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Before he discovered science, Lefkowitz wanted to be a baseball player. Like many boys in 1950s New York City, Lefkowitz aspired to be like Mickey Mantle. But a childhood photo showing him with the wrong bat grip for a right-handed hitter made clear that another goal might be in order.
By third grade Lefkowitz decided to become a doctor, a choice he attributes to the influence of their family physician. Lefkowitz scored high enough on New York City academic exams to qualify to attend the Bronx High School of Science. It has a rich tradition of excellence, counting among its graduates eight Nobel Prize winners, six Pulitzer Prize winners and diverse talents such as music synthesizer pioneer Robert Moog and Web visionary Dave Winer.
Lefkowitz excelled there and was offered early admission to Columbia University, where he whisked through in three years and stayed on for medical school. In 1966, he graduated at the top of his class at age 23.
He worked at NewYork-Presbyterian Hospital for his internship and medical residency. It was the height of the Vietnam War, and the dramatic escalation in troop numbers created tremendous demand for military physicians. In 1967, Congress severely restricted physician deferments and exemptions; as a result, two-thirds of graduating medical students were being drafted.
However, the Selective Service exercised its right to reactivate the "doctor draft" initiated during the Korean War. Doctors would be drafted but serve in the U.S. Public Health Service as commissioned officers. Doctors could meet their military responsibilities with two years of clinical service and basic medical research at the National Institutes of Health (NIH).
"It was extraordinarily difficult to get the assignment, so they took the best and the brightest," Lefkowitz says.
The program was a great opportunity, but at the time, Lefkowitz had zero interest in research. Still, he ventured to NIH's Rockville, Md., campus and interviewed with Dr. Jesse Roth, an endocrinology researcher. Roth, now a highly decorated physician-scientist who remains active in the field, remembers the date clearly: July 1, 1966, the first day of Lefkowitz's medical internship.
Lefkowitz was very anxious to return to New York. Yet he tried to convince Roth that he was passionate about medical research—even though he had done little at Columbia—and wanted to work on "receptaz." (For both Lefkowitz and Roth, the New York pronunciation remains evident today.)
Roth says he knew that Lefkowitz, sporting "a crew cut and horn-rimmed glasses," was more interested in doing his military service on home soil. But he was impressed by the fact that Lefkowitz had survived a very rigorous and highly selective medical training program, finishing at the top of his class and securing a competitive internship, and was clearly "smart and hard-working," Roth recalls.
So in the summer of 1968, Lefkowitz drove with his wife, Arna, and their three children to Maryland to begin his two years at NIH.
Roth says he had been working with another then "not-famous guy," Dr. Ira Pastan, to understand how hormones worked. Pastan and Roth had a project for Lefkowitz in which he would try to show the existence of hormone-receiving receptor sites on the outside of cells.
Specifically, Lefkowitz was trying to understand how the brain told the adrenal glands (one sits atop each kidney) to send adrenaline into the bloodstream—the same adrenaline that we talk about flowing in athletes when they're pumped up.
To appreciate how ambitious Lefkowitz's project was, it's important to understand the state of science at the time. The receptor concept had been proposed in 1905, but most scientists thought it was an abstract idea. Few believed that receptors were real, physical things—places on cells where naturally occurring or man-made chemicals could dock and, say, cause the heart to beat faster.
"If he had been a sophisticated researcher when he came," says Roth, "he probably wouldn't have taken the project."
Roth and Pastan suggested that Lefkowitz start working with ACTH, or adrenocorticotropic hormone. ACTH is made in the pituitary gland at the base of the brain and travels to the adrenal glands to prompt them to release corticosteroids when you feel stressed or threatened. At the time, ACTH was one of few hormones sold commercially. Roth knew it could be tagged with radioactive iodine, and its effect could be easily measured inside adrenal gland cells. No one had been able to get it to work in practice.
Neither could Lefkowitz. For the first time in the precocious young doctor's career, he was an unqualified failure. "I started for 12, 18 months; nothing worked," Lefkowitz says. "I was going nuts!"
"We had to be very encouraging," Roth recalls. "I had to spend a lot of time with Bob every week. 'Don't worry, Bob. Don't worry, kid. It'll work out.'"
At Thanksgiving of his first year, Lefkowitz traveled home to New York and talked with his father, Max, about his difficulties. Max counseled him not to worry, that he needn't work in the lab forever and he could always return to clinical medicine after he fulfilled his service commitment.
Lefkowitz returned to NIH, still dejected but knowing he had to tough it out. His father suffered his fourth and final heart attack a few weeks later, just before Christmas.
"There is no doubt that the combination of his death and my initial failures in research resulted in one of the bleakest, most difficult periods of my life," Lefkowitz said in a 2010 interview for the journal Circulation Research.
Lefkowitz slowly had more success in the lab, leading to two landmark papers published in top journals in 1970. Moreover, he benefited from what was one of the most productive training environments in modern medical research, one that Roth called "an intellectual bouillabaisse."
Four of the physician-scientists Lefkowitz trained with went on to win Nobel Prizes. "I was the schlep of the group," he says.
"There were some great mentors there. But you know," he pauses, "I'm a bit of a mystic myself and there's some things you can't understand. There was just something." Another pause. "Who knows what the hell it was."