Bruce Alan Beutler - 2011 Nobel Prize in Physiology

Bruce Alan Beutler (born December 29, 1957) is an American immunologist and geneticist.Together with Jules A. Hoffmann, he received one-half of the 2011 Nobel Prize in Physiology or Medicine, for "their discoveries concerning the activation of innate immunity" (the other half went to Ralph M. Steinman for "his discovery of the dendritic cell and its role in adaptive immunity").

Beutler is currently Director of the Center for the Genetics of Host Defense at the University of Texas Southwestern Medical Center in Dallas, Texas.

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 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 disease, psoriasis, 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, 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 such as systemic lupus erythematosus. The research on TLRs won him the Nobel Prize in 2011.

The positional cloning of Lps was completed in 1998. Beutler thereafter continued to apply a forward genetic approach to the analysis of immunity in mammals. In this process, germline mutations that alter immune function are created through a random process using the alkylating agent ENU, detected by their phenotypic effects, and then isolated by positional cloning. His work disclosed numerous essential signaling molecules required for the innate immune response, and helped to delineate the biochemistry of innate immunity.

ENU mutagenesis was also used by Beutler and colleagues to study the global response to a defined infectious agent. By screening mutant mice for susceptibility to mouse cytomegalovirus (MCMV), they identified a large number of genes that make a life-or-death difference during infection, and termed this set of genes the MCMV "resistome". These genes fall into "sensing," "signaling," "effector," "homeostatic," and "developmental" categories, and some of them were wholly unexpected. For example, Kir6.1 ATP-sensitive potassium channels in the smooth muscle of the coronary arteries serve an essential homeostatic role during infection by this microbe, and mutations that affect them cause sudden death during infection.

In the course of their work, Beutler and his colleagues identified genes required for other important biological processes, including the regulation of iron absorption, hearing,and embryonic development, since their disruption by ENU created strikingly abnormal visible phenotypes.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.

Other notable honors have included:

Nobel Prize in Physiology or Medicine (2011, shared with Jules A. Hoffmann and Ralph M. Steinman)

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

Will Rogers Institute Annual Prize for Research (2009)

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).

William B. Coley Award of the Cancer Research Institute, US (2006, shared with Shizuo Akira).

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).

Institute for Scientific Information has listed Beutler as an ISI highly cited researcher since the year 2001, marking him as an influential figure in the field of immunology. He has also been listed by Thomson-Reuters as a Citation Laureate.

Doctor honoris causa of the Norwegian University of Science and Technology, Norway (2015).