Yale physiologist elected to National Academy of Sciences

Steven C. Hebert, M.D., spent the early part of his career exploring the kidney’s basic processes using the tools of traditional physiology—radioactive tracers to track ions as they cross cell membranes and light microscopy to measure the volume of cells in the nephron, the complex and convoluted structure that forms the kidney’s basic unit.

Then in the late 1980s, he faced a choice: continue with the tried-and-true laboratory methods at his disposal or risk a leap headlong into the world of molecular genetics. Using a technique called expression cloning, in which genes are isolated according to their function, Hebert and his colleagues saw the chance to identify the molecules that transport salts across membranes and regulate calcium levels in the blood. Maintaining these functions is critical to a healthy heart, strong bones and normal blood pressure.

“My feeling at that time was the gamble was worth it because I didn’t see that we could advance in our understanding without doing these things,” Hebert said on May 3, the day he was elected to the National Academy of Sciences (NAS). Hebert is the chair and C.N.H. Long Professor of Molecular and Cellular Physiology and professor of medicine. “It was do or die.”

Apparently, the risk paid off. In the early 1990s, Hebert’s laboratory made three fundamental discoveries about how the kidney handles potassium, sodium and calcium. His group identified a channel that regulates potassium excretion and is involved in Bartter’s syndrome type II, an inherited disorder that causes sodium and potassium to be lost in the urine. He and his colleagues also identified two sodium chloride transporters that are the target sites for important diuretic drugs and explain their mechanism of action. His subsequent discovery of a calcium-sensing receptor known as CaSR led to the development of a new drug, Amgen’s Sensipar, which is used to treat hyperparathyroidism, a hormonal disorder that affects most of the more than 1 million patients worldwide with end-stage kidney disease.

“What’s really amazing,” says fellow nephrologist Peter S. Aronson, M.D., “is that Steve has made breakthroughs in three quite different areas.What he’s done is really remarkable.’

Hebert is a past recipient of the Homer W. Smith Award, the top prize given by the American Society of Nephrology, and he is traveling in June to Singapore to accept the A.N. Richards Award from the International Society of Nephrology (see related story, Kidney Researchers Celebrate a Banner Year). According to Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics, Hebert’s election to the NAS was no surprise, given the major contributions he has made to his field.

“One of the major thrusts of Steve’s work has been to put a molecular face on the abstract principles that have been defined by Gerhard [Giebisch] and other members of the physiology department here at Yale,” Lifton said at a ceremony honoring Hebert. “By identifying these molecules, he has really allowed us to begin to see how this very intricate and complex machine works in all its integrated glory.”

At the ceremony, Dean Robert J. Alpern, M.D., called election to the NAS “the greatest honor you can have as a scientist in the United States and certainly one that is reserved for a select few.” For his part, Hebert was clearly elated, and in his remarks he returned to the development of Sensipar as one of the most meaningful events in his career. “Being involved with the translation of your science into medicine,” he said, “is the greatest joy you can have as a scientist at a medical school.”