The threads of Dr. Bruce Beutler’s scientific career are inextricably woven into the fabric of UT Southwestern Medical Center’s history and its culture of research and clinical excellence. As an intern and resident, he took medical training from, and walked the hospital wards with, some of UT Southwestern’s most distinguished physician-scientists. As a mid-career independent researcher, he conducted pioneering investigations of the human immune system in his UT Southwestern laboratory, work that would earn him a Nobel Prize. Now, after a hiatus from the institution, Dr. Beutler has returned to UT Southwestern to direct the newly established Center for the Genetics of Host Defense, a collaborative effort across scientific disciplines that promises to create a new tapestry of scientific discovery.
In May 2011 UT Southwestern announced that Dr. Beutler, a pre-eminent immunologist who was then chairman of the Department of Genetics at Scripps Research Institute in La Jolla, Calif., would soon be joining the faculty. A half year later, just after making the transition to Dallas, Dr. Beutler shared the 2011 Nobel Prize in physiology or medicine for discoveries that revolutionized the understanding of the human immune system and how it is activated. His work has opened up new avenues for the development of preventive measures and therapy against cancer, infections and inflammatory diseases.
“HE WOULD DO GREAT THINGS”
Dr. Beutler embarked on his noble research endeavors at UT Southwestern, where he was a faculty member and Howard Hughes Medical Institute investigator from 1986 to 2000. But his roots here go even deeper. After completing his medical degree at the University of Chicago at age 23, he arrived on the UT Southwestern campus in 1981 to begin an internship in internal medicine and, later, a residency in neurology.
The intellectual environment that attracted Dr. Beutler to UT Southwestern for his medical training – and persuaded him to return, twice, as a faculty member – are rooted in the institution’s concerted efforts to build from the ground up a cadre of talented physician-scientists.
“I was conscious that I was at a place that had scientific excellence as well as excellence in clinical training. But when you’re an intern and a resident, there’s really no time for work in the lab,” said Dr. Beutler, who holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie Sr. Dr. Eugene Frenkel, who worked with Dr. Beutler in the 1980s and was instrumental in recruiting him back to the medical center in 2011, said Dr. Beutler’s drive, focus and integrity were evident.
“Bruce’s unusual talents and characteristics were so evident that I never doubted he would do great things,” said Dr. Frenkel, professor of internal medicine and radiology and holder of the Raymond D. and Patsy R. Nasher Distinguished Chair in Cancer Research, the Elaine Dewey Sammons Distinguished Chair in Cancer Research, and the A. Kenneth Pye Professorship in Cancer Research.
“OPENING THE FIELD OF INNATE IMMUNITY”
After completing a fellowship and serving on the faculty of Rockefeller University, Dr. Beutler returned to UT Southwestern’s Department of Internal Medicine in 1986.
His research, then and now, focused on the mechanisms by which the body detects bacterial or viral invaders, as well as how the body sounds the alarm that musters an army of biochemical defenders. This so-called innate immunity is the body’s first response against infection, and it contains a variety of cells and chemical components that target foreign substances. When this complex alarm system breaks down, however, disease can result.
In 1996 Dr. Jules Hoffmann of the University of Strasbourg’s Institut de Biologie Moléculaire et Cellulaire in France discovered a critical step that triggers the innate immune response in the fruit fly Drosophila. He found that a gene called Toll helps mount an immune defense against pathogenic bacteria or fungi in the fly host. Toll codes for a protein that sits on the outside of certain cells and acts as a kind of catcher’s mitt, recognizing a host protein called Spaetzle. This process trips the alarm of the innate immune system.
At the same time Dr. Hoffmann was identifying the fly receptor and the gene that makes it, in Dallas Dr. Beutler was searching for an “alarm” gene in mice. Specifically, he was looking for the mammalian receptor that detects a component of certain bacterial cell walls called lipopolysaccharide (LPS). When bacteria containing LPS infect humans, it can cause life-threatening septic shock, a condition that causes overstimulation of the immune system.
