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Dr. Lorne Tyrell

Location: Edmonton, AB

Award: Principal Award

Category:

Year: 2005

Innovation:

Discovered a unique system to identify compounds with antiviral activity. The drug lamivudine was then shown by Dr. Tyrrell to be a very potent treatment of chronic hepatitis B virus (HBV) infection and was the first oral antiviral agent licensed to treat this global disease.

News Release

World's First Oral Treatment for Hepatitis B Saving Lives

Edmonton researcher/physician wins top $100,000 Encana Principal Award

Calgary, AB — Dr. Lorne Tyrrell's scientific curiosity about a harmful virus led to his discovery of the world's first effective oral medication for hepatitis B, a life-threatening viral disease that has infected about two billion people.

Research by Dr. Tyrrell, his colleagues and students at the University of Alberta, which led to development of the patented anti-viral drug lamivudine for the treatment of chronic hepatitis B (HBV) infection, has won this year's top prize from the Ernest C. Manning Awards Foundation — the $100,000 Encana Principal Award, sponsored by Encana Corporation.

Lamivudine is now licensed in more than 120 countries for the treatment of chronic HBV infection, which causes over one million premature deaths annually. The drug, marketed by pharmaceutical firm GlaxoSmithKline, dramatically suppresses the virus's ability to reproduce in the body. Treatment with lamivudine has slowed or prevented the life-shortening consequences of the devastating disease, including cirrhosis and liver cancer. It has also reopened the door for HBV-infected patients with advanced liver disease to receive and benefit from liver transplants.

"There's no doubt that the drug markedly decreases the rate at which people develop cirrhosis or liver cancer," says Dr. Tyrrell, Professor at the U of A and holder of the GlaxoSmithKline Endowed Chair in Virology in the Department of Medical Microbiology and Immunology.

Dr. Tyrrell realized, while teaching a graduate course in virology, that the structure of HBV and the unique way it replicates itself in liver cells in ducks could be used to develop a drug that would block the virus from reproducing in liver cells in people. Working with then-U of A chemist Dr. Morris Robins, Dr. Tyrrell and his team developed a system to test chemical compounds called nucleoside analogues, some of which suppressed HBV from replicating. First with ducks, then with chimpanzees, and finally with people in clinical trials, Dr. Tyrrell's pioneering work showed that oral doses of lamivudine dramatically reduced the amount of hepatitis B in their blood.

"It is not hyperbole to write that there are few scientists who have done as much to advance the health of those infected with hepatitis B virus as Dr. Tyrrell," says Dr. Timothy Block, President of the Hepatitis B Foundation at the Pennsylvania Institute for Hepatitis and Virus Research.

Dr. Tyrrell, a former dean of the Faculty of Medicine and Dentistry at the U of A who has helped shape policy in education, health care and health research, is currently leader of the university's Centre of Excellence for Viral Hepatitis, recently funded by the Canadian Foundation for Innovation and the Alberta government through Alberta Science and Research Investments Program.

Dr. Tyrrell's numerous awards include the Order of Canada, the Alberta Order of Excellence, the national Prix Galien award, and the Canadian Medical Association's FNG Starr Award. A gifted teacher, he continues to teach virology to students, and to pursue research on both hepatitis B and C, with the ultimate goal of curing these diseases.

Since 1982, the Ernest C. Manning Awards Foundation's annual program (www.manningawards.ca) has rewarded leading Canadian innovators with $3.5 million in prize money. This year's four major winners, announced throughout September, will share a total of $145,000. All will be honoured at the annual gala awards dinner Sept. 30 in Winnipeg.

* For more information about Dr. Lorne Tyrrell's award-winning research, visit http://www.ualberta.ca/~mmi/faculty/ltyrrell/ltyrrell.html or contact him at (780)-492-6018 or email lorne.tyrrell@ualberta.ca

* For more information about the Ernest C. Manning Awards Foundation, contact Don Park, Executive Director, at (403)-645-8288 or e-mail Don.Park@encana.com

Media Backgrounder

$100,000 Encana Principal Award, Sponsored by Encana Corporation Dr. Lorne Tyrrell, Lamivudine Oral Treatment for Hepatitis B Virus

Dr. Lorne Tyrrell's discovery of the world's first anti-viral oral treatment for hepatitis B — a global disease with about two billion people infected — all started with a university graduate course and a flock of ducks.

Dr. Tyrrell became interested in chronic hepatitis B virus (HBV) infection in 1986, while teaching a graduate-level course in virology at the University of Alberta. In reviewing the scientific studies on HBV, he was fascinated by the unique way the virus reproduces or replicates itself in the body.

Hepatitis B replicates itself in liver cells through an intermediate step. The virus first makes infected RNA molecules, which are reverse transcribed to make one infected strand of DNA, which then serves as the template to make the second infected strand. HBV is the only DNA virus in mammals (including humans) that reproduces this way — which scientists discovered by studying duck liver cells infected by a strain of HBV that infects ducks but not humans.

Dr. Tyrrell recognized that because of the structure of HBV and the unique way it replicates, it should be possible, using infected duck cells, to develop a system to test compounds that would inhibit or block the virus from reproducing during its replication cycle. "If we got a compound that worked in ducks, maybe it would work in humans. I was excited about that potential when I realized it."

