Canada Medal award interview
Donald Weaver still remembers the day that defined the rest of his career, setting him on the path to working in drug research as a chemist.
It was just after he had graduated from medical school in 1981 and he was working in a hospital when the reality of the impact of Alzheimer’s on one elderly patient made him vow to dedicate his career to developing treatments for dementia.
‘I felt compelled, intellectually and emotionally, to dedicate my life to discovering a cure for Alzheimer’s disease, and chemists are the people who invent drugs,’ he wrote recently about the experience[1].
Weaver went to graduate school and completed a PhD in chemistry. Since then, he has worked for decades as a computational organic chemist on the design and commercialisation of therapeutics for neurodegenerative disorders, as well as working as a neurologist assessing patients with cognitive disorders.
Weaver is now the Krembil Chair in Alzheimer’s Disease Drug Discovery at the Krembil Research Institute, University Health Network, and professor in the Departments of Chemistry and Pharmaceutical Sciences, University of Toronto, and has had two compounds reach Phase 3 human clinical trials. Tramiprosate was one of the first drugs to be trialed as a disease modifying agent for Alzheimer’s dementia. He was recently awarded SCI’s Canada Medal, which recognises a business leader for outstanding service in Canadian industry.
Weaver has also co-founded six start-up biotech companies, including Neurochem and Treventis, and published more than 350 peer-reviewed papers. He holds 47 patents in drug design and discovery.
For now, a cure of Alzheimer’s remains elusive. ‘Over the course of the years, certainly I have seen 10,000 people with Alzheimer’s and I’ve cured no one. So, I like to say, that’s not why I went into medicine – but it’s exactly why I went into chemistry,’ he tells C&I.
‘You go into medicine to treat people to make them better. You don’t go into medicine to invent drugs, but you go into chemistry to invent drugs. That’s personally why I went into this - to make drugs for neurologic diseases in general, dementia and Alzheimer’s specifically.’
Weaver (below) says that drug discovery – and who does it – is still poorly understood, despite its vital contribution to healthcare.
‘Over the years I’ve spoken to many patients and said, ‘Who do you think invents drugs?’ And I guarantee you that even if they put out some suggestions, chemists would not be anywhere near their list. They just don’t think about it. And we have such a central and fundamental role to the advances that have been made in medicine,’ he says.
However, for all this, chemistry is not always linked with positive advances, he points out.
‘If you just talk to an average person and talk about chemistry, they think about pollution, pollutants, forever chemicals, and most of the things that pop into their mind have a fairly negative connotation associated with them. They fail to realise that the new materials that are coming out, that the cell phones that they’re holding in their hands, involve a wealth of innovative chemistry that enabled the electronics to happen.’
Medicinal chemistry presentations often start with an image of a funnel, he says, where millions of potentially useful molecules go in at the top, and out at the bottom comes one molecule – the drug. But, because that whole process is effectively invisible to most people, Weaver sees this process the other way around – not as a funnel but as an iceberg.
‘[People] see the drug, they see the clinical trials and stuff like that. What they don’t see is everything, that 80% of the iceberg, that lies beneath it, which was the med-chem efforts and all the fundamental science efforts into the creation of that drug. To forget the importance of medicinal chemistry is a titanic error,’ he says.
Weaver says that more needs to be done to emphasise the contributions that chemistry make to society.
‘We need people who reach out to engage the population, to let them see the beauty of molecules, the beauty of chemistry, and to appreciate how important that is to our society in going forward,’ says.
So, is he more optimistic about progress towards treatments for Alzheimer’s now than when he was starting out on his career?
‘To be a medicinal chemist who works on neurologic diseases, especially dementia, you have to be pathologically optimistic. You know, because let’s face it, you fail, you fail again. But sooner or later, the breakthrough is going to come, and please, please may it be from us, but if not, please may we have at least contributed to it,’ he says.
Currently his lab is also working on the theory that neuroinflammation could be a key player in Alzheimer’s pathology. Weaver says that the primary amino acid sequence of beta amyloid (one of the proteins implicated in Alzheimer’s disease) looks like an antimicrobial peptide. This suggests that beta-amyloid is part of our immune system, an immunopeptide within our brain, which goes rogue in certain circumstances and targets neurons.
‘Alzheimer’s is a disease in which we desperately need new thoughts, new ideas, people thinking differently. And we’re definitely contributing that,’ he says.
What makes Alzheimers’ so hard to treat? Weaver says it’s because of the underlying complexity; the real cause of Alzheimer’s is not yet clear. From a drug design point of view this issue is not a lack of targets to focus on, rather there are too many to choose from, plus the cost of trials themselves.
However, he says he is ‘extremely optimistic’ about the future of Alzheimer’s disease for multiple reasons. He points to advances in diagnostics as well as advances in therapeutics. ‘If you look at what’s in the pipeline, there’s a lot of really interesting molecules in the pipeline, and we’re at a better place than we have been at any time in the history of Alzheimer’s.’
‘I hear people say that Alzheimer’s is where cancer was 40 years ago,’ he says. ‘And hopefully just as cancer therapies have had really substantive improvement over the last several decades, that we’re just at that turning point where Alzheimer’s and the dementias will likewise see substantial improvements in the coming years.
‘But, you know, I’ve spent so many years seeing patients for whom I’ve done very little when it came down to it that, I want to get a drug. And I want to hopefully make a difference in the lives of these people. That would be absolutely wonderful,’ he says.
Visit Blog
