Bacteria are the most abundant type of life on earth and are constantly adapting to survive in different environments. The species we see today are highly diverse, reflecting adaptations to massive environmental changes over billions of years. Some adaptations are of significant medical concern because they result in new strains of disease-causing bacteria, greater virulence in existing bacteria, and increased resistance to antibiotics and other drugs that kill or suppress bacteria. These bacterial adaptations are associated with “genomic islands,” clusters of genes the bacteria appear to have acquired from other bacteria, viruses and organisms. The genes of hundreds of disease-causing and non-infectious bacteria have been identified. Morgan Langille is using this information to develop a database of bacterial genomic islands. He aims to identify the origins of bacterial genomic islands and their role in causing disease. This information may enable scientists to better understand and develop new drugs that target infectious disease-causing bacteria.
Research Pillar: Biomedical
Gold Nanoparticle-Conjugated Antibodies as Optical Contrast Agents for In Vivo Molecular Imaging of Cancer
Cancer is the leading cause of premature death in Canada, and the number of new cases continues to rise as the population grows and ages. Based on current rates, 38 per cent of Canadian women and 44 per cent of Canadian men will develop cancer in their lifetimes, many when they are 70 or older. Traditionally, physicians assess the severity of cancer tumours by removing tissue samples from a patient and assigning a severity score based on what they see under the microscope. This process can be time-consuming and yields limited information. Recent discoveries have identified a number of molecules produced by cancer cells. Gerald Li is working on an optical imaging system to detect and evaluate the presence of these molecules. In particular, his focus will be on the use of specially designed probes that will flag these molecules, allowing a physician to immediately identify malignant cells. This system will make it possible to image various parts of the body to detect cancer earlier, predict which pre-cancerous lesions will become tumours, and image tumours in the operating room to help determine the boundary between healthy and malignant cells. It will also assist in the selection of treatments targeting cells that create these molecules.
Mechanistic approaches to androgen-independent prostate cancer
Prostate cancer is the main form of cancer affecting men in the western world. Because cellular mutations within the prostate are regulated in part by androgens (male sex hormones), treatment of prostate cancer usually involves starving the prostate of androgens. While this therapy initially stops cancer progression, over time, the cancer continues to progress. Jennifer Locke is researching why prostate cancer progresses despite the apparent lack of androgens during treatment for the disease. Jennifer is testing the hypothesis that new androgens are produced within the prostate during androgen-deprivation therapy, causing the cancer to reoccur. Using molecular and analytical techniques, she is investigating androgen synthesis pathways. This research could enable identification and evaluation of inhibitors of these pathways, which may lead to new therapeutic options. Her ultimate goal is to improve treatment outcomes and quality of life for prostate cancer patients.
Identification of Genetic Alterations Involved in the Progression of Epithelial Cancers
Cancer causes six million deaths worldwide each year, and is the second leading cause of death in developed countries. Of 227,000 new cases diagnosed in Canada this year, about 80 per cent will be some type of carcinoma, a malignant tumor that begins in the epithelial cells lining the inner and outer surfaces of our organs. Carcinomas comprise a vast array of cancers, including lung, breast, prostate, colorectal, oral, esophageal and cervical. Although current treatments can be effective, survival rates vary for these different types of cancer. Mutations in genes are responsible for the development of all cancers. But the nature of epithelial cancer cells makes it difficult to distinguish which mutations initiate the process. William Lockwood is using new technology to define patterns of DNA change in people with early stage epithelial cancer and to identify the genes responsible for the progression of the disease. Ultimately, these genes may be used to predict which pre-cancerous lesions are prone to develop into tumours to improve early detection and treatment.
T Cell Therapy of Breast Cancer: Defining and Circumventing Barriers to T Cell Infiltration of the Tumour Microenvironment
T cells are white blood cells involved in a variety of our immune system responses, including detection and destruction of cancer cells. With T cell therapy, “tumour-reactive” T cells are isolated from a patient’s blood, and large numbers are grown outside the body. These T cells are then infused back into the patient to help the body recognize and destroy cancer cells, a method called adoptive immunotherapy. Michele Martin is studying the potential for using T cell therapy to treat breast cancer. Early results show about 19 per cent of tumours will regress or shrink with this treatment – unprecedented with other types of treatment – while the rest have partial or no regression. Michele is investigating how some of the tumours manage to exclude the T cells and also whether combining T cell therapy with low doses of chemotherapy can facilitate T cell infiltration into these tumours. If successful, this approach could improve breast cancer cure rates and reduce the side effects associated with current treatments.
