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Robert Lefkowitz
 
Robert Lefkowitz
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Robert Lefkowitz Biography

Nobel Prize in Chemistry

Robert Lefkowitz Date of birth: April 15, 1943

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  Robert Lefkowitz

Robert Lefkowitz was born in New York City and raised in the borough of the Bronx in a high-rise apartment complex known as Parkchester. All four of his grandparents were Jewish immigrants from Eastern Europe. His father, Max, was an accountant in the garment industry; his mother, Rose, was an elementary school teacher who set high standards of academic accomplishment for her only child. Max Lefkowitz was mathematically gifted, and enjoyed teaching his son mathematical tricks and games.

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A precocious reader, the young Robert was excited by Paul de Kruif's The Microbe Hunters and enjoyed Arrowsmith, Sinclair Lewis's tale of an idealistic physician. The family doctor became his role model, and he decided at an early age that he wanted to be a physician. An active Boy Scout, he also enjoyed experimenting with a chemistry set and a microscope, playing stickball in the street, and following the fortunes of the New York Yankees. After attending his local elementary and junior high schools, he won admission to the famed Bronx High School of Science, a public school that admits students on the basis of a competitive examination.

Then as now, academic standards at Bronx Science were high; Lefkowitz would become the eighth graduate of the school to receive a Nobel Prize. He graduated in 1959 at the age of 16 and entered Columbia University. Although he enjoyed his classes in organic and physical chemistry, as well as an advanced seminar in biochemistry, he remained committed to his goal of studying medicine. He completed his bachelor's degree at age 19 and entered Columbia College of Physicians and Surgeons. After his first year of medical school, he married Arna Gornstein and the couple quickly started a family. In the middle of his medical studies, Robert Lefkowitz became a father at age 21. Despite the demands of his family life, Lefkowitz thrived in medical school, just as he had in every other academic setting.

Graduating from medical school in 1966, he undertook an internship at Columbia Presbyterian Medical Center. For two years, he endured the grueling schedule expected of medical interns in that era, often going without sleep for two days and nights while on call at the hospital. In 1968, America's military involvement in Vietnam was at its peak, and all young physicians were subject to compulsory military service. One avenue open to doctors with exceptional academic credentials was a commission in the United States Public Health Service. Lefkowitz received one of the coveted commissions and relocated, with his growing family, to work at the National Institutes of Health (NIH) in Bethesda, Maryland, just outside of Washington, D.C. Medical research in the United States benefited enormously from the influx of talented young medical scientists in the Public Health Service during those years.

Dr. Lefkowitz arrived at NIH as new discoveries were disclosing the interaction of hormones and enzymes in the cells of living organisms. Many researchers discussed the possibility that individual receptor molecules somewhere in the cell membrane were responsible for detecting the presence of hormones such as adrenaline, histamine, dopamine and serotonin, but what or where these receptors could be found, or if they even existed, remained unknown.

Robert Lefkowitz Biography Photo
For his public health research project, Lefkowitz attempted to tag the adrenocorticotropic hormone (ACTH) with a radioactive isotope of iodine to track its progress through a plasma membrane derived from a mouse tumor. Lefkowitz was inexperienced in laboratory research and the first year of his work failed to produce the hoped-for result. Until this point, Lefkowitz had excelled at every intellectual challenge, and he found the routine setbacks of scientific research deeply disturbing. At the end of the year, Lefkowitz's father, Max, died at the age of 63. Robert Lefkowitz had enjoyed a close, supportive relationship with his father, and this loss, coming in a period of intense professional frustration, contributed to Lefkowitz's feeling of defeat.

Looking forward to the end of his term with the Public Health Service, Lefkowitz planned to undertake a residency at Massachusetts General Hospital in Boston. As he began his last year at NIH, he enjoyed a major breakthrough in the laboratory. He had at last developed the binding assay for ACTH he had sought, enabling researchers to observe the movement of the hormone through the plasma membrane. He published his first scientific papers and presented his findings at national medical conferences.

After fulfilling his commitment to the Public Health Service, Dr. Lefkowitz moved to Boston with his family, as planned, to take up his residency at Massachusetts General. Although he enjoyed the return to clinical practice, he soon missed the atmosphere of the laboratory and the pursuit of the unknown. After the first six months of residency, he was expected to choose an area of clinical practice for further study and undertake two years additional training in cardiology, but he broke with the hospital's rules for resident physicians and took a research position in the hospital's cardiology laboratory.

Robert Lefkowitz Biography Photo
Still fascinated by the possibility of discovering the elusive receptors he had first considered at NIH, he saw the potential for a whole new field of research. The first beta blocker had recently been approved for clinical use in the United States. Beta blockers (also known as "beta adrenergic antagonists") interfere with the cell's ability to respond to adrenaline, but the mechanism by which they accomplish this was not understood. Lefkowitz suspected that these drugs prevent adrenaline from interacting with a specific protein in the cell wall. In 1971, he began his hunt for this hypothetical "adrenergic receptor." Finding such receptors -- and determining their composition, properties and function -- would occupy him for the next 40 years.

