Académie royale de Médecine de Belgique

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Bruce BEUTLER

(Alan)

Prix Nobel de Physiologie et de médecine pour 2011 (la présentation, son discours).

Né le 29 décembre 1957.

Elu membre étranger le 26 septembre 2013.

 

Bruce BEUTLER est de nationalité américaine. Docteur en médecine, spécialiste en immunologie et en génétique, il dirige le ”Center for the Genetics of Host Defense at the University of Texas Southwestern Medical Center” à Dallas. Bruce Beutler est à l’origine de plusieurs découvertes fondamentales relatives à l’immunité innée qui assure une première ligne de défense vis-à-vis des agents infectieux. Il isola le facteur de nécrose tumorale (TNF) et démontra son activité inflammatoire. Il identifia ensuite le récepteur Toll-like 4 (TLR4) comme le récepteur au lipopolysaccharide bactérien responsable de la signalisation intracellulaire induite par l’endotoxine des germes gram-négatifs. Les contributions majeures de Bruce Beutler à l’élucidation des mécanismes de l’immunité innée lui ont valu le Prix Nobel de Physiologie ou Médecine en 2011.

Bruce Beutler a noué des liens étroits avec la communauté scientifique belge lors du séjour de Véronique Kruys, chercheuse de l’ULB, dans son laboratoire.  Elle y a contribué à plusieurs travaux essentiels sur la biologie moléculaire du  TNF et la régulation de sa synthèse. Bruce Beutler a gardé des liens étroits avec Véronique Kruys, qui dirige aujourd’hui le Laboratoire de Biologie Moléculaire du Gène à l’Institut de Biologie et Médecine Moléculaire (IBMM) de l’ULB à Charleroi-Gosselies.

 

Biography

Bruce Alan Beutler (born December 29, 1957) is an American immunologist and geneticist. Together with Jules A. Hoffmann and Ralph Steinman, he received the 2011 Nobel Prize in Physiology or Medicine, for "discoveries concerning the activation of innate immunity". Bruce Beutler is currently Director of the Center for the Genetics of Host Defense at the University of Texas Southwestern Medical Center in DallasTexas.

Between 1959 and 1977, Beutler lived in Southern California. He received his secondary school education at Polytechnic School in Pasadena, California. He attended college at the University of California, San Diego, graduating at the age of 18 in 1976. He enrolled in medical school at the University of Chicago in 1977 and received his M.D. degree in 1981 at the age of 23.

During his childhood and early adolescent years, Beutler developed a lasting interest in biological science. Some of his formative experiences in biology included studies in the laboratory of his father, and later, in the City of Hope laboratory of Susumu Ohno, a mammalian geneticist known for his work on evolution, genome structure, and sex differentiation. In addition, he worked in the laboratories of Abraham Braude, an expert in the biology of lipopolysaccharide (LPS), also known as endotoxin, and Patricia Spear, an authority on Herpes simplex virus. Later, Beutler was to perform extensive research on both LPS and herpesviruses, aimed principally at understanding inborn host resistance to infectious diseases, often referred to as innate immunity.

Beutler majored in biology as an undergraduate at the University of California, San Diego, where he graduated in 1976 at the age of 18. He attended medical school at the University of Chicago. From 1981 to 1983, Beutler continued his medical training at the University of Texas Southwestern Medical Center in Dallas, TX as an intern in the Department of Internal Medicine, and as a resident in the Department of Neurology. Between 1983 and 1985 he was a postdoctoral fellow at Rockefeller University in the laboratory of Anthony Cerami. He became an Assistant Professor at Rockefeller University in 1985. He was also an Associate Physician at the Rockefeller University Hospital between 1984 and 1986.

Beutler returned to Dallas in 1986 as an Assistant Professor in the Department of Internal Medicine of the University of Texas Southwestern Medical Center at Dallas, and an Assistant Investigator at the Howard Hughes Medical Institute, where he retained a position for the next 14 years. He became an Associate Professor and an Associate Investigator with HHMI in 1990, and a Professor in 1996. In 2000, Beutler moved to the Scripps Research Institute in La Jolla, California, as a Professor in the Department of Immunology. In 2007, he became Chairman of the newly created Department of Genetics at Scripps Research. In 2011, Beutler returned to UT Southwestern Medical Center to become Director of the Center for the Genetics of Host Defense. On October 4, 2011, Beutler was named regental professor of the University of Texas System.

Beutler is best known for his pioneering molecular and genetic studies of inflammation and innate immunity. He was the first to isolate mouse tumor necrosis factor-alpha (TNF), and to demonstrate the inflammatory potential of this cytokine, proving its important role in endotoxin-induced shock. Subsequently, he invented recombinant molecules expressly designed to neutralize TNF, fusing the binding portion of TNF receptor proteins to the heavy chain of an immunoglobulin molecule to force receptor dimerization. These molecules were later used extensively as the drug Etanercept in the treatment of rheumatoid arthritis, Crohn's diseasepsoriasis, and other forms of inflammation. Interested in the mechanism by which LPS activates mammalian immune cells, Beutler used TNF production as a phenotypic endpoint to identify the LPS receptor. Identification of the receptor hinged on the positional cloning of the mammalian Lps locus, which had been known since the 1960s as a key genetic determinant of all biological responses to LPS.  Beutler thus discovered the key sensors of microbial infection in mammals, demonstrating that one of the mammalian Toll-like receptors (TLRs), TLR4, acts as the membrane-spanning component of the mammalian LPS receptor complex. The TLRs (of which ten are now known to exist in humans) are now widely known to function in the perception of microbes, each detecting signature molecules that herald infection. These receptors also mediate severe illness, including shock and systemic inflammation as it occurs in the course of an infection. They are central to the pathogenesis of sterile inflammatory and autoimmune diseases. His work disclosed numerous essential signaling molecules required for the innate immune response and helped to delineate the biochemistry of innate immunity.

The research on TLRs won him the Nobel Prize in 2011. Furthermore, Bruce Beutler is the recipient of the following awards:

·         Shaw Prize (2011, shared with Jules A. Hoffmann and Ruslan M. Medzhitov)

·         Albany Medical Center Prize (2009, shared with Charles A. Dinarello and Ralph M. Steinman)

·         Balzan Prize for Innate Immunity (2007, shared with Jules A. Hoffmann).

·         Doctor of Medicine Honoris causa from the Technical University of Munich, Germany, (2007)..

·         Grand Prix Charles-Leopold Mayer of the Académie des Sciences, France (2006).

·         Robert Koch Prize of the Robert Koch Foundation, Germany (2004, shared with Jules A. Hoffmann and Shizuo Akira).

Bruce Beutler has been elected to numerous honorary academic societies. These include the United States National Academy of Sciences and the Institute of Medicine. Beutler is also an Associate Member (foreign associate) of the European Molecular Biology Organization (EMBO), and a member of the Association of American Physicians, and the American Society for Clinical Investigation.