(CIT): The Kinyoun Lecture The less you understand, the better forward genetics works, says Bruce Beutler, M.D., describing the technique he has used to unveil fundamental actions of the immune system. Forward genetics starts when scientists observe a novel trait or appearance in a mouse or other model organism, and then turn to the search for the responsible gene or genes. What this approach may tell us about how mammals detect infection is the topic of the 2007 Joseph J. Kinyoun lecture. Beutler, of The Scripps Research Institute (TSRI) in La Jolla, California, will present his lecture "How We Sense Microbes." At the core of immunology, notes Beutler, is the question of how we distinguish self from non-self. Ever since microbes were recognized as the cause of infectious disease, a corollary seemed obvious: plants, animals, and people must have ways to sense and respond to invading (non-self) microbes. For example, says Beutler, researchers observed decades ago that mammals react swiftly and dramatically to injections of what was originally called endotoxin a component of many bacterial cell walls now known to be a lipopolysaccharide (LPS). It was also observed years ago that some strains of mutant mice failed to react at all to LPS, adds Beutler, implying that the mice lacked a sensor. But the identity of the putative LPS sensor remained elusive, he says. In 1998, Beutler, who was then at the University of Texas, Southwestern, and his colleagues used forward genetics to explain the mutant animals inability to detect LPS. The researchers determined that the mice had mutations in the Lps gene, which eliminated the action of Toll-like receptor 4 (TLR4) protein and caused the mice to be insensitive to LPS. The finding, published in Science, was the first demonstration of an infection-sensing role for a mammalian TLR protein. The paper is regarded as a seminal contribution to understanding innate immunity. Bruce Beutler, M.D., Professor and Chairman of the Depar...