Bruce Beutler found the sensor that tells the body bacteria have invaded

Person: Bruce Beutler
Lived: b. 1957
Field: Immunology and genetics
From: American

The story

Bruce Beutler, born in Chicago in 1957 to a Jewish family whose members had fled persecution in Kiev and Nazi Berlin, had already shown in the 1980s that the inflammatory protein TNF is a key cause of the deadly shock that bacterial infections can trigger. But a more basic question remained: how does the body notice bacteria in the first place?

Many bacteria carry a molecule on their surface called lipopolysaccharide, or LPS, also known as endotoxin. Two strains of laboratory mice were known to ignore LPS completely, because of mutations at a location in their DNA called the Lps locus. Beutler reasoned that whatever gene was broken in those mice must be the sensor for LPS, and that finding it would reveal one of the immune system's first alarms.

From 1993 his team at UT Southwestern in Dallas hunted for the gene by positional cloning, analysing 2,093 mice and searching a region of DNA at least 5.6 million letters long with slow, hand-run sequencing gels. Years passed without a result, and his research funding was due to end. On the night of September 5, 1998, his computer searches turned up a real gene in the region: Tlr4, a relative of the fruit-fly gene Toll. Within days the team found a single-letter mutation in one resistant strain, and the gene was missing entirely in the other. They published the discovery in Science that December.

The finding showed that Toll-like receptor 4 is the receptor that senses LPS, and it pointed to a whole family of such receptors. Other scientists soon showed that different Toll-like receptors recognise molecules from most kinds of microbes, triggering inflammation and the first line of immune defence. In 2011 Beutler shared the Nobel Prize in Physiology or Medicine with Jules Hoffmann, who had shown that Toll protects fruit flies from infection, and Ralph Steinman.

The Nobel Assembly said these discoveries have made possible new methods for preventing and treating disease, for instance improved vaccines and attempts to stimulate the immune system to attack tumours, and that they help explain why the immune system sometimes attacks the body's own tissues.

Why it matters

Knowledge of Toll-like receptors guides research on sepsis, better vaccines, cancer immunotherapy and autoimmune diseases.

About Bruce Beutler

Grandson of Jewish refugees who isolated the inflammatory protein TNF, created the TNF blocker that became the arthritis drug Enbrel, and found how the body detects bacteria. Nobel Prize 2011.

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Bruce Beutler

b. 1957 · Immunology and genetics

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