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Sir Philip Cohen, the director of the MRC-PPU (the Medical Research Council Protein Phosphorylation Unit) and SCILLS (the SCottish Institute for ceLL Signalling) at the University of Dundee, has been described as “one of the world's top scientists” and he is now the world's most cited biochemist, having published over 500 research papers during his career. His pioneering work on protein phosphorylation prepared the way for the discovery of some of the world's most important new drugs for the treatment of c…
“It was 25 years before I received the first call from pharma,” says Sir Philip Cohen. It took scientists several decades to prove that protein phosphorylation regulates most aspects of cell life, and it took even longer to convince the pharmaceutical industry that drugs which target protein kinases would help in the treatment of killer diseases such as cancer. As recently as 1998, the head of research and development at one pharmaceutical company (which no longer exists) told Sir Philip that there was “absolutely no future in kinase drug discovery,” but later that same year researchers announced that a kinase inhibitor called Gleevec had proved remarkably successful in the treatment of chronic myelogenous leukaemia.
Today, according to Sir Philip, the market for drugs which target protein kinases is worth about $15 billion a year, and research on protein kinases accounts for about 30 per cent of the drug discovery programmes in the pharmaceutical industry and over 50 per cent of cancer R&D. Seventeen drugs targeting protein kinases have already been approved for the clinical treatment of cancer. And one of the remarkable aspects of protein kinases is that they often turn out to be useful in the treatment of multiple problems – for example, Gleevec is also effective in the treatment of gastrointestinal cancer.
Not many scientists can claim to have made such an impact, but having spent so many years investigating phosphorylation, Sir Philip then appeared to change direction when he announced that he was turning his attention to a very different branch of biochemistry called ubiquitination, inviting criticism by daring to suggest that phosphorylation and ubiquitination have many similar characteristics – and perhaps equal potential for providing drug targets. Until very recently, the conventional view among most biochemists was that ubiquitination was a mechanism mainly concerned with destruction (marking proteins for destruction by the proteasome), but Sir Philip points out that it also performs other key roles in cell regulation – for example, in immunity and how cells respond to DNA damage. Like phosphorylation, ubiquitination is also reversible and can therefore also act as a biological switch to alter protein function reversibly.
In Sir Philip’s view, phosphorylation and ubiquitination are simply two biological systems which can’t work without one another, and also help to regulate each other. And he wants to “popularise” further research in ubiquitination because our knowledge of this field is still rudimentary and in the future it will deliver many new drugs.
“I love looking at two processes that control everything,” says Sir Philip. “And ubiquitination is another ‘black box’ – another system I would love to get a handle on.”
Although there are “striking parallels” between the histories of phosphorylation and ubiquitination, wrote Sir Philip and his co-author Marianna Tcherpakov in a recent article for the journal Cell, including a delay of many years before the fundamental science was translated into practical products, in recent years more drugs that target protein kinases have been approved for clinical use than drugs which target a component of the ubiquitin system. However, in 2003, a protease inhibitor (which stops a particular protease breaking down ubiquitinated proteins) called Bortezomib was the first to be approved for clinical use in the treatment of a fatal lymphoma.
Several other promising drugs that target components of the ubiquitin system have been developed since then, which are currently undergoing clinical trials, and Sir Philip welcomes the challenge ahead. He and Tcherpakov conclude in their paper: “Predicting the future is notoriously difficult. However, given the diverse approaches and avenues that remain unexplored in developing drugs targeted at the ubiquitin system, [we] would be surprised if ubiquitin drug discovery was not far more important in ten years’ time than it is today. Nevertheless, only time will tell if ubiquitin drug discovery will eventually rival in its importance that of kinase drug discovery.”
Another key aspect of Sir Philip's research involves attempting to “unravel the signalling pathways in the innate immune system that control the production of pro-inflammatory cytokines and interferons during bacterial and viral infection.” And rather than seeing ubiquitination as a separate sphere of research, he sees it complementing his earlier work in phosphorylation, studying “the interplay” between protein ubiquitination and protein phosphorylation.
This journey to ubiquitination has taken many twists and turns already and Sir Philip admits he has “stumbled upon” many aspects of this new biological challenge, and now stands at another major crossroads in his career, just as he did years ago when he first got interested in phosphorylation.
The basics of phosphorylation were first understood in the mid 1950s, when it was shown to be a mechanism for controlling glycogenolysis (which produces glucose in the liver and energy for muscular activity), and gradually scientists unravelled more of its secrets. Sir Philip started doing his research into phosphorylation in the US in the late 1960s, and on returning to Dundee to set up his own laboratory in 1971, he set out to answer two major questions: how does insulin work and how are biological processes in cells regulated by phosphorylation?
His focus on how insulin works started in 1973, two years after he arrived in Dundee. Along the way, he learned about the mysteries of protein phosphorylation, with one discovery “cascading” into another as the pieces of the jigsaw fell into place. There were also many dead-ends, red herrings and wrong leads en route. For example, he once believed that phosphatases could be the key to insulin action, rather than protein kinases. As it turned out, this was wrong, but in the process he learned a lot about phosphatases – a fund of knowledge, which will also help in future research and drug development. For example, he discovered a phosphatase called calcineurin that was later found to be the target for cyclosporin, the immunosuppressant drug that has permitted the widespread use of organ transplantation.
