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ow he got here is one of those serendipitous chains of events, the kind Hollywood does so well. A remark here, a suggestion there, and the next thing you know, you're living in Casablanca. Or in this case, La Jolla, California. After receiving his Ph.D. in biochemistry from the University of Pennsylvania in 1971, someone mentioned to Ulevitch that the field of immunology might be a good one to look into for future research possibilities. The interesting thing is he doesn't remember who told him, although he sometimes wishes he did.

They married and raised two children. Today his wife is a licensed clinical social worker. His daughter Annie, now 24, works for the city of New York, and is on her way to law school; their 20-year-old son David, a computer whiz, is a student at Washington University in St. Louis.

But back in 1974, something else happened. Richard Ulevitch discovered endotoxins.

Endotoxins are odd pieces of molecular material. Composed of lipid and sugar chains, the lipopolysaccharide (LPS) molecules make up the cell walls of Gram-negative bacteria. Gram-negative bacteria include E. coli, Salmonella, Shigella, Pseudomonas, Neisseria, Haemophilus, and Meningicocci--in short, some of the most deadly infectious agents on the planet.

They are notoriously thin-skinned, and small pieces of endotoxin break off easily as they move through the body. When killed or broken, the bacteria release even larger amounts. In and of themselves, endotoxins are benign, but they serve as a warning sign announcing the presence of bacteria. As a result, the immune systems of many organisms--but especially humans--are remarkably sensitive to their presence.

And so endotoxins aren't the problem. The real problem is caused by the reaction of the immune system to them. In that sense, even the mildest intrusion of an endotoxin causes the body's immune system to go on alert, even overreact. An important thing to remember about endotoxins is that they alone can produce a fatal immune reaction or cascade even if the surrounding bacterium is dead.

One of things that led Ulevitch in the direction of endotoxins, or at least encouraged him, was the best selling book, Lives of a Cell, by Dr. Lewis Thomas, published the same year that Ulevitch began to develop his own attraction to them. Thomas characterized the body's response to the endotoxins as being "read by our tissues as the very worst of bad news. . . . There is nothing intrinsically poisonous about endotoxin, but it must look awful, or feel awful, when sensed by cells. Cells believe that it signifies the presence of Gram-negative bacteria, and they will stop at nothing to avoid this threat."

Ever since then, finding out exactly how the body handles an influx of endotoxins, and how science might modify that reaction has been the driving force behind his work.

While it might seem a small target, for Ulevitch the study of endotoxins opens up the entire immune system to scrutiny.

"These studies," he says, "are a window into the human immune system response to infection, and the mechanisms that control diseases where chronic and often harmful inflammation is present. That's why these infections are so horrible. In order to clear them away, there is an immediate response by the immune system. In some people, there is a complex underlying genetic pattern, as yet not understood, that allows this normally protective response to get out of control, and that can quickly lead to septic shock."

Septic shock starts out as sepsis, a condition that can slip easily into severe sepsis and shock, which means organ failure far from the infection site, most often the lungs, kidneys, and liver. This syndrome may include fever, tachycardia, hypotension and coagulation abnormalities, and is one that cannot be reversed with available treatments. What is most frightening about septic shock is that a substantial number of hospitalized patients develop it, and a great many of those die from it.

"It's an insidious disease," Ulevitch says. "It can't always be recognized, and by the time it is, much of the damage has been done. Its progression is difficult if not impossible to reverse. Even after years of research, septic shock continues to be a major cause of morbidity and mortality in intensive care units all around the world."

"So, because of the high incidence of septic shock, and the poor prognosis for patients," says Ulevitch, "we have two major long-term goals. First, we're studying the underlying mechanisms of the immune system and how it responds to infection. That understanding may lead to new therapies. Secondly, we're looking to identify new genetic markers that can ultimately be evaluated on an individual basis so we can predict who might be susceptible to septic shock and who isn't." One of their findings may one day lead to a new treatment for septic shock. This finding is the basis of a current clinical trial with a monoclonal antibody, and is sponsored by Icos, a Seattle based biotech company. The antibody selectively blocks the white blood cell receptor CD14, reducing the intensity of the immune system cascade that causes septic shock.

