Road to Research

The schematic representation shows some of the salient features (indicated in color) of a typical G protein-coupled receptor.

Lefkowitz himself is fundamentally a biochemist and molecular biologist who never intended to make research his career. As a child, he read medical fiction (and detective stories), and it was in the third grade that he decided to become a physician."Doctors were my heroes," he said. Thus, when the time came, he went to medical school at Columbia University, finishing first in his class. He got hooked on research, however, during a short stint at the National Institutes of Health—and never looked back.

When he started working on adrenergic receptors in the early 1970s, even Raymond Ahlquist, who coined the terms "alpha" and "beta" receptors, believed them illusory. Experiments suggested that they should exist, but scientists had seen only their shadows, the marks they made on the cell. No one had ever proven them real.

Ever the pragmatist, Lefkowitz was undeterred by the idea that receptors may not exist as separate entities. Logically, he was convinced that they existed, so he set out to isolate them.

"Especially when you are young, you have chutzpah... the brazen gall of youth," he says. "I didn't appreciate that it was a risk, and you know what, it never entered my mind that I wouldn't succeed; incredible isn't it? ... I had no reputation to lose."

But he soon gained a reputation, and it wasn't the one he had hoped for. The b adrenergic receptor whose identification he reported in a journal article turned out to be another adrenaline binding protein. The scientific press pilloried him.

"I watched his response through this period," said Lewis T. (Rusty) Williams, Lefkowitz's first graduate student and now chief scientific officer at Chiron Corp. "Here he was, a young faculty member trying to make his mark. He wasn't demoralized by the criticism. He just wanted to get the right answer. He probably doesn't even realize that watching his response to adversity made a huge impression on me. I watched him doggedly pursue this goal even through all the criticism. He kept going until he got it."

It took a couple of more years, but he found the receptor. Since then, Lefkowitz and his army of graduate students, medical students and residents, and postdoctoral fellows (some 160 since the mid-1970s) have methodically dissected and reassembled the essential elements of a signaling system that has been a model for receptor biologists.

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