Hepatitis B is a devastating disease. In addition to approximately two billion people infected worldwide, about 350 million (including an estimated 250,000 Canadians) have become chronic carriers. Chronic HBV infection leads to more than one million premature deaths annually — patients who die of cirrhosis or liver cancer.

At the time Dr. Tyrrell made the link between HBV replication in ducks and a possible medication for people, the only treatment available for chronic HBV infection was interferon, which had to be injected, was very expensive, and had serious side effects. A vaccine, which also had to be injected, was available to prevent HBV infection in the first place. But there was virtually no effective and affordable drug to help the hundreds of millions of people already suffering from the disease. "People who had end-stage liver disease from hepatitis B had, in the early 1990s, virtually become ineligible for transplantation operations because they re-infected their transplanted liver."

Dr. Tyrrell shared his insight with an American colleague and chemist, Dr. Morris Robins, who was then at the U of A (now at Brigham Young University in Utah). "We went to the faculty club for lunch and I drew out the virus's replication cycle on a napkin. I remember doing it so well. And he got excited, too. He said, 'You know, this looks like it could work.'"

Dr. Robins, whom Dr. Tyrrell credits as co-discoverer of the oral treatment for HBV, had already synthesized several nucleoside analogues. These chemical compounds could be tested in infected duck liver cells to see if they would suppress the virus from replicating. The two scientists, working with Satoru Suzuki, a post-doctoral student from Japan and with then-graduate student Karl Fischer (now a senior research associate), began laboratory tests on the duck cell system "and we found some of the compounds were just remarkably active in suppressing the virus," Dr. Tyrrell says.

The research team then gave the active compounds directly to infected ducks, either by mouth or injection. Tests showed the HBV virus all but disappeared from the birds' blood in just a week. Now the big question was: Would the medication work as well on the human virus in chimpanzees?

Getting to this stage had not been easy. Dr. Tyrrell had to balance a career in research with assuming some heavy administrative roles, including U of A's dean of medicine. "To keep up my research during that time was a huge challenge," he says. Remarkably, he published about 30 scientific papers during this period.

Other initial challenges included a lack of research funding and technical staff. "In the beginning, I had to raise the ducks out at my parents' farm west of Edmonton and collect the ducks' eggs. We hatched them here at university and then I housed them at the university farm. I didn't have technicians for this project at that time, and often my summer student, my two older children Kim and Ben, and my wife LeeAnn and I would go out and help clean up the ducks' cages and keep the research going."

As Dr. Tyrrell built his team and started getting results, funding came from the University Hospital Foundation, the Alberta Heritage Foundation for Medical Research, the then-Medical Research Council of Canada and, in what became one of the largest research contracts with industry for a Canadian university, from Glaxo Canada.

After showing that the chemical agent dramatically reduced the virus's ability to reproduce in ducks, Dr. Tyrrell and his team located a colony of chimpanzees in Louisiana that had been used in early tests of the vaccine for hepatitis B. They screened the chimps for the virus, and found that some of them and their offspring had become carriers of HBV.

Dr. Tyrrell then began treating the infected chimps with the anti-viral agent, mixing it with a drink of Tang that the animals liked to drink twice a day. Levels of hepatitis B virus in the chimps' bodies dropped dramatically. "We found the agent worked every bit as well in the chimps as it had in the ducks. That was a great Eureka! moment."

Lamivudine, the drug synthesized by the late Dr. Bernard Belleau at McGill University, is a nucleoside analogue similar to the compounds that Drs. Tyrrell and Robins discovered in their earlier studies to be active against HBV in ducks. Lamivudine was approved for use in Canada and the U.S. in 1998. Today, it is marketed by pharmaceutical firm GlaxoSmithKline and is licensed in more than 120 countries for the treatment of chronic HBV infection. Sales last year were over Cdn$300 million.

Lamivudine has not only lowered or prevented the life-threatening consequences of chronic HBV infection, it has reopened the door for patients with advanced liver disease to once again receive liver transplants. The drug has also stimulated research worldwide for other second-generation nucleoside analogues as oral anti-viral agents for HBV, including strains that have become resistant to lamivudine.

Dr. Tyrrell is spending more time these days in his laboratory, where he continues to do research on hepatitis B and hepatitis C, including potential methods to cure patients infected with these viruses. "I think I've been blessed to be a clinician-scientist who has had an opportunity to work with patients with these diseases, as well as working in the lab with very talented graduate students, post-docs and technicians."

For Dr. Tyrrell, who has previously received the Order of Canada, the Alberta Order of Excellence, and other awards for his work, winning the Encana Principal Award is "extremely important. The Manning Innovation Awards are unique because they recognize your contributions in Canada. This is the highest award for innovation in Canada, and I can't think of a nicer award to recognize the importance of basic research and its eventual applications to help patients."

The Ernest C. Manning Awards Foundation (www.manningawards.ca)

This year, Manning Innovation Awards presents $145,000 in prize money distributed among four leading Canadian innovators, as well as $20,000 among eight Canada-Wide Science Fair winners. Since 1982, the Foundation has awarded $3.5 million to recognize and reward Canadian innovators.