City of drug discovery
Dundee is called the “City of Discovery” in honour of the ship built in a local yard on Tayside, used by Captain Scott and Ernest Shackleton on their successful scientific expedition to the Antarctic (1901–04). In the future, however, the nickname may change to recognise the pioneering work done by the Drug Discovery Unit in the University of Dundee, set up five years ago and already producing exciting results...…
They are not called “neglected tropical diseases” for nothing. But if Professor Mike Ferguson and his colleagues in the University of Dundee's Drug Discovery Unit succeed in their mission, killer diseases such as sleeping sickness and malaria may not be so neglected in the future.
According to Ferguson, Professor of Molecular Parasitology and Dean of Research, neglected tropical diseases were “not in the lexicon” of the pharmaceutical industry only a few years ago. They are a problem which affects the poorest people in the world and simply don't receive the same attention as more 'profitable' problems such as cancer. In addition, major killers such as malaria present other problems – treatments must be inexpensive and must be delivered to the millions of people who need them, and the parasites which spread the disease can develop resistance to many new drugs.
This lack of interest is beginning to change now, however, and Ferguson says “pharma is engaging at all levels” of the problem, with philanthropic organisations such as the Bill and Melinda Gates Foundation funding projects at the point of delivery and the Wellcome Trust and other bodies such as the Drugs for Neglected Diseases Initiative and Medicines for Malaria Venture funding the translation of basic research – including Dundee's Drug Discovery Unit (DDU), where a team of researchers is developing lead compounds for diseases such as trypanosomiasis (sleeping sickness), Chagas’ disease, leishmaniasis, malaria and other protozoan pathogens.
The DDU was first conceived in 2002, when Ferguson and his colleague Professor Alan Fairlamb, now head of the Biological Chemistry and Drug Discovery Division, were “frustrated that the drug targets being identified could not be translated into therapeutics.” The pharmaceutical industry had all the resources they needed, but they realised they would need industry expertise in-house to design new medicinal compounds themselves, rather than waiting for pharma to pick up their leads. As Ferguson puts it: “If we couldn't go to pharma, then we would bring pharma to us.”
At about this time, the new Sir James Black Centre was being created, with one floor set aside for the new DDU. Even before it was opened, Ferguson and Fairlamb started raising the funds required to buy new equipment and hire key people, including Ian Gilbert, now Professor of Medicinal Chemistry and deputy head of the Division of Biological Chemistry and Drug Discovery, and Professor Julie Frearson, recruited from the Cambridge-based drug discovery company BioFocus.
This commitment to the DDU was one of the first “gambles” taken by Ferguson over the next few years – recruiting leading scientists without being sure where the next wave of funding would come from. Ferguson then spoke to Dr Mark Walport, the Director of the Wellcome Trust, and persuaded him the DDU could represent a timely opportunity. When the Trust reviewed the DDU's application, it agreed the unit needed to bring in more industry experts, and gave it more than £8 million over five years to pursue its new mission.
One of the first key appointments was Paul Wyatt, now Professor of Drug Discovery and Director of the Drug Discovery Unit – part of a team with over 170 years of industry experience in the pharmaceutical and biotechnology sector. According to Wyatt, “The unit was created to respond to a lack of capacity in the UK for early-stage drug discovery in the academic sector,” and its mission is “to translate basic science into lead compounds to validate putative drug targets, to use as tools to investigate disease pathways and, when appropriate, advance to pre-clinical drug candidates.”
The unit today is still the only one of its kind in the UK – a drug discovery research lab in the heart of a university campus. Other research labs are “virtualised” among several locations, but the DDU is fully integrated, bringing together assay development, high-throughput small-molecule screening, cell biology, medicinal chemistry, structural biology, computational chemistry and DMPK (drug metabolism and pharmacokinetics).
Sometimes a great notion...
The DDU's ultimate aim is to find “effective targets and pathways” that eventually lead to the development of cures for killer diseases, in-house and in partnership with leading pharmaceutical companies. Sometimes, says Ferguson, this noble quest can be highly frustrating. Academic researchers doing good basic science can come up with what look like promising targets, but some “great molecules” or prototypical drugs may turn out to be nothing more than interesting “notions” and never become actual products. One moment, you might imagine you have found a cure for cancer, and the next you are getting a nasty surprise. “There is no shame in that, however,” Ferguson adds, pointing out that only one or two out of every ten candidate targets proves to be valid. “We must expect attrition in the course of our research.”