From 1993 to 1998, Dr. Beutler and his team worked with a strain of mice that was resistant to LPS and septic shock, painstakingly analyzing the animals for biological mechanisms behind their resistance. In 1998 Dr. Beutler and his team not only identified the LPS receptor in mice, but also found that it was made by the same family of genes as those in the fruit fly. The specific mammalian receptor required to mount a defense against LPS turned out to be Toll-like receptor 4. (In mammals, Toll receptors and their genes are referred to as “Toll-like.”)
“Bruce Beutler’s discovery that Toll-like receptor 4 is the molecule that mediates gram negative sepsis is a seminal event in biomedical science, opening the field of innate immunity to a molecular dissection that was not hitherto possible,” said Dr. Joseph Goldstein, chairman of molecular genetics at UT Southwestern and holder of the Julie and Louis A. Beecherl Jr. Distinguished Chair in Biomedical Science and the Paul J. Thomas Chair in Medicine.
“STRONG GENETIC ORIENTATION”
The impact of Dr. Beutler’s research is far-reaching, informing not only drug development for autoimmune conditions such as rheumatoid arthritis, but also providing the scientific scaffolding for ongoing breakthroughs in immune-system studies.
Following on Dr. Beutler’s discovery, for example, scientists have identified more than a dozen different Toll-like receptors, each recognizing a different type of foreign molecule that alerts the immune system to invasion of the body by bacteria, viruses, parasites and virtually all other microbes that cause ill health, Dr. Goldstein said.
Dr. Beutler’s ongoing research could reveal other alarm-system genes, as well as the circuitry by which these alarms work, said Dr. Brown, director of the Erik Jonsson Center for Research in Molecular Genetics and Human Disease, and holder of the W.A. (Monty) Moncrief Distinguished Chair in Cholesterol and Arteriosclerosis Research, and the Paul J. Thomas Chair in Medicine.
“The end result of Dr. Beutler’s work may well be treatments that circumvent the invaders’ defense mechanisms, or that calm the alarm system so as to prevent inflammatory overreaction,” Dr. Brown said.
“BRINGING TOGETHER PEOPLE”
As the Center for the Genetics of Host Defense begins to take shape under Dr. Beutler’s leadership, he envisions a collaborative environment that will grow organically, combining the strengths of existing research programs with the infusion of new faculty members and new ideas. The goal is to build a team of high-caliber researchers who will tackle issues related to immunity from many different angles, each with an interest in the others’ work.
Research efforts within the new center will include generating new mouse phenotypes representing immune deficiency diseases. “The idea is to create mutant mice in the lab and use them to find diseases equivalent to those in humans, perhaps before those diseases are even recognized by physicians,” Dr. Beutler said.
Identifying new immune-deficiency mutations and pinpointing abnormal proteins related to those mutations is not the endpoint of the research. Investigators will then delve further into the functions of the proteins they identify and how they interact with cells and other proteins.
“About a third of our work is making phenotypes with mutagenesis, and two-thirds of it is using biochemistry to take the system apart to understand how and why those phenotypes occur,” Dr. Beutler said.
This so-called forward genetics research approach might be applied to many diseases, from heart disease and developmental disorders to inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis. By saturating the mouse genome, researchers could identify all the target genes within which a mutation might cause these particular phenotypes.
While Dr. Beutler’s return to UT Southwestern brings the promise of new research initiatives and the prestige of a Nobel Prize, his presence also continues the thread of excellence he began on campus more than 20 years ago. His decision to return now, at the pinnacle of his career, is a testament to the medical center’s unique place in the scientific community.
“I envision bringing together people with a general interest in host defense, including some who work with Drosophila, some who work with zebra fish, some perhaps with plants or worms, along with our group working with mice,” Dr. Beutler said.
“By bringing them all together and using classical genetics, we’re going to make a lot of discoveries.
“I thought at UT Southwestern I would have such an opportunity, and indeed, I do.”