Dr. Robert Lefkowitz: Durham, USA
With great pleasure, the Academy announces the award to Dr. Robert J. Lefkowitz of the Medal of Merit for his extraordinary lifetime of research, teaching and contribution to heart health in the world.
Dr. Lefkowitz was born in the Bronx, New York City in 1943. The only child of Max and Rose Lefkowitz, he had set his career goal of becoming a practicing physician as early as elementary school. Highly focused on this goal, he graduated from Columbia College with a Bachelor of Arts Degree at age 19 and from Columbia University College of Physicians and Surgeons at age 23. After an internship and 1 year of medical residency at Columbia Presbyterian Medical Center, he moved in 1968 to the NIH to fulfill his two year military obligation as a Clinical Research Associate at the National Institute of Arthritis and Metabolic Diseases (NIAMD, as it was then called). During the subsequent two years, he worked together with Jesse Roth and Ira Pastan and developed the first radioligand binding assay for ACTH receptors leading to his very first publication in The Proceedings of the National Academy of Sciences. This study was amongst the very first to ever label a membrane receptor with a radioligand and was contem- poraneous with the early work on the nicotinic cholinergic receptor. This first research experience greatly excited him, but he moved to Boston to finish his clinical training in General Internal Medicine and Cardiovascular Diseases at the Massachusetts General Hospital. During this period (1970-73) he began working in the laboratory of the Chief of Cardiology, Dr. Edgar Haber, a noted immunochemist, and initiated the studies that ultimately formed the basis for his life’s work on adrenergic receptors. In July of 1973, he moved to Duke University as an Associate Professor of Medicine and Biochemistry and started his own independent research program. In 1976, he became an Investigator of the Howard Hughes Medical Institute, a position he holds to this day. He became a James B. Duke Professor of Medicine and Biochemistry in 1982.
Working with the adrenergic receptors as models, Dr. Lefkowitz’s research has formed the basis for the now vast field of research into socalled G protein-coupled membrane receptors. This, the largest superfamily of membrane receptors, includes approximately one thou- sand members in the mammalian genome and regulate virtually all physiological processes from hormonal and neurotransmitter signaling to sensory signaling in the visual, olfactory and taste systems to chemo- kine signaling. Virtually all cardiovascular regulation is controlled by members of the seven membrane spanning receptor superfamily such as the adrenergic and muscarinic cholinergic receptors, angiotensin and endothelin receptors and many others.
In the early 1970’s, Lefkowitz and his numerous students and fellows systematically developed ligand binding approaches for the study of each of the then-known adrenergic receptors, both a1 and 2 and b1 and 2. They then developed methods to solubilize, photoaffinity label and ultimately purify by affinity chromatography each of these receptors. In the 1980’s, they were able to obtain small amounts of protein sequence from the purified receptors and clone their genes and cDNAs. His cloning, together with collaborators at Merck, of the gene for the b2-adrenergic receptor, announced in Nature in 1986, revealed its homology and secondary structure relationship to the visual pigment, rhodopsin. The common theme of seven membrane spanning domain receptors was rapidly confirmed by his laboratory on the other members of the adrenergic receptor family. This early work made possible the cloning of essentially all the other members of the vast superfamily of receptors by various homology techniques over the ensuing fifteen years.
Lefkowitz also unraveled the molecular mechanisms underlying the phenomenon of desensitization of receptors, in the process discovering and cloning the G protein-coupled receptor kinase and b-arrestin families of proteins which regulate this universally important regulatory phenome- non. More recently, he has found that G protein-coupled receptor kinases and b-arrestins not only desensitize receptors, but can link them to novel signaling pathways. Exciting new functions for the arrestins are being reported by laboratories around the world including their important role in mediating clathrin-mediated endocytosis of the receptors.
His laboratory has also made numerous other discoveries about the molecular mechanisms of functioning of the receptors, how they signal, interact with G proteins, etc. They also discovered the phenomenon of constitutively active mutant receptors, now known to be the cause of an ever-growing list of human diseases.
As he approaches his sixtieth birthday, he continues as actively engaged in his research as ever, with the major current focus being on unraveling the novel signaling roles of b-arrestins and G protein-coupled receptor kinases. His approaches range over the entire spectrum from genetically altered knockout and transgenic animals to detailed molecular and structural studies. Despite all of his accomplishments in research, the professional accomplishment of which he is most proud is the training of a large number of extremely successful and productive investigators. Almost 200 individuals have worked in his laboratory over the past 30 years, many of whom have gone on to distinguished careers as scientists and administrators in both the academic and commercial settings. Along the way, he helped raise five children, three boys and two girls, none of whom have pursued careers in Science or Medicine, but four of whom are involved in one or another aspect of the entertainment business.
For his research, Lefkowitz has been repeatedly recognized and honored. Some of his awards include: 1976 Howard Hughes Medical Institute Investigator; 1979 George W. Thorn Award for Scientific Excellence of the Howard Hughes Medical Institute; 1982 Ernst Oppenheimer Memorial Award of the Endocrine Society; 1982 Gordon Wilson Medal, American Clinical and Climatological Assn.; 1986 Goodman and Gilman Award of the American Society for Pharmacology and Experimental Therapeutics; 1987 North Carolina Award for Science; 1988 National Academy of Sciences; 1988 American Academy of Arts and Sciences; 1990 Association of American Medical Colleges Biomedical Research Award; 1990 American Heart Association Basic Research Prize; 1990 Honorary Member Japanese Biochemical Society; 1994 Institute of Medicine National Academy of Sciences; 1995 The Endocrine Society Gerald D. Aurbach Lecture Award; 1997 The New York Academy of Medicine, 2000 F.E. Shideman-Sterling Award, University of Minnesota; 2001 The Louis and Arture Lucian Award for Research in Circulatory Disease 2001 Jessie Stevenson Kovalenko Medal, The National Academy of Sciences; 2001 Peter Harris Distinguished Scientist Award, International Society for Heart Research (presented at the World Congress in Winnipeg); and 2001 Appointed as a Fellow in the International Academy of Cardiovascular Sciences and is now a most befitting recipient of the Academy’s Medal of Merit.