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Investigator Frank Chisari, M.D., has been studying hepatitis B and C for nearly 30 years.

lthough everyone pronounces it Chi-sa-ri, with the accent on the second syllable, Frank Chisari knows that the true Italian pronunciation is Key-sa-ri, with the accent on the hard C. In Italian, it means someone who knows how to laugh. It is a name that captures his personality. He laughs easily, enjoys his work and his life. His sense of ease keeps him at it.

It being his nearly thirty-year-old study of the hepatitis B and C viruses. That groundbreaking body of work recently got him elected to the National Academy of Sciences. Chisari is now one of fewer than 2,000 select members across the United States and one of 16 from The Scripps Research Institute -- where he serves as a professor in the Department of Molecular and Experimental Medicine and director of the General Clinical Research Center.

"The joy of my work is discovery and learning something new every day," Chisari says. "It also comes from the hope that what we're doing will have an impact on these terrible viruses and the hundreds of millions of people infected by them."

Chisari's life is uniquely his own -- while at the same time a replay of the classic American immigrant story writ large.

Chisari grew up surrounded by a huge extended family on and around the Bronx's Arthur Avenue, a microcosm of southern Italy transplanted to these American shores. His grandparents emigrated from Sicily at the turn of the century, raised a family of 10 children and began a successful contracting business. Chisari was born in the early 1940s into a thriving community of first and second generation immigrants who loved America but held their Italian culture dear.

Here is how one New York newspaper describes Chisari's old neighborhood: "Belmont, the 'Little Italy of the Bronx,' evokes memories of old New York: women shopping at outdoor markets along Arthur Avenue, kids lapping up gelati in the summer heat, old men slapping down dominoes in front of Joe's Deli. [The] area attracted Italian immigrants hired to build the Bronx Zoo in the 1890s. Today it remains quintessentially Italian -- and quintessentially Bronx."

Chisari himself is still something of a transplanted New Yorker. He learned winemaking from his grandfather, a man who had a box car full of zinfandel grapes shipped from California to his cellar in the Bronx each year, and kept his morning catch of live eels in his bathtub so they'd be fresh for dinner. Chisari himself produces about 500 bottles of wine each year in his mini-winery next to the large vegetable garden he tends with his wife behind their house -- that is when he isn't in the lab, or fly-fishing for trout (he doesn't like eels), his other main hobby.

He was only the second in his family to move away from the old Bronx neighborhood, a difficult decision, but one softened by the culture he has managed to carry with him all the way to Southern California.

MEDICAL INSPIRATION

Inspired by his father's best friend -- an old-fashioned family doctor -- Chisari went off to medical school expecting to emerge as a family physician. But, as he says, he got a little distracted along the way.

Part of it was his own curiosity. In med school he found that while he enjoyed the challenge of diagnosis, the routine of patient care dulled his interest. In words echoed by so many other researchers, Chisari says, "I enjoyed figuring out what was wrong and I enjoyed helping the patient cope, but I did not enjoy administering the treatment. That was my first realization that I was not going to become a family doctor."

The second thing was the Vietnam war. Opposed to the conflict, he applied for alternative service in the United States Public Health Service and got stationed at the National Institutes of Health for two years. It was that experience that jump-started his career as a researcher.

He did his postdoctoral work at places like Cornell and the Mayo Clinic, and later spent a year at the Pasteur Institute in Paris. Part of this bouncing around, as he puts it, was to gain experience as a pathologist and internist -- "in case I decided to practice medicine down the road." The other reason was more profound.

"I wanted my research to be medically focused, so I needed to know how disease affected people," he says.

THE LONG WAY HOME

Chisari took a circuitous route to his life's work, going from Washington to La Jolla to Paris and then back to La Jolla.

Chisari's first real exposure to infectious diseases was at the NIH. But a side project got him into viral hepatitis. Because the hepatitis virus would not grow in culture, NIH investigators were trying to transmit the infection to primates for study. With his training in pathology, Chisari volunteered to examine liver biopsies. That's when lightning struck.

"One evening, while was I looking at liver biopsies in the microscope, I found what I thought was a clear case of viral hepatitis, lots of inflammation," Chisari remembers. "When I told the lead investigator, he became very excited, and declared we'd finally transmitted the hepatitis B virus. I told him we wouldn't know that until we detected the virus in the tissues. The problem was, neither one of us knew how to do that."

But there was a pathologist at the then-Scripps Clinic and Research Foundation named Tom Edgington who did know -- he had developed an assay to detect the hepatitis B virus in human liver biopsies. Edgington told him to bring out the samples he wanted tested to La Jolla. So, Chisari gathered up his tissue samples, recruited his wife, and got on a plane to San Diego.

By 1981, he had become aware of the development of the transgenic mouse -- a genetically altered mouse that could mimic a wide variety of disease phenotypes. Chisari's next idea was simple but far-reaching: If he could insert the hepatitis genome into a mouse, he could have the perfect in vivo model to study host-virus interactions. Through a colleague, he managed an invitation to the Pasteur Institute to learn the molecular biology necessary to create his own strain of transgenic mice.

