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2012 International Innovation

Associate Professor Rupert Leong was featured by an international innovation research public relations online magazine in Jan 2013 regarding his research in Australia especially on inflammatory bowel diseases. See what he had to say.

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2012 International Innovation

  1. 1. Making internal biopsies redundant Associate Professor Rupert Leong is using laser light to probe the intestinal lining, a pioneering technique which can provide both structural and functional details of gastrointestinal diseases associate professor rupert leong for patients. Some patients need minimal barrier. The microscope allows us to visualise medication to reconstitute the barrier function, living tissue of the bowel and we can then but others require the ‘big-guns’ of treatment evaluate the endoscopy in the standard fashion, called biological agents. This concept of plus obtain functional information on the bowel personalised medicine works well using confocal wall lining. We have already obtained good endomicroscopy and proteomics. evidence that drugs used to treat inflammatory bowel disease can all reverse the barrier Have you been able to explore certain features dysfunction. In particular, biological agents are of inflammatory bowel diseases that other the best drugs to repair the barrier breakdown of procedures are unable to identify? the bowel lining. Yes, the functional effect of the bowel lining – The technology is constantly improving and we the barrier function. This is the barrier that stops have moved on to looking at other diseases that bacteria and other organisms from entering the include detecting Barrett’s mucosa pre-cancerous bloodstream. At present, the concept behind changes of the oesophagus and gastric intestinal inflammatory bowel disease is that this barrier metaplasia, which may also be pre-cancerous may be broken and leak bacterial products changes of the stomach. into the intestinal wall, resulting in chronic To begin, could you provide a broad outline inflammation in the bowel. Taking conventional And lastly, what have been your proudest of your recent project and your reasons for forceps biopsies kills the cells and they no achievements during your work so far? venturing into this area of research? longer function so you cannot evaluate the barrier function.  My research has attracted a level two (the Confocal endomicroscopy allows endoscopists highest) clinical Career Development Fellowship to view the cell structure of the lining of the When an intravenous contrast is introduced from the National Health and Medical Research bowel. The main function of the bowel is to at the time of the confocal endomicroscopy Council of Australia because the research protect the rest of the body from the bacteria procedure, the contrast leaks out of the bowel materials are novel and the topic is high in inside the bowel ‘lumen’ – the cavity where the into the gut. This is significantly more common impact. Only five of these fellowships were faeces reside. Using confocal endomicroscopy, in inflammatory bowel diseases than in age- awarded nationally at this level for clinical we are now validating the characteristics of the matched controls, ie. people who do not have research when I applied. In addition, I bowel wall barrier. This is really exciting because inflammatory bowel diseases. What we are enjoy seeing my previous trainees this has never been seen before. With confocal noticing may be the reason why patients have and fellows doing well in their endomicroscopy technology, we can see things inflammation in their bowels – the gut lining careers, and some have even that conventional microscopy misses because may no longer block the entry of foreign matter followed my footsteps we are viewing living tissue. For instance, the into the bowel wall. This could then trigger the into gastroenterology functional effect of the bowel lining is not seen inflammation cascade that results in ulcers research.  when taking forceps biopsies, because removing forming in the inner lining of the gut. In severe the cells from the bowel wall kills the cells and cases, the intravenous contrast floods through they are no longer functional. In vivo in situ into the bowel very rapidly and in multiple visualisation of the intestinal lining cells gives areas. This way we can measure the severity of us not only the information of their structure the leakage. and architecture, but their adequacy of barrier function as well. What advantages have you gained by fitting the flexible endoscope with a confocal laser Further to this, how are you integrating microscope, and where do you go next your dual research directions of confocal with the research? endomicroscopy and proteomics? Our ongoing research seeks In combination, proteomics and confocal to objectively measure endomicroscopy allows us to evaluate both the the dysfunction of the structure and the barrier function of the bowel, gastrointestinal and this is a new way of assessing the disease tract and to see if process. Confocal endomicroscopy can visualise medications can and measure the severity of the breakdown in the reverse this barrier of the bowel lining. Plasma proteomics breakdown then measures the bacteria products that escape in the into the bloodstream to quantitate the aftermath of the breakdown. In addition to the diagnosis and assessment of the severity of bowel inflammation, I also hope to be able to individualise treatment 64 International innovation
