Bruce Beutler

Bruce Alan Beutler (born December 29, 1957) is an American immunologist and geneticist.

Born in Chicago, Illinois, to a Jewish family, Beutler lived in Southern California between the ages of 2 and 18 (1959 to 1977).

For most of this time, he lived in city of Arcadia, a northeastern suburb of Los Angeles in the San Gabriel Valley.

During these years, he spent much time hiking in the San Gabriel Mountains, and in regional national parks (Sequoia, Yosemite, Joshua Tree, and Grand Canyon), and was particularly fascinated by living things.

These experiences impelled an intense interest in biological science.

His introduction to experimental biology, acquired between the ages of 14 and 18, included work in the laboratory of his father, Ernest Beutler, then at the City of Hope Medical Center in Duarte, CA. There he learned to assay enzymes of red blood cells and became familiar with methods for protein isolation.

He published his studies of an electrophoretic variant of glutathione peroxidase, as well as the inherent catalytic activity of inorganic selenite, at the age of 17.

Beutler also worked in the City of Hope laboratory of Susumu Ohno, a geneticist known for his studies of evolution, genome structure, and sex differentiation in mammals.

Ohno hypothesized that the major histocompatibility complex proteins served as anchorage sites for organogenesis-directing proteins.

He further suggested that H-Y antigen, a minor histocompatibility protein encoded by a gene on the Y chromosome and absent in female mammals, was responsible for directing organogenesis of the indifferent gonad to form a testis.

In studying H-Y antigen, Beutler became conversant with immunology and mouse genetics during the 1970s.

While a college student at the University of California at San Diego, Beutler worked in the laboratory of Dan Lindsley, a Drosophila geneticist interested in spermatogenesis and spermiogenesis in the fruit fly.

There, he learned to map phenotypes to chromosomal regions using visible phenotypic markers.

He also worked in the laboratory of Abraham Braude, an expert in the biology of LPS.

Beutler received his secondary school education at Polytechnic School in Pasadena, California.

A precocious student, he graduated from high school at the age of 16, enrolled in college at the University of California, San Diego, and graduated with a BA degree at the age of 18 in 1976.

He then enrolled in medical school at the University of Chicago in 1977 and received his M.D. degree in 1981 at the age of 23.

From 1981 to 1983 Beutler continued his medical training at the University of Texas Southwestern Medical Center in Dallas, Texas, as an intern in the Department of Internal Medicine, and as a resident in the Department of Neurology.

However, he found clinical medicine less interesting than laboratory science, and decided to return to the laboratory.

Beutler’s focus on innate immunity began when he was a postdoctoral associate and later an assistant professor in the lab of Anthony Cerami at Rockefeller University (1983-1986).

Drawing upon skills he had acquired earlier, he isolated mouse “cachectin” from the conditioned medium of LPS-activated mouse macrophages.

Cachectin was hypothesized by Cerami to be a mediator of wasting in chronic disease.

Its biological activity, the suppression of lipoprotein lipase synthesis in adipocytes, was thought to contribute to wasting, since lipoprotein lipase cleaves fatty acids from circulating triglycerides, allowing their uptake and re-esterification within fat cells.

By sequential fractionation of LPS-activated macrophage medium, measuring cachectin activity at each step, Beutler purified cachectin to homogeneity.

Determining its N-terminal sequence, he recognized it as mouse tumor necrosis factor (TNF), and showed that it had strong TNF activity; moreover that human TNF, isolated by a very different assay, had strong cachectin activity.

Human TNF, isolated contemporaneously by other workers, had to that time been defined only by its ability to kill cancer cells.

The discovery of a separate role for TNF as a catabolic switch was of considerable interest.

Of still greater importance, Beutler demonstrated that TNF acted as a key mediator of  endotoxin-induced shock.

This he accomplished by raising an antibody against mouse TNF, which he used to neutralize TNF in living mice challenged with lipopolysaccharide (LPS).

The often-lethal systemic inflammatory response to LPS was significantly mitigated by passive immunization against TNF.

The discovery that TNF caused an acute systemic inflammatory disease (LPS-induced shock) presaged its causative role in numerous chronic inflammatory diseases.

With J.-M.

Dayer, Beutler demonstrated that purified TNF could cause inflammation-associated responses in cultured human synoviocytes: secretion of collagenase and prostaglandin E2.

This was an early hint that TNF might be causally important in rheumatoid arthritis (as later shown by Feldmann, Brennan, and Maini ).

Together with Jules A. Hoffmann, he received one-half of the 2011 Nobel Prize in Physiology or Medicine, for "discoveries concerning the activation of innate immunity."

Beutler discovered the long-elusive receptor for lipopolysaccharide (LPS; also known as endotoxin).

He did so by identifying spontaneous mutations in the gene coding for mouse Toll-like receptor 4 (Tlr4) in two unrelated strains of LPS-refractory mice and proving they were responsible for that phenotype.

Subsequently, and chiefly through the work of Shizuo Akira, other TLRs were shown to detect signature molecules of most infectious microbes, in each case triggering an innate immune response.

The other half of the Nobel Prize went to Ralph M. Steinman for "his discovery of the dendritic cell and its role in adaptive immunity."

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