The prematurity test isn’t Quake’s first foray into prenatal health. When Athina was pregnant with Zoe, she had undergone amniocentesis, an invasive needle biopsy used to detect Down syndrome and other conditions. When it’s executed by doctors with lots of experience, the risk of miscarriage is low, but it exists—and that’s nerve-racking for expectant parents. “I thought, Oh my God, this is awful—that you have to risk losing the baby to ask a diagnostic question,” he says.

Convinced there had to be a better way, Quake got to work developing noninvasive blood tests to assess much of the same information as amniocentesis but with less risk to the pregnancy. He used bits of free-floating fetal DNA found in maternal blood to get a peek at the genetic makeup of the fetus. More than a decade later, multiple biotech companies offer a version of similar tests for Down syndrome and other conditions to pregnant women in clinics worldwide.

“I thought, Oh my God, this is awful—that you have to risk losing the baby to ask a diagnostic question.”

Likewise, blood tests, often called “liquid biopsies,” are in development for a number of applications, including detecting early-stage cancer and revealing whether a replacement heart is failing in the body of a transplant recipient. In 2014, Quake identified evidence of dying neurons in the blood circulation of Alzheimer’s patients, a step that is being used to develop tests for neurodegenerative and autoimmune diseases.

Predicting preterm birth would be another important breakthrough. Globally, more than one in 10 babies is born preterm, a public health problem that cuts across socioeconomic and geographic boundaries. Babies in poor nations like Malawi are born too soon—the country has an 18% rate of preterm birth, the highest in the world—but so are babies in the US, like Quake’s daughter in prosperous Southern California.

Complications from preterm birth are the leading cause of death worldwide in children under the age of five. Preterm babies can struggle with infection, learning disabilities, and problems with vision and hearing. In poor countries, babies born significantly preterm often don’t survive. In wealthy countries they usually do, but sometimes with long-term consequences including behavioral problems and neurological disorders such as cerebral palsy. There’s an economic factor, too: babies born preterm cost, on average, 10 times as much over the first year of life as those whose birth had no complications.

Just ask Jen Sinconis, whose twins arrived with no warning at 24 weeks’ gestation in 2006. Twin pregnancies are considered high risk, but Sinconis’s pregnancy had been uneventful until she started having what she assumed were Braxton Hicks contractions, which can occur weeks in advance of delivery as the uterus primes itself for labor. She was wrong, and her twin boys arrived within six hours.

One of the Sinconis boys in the ICU. Courtesy of Jennifer Sinconis

Aidan weighed 1 pound, 14 ounces (850 grams) and had to spend three months in the hospital; Ethan weighed 1 pound, 6 ounces, and was worse off. He was on oxygen for most of his first year of life and barely escaped needing a tracheotomy. Sinconis received a shot of surfactant to help develop her sons’ lungs as soon as she reached the hospital, but if a test had been able to alert her doctor that she was at risk for early labor, she could have been given the medicine sooner, when it could possibly have made a difference. “If I had known they would have been born prematurely, our entire life would be different,” says Sinconis, a creative producer at Starbucks corporate headquarters in Seattle.

The boys’ medical care cost more than $2 million and didn’t end when they left the hospital. They remained in isolation at home for the first three and a half years of their lives; Sinconis can barely keep track of the number of doctors and therapists they’ve seen through the years. She and her husband were forced to sell their home, liquidate their retirement and savings accounts, and eventually declare bankruptcy to deal with the nearly $450,000 that insurance wouldn’t cover. Now 12, the boys have mostly caught up developmentally to other children their age. But their parents are just starting to emerge from their financial struggles. “We’re way overdue for a way to predict preterm birth,” Sinconis says.

Jen Sinconis’s twins arrived at 24 weeks in 2006. Now 12, the boys are mostly healthy. Courtesy of Jennifer Sinconis

A new test

Zoe, now 17, “is all grown up and totally healthy,” says Quake, a professor at Stanford University for the past 14 years, but figuring out how to predict preterm birth had been in the back of his mind since she was born. It “felt like the next big mountain to climb,” he says. “We had gained confidence from noninvasive prenatal testing. Preterm birth was like Mt. Everest.”

Quake knew there were no meaningful diagnostics that could identify which pregnant women would give birth too soon. The biggest tip-off is having given birth to a preterm baby before, something of little use for a first-time mom. Additionally, preterm delivery can be caused by multiple factors: infection, twins, or even maternal stress. “We don’t have any understanding about what is triggering preterm birth,” says Ronald Wapner, director of reproductive genetics at Columbia University Irving Medical Center. “We have been shotgunning it.”