  2. 2. associate professor rupert leong Illuminating inflammatory bowel disease A new imaging technique pioneered in Australia is revolutionising our understanding of bowel diseases by bringing together laboratory and clinical research to analyse the microscopic structure of the gut Endoscopy is a medical technique disease – a genetically determined wheat in widespread use for the diagnosis and allergy disease – can be diagnosed immediately.  treatment of bowel complaints. It consists of a camera mounted on the end of a Typically, analysis of the cellular architecture flexible tube to allow direct visualisation (histology) requires biopsies to be taken by of the internal gastrointestinal lining (the forceps from the wall of the gastrointestinal mucosa). A new technique called confocal tract. However, the forceps often disrupt the endomicroscopy (CEM) is a revolutionary structure of the sample as well as removing improvement in endoscopic imaging as it the tissue from its living environment, resulting incorporates a confocal laser microscope into in artefacts that may lead to misdiagnosis. the tip of the endoscope. Furthermore, biopsies may result in false negative results from non-representative Associate Professor Rupert Leong from The specimens or failure to orientate tissue samples. University of New South Wales is pioneering In addition, using forceps biopsies carries the this technique. His research focuses on the rare risk of bleeding and bowel perforation. microscopic cellular architecture of the The advantage of CEM is that it allows for the bowel wall which is invisible to conventional analysis of the gastrointestinal mucosa in its endoscopes. CEM instantly diagnoses natural living environment. neoplastic growth in the gastrointestinal tract through the irregular arrangement, size Pioneering research and shape of cells. The microscopic hair-like projections of the small bowel (called villi) can In Australia, Leong has been the top contributing be instantly recognised using CEM and coeliac research gastroenterologist for two consecutive years at their annual national society conference and has achieved the highest level clinical Career Development Fellowship from the Australian National Health and Medical Research Council – only five such fellowships were awarded nationally in the year of Leong’s application. This reflects both the novelty and impact of his research. As an Associate Professor at The University of New South Wales, and as Head of the Inflammatory Bowel Diseases Services at Concord and Bankstown Hospitals, Sydney, Australia, Leong is ideally positioned to bring together laboratory and clinical research. Previously, he has shown CEM to be as least Image of confocal endomicroscopy of the bowel showing leakage of intravenous contrast into the lumen. as accurate as forceps biopsies in the diagnosis of coeliac disease, and has reviewed the safety 65
  3. 3. Intelligence of the intravenous contrast agent fluorescein bowel disease patients, Leong noticed that the that can be used to stain cellular structures fluorescein contrast agent given intravenously Proteomics and confocal for visualisation during CEM. Recently, Leong was leaking through the gut lining and into endomicroscopy in the has turned his expert eye towards CEM in the the lumen of the intestine. One of the most evaluation of inflammatory diagnosis and evaluation of inflammatory important functions of the mucosa is as a barrier bowel diseases bowel diseases. to separate the contents of the lumen, including OBJECTIVES digestive enzymes, bacteria and faecal waste, from the rest of the body. Therefore, a ‘leaky’ To measure the integrity of the Inflammatory bowel diseases lining, seen to a significantly higher degree in intestinal mucosal barrier. Confocal Currently, little is known of the causes of inflammatory bowel disease patients relative to laser endomicroscopy visualises leakage inflammatory bowel diseases, which include age-matched controls, represents a loss of this across the intestinal lining. Evaluation of Crohn’s disease and ulcerative colitis. Both barrier function. intestinal microorganisms contaminating genetic and environmental factors have been the bloodsteam is performed with a recognised. With no known causes, it follows With this discovery, Leong