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Chance and the Prepared Mind

Mention is often made about how a university teacher's involvement in research can overflow into the classroom with positive results. Less often acknowledged is the fact that it also can happen the other way.

Lorne Tyrrell,'64 BSc,'68 MD, has played a leading role in the development of the world's first drug for treatment of hepatitis B, a global health scourge of major proportions. He's also overseen the creation of the University of Alberta's new Glaxo Heritage Research Institute for Virology, which largely results from the research capability his research has fostered.

And it all began in the classroom.

Tyrrell is as busy a man as you're likely to meet. Besides his research program, he juggles an active clinical practice in infectious diseases and duties as chair of the Faculty of Medicine's Department of Medical Microbiology and Infectious Diseases. And he spends a considerable amount of time in the classroom — as much as any other department chair on campus.

In 1985-86 Tyrrell taught part of a new graduate course in virology. "One of the things I was assigned to teach was the hepatitis viruses," he says, recalling how his attention was caught by scientific papers published that year providing new information about how the hepatitis B virus was replicated.

"Through the teaching I became very familiar with the replication pathways and felt there should be ways to inhibit this virus selectively," says Tyrrell. He shared his conviction with a cross-campus colleague, Dr Morris Robins.

Robins, then a U of A chemistry professor and now a faculty member at Brigham Young University in Utah, specializes in the synthesis of nucleoside compounds. He could see what Tyrrell was talking about. "Morris got as excited as I did when he saw the pathways," says Tyrrell.

The two, who continue to collaborate despite Robins's relocation, went to work to find an antiviral agent to thwart the troublesome virus, which afflicts thousands of people in Canada and is a major health problem in the Third World. The research they initiated has led to a compound with the antiviral properties they were looking for, and the world's first hepatitis B drug is now making its way through clinical trials — two to three years away from pharmacy shelves, estimates Tyrrell.

"Chance," said Louis Pasteur, "favors the prepared mind." Those words could be used to summarize Tyrrell's career. "My whole career in medicine happened in some ways by accident, and in some ways by design," he says.

Tyrrell, who grew up on a farm in the Duffield area west of Edmonton, enrolled in the U of A in the fall of 1961. He planned to enter medical school in his third year, but in the preceding summer his father bought a bulldozer and obtained a contract to build a road for a local Indian band. Tyrrell had to help out and by the time he got back to campus it was too late for medical school. Instead he finished a degree in chemistry.

Looking back, Tyrrell sees that roadbuilding experience as pivotal in his career. "I had never built a road and here I was at 8:00 in the morning sitting on a Cat, not knowing where to start. In my nervousness I ate all my lunch. Then I started pushing the road and it was a real challenge. When one of the tracks came off, I had to jack up the cat for a whole day, and somehow get the track onto the sprockets. I learned to solve problems that seem insurmountable. After a week it really began to look like a nice road."

When he did enter medical school, Tyrrell's extra work in chemistry helped him win a Life Insurance Fellowship. The fellowship provided funding for a combined MD-PhD program, and once he had earned his medical degree and completed his internship, Tyrrell headed east to Queen's University for PhD studies. "Even in those early days I was fascinated with molecular biology," recalls Tyrrell.

He was also intrigued by viruses and the challenge that these "intracellular parasites" represented. "In my medical schooling, I can remember that when we talked about antiviral agents, we were told it would be very difficult to get a good antiviral agent because anything you did to inhibit the virus would be too toxic to the cell," he says.

The breakthrough came in 1978, the year that Tyrrell came back to Edmonton, having studied virology in Stockholm as a Medical Research Council Centennial Fellow. The breakthrough was the discovery of acyclovir for the treatment for certain viruses of the herpes family — including the virus responsible for cold sores, genital herpes and chicken pox. Selective, nontoxic and effective, acyclovir worked by attacking an enzyme specific to the virus.

For the first time, medicine had a weapon other than vaccination to selectively fight viral infection. But viruses have proven to be tricky targets, and one of the more elusive has been the hepatitis B strain. "This disease is a big problem world-wide," explains Tyrrell. "There are an estimated 300 million people who carry the virus and a million of them will go on each year to develop cancer of the liver resulting from chronic liver infection. Others will develop cirrhosis of the liver."

