Understanding the biology of the brain

Here is a trickier-than-you-might-possibly-suppose skill-testing question.

What does a Montreal drug company trying to market a memory-enhancing dietary supplement, an Irish firm testing a reconfigured vaccine against Alzheimer's disease and a Toronto biopharmaceutical firm's potential multi-million dollar windfall have in common?

The correct response is that they all emerged from discoveries about the causes and potential mitigation of brain-based degenerative diseases - and most notably Alzheimer's disease - made by molecular geneticist Peter St George-Hyslop and his colleagues at the University of Toronto's Centre for Research in Neurodegenerative Diseases.

While it is hardly surprising that St George-Hyslop, who has won the $5 million Premier's Summit Award, would have made discoveries that would prove useful to clinical medicine, the intense interest by the drug industry in his and his colleagues' findings has to be set against the backdrop of ignorance about Alzheimer's that existed as little as a quarter-century ago.

At that time, physicians couldn't even agree on what Alzheimer's was.

While one can find descriptions of the condition throughout human history - King Lear's precipitous decision to divide his kingdom is now considered a classic example of the poor decision-making that signals the onset of the disease - it was only in the latter part of the 20th century that all of Alzheimer's symptoms were understood to belong to a single disease.

"Alzheimer's was sometimes called senile sarcosis or hardening of the arteries or senility or just old age. Until it was seen as a single entity, it was not truly perceived as a major problem," reflects St George-Hyslop.

And even after the disease - which afflicts nearly 27 million people worldwide - was finally viewed as a unitary thing, its cause remained a huge mystery.

"When I came back to Toronto from Harvard in 1990, we knew there were genes linked with Alzheimer's. But nobody had been able to find them and nobody knew what those genes actually did," remarks St George-Hyslop.

What St George-Hyslop and his group have been able to do is discover five genes that are generally accepted to be associated with Alzheimer's. They have also found both natural and artificial substances that block the buildup of amyloid beta peptide, a substance that ultimately destroys Alzheimer's sufferers' brains.

Based on this, the Montreal company Bellus Health took one of the amyloid-blocking substances to final-stage clinical trials. Unfortunately, in 2007 they discovered that while the substance halted the progression of Alzheimer's in lab tests, not enough of the drug got through to the brain to make a difference in humans. Believing that even these small doses are good for you, Bellus is now marketing the substance as a memory-improving health supplement called VIVIMIND.

CRND also developed a vaccine against Alzheimer's that eventually failed early tests in humans because it caused brain swelling. However, CRND refined the vaccine in such a way to avoid this. This approach - although not CRND's exact formulation - is being used by Ireland's Elan Corporation in a new vaccine that is now being tested.

Even more hopefully, another CRND-discovered molecule is in clinical trials. This molecule blocks the brain-destroying proteins but can actually make it into the brain. These trials are led by Toronto's Transition Therapeutics, in partnership with Elan. If successful, the drug could be worth at least $185 million to Transition.

Progress, sure, but St George-Hyslop acknowledges that it is progress unlikely to result in a total cure or treatment because by the time Alzheimer's shows itself in a person's behaviour, a large percentage of the brain is already damaged beyond repair.

That's why he is now advocating a reconfiguration of Canadian research. "It should be Canada's mission to understand the fundamental biology of the brain. To discover how neurons are born, how they move to the right place, how they connect to each other. If we discover this, we may not only be able to repair the damage causing Alzheimer's," he says, "We may be able to do the same for a host of other diseases ranging from stroke to mental retardation."