from Oxford, is the study’s senior author. Key members of his team include H. Christina Fan, the lead author and a bioengineering doctoral student, and Yair Blumenfeld, a postdoctoral medical fellow in obstetrics and gynecology.
Diana Bianchi, president of the International Society of Prenatal Diagnosis, says the research amounts to “a tentative breakthrough.” Bianchi, a professor of pediatrics, obstetrics and gynecology at Tufts University School of Medicine, would like to see the initial results—which were based on the pregnancies of 18 women—validated by a larger number of samples gathered in a partially revised study.
Quake says he’s looking forward with confidence to a larger study, involving “hundreds of women,” that settles all remaining issues. “I think it’s going to get better,” he says of the research. “In our first study, we took women at all stages of their pregnancy, and I think what you’re going to find in a larger study is that we’re going to be able to do detection very early on, maybe as early as the fifth week. I’m very eager to see that progress.”
The leap forward in the work by Quake’s team involves the ability to employ cutting-edge technology in a way that identifies millions of short sequences, or fragments, of DNA from the blood samples. Those fragments could then be associated with the 23 pairs of chromosomes that are the norm for an individual. The process successfully found excessive DNA for the specific chromosomes that were present as a set of three instead of a pair in the fetus—chromosome 21, in the case of Down syndrome.
“The way I sort of try to explain it to a lay audience,” says biophysicist Quake, “is that we take all these DNA molecules from the mom’s blood—some are from the mom, some are from the baby—and we sequence them, millions of them, and then we let them all ‘vote.’ And they each . . . vote for a chromosome. And we go through and we tally up all the votes, and we’re basically looking for voter fraud. We’re looking for one chromosome that’s overrepresented beyond what it should be.”
Quake read an article in 2005 about the challenge of precisely measuring DNA for noninvasive testing. He immediately believed he could overcome the problem, but the methodology the team tried first “could never quite get there.” When success arrived, it was exhilarating. “We decided to take a radical change of approach and try counting molecules in a different way,” recalls Quake, “and then it all just—it was beautiful. It all just unfolded in front of us.”
Fan, who did the “benchwork” (handling patient plasma samples, for example, or performing data analysis), was working on her first project as a graduate student. She was rotating among different labs and landed in Quake’s at the time his idea was percolating. It resonated, she says, because “I come from a family of physicians and have always wanted to work on innovative, clinically related applications.”
She’s also intent on emphasizing the importance of everyone else involved, such as Blumenfeld (“the clinician who made this study possible”) and the genetic counselors and research nurses who helped recruit patients and delivered blood samples.
The ultimate reward is around the corner, they hope. Stanford has licensed the intellectual property, notes Quake, to two Bay Area companies—including Fluidigm Corporation, a South San Francisco firm that Quake co-founded—and they are working to bring the test out of the lab and into medical practice.
