September 2005
Dr. Charles N. Serhan, the Simon Gelman Professor at Harvard Medical School and director of the Center for Experimental Therapeutics and Reperfusion Injury at the Brigham and Women’s Hospital, will deliver the 2005 NIDCR Seymour J. Kreshover Lecture. The lecture takes place on Friday, September 23 at 3:30 p.m. in the Lipsett Amphitheater in NIH’s Building 10. Dr. Serhan, an NIDCR grantee, will present a talk titled, "The Role of Novel Anti-Inflammatory and Pro-Resolving Lipid Mediators in Oral Inflammation and Resolution." The lecture will be webcast at http://videocast.nih.gov/
In advance of the lecture, The Inside Scoop talked to Dr. Serhan about his career in science and ongoing research interests. Here’s what he had to say.
You grew up in New York. Where?
I was born in Brooklyn, but my family moved in the late 1960s to Oceanside, where I attended high school. Interestingly, neither of my parents were involved in the sciences. My mother was a cosmetologist in Manhattan, and my father was in business.
I've got to ask: Were you a Mets or Yankees fan?
I was a Yankees fan, but I also had to root for the underdog Mets, too. That’s just part of being a New Yorker, rooting for the underdog. Now, between work and family, I don’t have time to follow professional sports closely. If it’s not published in the Journal of Biological Chemistry, I don’t know about it.
As a kid, you aspired to be a musician. Is that correct?
That’s right. I studied music in grade school and learned all about percussion. Then, in my early teens, I made the transition to play the vibraphone, which I still play today.
Now, you spent a brief time on the road performing in a jazz band. How did that experience ultimately steer you to a career in science?
It’s an interesting story. When I was 17, I got a chance to go on the road as a drummer with a group of really seasoned professionals called the Chuck Bear Revue. These were guys who played six nights a week, two shows a night. So, as a then aspiring musician, I decided to delay going to college and pursue this opportunity.
How long were you on the road?
About a year. But three months was probably enough for me. What I learned was playing music for a living and being a musician are two different things. I just wasn’t cut out for the ups and downs of life on the road. But, getting back to your previous question, while I was traveling with the band, I found myself gravitating to books on scientific philosophy, biochemistry, astrophysics, the writings of Pasteur, and so on. So, when I got home and enrolled as an undergrad at SUNY-Stony Brook, there was no doubt. I was majoring in biochemistry.
Four years later, you ended up at the Sackler Institute School of Medicine to study experimental pathology.
Right. In 1978, my first year at the Sackler, I was on an NIH predoctoral fellowship. The fellowship had a major influence in shaping my career because it allowed me to work in the lab of the late Dr. Michael Heidelberger, one of the founders of quantitative immunology. He was more or less retired by then, but he was a real mentor to me in the old style. I’d ask him, "What makes a good scientist?" "How do you develop a career in the lab?" That kind of stuff. Dr. Heidelberger was the first really notable scientist who I had ever met, and he was just a tremendously nurturing person.
And a fine musician, too.
Absolutely. In addition to his interest in immunochemistry, Dr. Heidelberger composed several pieces of music.
Was it Dr. Heidelberger who steered you to a career in immunology?
He did. Dr. Heidelberger predicted that immunology would rise in prominence among the biosciences, and he said the study of inflammation would be a real promising field. He also directed me to Dr. Gerry Weissmann’s lab to work on my thesis, and that’s where I ended up.
Was it a good move?
A great move. While working on my thesis, I met Dr. Bengt Samuelson, a collaborator and good friend of Gerry Weissmann. Bengt told me that when I finished my thesis, he’d have position waiting for me in his laboratory in Stockholm. What that did was give me direction early in my thesis work, and I could concentrate on getting as much exciting science done as possible. After I finished my thesis in 1982, I spent four fantastic years in Stockholm. In fact, while I was there, Bengt received a Nobel in Physiology of Medicine for the structural elucidation of prostaglandins.
What did you work on in Stockholm?
First, a little background. While I was at the Sackler, we made a couple of key observations. One is that blood cells in particular can talk to each other via a process of transcellular biosynthesis. Meaning what? When cell type A communicates with cell type B, it sends a signal that is picked up by a receiver. A receptor-ligand type of interaction. We found early on that a compound that is made in one cell type could actually be transported, then converted by cell type B into a novel compound that would then talk to them both, which is pretty cool. When I got to Stockholm, we started to follow that conceptually. We came up with a new series of compounds that we made from arachodonic acid that had very unique structures. So, we worked out the structures of those compounds, then started to work on what their biological significance was.