When the DDU opened in 2006, Ferguson was delighted to “train our guns” on neglected tropical diseases, but he also recognised that in order to make the new unit sustainable over the long term, it would need a broader remit, so from the start it also focused on innovative targets and pathways for other diseases such as cancer, diabetes and eczema, through collaboration with local experts in these areas. With tropical diseases, the idea is to validate drug targets and to develop new drug candidates, which would then go for clinical trials. With innovative targets, the idea is to make the validated targets “more tempting to pharma” by de-risking the basic research – reducing a large number of 'potential targets' to a small number of 'druggable targets' which pharma translates into drugs.
One of the benefits of this approach, apart from the promise of future financial returns, is the economies of scale which it enables, with researchers in the two “parallel worlds” sharing expensive equipment which could otherwise be idle for some of the time – e.g. robotics for compound screening and analytical equipment for chemistry. Ferguson stresses the need to avoid any conflict between the two spheres of research, so that money intended for one project does not go into another. It's an unusual model, he says, but it's helped to attract over £30 million in funding so far. The first £4 million was spent on the laboratory, with generous contributions from the Wolfson Foundation
and the European Regional Development Fund, followed by almost £10 million from the Wellcome Trust and the Scottish Funding Council on equipment and recruitment to build the tropical diseases team and establish a Scottish compound screening facility – and significant progress has already been made.
The road to Dundee
Ferguson himself has dedicated most of his career to neglected tropical diseases, since he chose this as the topic of his PhD Thesis in 1979 at London University, before he went to New York's Rockefeller University to continue his research. At one time he believed that he would do research on cancer, but tropical diseases soon became his primary focus, specialising in membrane biochemistry – which plays a crucial role in cellular activities, with the membrane surrounding the cell acting as a barrier between the intracellular and extracellular environments, and as a site for diverse biochemical activities.
Neglected tropical diseases were an intellectual challenge which also satisfied Ferguson’s need to do something “good for mankind.” And as his work in membrane chemistry progressed, he made a breakthrough which would have an impact not just on the study of parasites and tropical diseases but also on our basic understanding of cells, working
out how a whole group of proteins are anchored to cells – not just in parasites but in all eukaryotic cells (all cells except bacteria). This pioneering work in GPI membrane anchors (GPI = glycosylphosphatidylinositol) occupied Ferguson for several years, and gave him a solid grounding in the “nitty-gritty” of science, including five years working out the “partial and then complete structure” of the anchors, studying billions of possible options. “It was a long gestation period,” says Ferguson, but later he started to dream of translating these ideas into druggable products.
His work in membrane biochemistry is now in the text books, but Ferguson confesses that it was not quite what he expected – or hoped for: “At first, I was bitterly disappointed that I hadn't discovered something unique to the parasites – an obviously druggable target,” he says. “But then I realised that this was an important discovery in fundamental science, creating a framework for future biological research.”
Ferguson then faced a choice: should he build on this discovery and specialise in GPI membrane anchors in general or continue to focus on neglected tropical diseases?
In recent years, he's also faced more difficult decisions and come out of his “comfort zone” to push for the creation of the DDU, so his dream of curing tropical diseases can come a few steps closer to reality.
DDU to double
In 2013, the DDU will expand into a new home, the Centre for Translational and Interdisciplinary Research (CTIR) – doubling the number of staff in the unit to 70 people.
As well as advancing the quest for new druggable targets, Ferguson believes the CTIR will also be an “experiment” in how such research centres work and evolve. The mission of the new centre is “to enhance translational research by expanding drug discovery capacity and to enhance computational and mathematical biology and informatics to meet the future of biomedical research” but the emphasis on interdisciplinary research is also a critical part of the project.
Dundee is very strong in imaging, mathematical biology and bioinformatics, says Ferguson, and when we hire new recruits, including biophysicists as well as astrophysicists, this will make for an interesting 'marriage,' allowing physical and computational scientists to “interact with experimental biologists” in a 'dry science' environment which allows them to work side by side, helping scientists “see different ways of doing things” and gain new respect for other disciplines at the same time as helping solve each other's problems. Mathematics, physics and computing are becoming more important in biology, for instance, and scientists with these skills know biologists are struggling with fast-increasing mountains of data and the need for predictive models in the quest to understand biology and to discover new drugs.
“The interface between biology and chemistry creates all sorts of new applications,” he says. “In the CTIR, we will also have physicists and engineers, mathematicians and computer scientists, helping biochemists and molecular biologists. I don’t think different disciplines should stay in their separate silos. It’s our job to break down the madness.”
Ferguson also believes that it’s time to end single degree courses and start to teach the ‘science of endeavour’, regarding each discipline as part of a continuum. “The critics say you have to learn to walk before you run, and that you need a good grounding in a specialist subject, but I think we should take a more interdisciplinary approach – e.g. spend a third of the time on biology, one third on chemistry and one third on physics.” Ferguson admits this is a cultural and also a “tribal” debate which will rage on for years, but hopes the new facility will blaze a trail for interdisciplinary research.