Quake also knew that direct DNA measurements wouldn’t help. Analyzing a baby’s DNA, inherited from his or her parents, is fundamental to testing for Down syndrome because it can reveal the presence of an extra chromosome. “It’s a genetic question,” says Quake. But research has shown that the baby’s genetic profile makes a minimal contribution to prematurity. So instead, Quake focused on DNA’s molecular cousin, RNA. These molecules are harder to spot in blood (they’re short-lived) but would provide a more relevant readout, Quake believed, because their levels go up and down according to what’s going on in a person’s body. Could it be that a pregnancy headed for trouble was sounding early alarm signals?

“Holy shit, might we have figured out a way to determine preterm birth?” he recalls thinking.

Quake and his team, including Mira Moufarrej, a grad student in his lab, scrutinized blood samples from 38 African-American women considered at risk for preterm birth, in some cases because they’d previously had a premature baby. Overall, black children in the US are born prematurely about 50% more often than whites. Thirteen of the women ended up delivering early. By analyzing RNA molecules in their blood, the researchers found seven genes whose changing activity signals, taken together, seemed to predict which babies had arrived prematurely.

Quake told me he was surprised by the result. “Holy shit, might we have figured out a way to determine preterm birth?” he recalls thinking. “We’re still trying to understand the biology behind these seven genes,” he adds; it’s not yet clear whether the signals are emanating from the mother, the placenta, or the baby. Quake suspects they are “reflecting the mom’s response to the pregnancy going off track.” In other words, he says, “the whole thing is derailing and the mom is responding to that.”

“The beauty of this approach is that it allows us to see a conversation going on between the mother, the fetus, and the placenta,” says David Stevenson, co-director of Stanford’s Maternal and Child Health Research Institute and principal investigator at its prematurity research center. “It’s like eavesdropping. Now we can access this as it’s being communicated, which helps us understand what’s going on throughout pregnancy.”

Treatment Hope

Five hundred years ago, fascinated by his anatomical dissection of the womb of a pregnant women who had died, Leonardo da Vinci wrote about his intention to unravel the secrets behind conception and preterm birth. He never did, and even today, there are relatively few answers. Perhaps because so little is known, pharmaceutical companies haven’t seen preterm birth as a promising area for investment. Indeed, it is “one of the most neglected issues,” says Sindura Ganapathi, co-leader of the Maternal, Newborn & Child Health Discovery & Tools portfolio at the Gates Foundation, which along with the March of Dimes and the CZ Biohub, a medical initiative funded by Mark Zuckerberg and his wife Priscilla Chan, has funded Quake’s work.

“We need many more interventions,” says Ganapathi. “We are pretty limited in our armamentarium.”

A test could be a first step toward new drugs or treatments. Knowing who is at risk would let women prepare—say, by picking a hospital with a neonatal intensive care unit or working with an obstetrician who could prescribe progesterone, a drug sometimes given to try to extend pregnancy. “It goes back to personalized treatment,” says Wapner. “We still haven’t been able to identify how progesterone works and who it works for better. RNA could help us better understand who should get these medications.”

The new window on pregnancy could lead to applications beyond preterm birth. “From the standpoint of where this could go, you could look at placental development, fetal development, and fetal-maternal interaction,” says Wapner. “RNA has been the stepsister of DNA until very recently. It’s a damn good clue about how to differentiate who’s at risk of preterm birth, and it could give us a better way of evaluating what’s going on during pregnancy.”

In line with that, Quake has formed a startup, called Akna Dx, with lofty goals. It’s raised more than $10 million from investors including Khosla Ventures of Menlo Park, California. “Our idea is to do blood-based tests to give key insights,” says CEO and cofounder Maneesh Jain. “What is a fetus’s gestational age? Are you at risk for preterm birth, or severe postpartum depression? Pregnancy tends to still be a big black box. We want to give you insights into what is happening internally so you can take action.”

Other experts say more evidence is needed that RNA can provide those insights. That’s because so many different factors can contribute to prematurity, and it’s not clear how well Quake’s biomarkers will do in a broader population. “The difficulty is that preterm delivery is not caused by one thing,” says Diana Bianchi, director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and an expert in noninvasive prenatal testing. Infection, a compromised placenta, maternal stress, a twin pregnancy—all of these and more can trigger preterm birth. “In really small numbers, Steve was accurately able to distinguish women at risk of delivering preterm,” says Bianchi. “But the numbers were really small.”