In Paris, he learned enough to produce a transgenic mouse that would model viral hepatitis, the first time that a human pathogen had been introduced by transgenic technology into a mouse. With this creation, Chisari suddenly found that interest in his laboratory at Scripps blossomed. Over the next 10 years, his staff would expand from three to 30 people. His research would evolve into a full-fledged study of the molecular biology, immunobiology, and pathogenesis of two of the world's most devastating infections.

THE UNKNOWN INFECTION

Hepatitis B and C are part of a small family of viruses that can cause chronic infections. The global hepatitis C epidemic -- infecting approximately 200 million people -- rivals HIV in terms of public awareness, if not mortality.

One reason that so few are aware of the seriousness of hepatitis B is that there is a highly effective vaccine that can prevent it. In the West, where the vaccine is available and people can afford it, hepatitis B simply is not considered a major threat.

"The other reason," Chisari says, "is that most of the people who get infected with hepatitis B live in the developing world. Here, we're basically unaware of the danger. The disease is lower on our radar screen, and that disappoints me because hepatitis B virus infection is devastating other parts of the world where the people are least able to cope with it."

Hepatitis B is dangerous. More than 350 million people are chronically infected throughout the world and more than a million, many of them children, will die from it each year. Chronic hepatitis B infections are the leading cause of liver cancer.

Chisari's disappointment grows directly out of his sense of purpose, born in the idealism of the 1960s, and undiminished by time. It helps drives much of his research and, perhaps, helps compensate for the path not taken as the family doctor.

"When I started in medicine, I wanted to have an impact on the lives of patients," he says. "Maybe the people who've been helped by my research are the patients I might have visited. In one way, this is my work as a family doctor, amplified a million fold."

While the study of hepatitis B remains, to some degree, a problem of funding, public awareness, and logistics, hepatitis C represents the kind of medical challenge that science faces with HIV. Hepatitis B is a DNA virus that makes few mistakes when it reproduces; consequently, it mutates at a relatively low rate. The hepatitis C virus -- an RNA virus -- mutates rapidly, enabling it to stay one step ahead of the human immune system. The hepatitis C virus spreads like wildfire in the liver, well before the immune system kicks in. Then the virus mutates so swiftly that the immune system is forced to play catch-up in a race it can never win.

US VERSUS THEM

"We use war analogies for the race between the virus and the immune system," Chisari says. "The war is carried out by opposing soldiers in the infected tissues. Sometimes the bad soldiers win; sometimes the good soldiers win. More often than not, there's a stand-off. In fact, we've found that the host can clear the virus without killing the infected cells."

The idea that the immune system could cure a viral infection without actually destroying infected cells was a breakthrough idea that many of Chisari's peers rejected at first. Indeed, most scientists believed viral clearance was due only to the destruction of infected cells by cytotoxic T cells. Chisari reasoned that curative mechanisms must also exist or we would self-destruct every time a vital organ like the liver became infected. In a landmark 1995 paper published in the journal Immunity Chisari and his colleague, Luca G. Guidotti, established a new paradigm in viral immunology. Using his transgenic mouse model, they demonstrated that the immune system could indeed contribute to viral clearance by stopping viral replication inside the cell without killing it. In a 1999 study published in the journal Science, he demonstrated that the same principles were operative during a natural hepatitis B virus infection.

Chisari believes that suppression of viral infections by the immune response rather than complete viral elimination will probably be the long-term outcome for infections like HIV and hepatitis C. The medical challenge will be to boost immunity to a point that if someone becomes infected, the virus won't spread, and the disease will remain in stasis. Patients might have to spend the rest of their lives on medication, but they will survive. Chisari admits that even that optimistic scenario carries risks. What if the immune system is weakened by another infection or by the aging process itself? Will the virus suddenly emerge late in life in a new and more virulent form? No one knows.

THE BIG DEAL

Despite that uncertainty, the difference between today and when Chisari began his research some thirty years ago couldn't be clearer. Back then, no one knew what happened when you got infected with a hepatitis virus.

"Thirty years ago, we knew there was something presumably a virus, in the blood of some people that caused hepatitis," he says. "We knew it was transmitted to others and made them sick too. We didn't know what the agents were or what the process was that caused the infection. While there are still some questions about the details of the infection, we now know a lot of the answers."

He credits the members of his laboratory and colleagues in the scientific community for a large part of that knowledge. While running a thirty-person lab might blunt the satisfaction of being the primary discoverer, it increases the opportunity for discovery, expanding the reach of Chisari's own innate curiosity with the talented help of others.

"This gets me back to the puzzle part," he says. "Being able to figure this out is a joy. The story of the race between the virus and the immune system wasn't known until just a few years ago. Using the models we created, we discovered a brand new concept, a whole new body of knowledge. You might say, 'Hey, what's the big deal?' The virus and the immune system fight it out to see who wins. The big deal is we didn't know how the game was played then. Now we do."