From Immune System Discoveries to Nobel Message on Cell Phone

By Mika Ono

Slightly after 2:30 AM on October 3, 2011, in La Jolla, California, Bruce Beutler glanced over at his cell phone. A message there read "Nobel Prize."

"I thought I should give close attention to that," said Beutler, who is chair of the Scripps Research Institute Department of Genetics and director of the Center for the Genetics of Host Defense the UT Southwestern Medical Center.

Beutler, who that morning was flying to Dallas where he is currently transitioning his lab for a full-time position at UT Southwestern as of December, was ever-gracious with the flood of questions from reporters from around the world. Of course he was thrilled by the news, he said. He was particularly delighted to share the prize with esteemed colleagues Jules Hoffmann and Ralph Steinman. But when notified that co-Nobel Laureate Ralph Steinman had passed away three days before the announcement, he was saddened.

He was also sorry his father, the late Scripps Research Chair of the Department of Molecular and Experimental Medicine Ernest Beutler, wasn't alive to savor the moment.

While he had not yet had time to think of formal celebrations, the many well-wishes from friends and colleagues had in itself been a type of celebration, he said.

Revolutionizing Immunology

The groundwork for the excitement of October 3 had been laid over many years by the three laureates' groundbreaking work on the immune system. The prize recognizes work on both lines of defense our bodies provide against dangerous bacteria, virus, fungi, parasites, and other organisms—innate immunity and adaptive immunity.

Innate immunity, our body's first line of defense, can destroy foreign invaders and trigger inflammation that contributes to their demise. If microorganisms make it past this gauntlet, the body calls on adaptive immunity. Here, T cells, B cells, antibodies, and killer cells come into play; our adaptive immune system also stores "memories" of the offending microorganisms to be on the alert for future attacks.

With all the power of these two lines of defense, sometimes things go wrong. If the immune system's activation threshold is too low, microorganisms gain a foothold. If the threshold is too high, the body's own "self" molecules could set off an immune response, resulting in inflammatory disease. These implications made scientists particularly interested in finding the body's gatekeepers to its immune responses.

In the work recognized by the Nobel Committee, Beutler was searching for a receptor that could bind the bacterial product, lipopolysaccharide (LPS), which can cause septic shock, a life-threatening condition in which the immune system becomes overactive. Beutler and his colleagues discovered that mice resistant to LPS had a mutation in a gene similar to the Toll gene of the fruit fly.

This dovetailed with Hoffman's fruit fly results. It also complemented Steinman's discovery of a new cell type he called the dendritic cell, which activates elements of the adaptive immune system. The independent discoveries of these three scientists triggered an explosion of research in the field.

Research Continues

Beutler's lab has continued to be at the forefront of these investigations of the innate immune system over the past decades.

The Beutler group has pioneered a technique called forward genetics in its search for genes involved in immune function and other areas of interest. Using this technique, the scientists induce genetic mutations at random with chemicals and look for phenotypic (observable physical or behavioral) changes.

"In forward genetics, you let the organism tell you what is wrong," Beutler said, "and we are seeing things none of us would have imagined before."

At Scripps Research, this work has led to new insights into inflammatory bowel disease, encephalitis, iron absorption, hearing, and vaccine adjuvants, among other topics.

Beutler also invented an inhibitor of tumor necrosis factor, an inflammatory mediator. Today, the inhibitor is used in the rheumatoid arthritis drug Enbrel®.

The research continues, as Nobel celebrations are planned.

Send comments to: mikaono[at]scripps.edu

Bruce Beutler awoke October 3 to learn he had won the Nobel Prize. (Photo by BioMedical Graphics.)

Links

"Bruce Beutler Wins the 2011 Nobel Prize in Physiology or Medicine"

"Colleagues React"

"On Genetics: An Interview with Bruce Beutler" (April 30, 2007)

The Nobel Prize website

Bruce Beutler's faculty information page

The Beutler lab website