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Doctors cite progress on illness tied to pregnancy

It was just a routine gathering of cancer specialists to review trials of new medicines. But the report on one particular cancer-fighting drug jumped out at Dr. Vikas Sukhatme, a gentle-mannered kidney specialist. Its side effects were all too familiar -- they were exactly the symptoms of pregnant women with preeclampsia, a long-baffling syndrome that kills an estimated 76,000 mothers worldwide each year.

"Holy smokes," he said, almost falling off his chair.

That insight about two years ago helped Sukhatme and a team centered at Beth Israel Deaconess Medical Center to crack a big piece of the mystery of preeclampsia. Yesterday, they reported in The New England Journal of Medicine that they have detected a marker for the disease in pregnant women's blood about five weeks before its onset.

The marker could help doctors screen women for preeclampsia, which can hit suddenly and progress rapidly from high blood pressure to life-threatening seizures and kidney failure.

The research also points the way toward potential drugs for preeclampsia. Currently, the main treatment for the 200,000 American women diagnosed with it each year is to try to control their blood pressure, but often the baby must be delivered early -- sometimes, too early to survive.

The team's work represents "the most promising lead yet in the pursuit of a life-threatening disorder that has defied all attempts to prevent or cure it," said Dr. Duane Alexander, director of the National Institute of Child Health and Human Development, in a statement released yesterday.

How the researchers did it -- how some kidney specialists trespassed into obstetric territory and seemingly grabbed a scientific prize -- may hold some broader lessons, they say.

One is that it pays to be both a scientific researcher and a clinical doctor. Without Sukhatme's clinical observations, it might have taken another five years to focus on the right culprit in the disease.

Another, said Sukhatme, who earned a doctorate in physics from MIT before becoming a medical doctor, concerns the freedom to take scientific risks. It was because he and his colleagues felt free to explore -- and had a little seed fund to support such high-risk projects -- that they could venture into a different field.

And then, there is the eternal power of serendipity in scientific discovery, said Dr. Benjamin P. Sachs, chief of obstetrics and gynecology at Beth Israel Deaconess. "You can plan for science," he said, "but in the end, it's happy chance and intuition."

The story of the team's success begins in the fall of 2001, when Dr. S. Ananth Karumanchi, a young doctor turned scientist trained in India, was just starting out as head of his own small lab in the division led by Sukhatme, his mentor at Beth Israel Deaconess.

Wanting to distinguish himself from his mentor, Karumanchi decided that preeclampsia might be a good topic for his research. He had worked for years on blood vessels, which are important in kidney disease, and he suspected they were the key to preeclampsia.

Working together with his only postdoctoral fellow, Dr. Sharon Maynard, a kidney doctor who had never done lab work before, Karumanchi gathered 40 placentas from the hospital's delivery rooms, where they are routinely thrown away after birth. Using new "gene chip" technology, the researchers compared placentas from women with preeclampsia with the placentas from women without it, to see which genes were more active in the preeclamptic women, and therefore possibly involved in the disease.

They came up with about 200 genes, narrowing them to 20 likely genes. One of them, sFlt1, seemed especially active.

The two presented their results at the Sukhatme lab's weekly meeting. As Maynard recalls it, "We were just discussing a list of molecules, and Vikas [Sukhatme] was there, kind of gazing at the screen in this thoughtful way he has. And then he turned to Ananth with this look of transformation on his face."

Pursue this hard, Sukhatme recommended. He had good reason for his enthusiasm.

A cancer specialist along with his kidney work, Sukhatme was a specialist on "antiangiogenesis" drugs, which stop the growth of blood vessels and have been promoted by Dr. Judah Folkman, who says that cutting off a tumor's blood supply can help fight cancer.

Clinical trials of the drugs were underway, and in two recent talks, Sukhatme had heard that some of the patients in the trials had mysteriously developed high blood pressure and protein in their urine -- also the classic symptoms of preeclampsia. The protein in the urine indicates that the kidneys are not working well as filters.

At the first talk, Sukhatme said, he merely pricked up his ears; at the second talk, about a different antiangiogenesis drug, he asked whether patients developed high blood pressure and protein in their urine. He was told, somewhat sheepishly, that they did, and "I fell off my chair," he recalled. "I said, `Holy smokes!' Now we have two drugs working in one common pathway that are structurally unrelated, and both block vegf," or vascular endothelial growth factor.

In other words, he said, the researchers were on their way to figuring out that preeclampsia was, in a sense, the opposite of cancer.

In cancer, substances called growth factors like vegf are spurring small blood vessels to grow and supply the tumor. In preeclampsia, other substances, like sFlt1, are inhibiting the growth factors and clamping down on the blood vessels.

So when patients awash in blood-vessel growth factors because of their cancer were being given growth inhibitors, the balance in some tipped too far, it seems, and they got symptoms of preeclampsia.

Theoretically, Sukhatme and Karumanchi say, the reverse might be true: if sFlt1 acts like an antiangiogenesis drug, then a patient with preeclampsia might be helped by taking drugs that stimulate growth, like vegf.

And there was a clinical clincher: Sukhatme knew of a current cancer patient who was on a third, similar antiangiogenesis drug. He quickly had the patient's urine checked: Sure enough, there was protein in it, he said. "That third patient was when I felt this was clicking," he said.

Karumanchi still needed better proof. So, with the help of a Children's Hospital Boston colleague who happened to have the sFlt1 -- it was a well-known molecule, it just had not been linked to preeclampsia -- he induced pregnant rats to produce it in excess.

The sFlt1 produced classic preeclampsia symptoms in the rats, including distinctive lesions on their kidneys. "That's when we got very excited," he said.

With their current paper, too, Karumanchi and company got lucky: In the mid-1990s, the National Institute of Child Health and Human Development had studied more than 4,500 pregnant women to see whether calcium supplements could reduce preeclampsia.

The calcium idea did not pan out, but the institute still had the blood samples in storage, and the study's director, Dr. Richard Levine, shared 240 of the samples so they could be checked for sFlt1. The researchers found that in the women who got preeclampsia, sFlt1 levels had risen earlier and reached higher levels than in normal pregnancies, Levine said.

Dr. Susan Fisher, a prominent preeclampsia researcher at the University of California at San Francisco, cautions that sFlt1 may be only one of many factors in the disease that need to be unraveled. But the Beth Israel Deaconess research "is a very solid piece of work that makes sense," she said.

The team's work appears promising enough that Beth Israel Deaconess has struck a licensing deal with Scios, an affiliate of Johnson & Johnson, to develop a preeclampsia drug, the hospital says. It would be years before such a drug would be available, but researchers are already beginning to contemplate clinical trials in pregnant women.

One thing Sukhatme knows, he said: If and when the trials begin, "Ananth and I will be there when the first patient gets the drug. We'll be up all night, and we will be watching very carefully."

Carey Goldberg can be reached at goldberg@globe.com.

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