DELINEATING THE UNDERLYING MECHANISM OF DISEASE

The practical aspect of discovering the underlying mechanisms of septic shock goes further than finding a treatment for this single disease, although that remains a critical goal. As Ulevitch suggests, the ultimate target is larger still. The same mechanisms operative in septic shock also contribute to chronic inflammatory disease. Whatever is learned about acute models of infection response can be applied with equal certainty--and equal benefit--to chronic inflammatory disease.

"Currently, there's only one drug that's approved for this condition," according to Ulevitch. "What we're looking for is a way to minimize the body's response to infection without compromising the immune system. The goal is to reduce the body's inflammatory response so that there's a sub-threshold of activity, but one that still allows the bacteria-killing mechanism to work effectively."

Some of his research has a more up-to-the-second application, specifically in the burgeoning area of bioterrorism since treatment of many toxic agents relies on the same host defense mechanisms. In the case of bioterrorism, that means improving a body's non-specific immunity to pathogens by developing molecules that could be added to increase the initial immune response to a vaccine, thus harnessing the protective aspects of immunity without the potentially dangerous consequences.

"I was asked to be chairman about eight years ago," he says, adding quickly that he feels little or no tension between his own research and time spent managing the department. "Most of my time is focused on my own research because of the way TSRI works. As head of the department, my job is to make certain our scientists have the resources they need to do their research. The faculty here is really pretty self-sufficient and the administration is highly supportive. But when they need something, I find a way to get it to them."

At present, Ulevitch oversees a staff of more than 400 professionals. Among them are about 60 faculty members, and more than 100 postdoctoral fellows. "Our immunology program is recognized worldwide for the breadth of the studies performed here," he says. "That includes efforts to understand the development of the immune system as well as disease-focused efforts in areas such as cancer, autoimmune disorders like diabetes, rheumatoid arthritis, Lupus, infectious disease, and inflammation. At the beginning, the department was focused on diseases where the immune system was central. Today, our research efforts are much broader."

What has been challenging, Ulevitch says, has been to keep one of the largest and most internationally diverse immunology research departments in the world growing and thriving in a world of rapid scientific and cultural change, something he says he's been able to do through a combination of support from both the Institute and its faculty. Ulevitch sees part of that change coming from the expansion of some of the department's work into early clinical development, offering interested scientists the opportunity to see how their research might benefit patients in a more practical way.

"I think there's a place in sophisticated research institutes like TSRI to do internal development on a limited basis to assess the therapeutic potential of certain compounds being studied," he says. "In immunology, for example, we might look at getting monoclonal antibodies into the clinic quickly for some selected diseases--in oncology, for instance. It's an idea that has to evolve and the Institute is well positioned to develop it. I think we have the kind of special infrastructure necessary to make it work effectively."

COMMUNITY INVOLVEMENT

When Ulevitch isn't working on his own research or helping find the right tools to help others with theirs, he can often be found working on a number of community boards in and around La Jolla. One longstanding commitment is with the La Jolla Playhouse, the one-time summer home of film actors like Gregory Peck who would come down from Hollywood to do stock productions during the off months. He became a board member in 1987, and helped chart the future of the playhouse just as it was re-emerging as an important regional theater.

"The playhouse received several grants in the 1980s to basically re-invent itself," he says. "As a result, it's become one of the top two or three regional theaters in the country." The La Jolla Playhouse has produced numerous plays that went on to Broadway including several Tony award-winning musicals.

"One of the reasons I do it is because I think it's important to help your community when you can," he says. "I try to make an impact. I've been on various boards for the last twenty years or so. I wish I had time to do more but I don't."

For that, Richard Ulevitch could point to the person who got him into immunology in the first place. Now if he could only remember his name.