Lost and found in translation
The first SULSA Symposium in June 2009 in Edinburgh provided a platform for some of Europe’s leading researchers in cell, systems and translational biology, including a Nobel Prize winner who talked about how scientific success can sometimes be an unexpected side-effect of failure… …
Two distinguished speakers, Professor Sir Tom Blundell, Chair of the SULSA International Advisory Board and Professor Sir Tim Hunt, 2001 Nobel Laureate, joined seven new SULSA Professors and Readers, to address an audience of 300 participants from all around Scotland. The event underscored the depth and the breadth of the research in life sciences being carried out today in Scotland and beyond.
Drug discovery does not always translate into products – or profits. Only eight out of every 8,000 lead compounds (chemical compounds with the potential to become pharmaceutical products) ever go on to clinical trials, said Professor Sir Tom Blundell, in the Opening Lecture of the SULSA Symposium, describing the “hit rate” of translational biology. And only one out of the eight compounds tested in clinical trials gets to market – with ‘blockbuster’ drugs typically costing over one billion dollars before they start to generate any returns.
Professor Blundell, the head of the Department of Biochemistry at the University of Cambridge and co-founder of Astex Therapeutics, which has cancer drugs in early stage clinical trials in the US and the UK , provided the perspective from the start when he talked about the high attrition rate in modern drug discovery and the huge costs involved in bringing new products to market – a model he described as “unsustainable.” The challenge, he said, was how to contribute to making the process more efficient, via automation, including new solutions such as high-throughput crystallography and structural bioinformatics. “We need proper computational systems,” Professor Blundell continued.
When there are 1,000 candidates for new therapeutic solutions, researchers need powerful models for testing, he said. “Drug discovery is not all about screening large libraries,” he added, “but changing those compounds into drugs.” And one of the priorities for Professor Blundell is to develop new treatments for neglected diseases, including malaria and tuberculosis.
As well as utilising informatics, we need a multidisciplinary approach to drug discovery, according to Professor Blundell, and also need to “move away from the old divisions between chemistry, physics and biology,” at the same time as building stronger partnerships between academia and industry.
Professor Manfred Auer (SULSA Chair in Chemical and Translational Biology, University of Edinburgh) elaborated on this theme in his lecture about strategies for identifying new drugs that interfere with protein-to-protein interactions – which represent potentially powerful but notoriously difficult targets for drug discovery. Auer’s group has developed a new approach to lead and drug discovery that integrates chemical, biological and physical techniques and is particularly suited to cracking the protein-protein interaction problem. Professor Andrew Hopkins (SULSA Chair in Translational Biology and Medical Informatics, University of Dundee) illustrated the complexity of “interactions in chemical space” whilst discussing a wide range of issues including automation of the drug design cycle and the need to make more libraries of lead compounds and informatics tools developed by industry available to academic researchers. Dr John Mitchell (SULSA Reader in Translational Biology, University of St Andrews) lectured on the chemistry of the reactions catalysed by different enzymes, the implementation of informatics databases to systematically capture this information and the need to “combine bioinformatics and chemoinformatics to identify and measure similarities in enzyme catalysis.”
Moving from drug discovery to more basic research on cell biology, development and disease, Professor Tibor Harkany (University of Aberdeen) outlined his work in “endocannabinoids, cannabis and the developing brain.” Hark any explained how cannabis affects the connectivity of the brain and its signalling networks, discussing implications ranging from pre-natal drug addiction and synaptic plasticity to cancer, obesity and memory loss. e highlighted the particular dangers of cannabis use for pregnant women and adolescents, due to the drug’s effects on brain development.
SULSA’s systems biology theme was represented by two leading international researchers recently recruited to Scotland by SULSA. Professor Peter Swain (SULSA Chair in Systems Biology, University of Edinburgh) posed the question of how cells make decisions, such as whether or not to eat a given sugar, particularly in a “noisy” environment where variable signals require complex cellular algorithms that have evolved to deal with the problem of uncertainty.
Professor Rainer Breitling (SULSA Chair in Systems Biology, University of Glasgow) described his interest in metabolomics – the systematic study of the thousands of natural chemicals (metabolites) within a cell. This metabolic fingerprint approach depends on sensitive mass spectrometry and advanced computational methods, including special algorithms developed by Breitling to eliminate the background noise and to make the fingerprinting of anonymous compounds at least “five times more accurate.” Breitling is using metabolomics to provide new insights into diseases such as sleeping sickness (African trypanosomiasis). Professor Ferenc Nagy (SULSA Chair in Systems Biology, University of Edinburgh) discussed the molecular aspects of light-regulated plant growth and development, pointing out that light is the single biggest factor in plant life, going on to explain phenomena such as signal transduction and the nucleo/cytoplasmic partitioning of the light-sensing phytochromes.
In closing the Symposium, Keynote Speaker Professor Sir Tim Hunt (Cancer Research UK, London Research Institute) talked about “getting in and out of mitosis” and the ups and downs of his recent research, which seeks to unravel the secrets of the biology of the cell cycle and how it all works, including the phosophatases that regulate mitosis – the process by which cells divide into identical pairs.
“Finding a good problem is critical,” Professor Hunt began, “but it isn’t easy to do so and it’s got to be one you can solve.” And according to Professor Hunt, his current research is still work in progress which has seen disappointments and failures en route – and still has a long way to go. “You only ever learn if you make stupid mistakes,” he said, describing the importance of experiments and the errors that he and his colleagues had made in their search to understand the secrets of mitosis – “the process at the very heart of life.”
Professor Hunt, who won the Nobel Prize for Physiology or Medicine in 2001 for his work on the regulation of the cell cycle, described his current research in considerable detail, including the search for enzymes that catalyse cell division, and how the famous enzyme activator called cyclin, discovered by Hunt and colleagues, is essential to get in and out of mitosis. He also described his more recent studies on other cell cycle regulators and how he had noticed “something funny going on with phosphatases.” His lecture was not just an insight into the more esoteric details of mitosis but a lesson in science in general, focusing on some of his failures as well as the joy of success – and the importance of experiments in an age when computers are beginning to dominate research.
Professor Hunt also confessed that his theory regarding the critical role of a particular phosphatase, called PP2A, had turned out to be somewhat off the mark: “All these experiments can be reproduced,” he explained, “but our interpretation was flawed – the PP2A phosphatase was not the key.” Even Nobel Prize winners don’t always prove to be right in the first instance and, borrowing a phrase from modern politics, Professor Hunt concluded that we need more “experiments, experiments, experiments.”
If the Symposium was one of those experiments, however, it was clearly a major success, not only providing a showcase for the exciting work already being carried out by the SULSA researchers but also highlighting the challenges lying ahead for everyone involved in life sciences – and its many applications in drug discovery and biotechnology.