One of the UK’s leading scientists, Professor Sir Philip Cohen recently earned an award for improving health through outstanding medical research. He tells Dr Richard Elliott how support from Diabetes UK has helped to shape his fascinating career
Professor Sir Philip Cohen is a true research pioneer. His work has produced dramatic changes in understanding the function of human cells and led to collaborations that have advanced the development of drugs and the economy of Dundee, where he works. Over the years, his studies have been referenced more often by the scientific community than those of almost any other scientist anywhere in the world.
Sir Philip has devoted his 40-year career to studying ‘phosphorylation’, which is a vital biological control mechanism. Once thought to be highly specialised, Sir Philip’s work has shown that phosphorylation is key to the function of all living cells. Accordingly, defects in this mechanism are now known to be a key cause of health problems such as diabetes, cancer and arthritis. As a result, treatments that target these problems have become one of the largest and fastest growing areas of drug development.
As with every journey of discovery, Sir Philip’s career has not been entirely straightforward. He began work at the University of Dundee in 1971 and has remained there ever since, but his first application for government research funding was initially turned down and then it took a staggering 25 years for the pharmaceutical industry to recognise the value of his research.
But Diabetes UK came to his aid: “It’s always very difficult for young researchers starting out. I was told at first that the problems I wanted to work on were already solved, but obviously that wasn’t the case. The first grant I ever got was from Diabetes UK (then the British Diabetic Association). That allowed me to start my work on how insulin stimulates the conversion of glucose into glycogen, the stored sugar that provides a key source of energy.”
Learning from the unexpected
Sir Philip was able to identify chemical on/off switches, controlled by the phosphorylation mechanism, that triggers this conversion process. “It sounds quite simple,” he says, “but it took a long time because there was a lot of basic research involved and, as you go, you can’t help but take a number of wrong turnings.
Diabetes UK was really instrumental in supporting me. I always had a Diabetes UK grant from 1973 until we solved this problem in 1998 – without that we probably couldn’t have done it. “We finally got a real handle on the mechanism in the early ‘90s by discovering the key enzymes that are switched on by insulin. By 1997, we worked out how the whole pathway worked and closed the gaps in the chain of events leading to the production of glycogen.”
Although Sir Philip’s main goal was to understand exactly how insulin works, he made many other ground-breaking discoveries along the way. “In doing research you will stumble into things that are unexpected and it’s often the ones that don’t make any sense that are the most interesting problems to solve, if you can get to the bottom of them.
We discovered components of our chemical signalling pathways that might provide good targets for new drugs to treat diabetes,” he says. “But even more importantly, we showed that the process of phosphorylation wasn’t just a device for regulating glucose, but was something that has roles in all aspects of biology. Through work in my lab, and in many others over about 25 years, it gradually became clear that we were studying a biological control mechanism that governs almost all aspects of cell life, and that defects in this process were directly linked to almost all of the major global diseases.”
Although the significance of phosphorylation was soon recognised by scientists, the companies that develop new drugs were slower to catch on. “Not a single pharmaceutical company showed any interest in anything I was doing until 1994,” says Sir Philip. “They thought that it was impossible to make drugs that could target these phosphorylation mechanisms and that, even if you could make them, they would cause unacceptable side effects. I got involved with a couple of these companies in 1994 and 1995 in collaborations that showed that this wasn’t actually the case.”
Boosting drug development
Sir Philip’s work helped to galvanise the pharmaceutical industry and what has happened in the 19 years since has been incredible. Phosphorylation has turned into the biggest area of drug development worldwide, incorporating around 30 per cent of all research and development projects and leading to nearly 25 approved drugs (with current sales of about US$20bn per year).
More than 150 additional compounds are also being tested in clinical trials, and Sir Philip predicts that this will double by 2020.
In February this year, Sir Philip’s outstanding contribution and commitment to medicalscience was recognised with a Millennium Medal – the highest award of the Medical Research Council. In addition to his work on phosphorylation, the prize reflects Sir Philip’s efforts in building the world’s largest collaboration between academic researchers and the pharmaceutical industry.
The deal, which has brought in more than £50m worth of funding in 14 years, involves six of the world’s biggest drug companies. It helps them to develop new drugs and technologies and accelerate current projects that are in turn useful for further research. It took several years and lots of hard work to set up, but today the collaboration is widely regarded as a model example of fruitful interaction between academia and industry.
“This collaboration involves running our lab in a different way to most other academic labs,” says Sir Philip. “But we find that this way is very beneficial to our research. In most labs, there’s a lot of the basic spade work that you have to do.
When you get a new researcher, it often takes them a year just to prepare all of the chemicals they’ll need to start their experiments. In our lab we can bypass all of that by using specialised support teams that we’ve set up, and our researchers get what they need on the day that they arrive and can begin the really interesting work immediately. In this way we can speed everything up.
“For example, there are a couple of drugs with GlaxoSmithKline that are expected to be approved sometime this year for the treatment of skin cancer. In one case, we identified the target for the drug and, in the other case, we actually had a hand in getting the development programme off the ground by providing the initial proteins for the screening and helping in other ways.”
Shaping the economy
During his career, Sir Philip has published more than 500 research papers and spoken about his work at over 300 scientific meetings in 34 different countries. Closer to home, he’s also played a significant role in developing the study of Life Sciences at the University of Dundee by attracting new minds and new investment into the city, and helping them to thrive.
“When I first arrived at Dundee in 1971, life sciences was a terribly small field – there must have been less than 50 people involved. Today, in Dundee as a whole, we’ve got nearly 5,000 people working in life sciences and biotechnology, which has helped to create something like 10,000 jobs in the service industry and works out at nearly 15–20 per cent of the economy of the city.” Having expanded the study of phosphorylation far beyond the scope of his initial research, Sir Philip is now turning his attention back towards the field of diabetes.
“In the last five to 10 years, I’ve switched the focus of my whole research area to try and understand how the immune system works,” he explains. “I felt that we had solved the outlines of how insulin signalling works, so that it was no longer a ‘black box’, and I wanted to see if I could do it all over again in another area.”
“It’s becoming clear that both Type 1 and Type 2 diabetes are really inflammatory diseases. In these types of diseases, one problem is that you can’t resolve inflammation once it has done its job in fighting infection and it ends up giving you a lot of tissue damage, which, in turn, causes the disease. We have identified a new signalling system that controls the conversion of immune cells from so-called proinflammatory to anti-inflammatory cells. These are vital in resolving inflammation, so if we could find and help to develop a drug to activate this process, it might be very beneficial as a treatment.”
There is still much to learn, but Sir Philip is nevertheless optimistic about the future: “In the whole field of what we call ‘protein phosphorylation’, the more you learn, the more you realise how much that you still don’t know. In a way, we are still just nibbling at
the edges, but I think research in this area has reached a stage now where the future will be much more translational – where we can really start to see how to manipulate these biological systems for therapy much more clearly than we could before.”