The hepatitis B virus strain wasn't discovered until the 1960s, and a vaccine was developed late in the following decade. But a vaccine can't help those already infected, and hepatitis B spreads quickly — it's passed on in much the same way as the AIDS virus but spreads much more readily.

While the onset of hepatitis B infection can involve severe symptoms, including a characteristic jaundice, most adults who contract the virus are not greatly bothered by it. They have a bout of flu-like illness and then recover. However, somewhere between five and 10 per cent of those infected become chronic carriers. It is these people who are at greatly increased risk for liver cancer and cirrhosis of the liver.

What makes hepatitis B an even greater health problem is the fact that it easily passes from mother to child at birth and the odds faced by the infected infants are not good. Ninety per cent of these children become chronic carriers. The boys face a 50 per cent chance of succumbing to liver disease, usually in their 30s or 40s. For girls the risk is 15 per cent.

Tyrrell knew these statistics when he and Robins began their research. However, as a practicing clinician he knew hepatitis sufferers not only as statistics. They had the faces of his patients, and that gave an added ar dimension to the work.

An early stumbling block for the U of A, researchers was creating a cell-culture system for testing likely compounds. "The problem in developing anti-viral therapy for heptitis B is that nobody had a way of growing the virus in cell lines. Even today it's not an easy task to infect a cell with hepatitis B," says Tyrrell.

There are two good animal models for hepatitis B infection. The eastern woodchuck is victim to a closely-related form of hepatitis, but in the woodchuck the infection rapidly progresses to fatal liver cancer. Ducks, on the other hand, are prey to a virus from the same family but survive without damage from the chronic infection.

Clearly, the duck virus — which is not infectious to humans— showed the most promise. To learn how to culture duck liver cells, Tyrrell sent Dr Satoru Suzuki, then working in his laboratory as an AFHMR post-doctoral fellow, to Philadelphia to work with Dr Jesse Summers, who had pioneered the procedure.

Once Suzuki had returned, Tyrrell and Robins began testing compounds, their initial work funded by an AHMFR technology-transfer grant. By 1988 the U of A researchers had isolated a class of compounds that showed strong anti-viral capability, almost completely eliminating the virus in cell cultures. This was enough to attract the support of Glaxo Canada Inc., and the pharmaceutical firm pumped $1.5 million into the work over a three-year period. That support has since been extended and has led to the creation of the Glaxo Heritage Research Institute.

The collaboration with Glaxo proved fruitful in the laboratory as well. "Our work led to our using our hepatitis system for screening other compounds Glaxo had in house," explains Tyrrell.

One of the compounds that the U of A researchers tested had been synthesized by Biochem Pharm of Montreal and later obtained by Glaxo as a possible AIDS treatment. That compound, which has been given the name Lamivudine, has since become the lead compound in Tyrrell's work on antivirals for hepatitis B.

A bonus was the fact that Lamivudine had already undergone some of the rigorous testing that precedes the marketing of any new pharmaceutical. "There had been a lot of toxicology work done and it had already started to be used in some AIDS patients," says Tyrrell.

The compound has now gone through the first set of clinical trials testing its effec tiveness against hepatitis B. The tests took place not only in Edmonton but at Yale   niversity and in places as distant as Eng land, Belgium, and the Netherlands. So far the results have been all that Tyrrell could hope for. "It's remarkably non-toxic and is a potent antiviral agent for hepatitis B," he says. "We are not 100 per cent sure whether we can cure with this compound yet — we may be just suppressing the virus, which would mean the patient would have to stay on therapy — but the work with the compound has progressed nicely."

Looking back on the six years since he began his hepatitis B research effort, Tyrrell finds great satisfaction not only with the speed at which the work has progressed but in the learning opportunities it has provided. "It's been very satisfying to work with students on a project where we have progressed from work on very early concepts, to designing compounds, to screening them, to doing animal work, and then carrying it right through to clinical work."

And best of all is the hope that he is able to give to his patients. "I've really found it terrifically gratifying to work with the hepatitis B patients and discuss with them the possibility of antiviral therapy. Many of them are really quite devastated with their disease, particularly if they have seen relatives suffer the consequences of carrying hepatitis B virus."

Published Spring 1994.

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