Sweating the Small Stuff

They exist at the very edge of life: not alive in the way we normally imagine life, but not exactly lifeless, either. Outside the cell of a susceptible host, a virus is no more alive than a grain of salt. Once it penetrates a targeted cell, however, it commandeers the cell's reproductive technology and puts it to its own use, churning out copy after copy of itself.Viruses are the most abundant biological entities on earth, outnumbering all others put together. Viruses are studies in minimalism. They are simply a snippet of genetic material (DNA or RNA) wrapped up in a protein coat and, in some viruses, augmented by an outer coat of lipid material torn from the cell of a host. It wasn't until after the advent of the electron microscope in the 1930s that anyone actually saw a virus and witnessed their amazing diversity of shapes.

Viruses have afflicted humankind since the dawn of history, and, despite some medical triumphs-perhaps most notably the eradication of smallpox and the suppression of polio-viruses continue to have enormous impact on human health and mortality throughout the world. "Back in the '60s and '70s, we thought we had pretty much conquered infectious disease," wryly notes Michael Houghton, who holds the Canada Excellence Research Chair (CERC) in Virology at the U of A. But then came HIV and SARS, new pandemic influenza strains and an awakening to the damage wrought by hepatitis viruses. Any sense of complacency was shattered, and the war on viral diseases was stepped up. Fresh efforts were made to understand exactly how viruses are able to enter cells and hijack their reproductive capability.

British-born Houghton is a veteran of the war against viral disease. In 1989, working with colleagues at the California-based biotechnology company Chiron, he was the first to identify the hepatitis C virus. "It was like looking for a needle in a haystack," says Houghton, recalling the seven-year search for the virus, which infects more than 170 million people around the world, including 300,000 Canadians. This year, more than 15,000 people in North America will die from hepatitis C, which can lead to cirrhosis of the liver and liver cancer.

The hepatitis C virus (HCV) is most readily spread through blood, so once the virus was identified, Houghton was able to develop a blood-screening test to protect patients who receive blood transfusions. Previously, those receiving a blood transfusion had a one-in-20 chance of contracting hepatitis C. "Now the risk is so low we can hardly measure it," says Houghton. Since developing the blood-screening test, Houghton has been working on a vaccine for hepatitis C. Given the variability of HCV-there are at least six major strains with hundreds of subtypes, and the virus is constantly evolving-many researchers thought it would be impossible to develop one vaccine that could neutralize the many types.When the Li Ka Shing Institute of Virology was created at the U of A two years ago, Houghton accepted the Canada Excellence Research Chair (CERC) in virology and came to Alberta to continue his quest for a vaccine. "The virology and immunology work being done at this university is outstanding. It's one of the best departments of its kind in the world," he says.

The new institute aims to reduce the burden of viral disease around the world. It unites a consortium of researchers that supports discoveries in vaccines, treatments and diagnostic tests for viral diseases affecting humans. Its two dozen principal researchers bring a diversity of backgrounds to research, focused on everything from how to prevent organ transplant recipients from viral disease to how viruses evade the body's killer cells.

Houghton's work since accepting the CERC has already led to a major breakthrough. In February 2012, he revealed at a CERC summit in Vancouver that a vaccine prototype developed in collaboration with his research associate, John Law, is capable of causing an immune response.

Over the next few years, Houghton and Lorne Tyrrell, director of the Li Ka Shing Institute, will test an augmented version of the vaccine in a group of Canadians with the highest risk of contracting hepatitis C-intravenous drug users.Houghton's huge step toward a hepatitis C vaccine is the latest of several important contributions U of A researchers have made to the advancement of virology.A seminal figure in virology at the University is John S. Colter, '45 BSc. As chair of the University's biochemistry department from 1961 until 1987, he attracted talented young researchers and built the department into one of the best in North America. A renowned virologist himself-for 27 years an associate editor of the journal Virology-Colter did pioneering work isolating infectious RNA from mammalian viruses. In 1957, he published the revolutionary finding that genetic material from positive-strand RNA viruses was itself infectious.It was through Colter that Tyrrell-the visionary behind the Li Ka Shing Institute-developed his interest in virology. Tyrrell, a former dean of the U of A's Faculty of Medicine & Dentistry, is one of the most honoured individuals in Canadian medicine. In 1986, having taught part of a new graduate course in virology, he developed an interest in the hepatitis B virus (HBV), which is a major problem in the developing world. A colleague in the chemistry department, Morris Robins, shared his enthusiasm, and together they went to work to find an antiviral agent. That work continued even after Robins relocated to an American university and, in 1998, resulted in the licensing of the first oral antiviral agent to treat chronic HBV infection. Today, that antiviral agent, lamivudine, is licensed in more than 200 countries, with cumulative sales of about $5 billion. Second- and third-generation oral antivirals have followed.Tyrrell was also involved in another of the University's important contributions to virology. With Norm Kneteman, a U of A professor of surgery, and graduate student David Mercer, '92 BMed Sc,'94 MD, '00 PhD, Tyrrell was part of the team that developed a novel mouse model for hepatitis testing. This breakthrough, published in the journal Nature Medicine in 2001, provided the first non-primate animal for practical testing of drugs intended for treatment of hepatitis C. The company formed to commercialize the patented technology, KMT Hepatech Inc., now does testing for clients around the world and acts as the U.S. National Institutes of Health's primary site for animal-model testing of antivirals against hepatitis C. Lorne Babiuk is another highly acclaimed researcher involved in the Li Ka Shing Institute. As the U of A's vice-president (research), Babiuk doesn't get to spend much time in the laboratory these days, but shares his expertise as one of the institute's principal investigators. Babiuk is a top-ranked researcher in zoonotic diseases-diseases that pass from animals to humans. He came to the U of A from the University of Saskatchewan school of veterinary medicine, where he played a key role in growing the Vaccine and Infectious Diseases Organization (VIDO) from a little-known operation to an internationally recognized institute with more than 170 researchers.

