Relief in sight for IBD

Inflammatory bowel disease (IBD) is the generic name for a group of chronic inflammatory conditions of the intestine that affect about five in every 1000 Australians.

Although not associated with high mortality, IBD causes significant morbidity in its sufferers and can be chronically debilitating. Crohn's disease and ulcerative colitis (UC) are the two major IBD disorders - Crohn's can affect any part of the gastrointestinal tract, while UC is restricted to the large bowel.

Despite the significant clinical and societal burden, therapies for IBD are limited and we only have a few clues as to the underlying mechanisms and genetics of the disease.

Dr Graham Radford-Smith, a gastroenterologist at the Royal Brisbane and Women's Hospital, has spent his career trying to improve this situation by establishing a specialised clinical unit in his department in Brisbane and developing an extensive information and research database.

After more than a decade of building links and doing some hard science, he is "on the cusp" of some major advances in the understanding and clinical management of IBD.

Radford-Smith originates from the UK and completed his medical training at the Universities of Cambridge and Oxford in the late 1980s. His natural curiosity and increasing interest in the area of chronic inflammatory diseases led him to a PhD at Oxford under the tutelage of a household name in IBD research, Prof Derek Jewell.

Studying such disorders was appealing to Radford-Smith as a clinician because there were (and still are) so many unanswered questions concerning disorders of chronic inflammation, particularly of the gut. In addition, these are complex diseases affecting mostly younger people and present a huge hidden cost to society.

The other appeal for Radford-Smith research-wise is that IBD involves a complex interplay between environmental factors and host susceptibility in terms of genetics and immunity.

"There is likely to be a lot of overlap amongst all chronic inflammatory diseases, which is only just starting to be realised," he says.

National IBD resource

Radford-Smith followed his heart to Brisbane in 1994 and quickly established himself as a gastroenterology physician and researcher. It was an easy decision to continue with this dual role as on arriving, he found a huge amount of clinical material not being utilised for research in the area of IBD.

One of his first major achievements was to develop a specialised IBD Unit within the Gastroenterology Department at the Royal Brisbane Hospital (RBH) with the goal of linking clinical practice and research.

His group comprises a clinical research team located in the hospital environment and a scientific laboratory situated within the Queensland Institute of Medical Research, conveniently co-located on the hospital campus.

The clinical research unit primarily drives the group's ongoing population study, looking at the incidence and prevalence of IBD in Brisbane in both the paediatric and adult populations.

This is a huge study - with a population of around 1.8 million in greater Brisbane, the study involves over 7000 patients. Studies such as this would not be possible without access to a bank of clinical and scientific data, and another of Radford-Smith's initiatives once he set up in Queensland was to invest in DNA and build up a resource from cases, controls and affected families.

Particularly with the varied disorders he studies, it is important to collect good clinical samples (serum, DNA, tissue) and information about individual cases and Radford-Smith has been diligent in this since 1995. The resulting database has now evolved into a vital clinical resource and critical piece of the research machinery.

Radford-Smith and others are currently trying to organise a national IBD resource. A long-standing collaboration with Dr Tim Florin at the Mater Hospital is leading this endeavour with a new, web-based version of the database.

There are currently six other groups around Australia contributing to this resource, enabling more powerful and wide-ranging studies.

Mention of the laboratory-based part of the IBD unit at QIMR engendered even greater enthusiasm in Radford-Smith.

"We are moving in a very exciting direction with the introduction of new personnel with specialised skills," he says.

In addition, he has been more able to commit more time to basic science over the last year with the help of RBH Foundation funding and Smart State Fellowships from the Queensland government to cover some of his clinical duties.

Innate immunity

Many genes have been implicated in the pathogenesis of IBD, the most promising thus far being NOD2 (also known as CARD15), which was implicated in Crohn's disease by back-to-back papers in Nature in 2001.

NOD2 encodes a protein involved in recognising bacterial peptides as part of the innate immune system. The discovery of NOD2 highlighted the importance of innate immunity in chronic inflammatory diseases of the gut.

However, the mechanisms underlying its role in IBD remain unclear, as do associated players in the disease development and progression.

It has been proposed that NOD2 regulates secretion of molecules like defensins from the Paneth cells that line the bottom of the ileal crypts and help to regulate the microbial flora that are so important in maintaining a healthy status quo in the gut.

Radford-Smith's group has just finished conducting an extensive DNA and RNA expression study on inflamed and uninflamed samples from the terminal ileum of Crohn's disease patients collected over the last five years.

The terminal ileum is classically where Crohn's disease occurs in up to 75 per cent of cases. This study has yielded some exciting and important results, including novel data on the involvement of NOD2 mutations in Crohn's and hints to other major players in the chronic inflammatory process.

The group is now vigorously pursuing these molecules and their potential therapeutic role for patients with IBD. The huge genetic population resource they have available is key to their progress and will allow immediate genetic analyses of candidate molecules followed by protein expression, signalling and regulation studies on their population of patients and controls.

It is exactly the type of discovery pathway that the group has been working towards and Radford-Smith is justifiably excited about the potential clinical benefits of this research for his patients.

Lab to clinic

Radford-Smith estimates a lead-time of only two to three years for translation into the clinic once a strong candidate with proven links to the disease is identified.

This relatively short time is possible because all the basic research work is conducted on human material, and has already been approved by an ethics committee.

In addition, the availability of common inhibitory or agonist drugs for some of the candidates means they can be tested along the way in patients with Crohn's disease.

One of Radford-Smith's latest collaboration is with the Helminth group at QIMR to investigate the idea of using worms, or peptides derived from worms (which will be eminently more appealing to his patients), to reduce the severity of IBD.

It has become apparent in the last few years that worms generate these antimicrobial peptides that are so important in activating the immune response, but that are downregulated in chronic inflammation.

Although seemingly left field, this work has already provided tantalising clues to the emerging question of how the innate and acquired immune systems interplay in diseases such as IBD.

Radford-Smith enjoys this multidisciplinary crossover between basic science and the clinical arena and wants to establish more such links in the future.

Such initiatives will become increasingly important with several buildings/institutes planned for construction on the hospital campus within the next five to 10 years, including the UQ-driven Clinical Research Centre and extensions to QIMR.

This can all mean only good news for patients.