Clinical Research - Across the great divide: Scotland gets translational

Across the great divide: Scotland gets translational

With translational research now at the forefront of Scotland's healthcare strategy, Peter Mansell looks at how the University of Dundee is answering industry's call for more end-directed innovation

Getting academic researchers and the pharmaceutical industry to meet each other halfway has been a consistent theme of the life sciences sector in recent years.

Policy documents such as the Cooksey report on health research funding have underlined the need for translational approaches that shorten the journey from bench to bedside. Recent initiatives like the UK Drug Discovery Consortium illustrate just how much the two sides of the equation now recognise that need and are ready to act on it.

This convergence of interests is hastened by financial constraints and strategic imperatives in R&D and healthcare. Patent expiries are cutting into industry's revenue flows and magnifying its reliance on external sources of innovation to replenish tired drug pipelines. At the same time, hard-pressed healthcare systems are demanding added value at a manageable price, which means R&D costs, timelines and attrition rates have to tighten up.

While the hierarchy of need may appear to favour academic researchers, they too are under pressure to show added value. Public funding for research in the UK now pays closer attention to prospects for 'knowledge transfer' that directly benefits the economy, while the recession is hitting charitable donations.

Partnering with industry can plug some of those gaps. But pharmaceutical companies want to see more end-directed innovation that mitigates some of the risks of early-stage drug development. One academic institution answering this call on a number of levels is the University of Dundee in Scotland.

Life sciences explosion

What is happening in Dundee has to be seen in the wider context of a life sciences explosion in Scotland, which has carved out a niche in cutting-edge fields such as stem cell technology. Much of the activity is characterised by a networked approach that ties together the various strands of public and private sector input from industry, academia and the NHS. The resulting capabilities range from basic science through to manufacturing, more than 40 contract research and other support organisations, and companies such as Roslin Cells, CXR Biosciences, Axis Shield and Cellartis.

Scotland has put translational research at the forefront of its healthcare research strategy. The government's recent update, Investing in Research/Improving Health: the research strategy for health and healthcare, sets out its ambitions to "place Scotland at the international forefront of clinical translational research and the development of systems medicine".

As was clear from a recent tour of life sciences facilities organised by Scottish Development International (SDI), academic institutions can forge a number of links along the translational research chain. These include identifying and exploring novel disease mechanisms; 'de-risking' early-stage research for companies that want leaner, more efficient and more cost-effective research pipelines; developing biomarkers and assays based on DNA replication to enable 'smarter' use of existing drugs; and tackling neglected tropical diseases of limited commercial interest to the mainstream pharmaceutical industry. All of these activities may be found in some form at the University of Dundee.

The university is also a member of the UK Drug Discovery Consortium, under which non-industry organisations conduct 'pharma-like' research that can be taken into the clinic through partnerships.

The city's life science activities have been pivotal to Dundee's economic regeneration in recent years as a centre for high-tech research and industry. Indeed, life sciences account for an estimated 16% of the local economy.

Blazing a trail

While the University of Edinburgh's Roslin Institute and the cloning of Dolly the sheep will forever be imprinted on the public mind as symbols of Scotland's expertise in forward-looking fields such as regenerative medicine, Dundee University has blazed its own trail, notably with the MRC (Medical Research Council) Protein Phosphorylation Unit headed by Sir Philip Cohen.

This is a research centre whose collaborations with leading pharmaceutical companies such as AstraZeneca, Pfizer, GlaxoSmithKline and Boehringer Ingelheim embody the translational ethic in academia. However, crossing that bridge has taken time and effort, and as Sir Philip explains, the attachment and removal of phosphate is one of the main mechanisms involved in protein regulation. Malfunctions in the process are associated with major diseases such as cancer, diabetes and hypertension.

Although the MRC unit has been in place since 1990, Sir Philip's investigations started around 40 years ago. For 25 of those, there was no industry interest in protein phosphorylation, but in the past 15 years the field has transformed from "undruggable" to a platform for 30% of all drug discovery, with 50-70% of that in the must-have category of oncology, he says.

Among the better known medicines with roots in protein phosphorylation are cyclosporine, the immunosuppressant widely used in organ transplants; and the anticancer Glivec (imatinib), the first drug developed by targeting a specific protein kinase. And according to Sir Philip, the Dundee unit has attracted ?40 million in research funding over the past four years and constitutes probably the largest collaborative effort in Europe between the pharmaceutical industry and academia.

The MRC Phosphorylation Unit has also been an example of long-term industry commitment, with AstraZeneca, Pfizer and GlaxoSmithKline (then SmithKline Beecham) still on board from the initial collaborative agreement in 1998.

