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Today's New Yorker Birthday Honoree is Nobel Laureate Dr. Robert Lefkowitz.

Robert Joseph Lefkowitz was born April 15, in 1943 in The Bronx, New York to Jewish parents of Polish ancestry, Max and Rose Lefkowitz. His father Max was an accountant who worked in the garment district in Manhattan and his mother Rose, was an elementary school teacher. An only child, he was raised in the Parkchester neighborhood, and attended the Bronx High School of Science and Columbia University. For his groundbreaking discoveries, Lefkowitz shared the 2012 Nobel Prize for Chemistry with American physician and molecular biologist Brian K. Kobilka.


Dr. Lefkowitz is the physician and molecular biologist who demonstrated the existence of receptors—molecules that receive and transmit signals for cells. His research on the structure and function of cell-surface receptors—particularly of G protein-coupled receptors (GPCRs), the largest family of signal-receiving molecules found in organisms—revolutionized scientists’ understanding of how cells respond to stimuli such as hormones and how certain types of drugs exert their actions, leading to major advances in drug development.


Today, as many as 50 percent of all prescription drugs are designed to "fit" like keys into the similarly structured locks of Lefkowitz' receptors—everything from antihistamines to ulcer drugs to beta blockers that help relieve hypertension, angina and coronary disease.

Lefkowitz made a remarkable contribution in the mid-1980s when he and his colleagues cloned the gene first for the β-adrenergic receptor, and then rapidly thereafter, for a total of 8 adrenergic receptors (receptors for adrenaline and noradrenaline). This led to the seminal discovery that all GPCRs (which include the β-adrenergic receptor) have a very similar molecular structure. The structure is defined by an amino acid sequence which weaves its way back and forth across the plasma membrane seven times. Today we know that about 1,000 receptors in the human body belong to this same family. The importance of this is that all these receptors use the same basic mechanisms so that pharmaceutical researchers now understand how to effectively target the largest receptor family in the human body.


BACKGROUND


In 1959 Lefkowitz graduated from the Bronx High School of Science. He received a scholarship to study at Columbia College, Columbia University, New York, where he earned a B.A. in Chemistry in 1962. Having decided at an early age that he wanted to be a physician, he remained in New York to study at the Columbia University College of Physicians and Surgeons, receiving an M.D. in 1966. Two years later, after a residency at Columbia, he took a position at the National Institute of Arthritis and Metabolic Diseases (NIAMD; later the National Institute of Diabetes and Digestive and Kidney Diseases), part of the National Institutes of Health in Maryland, where he set to work on validating the existence of receptors. His initial research focused on developing a procedure (an assay) by which radioactively labeled adrenocorticotropic hormone (ACTH) would bind specifically to the membranes of cancer cells; such an assay would facilitate the purification of receptors.

By 1970 he had successfully developed the procedure and had published evidence for the existence of cell-surface receptors. That year he left NIAMD for a residency and training in cardiovascular disease at Massachusetts General Hospital in Boston. In 1972, while working in the laboratory of German American physician and researcher Edgar Haber, he published a report detailing his purification of beta-adrenergic receptor protein from heart muscle cells (cardiomyocytes) in dogs. The beta-adrenergic receptor would later become a model system for the study of GPCRs.

In 1973 Lefkowitz joined the faculty at the Duke University Medical Center in Durham, North Carolina, where he later found that adrenergic receptors transmit signals to an intracellular molecule called a G protein (guanine nucleotide-binding protein), which had been discovered earlier by American pharmacologist Alfred G. Gilman and American biochemist Martin Rodbell (Gilman and Rodbell shared the 1994 Nobel Prize for Physiology or Medicine for their independent discovery of G proteins). When activated, G proteins stimulate an enzyme known as adenylate cyclase, which converts the energy-carrying molecule ATP (adenosine triphosphate) to cAMP (cyclic adenosine monophosphate), a process responsible for producing physiological responses prompted by hormone-receptor binding. Lefkowitz also discovered a molecule known as beta-adrenergic receptor kinase (beta-ARK), which regulates GPCR activity.

AWARDS AND RECOGNITION

Dr. Lefkowitz has received a great deal of recognition for his research including election to the National Academy of Sciences and the Institute of Medicine of the National Academy of Sciences as well as the receipt of numerous awards. Most recently these have included the Louis and Artur Lucian Award for Research in Circulatory Disease, The Fred Conrad Koch Award - The Endocrine Society, The 2001 Jessie Stevenson Kovalenko Medal - The National Academy of Sciences and The Peter Harris Distinguished Scientist Award, International Society of Heart Research. Dr. Lefkowitz writes numerous review articles in the areas of hormone and drug receptors and their regulation and is a consultant for several drug companies which specialize in drugs which may affect signal transduction processes such as Norak, Lexicon Genetics and Genentech.

Since 1973 he has worked at Duke University and the Howard Hughes Medical Institute in Durham, North Carolina. Robert Lefkowitz is married with five children. Check out his extraordinary story in his own words on the Nobel Prize website.


(Other sources: Wikipedia; brittania.com)

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