Applying the radioactive techniques he had pioneered at NIH, Lefkowitz attempted the receptor for adrenaline, but developing the necessary research techniques and testing hundreds of thousands of possible receptor molecules would take many more years. Lefkowitz had to divide his time between his research and his ongoing duties as a medical resident and cardiology fellow at Massachusetts General. The fourth of his five children was born in 1971, and Lefkowitz took a number of part-time jobs on the side to support his family, working as an emergency room physician, as a medical examiner for insurance companies, and as team physician for a high school football team.

Although his research did not yield immediate identification of the adrenergic receptor, Lefkowitz continued to publish other discoveries he was making along the way. By 1973, he had completed his fellowship in Boston and accepted an appointment as Associate Professor in charge of a new program in molecular cardiology at Duke University in Durham, North Carolina.

After his first year at Duke, Lefkowitz and his postdoctoral fellow Marc Caron developed the binding assays for adrenergic receptors. Now that the receptors had been found, direct study of them could proceed. In 1976, Dr. Lefkowitz was selected as an investigator of Howard Hughes Medical Institute (HHMI). At the time, only 50 medical scientists in the world enjoyed the support of HHMI, which is given directly to the individual investigator, rather than to an institution or a specific project.

Robert Lefkowitz Biography Photo
Over the next decade, Dr. Lefkowitz and a succession of dedicated graduate students and postdoctoral fellows developed new tools for detecting and analyzing the receptors he had discovered. Among the many exceptional young scientists trained by Dr. Lefkowitz, a particularly notable one arrived in 1984. Brian Kobilka stayed at Duke for five years before moving on to lead a laboratory of his own at Stanford University, where he would further develop the concepts he explored with Dr. Lefkowitz.

The Lefkowitz laboratory made a huge breakthrough in 1986. Having isolated one "G Protein coupled receptor" (GPCR), Lefkowitz and his team were able to clone it and decode its complete sequence of amino acids. When they checked this sequence against the database of known DNA molecules, they found that it was nearly identical to rhodopsin, the molecule that registers light and allows the eye to see. If the receptor for light and this newly discovered receptor for adrenaline could be so similar, it suddenly seemed probable that the receptors for a large number of other hormones might be as well. Within a few years they had discovered nearly a dozen such receptors. Today we can identify a family of roughly 1,000 different receptors in the human body. Mutations of some of these are known to cause both acquired and inherited diseases.

Dr. Lefkowitz's discoveries have had the greatest impact on the development of new drugs. Nearly half of all prescription drugs are designed to engage the receptors that Lefkowitz identified. Beta blockers, antihistamines, ulcer drugs and others are used to treat a wide variety of disorders, including hypertension, angina, coronary disease, diabetes, anxiety and depression. Although Dr. Lefkowitz did not patent any of his early discoveries, he has founded a company called Trevena to develop a new class of drugs, based on his latest research.

Robert Lefkowitz Biography Photo
Robert and Arna Lefkowitz had five children between 1964 and 1975. The marriage ended in divorce, and both partners have remarried; Robert Lefkowitz married Lynn Tilley in 1991. After years of working a relentlessly demanding schedule, Robert Lefkowitz was diagnosed with angina at age 50. There was a strong history of coronary artery disease in his family, and he has made a number of adjustments in his way of life. Since undergoing quadruple bypass surgery in 1994, he has managed his condition with medication and daily exercise, and by observing a vegetarian diet. In 2003, he discontinued teaching rounds and clinical work to focus entirely on research. That same year, 100 of his former students returned to Durham to celebrate his 60th birthday.

Today, Robert Lefkowitz is the James B. Duke Professor of Medicine and Professor of Biochemistry at the Duke University Medical Center. He is still an Investigator of the Howard Hughes Medical Institute (HHMI). Although there are now more than 300 HHMI investigators, as of 2014, Dr. Lefkowitz was one of the two longest serving investigators.

Dr. Lefkowitz has received almost every major award in American science, including the National Medal of Science and the Bristol-Myers Squibb Award, as well as honors from the American Heart Association, Canada's Gairdner Foundation and the Grand Prix of the Institut de France. For a number of years his name had been mentioned as a candidate for the Nobel Prize in Medicine or Physiology. He was caught off guard when he received the Nobel Prize in Chemistry in 2012. The award was shared with his former student and longtime collaborator, Dr. Brian Kobilka of Stanford University. When he traveled to Stockholm, Sweden to accept the award, he was accompanied by his wife Lynne, all five of his children and two of his five grandchildren. More than 40 of his former students flew to Stockholm at their own expense to celebrate the occasion.




This page last revised on Oct 02, 2015 19:42 EDT
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