The 2007 Prize in
Life Science & Medicine
for his relentless elucidation of the major receptor system that mediates the response of cells and organs to drugs and hormones.
Cells in the body communicate by releasing chemicals that travel to other cells and direct their behavior. These chemicals control vital processes, ranging from brain function to heart pumping to sexual reproduction. In work extending over 35 years, Professor Robert Lefkowitz showed us how chemical messengers are received and interpreted by target cells. The key is a family of proteins called G-protein coupled receptors (GPCRs) embedded in the surface membranes of receiving cells. GPCRs are distinguished from other receptors because they crisscross the membrane seven times, thereby giving rise to the alternate name of 7-transmembrane receptors. The GPCRs were theoretical concepts in the early 1970’s when Lefkowitz began the painstaking process of isolating a receptor and determining its structure. A milestone was reached in 1986 when Lefkowitz and collaborators at Merck Sharp and Dohme Research Laboratories isolated the gene encoding one receptor and used it to elucidate the protein’s primary structure. With this information as a starting point, Lefkowitz and others soon found that the genome encodes hundreds of related receptors, each specific for a different chemical messenger. Lefkowitz’s work up to this day continues to contribute to our understanding of the properties of these receptors. He demonstrated that receptors are not always active.
After they transmit their signals the receptors are silenced by a feedback mechanism that prevents over-stimulation. In elucidating feedback silencing, Lefkowitz discovered novel proteins that not only silence receptors, but also play diverse roles in physiology, controlling processes that include cell growth and differentiation. Although many scientists contributed to solving the signaling problem, Lefkowitz led the way throughout. As a result of his work, pharmaceutical companies now understand the mechanism whereby many of their classic drugs control pathologic processes. Examples include β-blockers (such as propronolol) for high blood pressure and congestive heart failure, H2 antagonists (such as cimetidine) for peptic ulcers, H1 antagonists (such as chlorpheniramine) for allergy, and dopamine antagonists (such as clozapine) for schizophrenia. This knowledge now permits companies to search for even more powerful drugs that target a wide variety of G-protein coupled receptors, thereby treating a wide assortment of diseases.
An Essay on the Prize
The human body is made up of many different types of tissues and many different kinds of cells. To co-ordinate body functions, cells signal to other cells in the same organ and in different organs by releasing chemical messengers that travel through the bloodstream. The chemical messengers control all of the vital body processes. For example, they determine the force of a heartbeat and the number of beats per minute, the height of the blood pressure, and the propulsive energy of the intestine. In the brain these chemicals profoundly influence our moods and our behavior, including our drives for food and sex. When Lefkowitz began his work in the late 1960's, scientists had already identified several chemical messengers but they did not know how these chemicals affected the target cells so as to alter their behavior. Over the subsequent 35 years Lefkowitz and his students painstakingly elucidated a family of molecules on the surface of target cells that receive the chemical messages. These receiving molecules are known as G protein-coupled receptors (GPCRs).
GPCRs are proteins embedded in the surface membrane of target cells with their receiving ends facing the outside fluid. Each cell produces many different GPCRs, each tuned to respond to different chemical messengers. For example, certain GPCRs called beta-adrenergic receptors located on heart muscle cells recognize adrenalin secreted by the adrenal gland and thereby control the heartbeat. When a human is physically threatened, the adrenal gland releases adrenalin which travels through the bloodstream and attaches to beta-adrenergic receptors on heart muscle. Once stimulated by the adrenalin, the receptors initiate a cascade of events that causes the heart to beat stronger and faster. This prepares the threatened person for "fight or flight".
Robert Lefkowitz, born 1943 is an Investigator of the Howard Hughes Medical Institute, the James B Duke Professor of Medicine and a Professor of Biochemistry at the Duke University Medical Center in Durham, North Carolina.
Professor Lefkowitz was born in the United Kingdom. He received a Bachelor Degree in Chemistry at Columbia College, New York in 1962 and then went on to graduate from the Columbia University College of Physicians and Surgeons in 1966 with an MD. He is a member of US National Academy of Sciences and The American Academy of Arts and Sciences.
12 June 2007, Hong Kong