Medicine and Translational Research, Physiology
Beth Israel Deaconess Medical Center
Dr. Karumanchi is also an associate professor of medicine at Harvard Medical School and an attending physician in the Nephrology and Molecular and Vascular Medicine Divisions at the Beth Israel Deaconess Medical Center.
Behind the blissful togetherness of a beaming mother and her newborn baby, there is sometimes a back story of biological rivalry. In the last weeks of gestation, a sharp conflict of interests may pit fetus against mother in a potentially deadly struggle for survival. About 5 percent of pregnancies are complicated by preeclampsia, a dramatic rise in the mother's blood pressure accompanied by faltering kidney function that sends protein surging into the urine. Unchecked, it can lead to seizures, coma, and, rarely, death of the mother and/or fetus. Usually, the crisis is defused by immediate delivery of the fetus and placenta. This protects the mother but can lead to severe consequences for the infant if it is delivered early in the pregnancy.
Ananth Karumanchi, a kidney specialist at Beth Israel Deaconess Medical Center in Boston, had treated several women with the condition and was intrigued by the problem. When he began studying preeclampsia in 2001, it had been recognized for centuries, but its cause remained an enigma. Evolutionary biologists had proposed that the placenta, which commandeers blood from the mother during pregnancy, triggers preeclampsia as a strategy to ensure survival of the fetus. In this model, the fetus or placenta provokes a rise in the mother's blood pressure when it senses a shortage of nourishment, thereby driving more blood and nutrients to the fetus. But what is the trigger? Despite many hypotheses, the riddle remained.
Karumanchi obtained postdelivery placental tissue and used DNA microarray analysis to look for genes that were expressed at unusually high levels in the placentas of women who had had preeclampsia. Surprisingly soon, a likely culprit popped out of the data: a protein called soluble FLT, or sFLT1.
To maintain normal blood pressure and prevent protein leakage into the urine, blood vessels in the kidney and elsewhere in the mother's body require growth factors to maintain the endothelial lining. Excess sFLT1 prevents two proteins—vascular endothelial growth factor and placental growth factor—from carrying out this maintenance, leaving the vessels tattered and susceptible to hypertension and kidney damage. Although this damage appears to resolve after delivery, even mild preeclampsia is associated with increased risk of heart disease and stroke later in life.
When Karumanchi published his initial findings in 2003, they created a stir in the field. Some thought the report brilliant; others argued that increased sFLT1 didn't explain all the pathology of preeclampsia. In later studies, Karumanchi uncovered another weapon in the placenta's arsenal: a circulating protein called soluble endoglin, which acts synergistically with sFLT1 to create a more severe, early-onset form of preeclampsia. Endoglin is responsible for some of the hematological and liver problems not explained by excess sFLT1 alone.
Excitement over the initial discovery grew when, in a large collaborative study with Richard Levine at the National Institute of Child Health and Human Development, Karumanchi found that levels of sFLT1 began to rise about five weeks before women experienced symptoms of preeclampsia. Suddenly, there were remarkable implications. An early-warning blood or urine test might identify women who should be closely monitored. Preventive drugs might be developed to keep the disorder at bay until the fetus is mature enough to deliver.
Because of pregnancy-related safety issues and the relatively small potential market—200,000 women in the United States develop preeclampsia annually, with 20,000 to 30,000 severe cases—pharmaceutical companies have not been very enthusiastic about developing therapies in this area. Karumanchi says, however, that a diagnostic test could come sooner. An early-warning test has the greatest potential to save lives in the developing world, he says, giving women in remote areas time to reach skilled prenatal care.
Karumanchi is following up his discoveries in an effort to understand what regulates production of the placental molecules and how the soluble factors cause the symptoms of preeclampsia. He would also like to determine whether some women are genetically predisposed to the condition. “And then, finally,” he says, “we would like to come up with therapies that block either the production or the action of these toxic proteins.”
The story of how Karumanchi solved the long-standing puzzle of preeclampsia was so compelling that renowned physician-author Jerome Groopman recounted it in a feature article in The New Yorker in 2006. Despite an initial reluctance to be interviewed for a popular magazine, Karumanchi has found the attention to his work and the awareness of preeclampsia a positive outcome of the story.
The article had an unforeseen personal benefit as well. Karumanchi sent a copy to his parents, who are retired and live in India where he was born. “My father, who is an engineer, had been trying to persuade me to do more clinical work and not spend so much time on laboratory research,” Karumanchi says. “When he read the article, he said, `I guess what you're doing is a good thing after all. So keep on with it!'”