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Of Vaccines, Virtuosity and Viruses

Not long ago John Elliott,'82 MD,'87 PhD, was asked to provide a title for a talk he was scheduled to give, a discussion of the research currently taking place in his laboratory. What sprang to mind, says Elliott, was the bit about the fellow who "jumped onto his horse and rode off in all directions."

It's not hard to see why.

Elliott remains active in the malaria research that has occupied much of his attention in recent years, but he is also excited about work he's begun in collaboration with University of Alberta researchers on the front line of the world-wide effort to conquer diabetes. And now he's a principal researcher in the University's new Glaxo Heritage Research Institute set up to fight viruses, particularly the viruses associated with AIDS and hepatitis B.

After earning his U of A medical degree in 1982, Elliott did a year's internship and then returned to campus to pursue a PhD degree in biochemistry, specializing in molecular biology and immunology. During this time, he caught the eye of Lorne Tyrrell, now the Glaxo Institute director, and when Tyrrell was establishing the Institute he invited Elliott to join him. And Elliott did, although he had never had more than a passing interest in viral diseases.

So what's he doing at an institute of virology?

"I've asked Lorne Tyrrell that several times," laughs Elliott. However, the answer is rather obvious. At first glance, Elliott's research might seem to be all over the map, but he has been consistently cultivating an expertise in gene cloning. And it's that virtuosity Tyrrell found attractive.

Elliott's background in immunology is also welcome. Both hepatitis B and AIDS are caused by viruses, but they and many other viral diseases involve an immune system response that is central to the disease. In fact, in some viral diseases more harm is caused by the body's immune system response than the actual viral invader.

A native Albertan who grew up in Camrose, Elliott came back to the University as an assistant professor of medical microbiology and infectious diseases in 1990. He brought with him experience gained during post-doctoral appointments at Stanford University and at a California gene-cloning company, where he began investigating the molecular biology of the parasite that causes malaria.

His interest centred upon the parasite's surface antigens — its molecular fingerprints —which trigger the production of antibodies in an infected individual and determine the antibodies' shape. With funding from the World Health Organization and Canada's Medical Research Council, Elliott has been cloning the genes that encode the malaria surface antigens expressed at various stages of the parasite's development. His goal is to use these genes to develop vaccines.

He has had some success that could lead to a vaccine that would block transmission of the disease by attacking the parasite when it is especially vulnerable. "The idea," explains Elliott, "is that when the mosquito takes up its blood meal it takes up the parasite, but it also takes up antibodies from the infected human." And inside the mosquito gut the parasite is soon stripped of the red-blood-cell coat that had protected it inside the infected human. Reaching the parasite at this vulnerable time would involve an "altruistic vaccine" — one that would be administered to infected individuals but would not help their fight with the infection. But it would introduce into their blood antibodies that would later work within the mosquito gut to prevent spread of the disease.

Elliott also has his sights set on developing a vaccine which would protect the individual to whom it is administered. To this end, he's using a new gene cloning technique called eukaryotic expression. "The technology is really exciting and developing quickly," says Elliott. Using antibodies4W from Africans who have developed immunity to malaria, he is establishing gene libraries to help identify the genes responsible for shaping the antigens on the surface of the malaria parasite when it is inside a human. Once these genes have been identified, they will be used to produce large quantities of the antigens for tests to see which ones are likely to be useful in a vaccine.

Although Elliott has continued his malaria work since returning to Edmonton, he prefers to work with a disease he can observe in a clinical setting — and there are very few malaria cases in Alberta. Unfortunately, the same can't be said about diabetes, and Elliott now works with the network of diabetes researchers funded at the U of A by the Juvenile Diabetes Foundation International. He is contributing his expertise to attempts to understand the cause of the form of diabetes that develops in children and young adults.

"The thing to realize is that it is a tiny volume of tissue that produces the insulin that keeps an individual non-diabetic," says Elliott. Juvenile-onset diabetes results when these insulin-producing cells, found in the islets of the pancreas, are destroyed by the body's own immune system. Elliott and his,-ms colleagues want to know why this happens.

A starting point is provided by research I which shows that, although auto-immune diabetes runs in families, often one member of a set of identical twins will develop it and "the other won't." Since less than half of identical twin pairs both develop the disease, it is clear that auto-immune diabetes results from the interplay of a genetic predisposition together with one or more environmental factors," says Elliott.

One possibility is that an immune system response against something in the environment — perhaps a virus — triggers the diabetes. The disease, in other words, could be the result of some sort of cross-reactivity or confusion. "Something about the insulin-producing cells might remind the immune system of a virus, causing it to attack and destroy these cells as well as the invader," says Elliott.

Another possibility — one that Elliott favors — is that a certain amount of stimulation of the body's immune system is necessary to teach it what is "self" and what is not. This stimulation could involve not only our own body tissue but also environmental factors such as the food we eat and the bacteria that live in our gut.

"Perhaps people who are genetically susceptible to diabetes are poor at learning self-tolerance," says Elliott. The balance as to whether or not the body learns to tolerate its own insulin-producing cells, he suggests, could be tipped by the nature of the stimulation received from one or more of the environmental factors.

Wherever the truth lies, says Elliott, the real challenge is to discover the nature of the environmental factors that play a role in auto-immune diabetes. Towards this end, his laboratory is cloning the genes for the antigens that give the insulin-producing cells their surface characteristics. These are being used to determine what it is about these cells that prompts the immune system to single them out for destruction.

In addition, Elliott is working with the U of A team that was the first in the world to successfully transplant insulin-producing cells in humans. "We've started looking at the idea of putting genes back into the islets to give them a survival advantage," he explains.

Elliott's involvement in both the malaria and the diabetes projects centres on his expertise in cloning genes, sequencing DNA, and making and purifying genetically-engineered proteins. As part of the Glaxo Institute, he's now bringing that same bag of tricks to bear on viral diseases, working closely with Tyrrell and AIDS researcher Lung-Ji Chang.

For Elliott it's new territory — but he's riding the same horse in the same direction. It's really only the scenery that's changing.

Published Spring 1994.

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