Research Profile - Saying “au revoir” to “diagnose and adios”

According to Dr. Donald Weaver, neurology is the field where "we see you, we diagnose you and we say goodbye." It's not that neurologists don't like to help people – it's just that there's so little they can actually do.

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Dr. Donald Weaver 
Dr. Donald Weaver

Dr. Weaver wants to change that – at least as far as Alzheimer's disease is concerned. And he's using special technology to do it.

But first, the background. In 2010, more than half a million people in Canada suffered from Alzheimer's disease and related dementias. By 2035, that number is expected to climb to more than one million. Alzheimer's disease is thought to be caused by two misfolded proteins in the brain – beta amyloid, which causes plaques, and tau, which causes tangles. Because a protein's shape affects its function in the body, any change in shape can cause problems. But it's not quite that simple. There is much debate among neuroscientists as to whether beta amyloid or tau is the real culprit.

"Our view is that it's both," says Dr. Weaver. So when he set out to develop a drug to fight Alzheimer's disease, he wanted to inhibit both proteins and stop them from misfolding.

Dr. Weaver definitely has the right résumé for the job. For one, as well as being a practicing neurologist, he is also a chemist. He undertook a doctorate in chemistry after he finished his medical training.

"There aren't many physicians who are medicinal chemists," he says.

He started on this unique path after a late-night encounter with the chair of the chemistry department at Queen's University, when he was a graduate student. That encounter led to a year of studying quantum mechanics – a year he describes as "challenging at the time but absolutely wonderful in retrospect."

Challenging because it involved one-on-one sessions with a post-doctoral fellow, where there was no one else in the class to pick up the slack. Wonderful because it gave him the skills he needed to undertake computer-assisted molecule design.

In the case of Alzheimer's disease, his first step was to find receptor regions within both proteins – beta amyloid and tau – that are implicated in their misfolding. Fortunately for him, the receptor areas he found within both proteins showed a high degree of structural commonality.

The next step was not what you might think. Dr. Weaver didn't head into the lab, he didn't start mixing things in beakers – he didn't even put on a white lab coat. Instead, he sat down at the computer to design molecules that would bind to those receptor regions, stopping them from helping the proteins misfold. Researchers refer to this kind of work, performing experiments on computers, as "in silico", and Dr. Weaver's ability to do so is a direct result of his year's immersion in quantum mechanics.

Once he and his team found a compound – a task that's somewhat analogous to searching for a needle in a haystack – they undertook the next step, testing it in the laboratory. When they put the compound into a culture with neurons and then sprinkled the neurons with beta amyloid protein, the neurons didn't die – a very promising sign.

Then, with a US collaborator, they tested the compound in transgenic mice – mice bred to develop the mouse form of Alzheimer's disease. The mice who received the compound showed a statistically significant improvement in their ability to navigate a number of different mazes. And after they died, autopsies showed a 60% reduction in amyloid plaques.

So that's it – success. Right?

Wrong. A compound doesn't make a drug, Dr. Weaver emphasizes.

"We have a molecule that's an interesting academic model – but can we make the knowledge translation to make a drug?"

To do so, Dr. Weaver has to find out whether the human body can tolerate the drug, or whether the drug causes harm – a process known as toxicology testing. He also has to find out how the drug behaves in the human body – whether it goes where it's supposed to go, does what it's supposed to do, how long it lasts in the body – an area of study known as pharmacokinetics. This testing is his current focus.

Dr. Weaver knows what he's doing is a long shot. "Making molecules into drugs is difficult – and most of them fail," he says.

Nonetheless, frustrated by what he calls the "relative therapeutic impotence of neurology,"
Dr. Weaver is hoping that, if all goes well, a pharmaceutical company will be interested in his compound.

The Study

Currently, there are no disease-altering drugs available to treat Alzheimer's disease; available drugs can only temporarily help with symptoms. Dr. Donald Weaver has discovered a new class of compounds that prevents the protein misfolding that is thought to cause Alzheimer's disease. He is now receiving funding through the Canadian Institutes of Health Research's Proof of Principle program to conduct toxicology and pharmacokinetic testing on the compound to determine its suitability as a drug.

"Making molecules into drugs is difficult – and most of them fail."
- Dr. Donald Weaver, Dalhousie University

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