What researchers are learning as they sequence, map, and decode species’ genomes
From Private to Public As head of a unique pharma-academia consortium, Aled Edwards has helped scientists solve the 3D structures of hundreds of disease-related proteins and deposited them in an open access bank—at half the usual cost. By Victoria Stern As an undergraduate at McGill University in Montreal, Aled Edwards spent most of his time playing football and enjoying various intramural sports, like baseball and basketball—and in th
January 14, 2010|
As an undergraduate at McGill University in Montreal, Aled Edwards spent most of his time playing football and enjoying various intramural sports, like baseball and basketball—and in the biochemistry lab, completing the coursework for his degree. “I was surprised that I could successfully combine my intellectual pursuits and my athletic and social interests,” says Edwards.
His ability to marry such different passions proved to be a valuable skill when, in 2003, he became the director of the Structural Genomics Consortium (SGC), a nonprofit organization that leads a consortium of pharmaceutical and academic scientists as they work together to solve the 3D structures of proteins involved in disease and use those structures to design new drug targets.
“Aled is a scientific matchmaker,” says Stephen Frye, a member of SGC’s scientific committee and former head of lead discovery at GlaxoSmithKline (GSK). “He’s a master of understanding how different groups are motivated, and can come up with a plan that each will agree to and thrive on.”
Before becoming the director of SGC, Edwards completed his PhD in biochemistry at McGill University, then spent 4 years as a postdoc at Stanford University, crystallizing yeast and human RNA polymerase II in the laboratory of Roger Kornberg, the 2006 Nobel Laureate in Chemistry.
While at Stanford, Edwards realized that working on one or two proteins wasn’t enough for him. “The human genome is full of unknown proteins, and the biological community is only focused on a small subset of them,” he says. He wanted to take a broader view.
Edwards moved to Toronto in 1997 as a professor of biochemistry at McMaster University and started collaborating independently with Cheryl Arrowsmith, also a biochemistry professor there. He discussed with Arrowsmith and other colleagues how they could provide structural information for more unknown proteins.
“Aled’s very much a big thinker and is always one step ahead with new concepts,” says Arrowsmith, now head of the Toronto branch of the SGC. “At this particular time, he recognized that structural information on proteins was really lacking.”
In 2000, they helped found the National Institutes of Health’s Protein Structure Initiative, which mostly explores bacterial proteins and currently has nine branches in the United States.
While Edwards and Arrowsmith were deeply immersed in several genomics projects, a group of GSK scientists who felt existing methods of drug discovery were wasteful was laying the groundwork for the Structural Genomics Consortium, which would help scientists work together and not duplicate their efforts.
“Within pharma, most companies are working on the same targets in parallel and in secret,” says Chas Bountra, a chief scientist for SGC at University of Oxford and former GSK scientist. Academic institutions are more likely to work together, but often can’t afford to determine protein structures and do drug discovery on their own dime, says Frye.
After the bacterial protein project, Edwards decided to focus on solving the structure of human proteins in order to accelerate drug discovery and disease research. These goals matched those of SGC, and in 2003 he was hired to run the consortium. “There were several other structural genomics efforts going on in the world at the time (like the Protein Structure Initiative), but very few looked exclusively at human proteins,” says Edwards.
At SGC, academic and industry scientists work together to determine the three-dimensional structure of human proteins of medical relevance to diseases such as cancer and diabetes metabolic disorders. Once solved, these structures are put into an open access Protein Data Bank (www.wwpdb.org). “We are proponents of the idea that early-stage drug discovery is best done in the open, without patents,” says Edwards.
SGC soon evolved into an international effort, which now includes Canada, the United Kingdom, and Sweden. Initially funded by the Wellcome Trust and GSK, SGC now receives money from the Canadian and Swedish governments. Donations from the public sector provide about 85 percent of the total funding. SGC’s pharmaceutical funders now include Novartis and Merck, as well as GSK. All donating institutions get to pick a percentage of the structures that SGC will solve.
Today, funding totals more than $20 million per year. Each protein costs an average of $145,000 to crystallize, which includes overhead costs like equipment and salaries. This is about half what it costs to obtain a structure in an academic or industry setting, Edwards says. The lower cost is due, in part, to the fact that the SGC focuses on families of proteins, which tend to have structural similarities, and has amassed a crew of top structural biologists to work on them.
All SGC labs are based at universities, including the University of Oxford, the University of Toronto and Karolinska Institutet in Sweden. A lab is being built in Qatar. Currently, there are 80 sites in Toronto, 60 in Oxford, and 25 in Stockholm, with about eight to 10 principal investigators at each. Edwards has recruited about 10 percent of his scientists from industry and about 90 percent from academia. “We believe that the different sites allow us to access a much broader network of scientists,” he says.
Edwards recruits new scientists and directs the operations from SGC’s Toronto-based laboratories. He also oversees the decisions made by his Chief Scientific Officers and PIs, which involve the input and consensus of all members. “I can’t think of one decision that did not involve the group,” Edwards notes.
“SGC is a great example of how a public/private partnership can advance science and human health,” says Frye. “SGC does not try to create intellectual property. Instead, it freely shares results with whole scientific community to benefit science, even before SGC scientists can publish and get credit for their discovery.”
Each year, SGC deposits approximately 30 percent or more of the world’s new human protein structures into the public database, for a total of 1,000 since its inception.
“SGC has a very valuable goal of providing structural coverage of human proteins,” says Barry Honig, a structural biologist at Columbia University. “However, it is still early in the process and the data are just now being exploited for drug discovery.”
Stefan Knapp, from SGC’s Oxford branch, has been studying the SGC-solved structure of Pim-1 kinase, which plays a pivotal role in cytokine signaling and may contribute to the progression of certain leukemias. Knapp’s group is identifying and testing several high-affinity inhibitors of Pim-1 kinase (J Med Chem. 48: 7604–14).
Raymond Hui, a Principal Investigator for SGC’s malaria team, has collaborated with scientists at the University of Dundee to help characterize a small molecule that will kill Trypanosoma brucei, a parasite that causes sleeping sickness. Hui also recently teamed up with David Sibley, a molecular microbiologist at Washington University School of Medicine, to identify a compound that can kill the parasite Toxoplasma gondii, which causes toxoplasmosis.
“Aled is a real visionary,” says Gaetano Montelione, a structural biologist at Rutgers University who works with the NIH-funded Northeast Structural Genomics, a branch of the Protein Structure Initiative. “He has led the field in a positive direction, crystallizing a lot of potentially medically important human proteins, creating an open access policy, and now taking the next step to understand function and which proteins are candidates for therapeutic intervention.”