“Ultimately we have to go to the mouse and then to humans to see if the genes we're finding are relevant,” he notes. “But the frog work has allowed us to move the field forward very quickly.” Wallingford has found two major groups of genes critical for closing neural tubes. Recently, his group showed that certain gene mutations prevented a key process called convergent extension where neighboring cells cozy up and slide between one another to bring the neural folds closer together. At least one similar gene mutation has been found in humans with NTDs.

Here, John Wallingford stained individual cells in a frog embryo to see how they move as the neural tube closes.
John Wallingford and Chanjae Lee

Finding more of those human genes is the real goal for both Wallingford and Niswander. “I'm not out to solve the problem of neural tube closure for frogs,” says Wallingford. These birth defects are almost never due to a single gene mutation in humans; they are most often the result of multiple gene variations and their interaction with the environment. What the researchers would like to see in the future is a panel of known neural tube closure genes for screening. Then, when a couple is considering pregnancy, a blood test could determine whether they would be at high risk for a NTD pregnancy. From there, physicians might even personalize a woman's dose of folic acid. Niswander's early findings suggest that an average dose may not be right for all genetic situations. For some mutations, a higher dose is needed to rescue the NTD; for other mutations, a lower dose works better.

Work from another HHMI investigator's lab might also lead to a blood test to assess a woman's risk for a common complication of pregnancy that puts both mom and baby in harm's way. Five to 10 percent of all expectant mothers develop pre-eclampsia, characterized by high blood pressure and “leaky” blood vessels that can lead to kidney damage, liver damage, and even seizures and coma.

In the developing world, pre-eclampsia kills an estimated 75,000 women each year. In the United States, the total health care costs for pre-eclampsia treatment for both mothers and babies run about $7 billion a year. The only treatment available today is to deliver the baby and placenta, the real root of the problem, as early as possible after severe pre-eclampsia develops. Pre-eclampsia therefore contributes significantly to the problem of premature births. How and why the placenta becomes destructive in some pregnancies has remained an enigma since the condition was first described some 2,000 years ago.

As a kidney specialist at Beth Israel Deaconess Medical Center in Boston, HHMI investigator Ananth Karumanchi diagnoses tricky cases of pre-eclampsia, ruling out other possible kidney problems to ensure no baby is delivered unnecessarily early. His research, however, may soon make this duty obsolete.

“We've identified biomarkers that, in a very simple blood test, could potentially replace a kidney biopsy down the line. The markers could tell us who has pre-eclampsia, who doesn't, and maybe even how severe it is,” says Karumanchi.

Karumanchi, whose early research focused on blood vessel formation, or angiogenesis, brought a new approach to the riddle of pre-eclampsia. The placenta is just a bag of blood vessels, after all. “No one had looked at it from the angle of blood vessels and I thought, here is a disease where I could have a 200 percent impact—on both the baby and the mother.” But as a young investigator at the time, he wanted to run his idea by his mentor down the hall, a kidney expert named Frank Epstein.

“He grabbed me and said, “Let's go down right now to the labor and delivery floor and see these patients,’” Karumanchi recalls. There, it dawned on him that every day doctors threw away placentas from both healthy and pre-eclamptic women.

He obtained those tissues and used gene microarrays to look at which gene expression levels were turned up higher or squelched in pre-eclampsia placentas compared with normal ones. Karumanchi's research team found that two proteins, sFlt-1 and soluble endoglin, are pumped out by pre-eclamptic placentas. The proteins appear to disrupt the health of a mother's blood vessels, which damages her organs and makes her blood pressure rocket upward.

Karumanchi says that clinical trials of a blood test to measure sFlt-1 levels as a way to detect pre-eclampsia are ongoing in the U.S. He predicts such a test will be available in two or three years. As evidence piles up that sFlt-1 not only indicates pre-eclampsia but also causes much of the problem, Karumanchi is developing antibodies to sFlt-1 as a potential treatment.

Although the work is still in early stages, he says that finding women to help test such a drug will not be hard. Severe pre-eclampsia results in babies being delivered at 24-26 weeks, when the chance of losing a baby can be as high as 80 percent in areas of the world where NICUs are lacking, and most babies who do survive will have long-term mental and physical disabilities.

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