According to Sir Philip, the discovery he is most proud of is working out how insulin stimulates glycogen synthesis in muscle – a quest which continued for more than two decades and culminated in the discovery of the “missing link” in this process, a kinase called PDK1, by Professor Dario Alessi, a Programme Leader in Sir Philip’s Unit. In his autobiography, For the love of enzymes, Nobel Prize-winning biochemist Arthur Kornberg said that “There is no such thing as a boring enzyme,” but with regard to PDK1, Sir Philip adds: “Some enzymes are more interesting than others.”
Sir Philip’s approach to phosphorylation involved “working backwards” – going from the final biological event (e.g. the synthesis of glycogen) to the root of the problem, step by step. He knew that insulin worked by removing a phosphate but then had to find out how it happened – a journey which led him to study a series of different events, including the discovery of different protein kinases and phosphatases and a myriad of phosphorylation “sites” on the enzyme, glycogen sunthase, where phosphorylation took place.
Eventually, Sir Philip and his team of researchers began to understand how even very small amounts of insulin could amplify the signal by triggering a “cascade” of phosphorylation events to speed up the synthesis of glycogen, with PDK1 playing a critical role in the process.
One observer commented that Sir Philip’s approach to research was like playing a game of chess – which happens to be one of his favourite games. The metaphor suggests that although you can plan several moves ahead, you can never predict every move or how the match will end, and have to be ready to respond to unexpected events, or “a logical system of continuations” which flows through the process.
Among Sir Philip's other key achievements are the classification and characterisation of serine/threonine-specific protein phosphatases and the elucidation of mitogen activated protein (MAP) kinase cascades.
With many big discoveries like these, Sir Philip says, scientists are tempted to think “this is it!” But progress often comes from “nibbling at the edges” – being persistent and patient enough to make the small incremental advances that hopefully lead to a breakthrough in knowledge.
In 1997, his pioneering work with insulin seemed to have answered in outline how this molecule worked. So he started exploring new fields of research, and eventually decided to tackle innate immunity and the role of ubiquitination in this process – a system which was “poorly understood” but had the potential to lead to the development of new anti-inflammatory drugs. “This is a chance to make a big contribution,” Sir Philip declares – believing that the interplay between ubiquitination and phosphorylation, with its “increased potential for complexity,” is going to become a dominant theme in the study of cell regulation in years to come.
Doing research on innate immunity – breaking open cells to find proteins of interest – is just as exciting for Sir Philip today as the study of insulin and phosphorylation was four decades ago, and he hopes that when it comes to deciding the future of the MRC-PPU, which he founded in 1990, and the Protein Ubiquitination Unit, a division of SCILLS, which opened in 2008, the two units will be integrated and continue to complement each other’s work. SCILLS received initial funding worth £10 million over five years from the Scottish Government, while the current round of funding for the MRC-PPU will run out in April next year.
Doing the business
Sir Philip, who is also Co-Director of the Division of Signal Transduction Therapy (DSTT), “the UK’s largest collaboration between a basic research institution and
the pharmaceutical industry,” has clear views on how to establish research units and attract funding.
What distinguishes Sir Philip's approach is that he seeks support for the team as a whole, rather than specific individual researchers or projects. In this way, strategic decisions can be made to put in place the support infrastructure that enables the team leaders to respond much more quickly to developments as they arise, because they have the money to do so. This set-up also enables post-doctoral researchers and PhD students to tackle the important aspect of their projects as soon as they arrive because the production of all the materials that they need has already been completed by the support staff.
The key to success, he repeatedly stresses, is “critical mass” – building up a team not only capable of doing broad research but also providing many aspects of technical support. This attracts biotechnology companies to Dundee to market reagents and services on the back of this infrastructure, which benefits the local economy, as well as basic fundamental research, and means “you also have much more to offer in collaborations with partners from industry.” For example, the Unit generates 5,000 new DNA clones every year, as well as producing hundreds of proteins and antibodies.
“The weakness of many departments,” he says, “is too many individuals working alone, running their own little empires, with too many scientists focused on fine detail and not enough people looking at the big picture.” Creating critical mass in academia in areas of special interest to industry “would greatly increase the chances of biotechnology taking off in a big way in Scotland,” he adds.
The benefits of working very closely with the pharmaceutical companies also go far beyond money (the collaboration has so far attracted more than £40 million in funding, plus royalties). For example, says Sir Philip, researchers become more interested in clinical significance and have to work to more stringent industrial quality control standards. “I've come to learn how terrible quality control can be in academia,” Sir Philip continues.
Having major pharmaceutical companies visit the unit for several days two or three times a year also challenges everyone to come up with important new findings and exposes students to the industry mindset.
Why life sciences?
Sir Philip’s advice to young people thinking about a career in life sciences is to “do what you are passionate about.” When he was at school, his passion was natural history, particularly bird watching, and when he went to study biochemistry at University College London, he was disappointed that it wasn’t a cross between chemistry and ornithology. Two years later, however, when he started his first research project, he discovered the excitement of finding something “just around the corner” that no-one else had found before. Although he will step down as director of the MRC-PPU and SCILLS in April 2012, the passion still burns bright – Sir Philip has signed a new
six-year contract to continue his research and says that his work on innate immunity is “just getting to the exciting stage.” And unravelling the secrets of ubiquitination in this process is one of the passions which still drives him on.
Sir Philip loves to look at the processes that control everything – and judging by his appetite for science, he will never be happy to settle for less.
Further reading: “Will the Ubiquitin System Furnish as Many Drug Targets as Protein Kinases?” by Philip Cohen and Marianna Tcherpakov, Cell 143, November 24, 2010