An unconventional approach to research led to a Nobel Prize-winning discovery by Bruce Beutler, MD’81. Photo by Dave Gresham, UT Southwestern

Nobelist Revolutionizes Immune Response

Alumnus Bruce Beutler, MD’81, one of three winners of the 2011 Nobel Prize in Physiology or Medicine, has been recognized for his pioneering discoveries in immune response. Specifically, his team identified the receptor proteins able to bind the bacterial product lipopolysaccharide (LPS), which can cause life-threatening septic shock. Beutler’s work has opened up new avenues for the development of therapy and prevention of infections, cancer, and inflammatory diseases. Below, Dr. Beutler answers our questions about his discoveries, his University of Chicago experience, and the future of medicine.

Catalyst: would you share some of the details of your discoveries?
Bruce Beutler: We discovered the family of proteins that’s most involved with detecting infection when it occurs. That answered a longstanding question. For about 100 years people had known that microbes were what caused infection, but they didn’t know exactly how the body launches a response. It turns out that when we have shock or sepsis, it’s because of the body’s overreaction to the microbes. This really is an extension of what the immune system is intended to do, but it normally does it on a very small scale. We found the receptors that make this occur.

C: HOw did your time at the University of Chicago play a role in the direction you've taken?
BB:  My father suggested that I go to medical school at the University because it had the reputation for training so many biomedical scientists. I was always interested in research rather than going into clinical practice, but while I was a medical student, I learned broadly about medicine—all of which played into what I did later. That was what the University gave me: an extremely broad foundation on which to build. If you understand what the most important questions are, you’re likely to be much more productive and to make a big discovery.

C: What were some of your biggest challenges as a student and later
as a researcher?

BB: When I came to medical school, I was really quite overwhelmed by the volume of what I needed to learn. Anatomy class, for example—just so much information—very difficult, for me, anyway. I ended up doing all right, but they didn’t keep class rank, and I’m glad of that! As a researcher, I found the biggest challenge was the need to coordinate personnel and to keep them inspired and motivated. If you really want to do something as a group, which can lend itself to a great achievement, then you have to make people see the value of it. That was the toughest aspect of finding the LPS gene.

C: what happens next?
BB: I expect we’ll study more immunologic problems, again creating mice that have new immune diseases, and then solving them. But now it’s possible to solve them very rapidly. The LPS mutation took about five years to solve. The entire lab was working on it. Now, something of that scope would only take us a few seconds to sequence because of new technologies for sequencing. It’s really a completely different game now.

C: Was there a creative aspect to your approach?
BB:
There was. Many people wanted to go after the LPS receptor using immunologic methods or protein chemistry. We used strictly a genetic approach quite early. When we started our work, you couldn’t map with the resolution that you can today, and we had to sequence by hand, reading off of X-ray films. The genome was complete terra incognita. It was speculated there were 100,000 genes in the mouse and human genomes. That turned out to be a gross overestimate. Nobody knew how the genes were arranged or where the great majority of them were. Once we mapped the mutation, we had to go hunting for genes ourselves. These were not completely unique methods, but it was still pretty brave to set out to find the receptor that way. Maybe that sounds boastful, but it was unconventional—it was never assured of success—and that’s sort of part of the charm of what we did.

C: what do you see as the future of medicine in your lifetime?
BB: I’ve always been a mechanist and a strong reductionist. We started with a very complicated syndrome, septic shock, and we reduced its origins to one gene, and really one nucleotide change that made all the difference in whether a mouse would get shock or not. In the future, I look toward things being understood mechanistically more and more, so that we really understand immunity as well as we would how a clock works, if we took it apart. In this way disease can be predicted, not only by genetics, the way people are talking about now, but really by mechanistic understanding. It could be applied to many different areas. For example, maybe one day we will understand the mechanism of memory or how emotion occurs mechanistically. Also, I think in my lifetime, there will be great increases in longevity. I remember as a child, which isn’t so very long ago, the average lifespan of a man in America was about 67. Now we’re up to the low 80s, and I understand that a child born today is expected to live to be about 100. That certainly may go much further—all conditions being right, of course. A lot of it will be accomplished by basic science.