Battles in the bowel
Dr. Donna-Marie McCafferty studies how the immune system can go awry, leading to inflammatory bowel disease.
Story by Julie Sedivy/Illustration by Sander Henriksen
Dr. Donna-Marie McCafferty has chosen to focus her research on inflammatory bowel disease (IBD) partly because of the disease's enormous impact on public health. IBD, which includes both Crohn's disease and ulcerative colitis, occurs more frequently among people living in industrialized than in developing countries. Canada has one of the highest rates in the world; about 200,000 Canadians suffer from IBD, making the illness roughly three times as common as human immunodeficiency virus infection or multiple sclerosis. IBD results in chronic inflammation of the bowel and leads to symptoms that can drastically affect patients' quality of life. In addition, those who suffer from this disease are about 20 times more likely to develop colon cancer than the general population.
Current science suggests that IBD results from a genetic predisposition to respond to bacteria in the gut in an abnormal manner. When enough harmful bacteria are detected, the immune system launches an attack on them, resulting in inflammation. Dr. McCafferty explains that, in people with IBD, the immune system's balance shifts such that the inflammation is out of control. Some research programs focus on identifying the specific bacteria that cause an inflammatory response in the hope of controlling the bacterial environment in the body. Dr. McCafferty's research looks at genetic predispositions that give rise to the abnormal response.
Dr. McCafferty is studying the genetic trait that affects how the harmful bacteria are recognized. She has focused her attention on the role of certain receptors that recognize bacteria and then activate an inflammatory response. Although these receptors were initially thought of as culprits in instigating excessive inflammation, Dr. McCafferty has shown that their absence leads to chronic inflammation and cancer. She is now trying to better understand their role in regulating the inflammatory response.
Her work on some of the effects of these critical receptors has led her to other discoveries. In particular, she became interested in the fact that these bacteria-identifying receptors release a particular enzyme that produces nitric oxide. Nitric oxide is a free radical, a type of unstable molecule that combines eagerly with other molecules to form powerful toxic products. According to Dr. McCafferty, that's what leads to the increased likelihood of colon cancer.
Free radicals have received a lot of bad press because of the role they play in causing mutations that can lead to cancers. Most of the scientific literature has proposed that nitric oxide contributes to the development of cancer and that chronic production of nitric oxide in a patient with IBD is bound to be dangerous for this reason. As a result, some researchers have suggested that inhibiting the enzyme that produces nitric oxide may be a promising approach for drug treatments in IBD patients. But some of Dr. McCafferty's most important results suggest otherwise. She has studied mice that fail to produce nitric oxide and found that chronic inflammation in these mice led to an increase—rather than a decrease—in cancerous tumours. This leads her to believe that nitric oxide can also play a role in preventing cancer from developing.
Clues about the beneficial aspects of nitric oxide already existed on the basis of test-tube studies of isolated cells—but they existed alongside contrary evidence that pointed to the role of nitric oxide in promoting cancers. Test-tube studies, says Dr. McCafferty, lend themselves to ambiguous results, because you're looking at one cell type at a time, with one stimulus. "Depending on the cell type or the stimulus you're looking at, nitric oxide flip-flops in its role. My research has been interested at looking at the role of the enzyme in the whole body."
This approach reflects Dr. McCafferty's research philosophy, which is to study IBD in a way that is as clinically relevant as possible. For example, rather than chemically inducing inflammation, she believes in studying inflammation that arises spontaneously as a result of specific genetic abnormalities. The hope is that this research will yield a more direct route to treating those suffering from IBD and to reducing the associated cancer risk.