A Conversation with Bruce Beutler

A conversation with Bruce Beutler Ushma S. Neill J Clin Invest. 2013;123(9):3637-3638. https://doi.org/10.1172/JCI71317. Conversations with Giants in Medicine A legend within the field of innate immunity, Dr. Bruce Beutler (Figure 1) of the University of Texas Southwestern Medical School is best known for two seminal discoveries: identifying mouse tumor necrosis factor and discovering Toll-like receptor 4, the receptor for lipopolysaccharide. With this discovery, later rewarded with the 2011 Nobel Prize in Medicine, we finally understood how immune cells could recognize and react to bacteria. The full interview, with many more stories on developing etanercept, searching landfills for sequencers, and falling in love with genetics can be seen on the JCI website, http://www.jci.org/kiosk/cgm. JCI: Could you start by telling me a little bit about where and how you grew up? Beutler: I was born in Chicago, but from the age of two I was raised in Southern California. My father was a biomedical researcher himself, Ernest Beutler, a renowned hematologist with eclectic interests interested in the genetics of anemia, glycolipid storage diseases, iron deficiency, and cancer. Most definitely he encouraged my interest in science from an early age. I started off with a broad interest in nature, and I remember being fascinated by animals from the time I was a small child, thinking how interesting it was that they could move and showed evidence of free will. I was just taken by the beauty of nature. At some point, […] Find the latest version: https://jci.me/71317/pdf Conversations with giants in medicine A conversation with Bruce Beutler A legend within the field of innate and a trainee, and I thought remarkable Beutler: I actually was surprised because immunity, Dr. Bruce Beutler (Figure 1) things were happening. People were begin- it had been said in the lab that this had of the University of Texas Southwestern ning to clone cDNAs by the time I was in been ruled that out — that others had Medical School is best known for two college, and molecular biology was under- done assays for TNF activity in cachectin seminal discoveries: identifying mouse going a revolution and I wanted to be a preparations and had found no relation- tumor necrosis factor and discover- part of all that. ship between the two. However, the most ing Toll-like receptor 4, the receptor for JCI: Why did you choose to go to medical important part of the discovery was the lipopolysaccharide. With this discovery, school, and why University of Chicago? fact that TNF, far from being a benign later rewarded with the 2011 Nobel Prize Beutler: I applied to many medical protein as portrayed by those using it in Medicine, we finally understood how schools, but I was only accepted to one. for cancer chemotherapy, was a powerful immune cells could recognize and react Maybe this was because I was only 18 inflammatory mediator, responsible for to bacteria. The full interview, with many years old when I was applying. Also, I was many of the effects of LPS. This led to the more stories on developing etanercept, unabashedly saying to all the people who next phase of my work, in which I tried to searching landfills for sequencers, and interviewed me that I was interested in find the receptor for LPS. falling in love with genetics can be seen science rather than clinical medicine. I JCI: You transitioned back to Dallas to on the JCI website, http://www.jci.org/ think the attitude was, “Well in that case, establish your first lab, as an HHMI-fund- kiosk/cgm. why don’t you get a PhD?” I had advice to ed investigator wherein you switched focus JCI: Could you start by telling me a little the contrary from my father — he felt that from TNF to trying to sort out the LPS bit about where and how you grew up? if I wanted to be a biomedical scientist, I receptor. Beutler: I was born in Chicago, but from should study medicine. I should learn at Beutler: This was a gradual process. the age of two I was raised in Southern least what the big challenges were, I should At first, it was something that I just California. My father was a biomedi- understand anatomy, physiology, pathol- wondered about. I was familiar with the cal researcher himself, Ernest Beutler, ogy, pharmacology, and knowing all of C3H/HeJ mice that were endotoxin resis- a renowned hematologist with eclectic those things I’d be in a position to work on tant. It was speculated quite widely that interests interested in the genetics of almost any problem I chose. they had a mutation in the LPS recep- anemia, glycolipid storage diseases, iron JCI: You chose UT Southwestern for your tor and nobody knew what that recep- deficiency, and cancer. Most definitely he internship and residency in neurology. tor was; it was peculiar that nobody encouraged my interest in science from Beutler: There I did have some choices, understood how microbes were per- an early age. and I ranked UT Southwestern first because ceived in general — how macrophages, I started off with a broad interest in I thought that if I was going to do a resi- neutrophils, and other cells “knew” nature, and I remember being fascinated dency, it should be a tough residency — one when an infection was in progress. The by animals from the time I was a small where I would be challenged and learn all fact that nobody knew elevated the child, thinking how interesting it was that I could about internal medicine and then stature of the question in my mind. they could move and showed evidence of neurology — in the shortest possible time. I first worked on it in a back burner sort free will. I was just taken by the beauty of I certainly was not disappointed in that of way. Starting maybe in about 1986 or nature. At some point, my father tried to regard. It was a stringent experience being ‘87, we began cross-immunizing C3H/ influence me by pointing out that all of an intern at Parkland Hospital. HeJ mice with C3H/HeN cells and vice my birding expeditions weren’t really sci- JCI: After your residency, you decided versa hoping to raise an antibody that ence; I was merely being observational, to do post-doctoral research with Tony would detect the difference. We never and he invited me to work in his lab. I was Cerami at Rockefeller. Your project was could. I thought maybe I could see a pro- certainly eager, and from the age of 14, I on cachectin, a putative mediator of tein that was missing in the membrane started working in his laboratory through wasting. fraction of C3H/HeJ macrophages, and the summer and then on weekends there- Beutler: When I arrived in that lab I had this too was unsuccessful. We tried also after during the school year. I learned how a choice to work either on cachectin or on cDNA cloning as a strategy to identify to assay erythrocyte enzymes, how to do non-enzymatic glycosylation in diabetes. the critical gene, and I began incorporat- electrophoresis in starch gels, and to puri- I chose to work on the cachectin project ing more and more people into the proj- fy proteins. because I felt I could purify the protein. ect. But it was going nowhere and that JCI: You went to college young, and fin- When I began to assay it, and to define the was when I turned to genetics. Positional ished very quickly. best conditions for an assay, there was a cloning was something I tried to avoid, Beutler: I was trying to emulate my father strong signal, and I thought isolating the but when I did start it, I became com- to some degree because he went to college protein would be straightforward. In fact pletely addicted to it. It was something so at 15 and finished medical school at 21. I it did go quite quickly. It took about a year compelling, the idea that you could start always set that as a standard to be followed to purify cachectin to homogeneity and to with a strong phenotype, and gradually for academic excellence, but also, I remem- sequence it. restrict the area of the DNA to a smaller ber just being impatient to start practicing JCI: It turned out to be the mouse version and smaller region, and then clone all of science instead of being mostly an observer of tumor necrosis factor. it, and then find the gene. The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 9 September 2013 3637 conversations with giants in medicine JCI: You covered about 90% of the critical ing. The day before, I had seen my older region before you finally landed on TLR4. brother, Earl, who also is in a biomedically- Beutler: That was bad luck. We nar- related area, as he developed bibliographic rowed the interval. We started in the software for reference retrieval program middle and worked toward the margins, called Reference Manager. He had asked because the middle would be the area of me in the casual chiding manner of a big highest probability. And yet, it turned out brother, “You think you’re going to win the to be quite close to one of the markers at Nobel Prize this year?” the edge. That was a little bit on my mind and JCI: Can you describe how it felt to actu- as I sat there jet-lagged, I looked at my ally land on TLR4? cellphone and I saw a single e-mail that Beutler: It was something that happened said “Nobel Prize” in the subject line.

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