Cheryl Arrowsmith leads efforts to identify chemical compounds that modulate every protein in the human body.Credit: University of Toronto
“If the world could have a pharmacological modulator for each human protein, just imagine how impactful that would be,” says Cheryl Arrowsmith, a professor of medical biophysics at the University of Toronto (U of T) and a senior scientist at the Princess Margaret Cancer Centre – University Health Network. Such molecules could help reveal the function of myriad proteins, home in on potential drug targets and identify drug candidates, she says. “It would revolutionize our ability to understand biology and to create medicines.”
That’s exactly the work that Arrowsmith and her colleagues at the Structural Genomics Consortium (SGC) have begun. With the help of collaborators in an initiative called Target 2035, within 15 years they aim to identify chemical compounds to modulate each of the roughly 20,000 proteins in the human body1.
The initiative is part of a broader effort by the University of Toronto-based SGC to develop new medicines by investigating regions of the human genome that have not yet been researched extensively. The SGC is a public-private partnership that includes five other universities and 10 biotech and pharmaceutical companies. Since its launch in 2004, the SGC has solved thousands of protein structures and created chemical probes to enable research into potential new medicines.
The SGC is just one of several initiatives in a unique research ecosystem anchored by the University of Toronto. Between the university, its component research institutes, and Toronto-based hospitals like the Hospital for Sick Children, the local biomedical research community has the expertise needed to drive better health and healthcare worldwide.
“U of T and its hospital partners have collaborated on many life-saving advances, ranging from vaccines to the discovery of stem cells, to pioneering genetic research,” says Leah Cowen, the university’s associate vice president, research. “It's an amazingly inspiring community to be a part of.”
Open drug discovery
University of Toronto research has been improving healthcare for more than a century. In 1921, Toronto researchers Frederick Banting and Charles Best were the first to use an extract of pancreatic tissue to control blood sugar in animals, and, with U of T biochemist James Collip, they were the first to purify insulin. They believed insulin should be accessible to everyone, so they sold the manufacturing patent to the university for just one dollar2.
Aled Edwards leads a global consortium that shares pharmaceutical research findings freely to advance health and drug discovery.Credit: University of Toronto
The same generous spirit underlies the SGC’s approach to drug discovery, says Aled Edwards, a U of T professor of molecular genetics and medical biophysics and Temerty Health Nexus chair in innovation and technology. As SGC’s chief executive officer, he leads a rare venture in the world of drug development — one that makes knowledge from pharmaceutical research freely available for further research into health and drug discovery. This includes the consortium’s research outputs, from lab notebooks and publications to software and molecular tools.
To ensure that shared methods work and that other researchers can reproduce SGC’s results, the SGC employs rigorous documentation and internal quality standards. This appeals to prospective partners — even biotech and pharma companies who might otherwise play their cards close to the chest.
It also means the SGC eschews its right to patent discoveries, even in chemistry, a field where newly created molecules are often considered patentable. “We and our pharmaceutical partners think this basic knowledge about human biology is more valuable in the public domain,” Edwards says.
Teaming with industry
After Banting and Best used their pancreatic extract to control blood sugar in lab animals, they tested it at Toronto General Hospital on a 14-year-old boy with diabetes. He weighed 65 pounds and had been drifting in and out of a diabetic coma, but he recovered. Connaught Labs, then owned by U of T, began manufacturing insulin for Canadians, then partnered with Eli Lilly to produce the world’s first commercial insulin product. A century later, U of T researchers continue to partner with researchers at 14 hospitals in the Toronto area.
Among them were James Till and Ernest McCulloch, research scientists at the hospital now known as Princess Margaret Cancer Centre and professors at U of T, who in 1961 discovered hematopoietic stem cells — a finding that eventually helped launch a vast field focused on replacing damaged cells, tissues and organs. “One of the areas of strength in Toronto is regenerative medicine,” Cowen says. U of T’s Medicine by Design initiative unites stem-cell researchers from different Toronto-area hospitals and U of T labs.
The Medicine by Design programme also fosters entrepreneurship, supporting early-career researchers who aspire to commercialize their discoveries. Another collaboration between the U of T and industry is the Acceleration Consortium, which facilitates AI-driven discovery of new molecules and materials for drugs and medical devices. “The university has put a lot of emphasis on facilitating and enabling really thoughtful partnerships,” including international and business partnerships, Cowen says.
Exposure to academic and industry collaboration helps the SGC attract students and postdocs, Arrowsmith says. “A lot of our trainees really like that exposure,” she says. “It gives them a wider perspective on career options.”
Epigenetics points the way
Among Arrowsmith’s collaborations is one focused on epigenetics — specifically, on a process in which the cell places chemical tags called methyl groups on proteins called histones, which in turn regulate gene expression by controlling access to the DNA. Among the proteins they focused on was a little-known protein called WDR5.
An experimental cancer drug developed by collaborators in the Toronto research ecosystem alters gene expression by blocking the WDR5 protein (shown) and is being tested in clinical trials.Credit: modified from Emw, CC BY-SA 3.0, via Wikimedia Commons
By teaming up with the chemistry and drug discovery group of the Ontario Institute for Cancer Research, Arrowsmith’s team and their collaborators identified a chemical probe that inhibits WDR5. But rather than patent it and restrict its use, they shared it freely with researchers in Austria and the United States who were studying WDR5’s role in cancer.
A few months later, they published the results of their work in Nature and Nature Chemical Biology, showing that the WDR5 inhibitor was able to stop the growth of breast cancer cells and leukemia cells by interfering with the epigenetic pathways that would otherwise encourage the cancer cells to proliferate3,4. This led to new opportunities for research and drug discovery. Researchers around the world have used the WDR5 probe in more than 140 published studies, and a large pharmaceutical company developed a modified version of the probe into an experimental cancer drug that is now in late preclinical testing.
This success story showcases the power of the Target 2035 initiative, Arrowsmith says. Chemical probes against all 20,122 known human proteins will help researchers solve scientific puzzles, then develop treatments for a wide variety of conditions. “We certainly can't do it all ourselves,” Arrowsmith says, “but if we try to reach this goal as a global community, it could be achievable.”