Then you moved your research to Harvard.
Right. I accepted a position as an assistant professor in 1987. We started to look at the pathology and molecular pharmacology of the compounds simultaneously with their structural elucidation and biochemistry. What became very clear is these compounds are endogenous, anti-inflammatory substances. It was a 180- degree difference in what these lipid mediators were thought to be doing. Most of your non-steroidal anti-inflammatory drugs, such as aspirin and Motrin, are known to block the production of pro-inflammatory prostaglandins. Thus, the mechanism of action was thought to be restricted to blocking pro-inflammatory mediators. It turns out that aspirin triggers the formation of some of these compounds, which are called "aspirin triggered lipoxins." Lipoxins are novel, naturally occurring lipid compounds, and it was very clear that they carry anti inflammatory actions. So, then I decided some years back to make analogues of those compounds.
How tough was it for you to head down this alternative road and receive funding to pursue your ideas?
Well, it was a lonely path. But I was very lucky. Even though I was taking a not-well-appreciated path, people knew that we were doing rigorous work. I also got a Pew Scholar in the Biomedical Sciences award that let us early on take big risks. That helped. In the meantime, very careful analysis made it abundantly clear these compounds were anti-inflammatory pharmacologically. Then we started to patent them, and the work has been licensed by a major pharmaceutical company for development. In other words, the concept underlying this work is that you can treat inflammation with a response-triggering agonist rather than an inhibitor.
But you had only scratched the surface, correct?
Yes, with that work perking along, we got into what really is ambient, endogenous inflammation. People didn’t appreciate it, but you have these self-limited events that occur with inflammation. By self limited, I mean that it would turn into a major event every time, for example, you had a pimple, if the inflammatory process wasn’t self limited. So, we started to work out some of these pathways. Then, we discovered that other classes of compounds and pathways were turned on specifically during the resolution phase. We call these compounds the resolvins.
How were the resolvins accepted when you started publishing on them?
Well, like all science initially, there was skepticism. Then, once people get a taste, they get excited. Now everybody is pretty excited about the resolvin work because it makes sense. But also because we laid down intellectual groundwork for about 10 years before that.
You've received support from the NIDCR for several years. How did you become interested in oral immunology?
I’m glad you asked that. We had done a lot of the basic research in mice, and I began to think about extending our work to people. But to move from bench to bedside is not always so apparent. It’s something that you’re not taught in school as a scientist, and it’s unfortunate. We gave a symposium on neutrophil activation at FASEB [Federation of American Societies for Experimental Biology] back in the 1990s. Neutrophils are a type of white blood cell that when overactivated, lead to tissue degradation. NIDCR’s Dr. Dennis Mangan attended our symposium, and we talked afterwards about NIDCR’s programmatic interests on the periodontal diseases. I kept our conversation in the back of my mind, thinking periodontal disease might be a place where all of my interests could be focused in terms of pathophysiology, inflammation, vascular biology, and bone and tissue destruction. But obviously, I could use this information to move the work into people.
What happened next?
Dennis steered me to some publications, and I got really excited the more I read about periodontal disease. Thereafter, I started to collaborate with Dr. Tom Van Dyke, a dentist and periodontologist who now conducts research around the corner here at Boston University. Our groups made mouse and rabbit models of periodontitis, which allowed us to do genetic manipulations and show that they would get protection by quiescing inflammation of the periodontium. We also could make stable analogues of these endogenous anti-inflammatory mediators, which we found would protect against bone destruction in the rabbit model. So, we now have a program project from NIDCR, and the work has been going like gangbusters.
Will any of these compounds be moving into human clinical trials in the near future?
Not quite yet. We’re in the midst of closing the loop between learning from disease mechanism - that is, the basic biological processes - and the utility of learning how to use them. We’ve been successful in making tool compounds that I think may be very good drug candidates for new ways to treat periodontal disease.
Have you attended the previous Kreshover Lectures?
Unfortunately, I haven’t. But I’ll tell you, it’s a real honor to have been selected to give this year’s lecture, and I look forward to coming to Bethesda and meeting Dr. Kreshover and his family.