Basic science to save babies: Lee Niswander and David Rowitch are bringing their expertise in molecular science to study the causes of premature birth and developmental problems.

The research of several HHMI investigators is aimed at these most vulnerable patients—developing fetuses and babies that are born too early. They want to prevent and treat conditions that lead to a lifetime of disability for affected babies: defects in the formation of the spinal cord, a hypertensive disorder in pregnant women called pre-eclampsia, and brain damage in premature infants.

Rowitch, an HHMI investigator at the University of California, San Francisco (UCSF), and the other researchers who are trying to solve some of the most persistent problems of pregnancy face an uphill battle. No one really understands, for example, why the third trimester is so important for normal brain development. It's difficult for scientists to make observations in utero, and medical research to test treatments on pregnant women, their fetuses, and newborns is often considered too risky.

However, researchers have begun to gain traction on some of these problems. Using advanced techniques in genetics and molecular and developmental biology, they are making progress without poking or prodding pregnant bellies or newborn babies. They've found clues to the causes of pre-eclampsia, neural tube defects, and cerebral palsy. Their insights may lead to better, noninvasive diagnostic tests for the women and babies at highest risk. The findings will also build the foundation for designing treatments tailored to each patient's genes and risk level.

Advances in neonatal care have dramatically improved the survival rates of babies born between 24 and 26 weeks of pregnancy. But, Rowitch explains, about half will have lasting neurological damage—from mild learning impairments to cerebral palsy, a lifelong physical disability. “We don't know the root causes of these neurological injuries,” says Rowitch, a neonatal pediatric specialist.

About 800,000 people in the United States have cerebral palsy (CP), which can cause loss of muscle coordination, sensory problems, and mental impairment. And because more extremely premature infants are surviving, the incidence is increasing, Rowitch explains. In one country that keeps national figures, the United Kingdom, a recent study found that, between 1994 and 2005, the survival of babies born at 24 and 25 weeks increased by 17 and 11 percent, respectively.

“Is it the stress of being delivered early, infection, and/or the inflammatory response that happens in these babies? We don't know,” he says. Rowitch speaks with the reserved demeanor of someone who has consoled countless families, and he talks about his patients as if they were fully formed adults. His tone reveals his commitment to see them reach their full potential.

Something about the third trimester of pregnancy—which these babies experience in the alien environment of a neonatal intensive care unit (NICU)—is critical for brain development. Because of their limited ability to peer inside the newborn brain, Rowitch's laboratory group has turned to some clever research models to gain a better view of brain damage and the brain's repair processes.

Using mouse models of brain damage similar to CP and looking at other cases of human neurological damage, Rowitch's group has identified problems in two sets of precursor cells in the brain. One precursor becomes the oligodendrocytes, which act like road crews repaving damaged surfaces along nerve tracts, the information highway connecting brain cells. The researchers found that the cells in the brains of premature infants sometimes remain stuck in the precursor stage—in part due to flawed signaling—and fail to repair.

Using a mouse model, Rowitch's team investigated the neuron precursors that drive the burst of growth in the cerebellum in healthy babies just before and after birth. The cerebellum is the part of the brain that integrates coordination and motor control. His group found a key connection: They showed how steroid drugs, like those given to help premature lungs develop, can inhibit growth of these cells. When the team artificially turned on a natural defense mechanism in the cells against the steroids, the problem was alleviated.

Photos: Niswander: Anthony D. Kapp; Rowitch: Andy Kuno / PR Newswire, ©HHMI

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