Sir Philip Cohen

He has written hundreds of publications. The list of honors he has racked up is as long as your arm. Most recently, he was inducted into the National Academy of Sciences. Not to mention he’s a knight. What could possibly be next for Sir Philip Cohen?

For this jovial Scottish biochemist, known for his contributions to the study of protein kinases—and particularly for his elucidation of the insulin-signaling pathway—the second phase of his career is shaping up to be just as prolific as the first. After nearly four decades devoted to understanding how a misplaced phosphate on a protein causes disease—work that has led to the discovery of countless cancer, diabetes, and inflammatory disease drug targets—Cohen has set his sights on the small regulatory protein ubiquitin. He is convinced that figuring out the cell-signaling pathways for protein ubiquitylation could lead to the next hundred targets for the drug industry to tackle.

Cohen, 64, is the director of the U.K. Medical Research Council's Protein Phosphorylation Unit, an expansive group in Dundee, Scotland, devoted to studying how putting on or taking off a phosphate modifies the activity of protein kinases, enzymes highly involved in cell regulation. The 200 or so scientists working in the unit benefit from a support system not often found in academic labs. The site boasts a DNA-cloning team, a protein production/assay development team, mass spectrometry services, an antibody production team, and kinase-profiling services.

The scientists collaborate with the College of Life Sciences at the University of Dundee and five drug companies—AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck Serono, and Pfizer—to translate their basic research into drug candidates. The Division of Signal Transduction Therapy (DSTT), a consortium Cohen launched in 1998, works to speed up the development of molecules that block kinases and phosphatases by sharing results, reagents, and technology. The members of the consortium have first rights to any intellectual property generated.

But that infrastructure took many years to develop. For years, big pharma was not convinced that kinases were “druggable” targets, even after a Nobel Prize went to Edwin G. Krebs and Edmond H. Fischer, with whom Cohen did his postdoctoral studies, for their work on protein phosphorylation. Cohen struggled to find partners when he began to put together DSTT. “The head of R&D at one company—which by the way no longer exists—told me they weren’t joining because they had realized that there was no future in kinase drugs,” Cohen recalls.

A decade later, the drug industry has changed its tune. As Giovanni Ferrara, a life sciences consultant, pointed out last month at a panel discussion at the Biotechnology Industry Organization’s annual conference in Atlanta, kinase inhibitors are expected to bring in roughly $50 billion in sales this year. More than 380 kinase inhibitors are on the market or in development.

But now that his team has figured out the skeleton of the protein kinase pathways involved in mediating insulin, Cohen’s interests have shifted. About eight years ago, he concluded that other “people can do the rest of it as easily as I can, maybe better, and I’ll try and look for something new.”

One of Cohen’s new preoccupations is ubiquitin, a regulatory protein that is found, as the name suggests, in all cells. Attaching a single ubiquitin molecule or a chain of them onto other proteins can turn on a wide range of cellular processes, such as immune response, DNA repair, and cell death. “I think this is going to be a huge growth area in the understanding of cell regulation in the next 10 to 20 years,” he predicts.

As a control mechanism, ubiquitylation is strikingly analogous to phosphorylation. “The principle is the same, except ubiquitylation is probably even wider and more versatile because there are polyubiquitin chains made in varieties you don’t have in phosphorylation,” Cohen says.

The number of enzymes whose job is to attach ubiquitin to proteins is similar to the number capable of adding a phosphate group. Likewise, the number of deubiquitinases, which take off the small protein, is on the same scale as the number of phosphatases. “Potentially, they have a similar number of drug targets,” Cohen says.

He’s attacking ubiquitylation in much the same way he approached phosphorylation: by meticulously working out the cell-signaling pathways and finding the weak points where a drug could most easily intercede.

Cohen convinced the Scottish government to fund a protein ubiquitylation unit, which will eventually have the same kind of support as his protein phosphorylation unit. The group started up last October and moved into its space in Dundee in January.

Not surprisingly, big pharma isn’t taking quite as long to warm to the idea of ubiquitylation as it did to phosphorylation. “I’ve been surprised how much pharmaceutical interest there is,” Cohen says. Activities in his new research unit have barely begun, and already he has been contacted by several drug company researchers.

He envisions that his protein ubiquitylation operation will mirror his successful protein phosphorylation unit. He sees the potential to launch a reagent company and to offer drug company researchers ubiquitin-profiling panels, complete with conjugated enzymes to test the specificity of their drugs.

“I don’t really see any reason why it shouldn’t work,” Cohen says of ubiquitylation. “It’s basically the same thing rolled out again but with a lot of exciting new biology thrown in.