is focusing his sensitive tool called proteomics. Together, that there are no known cures for these diseases; research on using CEM to study the integrity they support the theory that the bowel current medication focuses on controlling the of the intestinal mucosa in the pathogenesis wall barrier is broken in inflammatory symptoms and disease progression. of inflammatory bowel disease: “We are now bowel diseases. validating the features of a ‘leaky gut’ – this is A major symptom is the development of ulcers really exciting because it has never been seen KEY PARTNERS in the gastrointestinal tract. Ulcers are typically before”. He theorises that invasion of the gut the cause of bleeding from the bowel, severe wall by foreign matter from the intestinal lumen Bankstown-Lidcombe Hospital abdominal pain, weight loss and diarrhoea. may trigger the inflammatory cascade, resulting Concord Repatriation General Hospital In addition, patients often become iron- in ulceration of the mucosa. deficient and hence anaemic, afflicting them NSW Health with additional symptoms such as fatigue. In Proteomics extreme cases, patients may develop cancer University of New South Wales or require extensive surgery to remove whole To explore the effects of the leaky gut, Leong FUNDING sections of the bowel. Up to three in 1,000 is searching for the presence of bacterial people suffer from inflammatory bowel proteins in the blood of inflammatory bowel National Health and Medical Research diseases. Unfortunately, many patients are disease patients. And in order to do this, he is Council of Australia in the formative years of their lives and the using proteomics – the identification of the CONTACT debilitating impact of Crohn’s or ulcerative constituent proteins of a system from protein colitis can be highly inconvenient. fragments known as peptides. Peptides, or Associate Professor Rupert Leong combinations of peptides, are unique to MBBS, MD, FRACP, AGAF Normally, inflammatory bowel diseases their parent proteins. As different organisms Director of Endoscopy, Concord and are diagnosed by a colonoscopy to look for (and indeed different cells) are composed of Bankstown Hospitals inflammation and ulcers, followed by biopsies different sets of proteins, proteomics can be Conjoint Associate Professor of Medicine for further study by pathologists. Leong instead used to detect the presence of foreign bodies. has been using CEM not only to diagnose and If the leaky mucosa of inflammatory bowel Bankstown Hospital evaluate inflammatory bowel diseases at disease patients is indeed allowing gut bacteria Eldridge Road Bankstown Hospital – his instrument is the only and other foreign matter to cross the gut wall, Bankstown one in the state of New South Wales – but now then there will be higher concentrations of NSW 2200 to also assess the barrier function of the bowel gut bacterial proteins in the blood of these Australia lining. From these clinical investigations, he patients relative to healthy individuals. has shown that CEM is superior to biopsies and T +61 2 9767 6111 has furthermore revealed that the lining of the Leong hopes to use the presence of these F +61 2 9767 6767 gastrointestinal tract of inflammatory bowel proteins as a measure of leakiness and to help E disease patients becomes ‘leaky’. confirm the findings of the impaired barrier function of the bowel. By combining CEM and RUPERT LEONG is a consultant Senior proteomics, both the structure and function of Discovering a ‘leaky’ lining Staff Specialist gastroenterologist at the mucosa can be evaluated, and the result of Bankstown, Concord and Macquarie CEM has allowed Leong to view the function the loss of bowel integrity can be measured. University Hospitals, and Associate as well as the structure of the gut lining. Reversal of the abnormal changes and Professor of Medicine at the University Biopsies disrupt the natural environment of normalising the protein constitutent of the of New South Wales and Macquarie and kill the extracted cells, resulting in a loss of blood may be an end point of treatment. He University, Sydney, Australia. His function. Therefore, biopsies can only provide has already extended this combined approach expertise includes interventional information on the structure of tissue. In to other diseases such as pre-cancerous endoscopy and management of contrast, CEM visualises living tissue, providing changes of Barrett’s oesophagus, gastric inflammatory bowel diseases. Leong is information on both structure and function. intestinal metaplasia and pre-cancerous committed to individualised, high-quality When examining the mucosa of inflammatory changes of the stomach. management, and fostering novel research. By combining confocal endomicroscopy and proteomics, both the structure and function of the mucosa can be evaluated, giving a more in-depth analysis of the pathogenesis of inflammatory bowel disease 66 International innovation