Among Babiuk's important contributions to virology is his work related to rotavirus, a virus identified in animals and children suffering from acute diarrhea. After developing a new technique to grow the virus in the laboratory, Babiuk created a vaccine to control the disease in calves, saving the cattle industry about $300 million annually. The same technology was then used to produce a vaccine for children. Before the vaccine, rotavirus infections had claimed the lives of about 500,000 children each year. The disease is now all but eliminated in North America and significantly reduced elsewhere.Babiuk's primary focus these days is on improving existing vaccines and finding better ways to administer them without using needles. He recently received one of the world's most prestigious awards for medical research, the Canada Gairdner Wightman Award, for his work in vaccine development.In his role as research vice-president, Babiuk supported Tyrrell's vision and hard work, which brought about the Li Ka Shing Institute. The institute was created in 2010 thanks to a $25-million donation from Hong Kong businessman and philanthropist Li Ka Shing and a commitment of $52.5 million in new related funding from the Alberta government. Li's donation, the largest cash gift in the University's history, recognized the U of A's excellence in virology. It was also the result of some interesting points of convergence. "There were some mutual interests-a perfect storm if you will," explains Tyrrell. "With our development of a hepatitis B treatment, we had done something of benefit to the people of China, where there are about 150 million infected with the virus," he says. (Worldwide, the number is close to 400 million people infected.) And, Tyrrell notes, Alberta has contributed to the fortunes of Li, the majority shareholder in Husky Oil.Today, the reputation and expertise of the Li Ka Shing Institute's senior faculty has enabled recruitment of some of the best and brightest young researchers.

Among these is Maya Shmulevitz, '96 BSc, who joined the Faculty of Medicine & Dentistry at the U of A in 2011, relocating from Dalhousie. There, she worked with U of A alumnus Patrick Lee, '70 BSc, '78 PhD, who in 1995 discovered that a medically benign virus, the reovirus, could infect and kill cancer cells.

"One of the very attractive features of joining the institute was the sheer number of world-class virologists all working together in one space. The close proximity means that different laboratories share common reagents (substances used in chemical reactions) and methodologies, and have stimulating discussions about viruses on a daily basis. The atmosphere is as exciting as I hoped it would be," says Shmulevitz.Shmulevitz works on "supercharging" oncolytic viruses and exploring their potential in cancer therapy. "We commonly associate viruses with disease, but some viruses can also be used for therapy. Oncolytic viruses are viruses that replicate efficiently in cancer cells but not in normal cells. Such viruses offer tremendous potential for cancer therapy," says Shmulevitz."We anticipate that within 20 years, therapeutic viruses will be viable health solutions. We believe that understanding and optimizing oncolytic viruses now, will ensure the success of virotherapy in the near future," she adds.
Another recent addition to the U of A virology faculty is David Marchant. The native of British Columbia did his PhD in HIV molecular biology at University College, London, where he became interested in respiratory viruses. Marchant, who took up duties this spring at the U of A as assistant professor, plans to focus his research on respiratory infections that cross from the lungs into the heart, causing myocarditis.The Li Ka Shing Institute shares a close working relationship with the Alberta Provincial Laboratory of Public Health and its virologists. Recent recruit Julian Tang works in all aspects of clinical virology, including the epidemiology, diagnosis, pathogenesis and treatment of viral diseases. A native of Singapore, he has a particular interest in viral diseases spread through the air.Lilly Pang, also working at the provincial lab, brings an expertise in gastrointestinal infections to collaborations with U of A researchers. She has done notable work relating to the norovirus, its associated gastroenteritis outbreaks and its unique patterns of infections."Alberta is an ideal place to study norovirus infection and its pathogenesis," she says, pointing out that the province is relatively isolated from sources of new infection, has long winters and has an excellent system in place for monitoring gastroenteritis.While discovery is the lifeblood of the institute, both Tyrrell and Houghton agree that the equally vital focus must be on taking research findings from the laboratory to the hospital bed. "We are all about taking discovery research and translating it," says Tyrrell."We recognize the importance of using our research to help patients, and to help the economy," says Houghton, referring not just to the possible commercialization of discoveries but also to the reduction in medical costs.

Houghton has begun to explore the possible involvement of viruses in a variety of diseases not firmly linked to viral infections-conditions such as Alzheimer's disease, multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis. "There are probably viruses causing a lot more disease than we currently know about," he says."To be able to affect human health positively has always been my goal," says Houghton. Through groundbreaking research at the U of A, he and his colleagues waging the war on viruses are doing just that.