Dr. Bruce Beutler

“The less you understand, the better forward genetics works,” says Dr. Bruce Beutler, 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 in La Jolla, Calif., will present his lecture Thursday, Oct. 25 at 2 p.m. in Lipsett Amphitheater, Bldg. 10.

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, he adds, implying that the mice lacked a sensor. But the identity of the putative LPS sensor remained elusive.

In 1998, Beutler, who was then at the University of Texas Southwestern Medical Center at Dallas, 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 because it revealed a way self and non-self are distinguished during the first minutes following infection.

Since moving to Scripps in 2000, Beutler has continued to explore TLR signaling and the functions of innate immunity via forward genetics. In his lab, the technique involves introducing random genetic mutations into the sperm of mice. By chance, these mutations result in mice with unusual characteristics, such as a heightened or lessened ability to respond to infection. Rather than starting with a hypothesis such as “gene X might be required for normal immune function,” Beutler’s approach begins with an observation such as “this mouse has an unexpected immune response,” which drives the search for the mutation that gave rise to the unusual response and, by inference, can show which genes support a normal response.

Notes Beutler, starting with an observation rather than a hypothesis helps avoid bias that may arise through the tendency people have to favor hypotheses they create. To date, about 60 of the more than 150 transmissible mutations created by the Beutler team have been shown to affect immunity and about 20 of those were unpredicted by any other method. This fact highlights one of the best features of forward genetics, he said. “With forward genetics,” he observed, “you keep yourself open to the possibility of surprise.”

Beutler is chairman of the department of genetics at Scripps. Among his many honors are the Robert Koch Prize (2004), the William Coley Prize (2006), the Gran Prix Charles-Leopold-Mayer (2006) and the Balzan Prize (2007).