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Need Proteins? Just Do It in Canada


By Mark D. Uehling

Nov 15, 2005 | TORONTO — Shorts, sandals, and a polo shirt. In autumn. Maybe that is what Aled Edwards always wears to work. Maybe his wardrobe was designed to challenge American preconceptions of Toronto winters that last 11 months of the year.

Or maybe no one cares what you wear when you drive the cost of finding a sinewy, convoluted protein structure down to $125,000 — perhaps a quarter of the typical cost at less-efficient centers.

Edwards has a cross-appointment in the Medical Biophysics and Medical Genetics and Microbiology departments at the University of Toronto. He trained as a biochemist at McGill and Stanford. But Edwards introduces himself in a self-deprecating manner as the CEO of the Structural Genomics Consortium (SGC). He describes the SGC as a charity, as if it were researching his favorite disease of the week.

In fact, with a staff of 60 in Canada and 90 in Britain and Sweden, Edwards is doing pharma’s bidding on an industrial scale. There’s a twist: The nonprofit SGC deposits all its three-dimensional protein structures into the public Protein Databank, a repository similar to those for genes and single nucleotide polymorphisms.

No Bacteria Need Apply
Unlike the Protein Structure Initiative (PSI) effort in the United States, the SGC works almost entirely on human proteins. The proteins on the SGC hit list are the body’s biological “target” enzymes into which a drug can dock. Such structures cannot be patented and thus are of precompetitive scientific interest.

With a budget one-third as large as that of the PSI effort, the SGC has three principal academic groups doing X-ray crystallography (versus 10 supported by the PSI). So its output is all the more impressive. “We can do it first and fast,” Edwards says. “We can do it cheaper than anybody.”

SGC has funding from the Wellcome Trust, GlaxoSmithKline, Genome Canada, and other rarely cooperating Canadian government and academic agencies. It is working its way through a list of 2,000 proteins that bind to small molecules and are thus relevant to drug discovery. In 2004, the first two SGC centers to come on line were his own, in Toronto, and Michael Sundstrom’s lab in Oxford, United Kingdom. A third, in Sweden, was added this year.

The SGC goals are ambitious: 50 structures in the first year (79 were actually finished), 100 in the second year, and 200 in the third. “We’re going to blow through our Year Two milestones,” Edwards predicts. Three of the 125 proteins structured by the SGC to date are located in cell membranes, some of the trickiest of all. The PSI has finished almost 700 unique proteins after a three-year head start.

Productivity Is All
Despite his academic credentials, Edwards is obsessed with productivity. “The main focus is the delivery of structures,” he says tersely. “There is no magic elixir or special machine.” Edwards himself is vigorous, blunt, and irreverent — a Mel Gibson for the life sciences.

Edwards once proposed an effort similar to the SGC to the Canadian Medical Research Council. “I got the lowest score ever on a grant. People giggled when you started talking about doing this genomewide.” Edwards seems to enjoy goading American and European colleagues to pick up the pace. “This idea that human protein structures are going to cost a lot more than bacteria is not the case,” says Edwards.

With neither remorse nor delay, Edwards spurs on his colleagues. Some experimentation with his recipe is permitted, but delays and departures from best practices are ruthlessly scrutinized. IT projects are kept small, contained, and manageable. He’s kidding, mostly, when he says that “every dollar spent on bioinformatics is a wasted dollar. One has to have a foil that challenges every IT project. Otherwise they metastasize.”

In a pay-to-play model, SGC board members get to select and prioritize which proteins get structured next. The fee to join the board is $15 million Canadian. A Swedish consortium recently signed on, which will add Stockholm’s Karolinska Institute as a major center in the effort. A few U.S. collaborators are also assisting.


Canadian David vs. NIH Goliath

The output of the NIH's PSI surpasses Canada's SGC but so does its funding. The priority of the PSI is finding one structure in every major protein family. At the SGC, the structures of human enzymes that bind with small molecules are the goal.

SGCPSI
StartedSeptember 2003September 2003
Funding, Source


~$20 million annually from Canada, Wellcome Trust, GSK, through 2007. Total budget: $80 million.~$60 million annually from U.S. NIH through 2010. Total budget: ~$600 million.
Estimated # of structures/month13-15
19-37
# of centers
3 (Toronto, Oxford, and Stockholm)10 in U.S. (4 major, 6 specialty)
Brags about ...

Finding structures of eight malaria-related proteins
Finding structure, function of key protein in TB Pseudomonas
Current approx. cost/structure$100,000-$125,000

$83,000-$180,000

# protein structures deposited in public databases~125 with <30% sequence similarity to known proteins
~723 with <30% sequence similarity to known proteins
Source: www.sgc.utoronto.ca/SGC-WebPages/sgc-toronto.php; www.nigms.nih.gov/psi/

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