Over the past year and a half, Sir Philip has also devoted his attentions to the parallel field of protein ubiquitylation, as founding director of the government-funded Scottish Institute for Cell Signalling (SCILLS). Launched in October 2008, the Protein Ubiquitylation Unit is the first research division of SCILLS and targets mechanisms with drug potential in areas such as cancer and inflammatory diseases.

Scientific progress in protein ubiquitylation has been rapid: the field has already reached the point where protein phosphorylation was 14 years ago. The first drug based on the ubiquitin process, Millennium Pharmaceuticals' (Takeda) anticancer Velcade (bortezomib), was launched in 2007. And Sir Philip says the new unit has been "deluged" with telephone calls from interested pharmaceutical companies.

Another standard-bearer for translational research at the University of Dundee is the Drug Discovery Unit in the College of Life Sciences, which combines integrated capabilities such as high-throughput screening, computational drug design, medicinal chemistry, drug metabolism and pharmacokinetics, and structural biology. Fittingly, Professor Julie Frearson, the chair of biotechnology who has established a state-of-the-art assay development and small-molecule screening facility in the university's James Black Centre, joined the Dundee team from industry. She was recruited from BioFocus, where she was director of biology. As she explains, the Drug Discovery Unit (DDU) has all the disciplines needed to take compounds up to the preclinical trial phase, where partnerships can be sought with industry or other suitable collaborators. Just how far the Dundee researchers will take the drug discovery process depends on the compound involved and the wider economic/industrial context.

De-risking early-stage research

The DDU is all about de-risking early-stage research by "meeting industrial partners on their own terms and getting that dialogue working", comments Professor Mike Ferguson, dean of research at the College of Life Sciences, who points to the Cooksey report's call for a "translational engine" to galvanise the UK health research sector.

Frearson describes the DDU as "very much an enabling mechanism", one distinguished by having drug discovery expertise embedded within an academic environment. It is also largely concept- and target-driven, rather than wedded to a particular therapeutic focus.

"Conventionally, a lot of other universities have translational research projects running, they win an award around a particular project, they put staff on that project, and then they run that project sometimes beyond its useful lifetime because [the award is for] three years and you've recruited staff, etc," Frearson comments. "We don't do it that way. We have a pool of people and we manage projects as they move through the process."

Devolved portfolios

That agility is reflected in the choice of Dundee University as one of five academic centres piloting devolved portfolios - financial awards used to support goal-oriented translational research projects - under the MRC's Developmental Pathway Funding Scheme (DPFS), the flagship of the MRC's translational research strategy.

Eight of 10 new projects recently initiated by Dundee under the scheme have been consolidated into a single 'super-project' under Frearson's management, with potential applications in cancer, Huntingdon's disease, eczema, type-2 diabetes and bacterial infections. Ferguson sees the devolved portfolio pilot as a "very healthy direction of travel" that allows for quick decision making. The two main streams of activity at the DDU are the Drug Discovery for Tropical Diseases initiative (DDTDi) and the Scottish Hit Discovery Facility (SHDF) - Frearson is director of the latter.

The DDTDi is funded by the Wellcome Trust and has set itself the target of having at least one drug candidate for human African sleeping sickness ready for entry into formal preclinical development by March 2011. It will advance these candidates to the lead optimisation stage, demonstrating activity in animal models of disease. A transferase inhibitor and one other orally active compound for African sleeping sickness have currently reached this milestone. The choice of a candidate for preclinical trials will depend on costs.

The DDTDi's partners are the Drugs for Neglected Diseases initiative and the Medicines for Malaria Venture. Nonetheless, Professor Alan Fairlamb, head of Dundee University's Division of Biological Chemistry and Drug Discovery, highlights the importance of having industry experience available in the form of Frearson and Paul Wyatt (ex-Astex Therapeutics and GlaxoSmithKline), the initiative's directors of drug discovery. These people understand the need for clear project timelines and go/no go decisions, he comments.

The SHDF develops projects with academic collaborators up to in vivo proof-of-concept, then looks for partners. In this context, Frearson suggests, the best place for lead optimisation is in the pharmaceutical industry, even if the compound then risks getting "lost" among other priorities.

"A little bit of extra risk"

The DDU's approach means it can offer drug candidates that fit into existing R&D pipelines, she adds. It also enables the unit to take a "little bit of extra risk" in determining whether a concept is therapeutically valid.

"I think in standard pharma HTS [high-throughput screening] groups they would probably initially run a mile from… this type of work," Frearson says. "They have a minimalist, reductionist approach, they want to know the individual target, develop a recombinant equivalent system, do relatively straightforward screening to get to a start point, and then check whether or not that translates into useful activity… And quite often there's massive attrition there."

As the activities at Dundee University show, Scotland is busy putting its translational ambitions into practice. In doing so, it can help not only to restore the UK as a pharmaceutical research venue of choice but to resolve some of the paradoxes facing an industry caught between the pressing demands of innovation and cost-efficiency.