System-based proteomic analysis of infectious Hepatitis C virus: towards the development of host-based anti-HCV therapeutic strategies
More than 123 million people worldwide are infected with Hepatitis C virus (HCV), including approximately 250,000 Canadians. There is no vaccine for HCV, and current treatments are less than 50 per cent effective against the predominant HCV genotype in North America. Since the outcome of HCV infection can be so severe and prevalence is so high, a better therapy is urgently required. Developing an effective treatment for HCV calls for a more detailed understanding of host and viral factors that influence infectivity of the virus. Through her research of two cell lines infected with HCV, Andrea Olmstead aims to gain a clearer understanding of the relationship between HCV and human cells. Although these two cell lines are related, the rate at which HCV multiplies in each of them differs. By exploring the significance of different patterns of protein expression between the two cell lines, Andrea hopes to identify novel interactions between host cellular proteins and HCV virus proteins that contribute to the outcome of infection. By uncovering host/virus interactions, her research may reveal new inhibition targets for generating effective therapies against HCV.
Interleukin (IL)-7 induced signals essential in T cell development and transformation
The molecule interleukin-7 (IL-7) is an important regulator of the development and signalling function of T cells, the white blood cells involved in fighting off infection and coordinating an efficient immune response. After T cells mature, they circulate through the blood, searching out invading pathogens, mounting an immune response and clearing the infection. This process generates specialized memory T cells, which are able to mount a stronger and more efficient immune response upon subsequent encounters with the same pathogen. Growing evidence indicates that not only is IL-7 essential in the development of these memory T cells, but that its overproduction is also implicated in a number of immune system cancers. Using a number of genetic models of IL-7 signalling, Lisa Osborne’s research will clarify the IL-7 mediated biochemical pathways necessary to ensure proper development and maturation of the T cell compartment, that are involved in the viability of mature T cells and the generation of memory T cells. She aims to demonstrate which molecule or pathway is primarily involved in the de-regulated growth of T cells that leads to cancer. Ultimately, this research could guide the development of vaccines that rely on the generation of memory T cells against a particular pathogen. Lisa’s work will also provide insights into the development of immune system cancers, and potentially a novel treatment approach.
Interaction and functional consequences of HCN channels and cytosolic SAP proteins in the cardiac sinoatrial node
Heart function is regulated in large part in the upper right hand corner of the heart, where a cluster of pacemaker node cells generate the pulsatile electrical signals that spread throughout the heart muscle. These signals cause the heart to rhythmically contract and relax, leading to the smooth flowing of blood through the circulatory system. In order to send pulsatile signals and coordinate the heart’s activity, pacemaker node cells possess a unique collection of proteins. This includes ion channels, that selectively permit charged ions to cross the membrane barrier surrounding cells, generating an electric field that can be spread to surrounding cells. A distinguishing feature of the pacemaker is that it spontaneously generates these electrical impulses. Specific ion channel proteins, called HCN channels, are largely responsible for this spontaneous activity. But how and why HCN channels express as they do in these pacemaker cells is largely a mystery. Christian Peters is exploring how the functioning, or even the presence of these proteins, is affected by their interactions with accessory proteins on the interior of the cell. By developing an understanding of these interactions, his research will contribute to our knowledge of the workings of a healthy heart, and contribute to the prevention or cure of ailments associated with a malfunctioning of the myocardium, the muscular tissue of the heart.
Developing innovative nanopharmaceuticals for the treatment of relapsed breast cancer
Therapeutic antibodies are a popular and effective class of cancer drugs, particularly when combined with more traditional treatments. While natural antibodies are found in our blood all the time, they do not recognize cancer. Therapeutic antibodies are designed to recognize special molecules found only on the surface of cancer cells, allowing them to target and kill those cells without harming healthy ones. This results in a dramatic decrease in the side effects of chemotherapy such as nausea, fatigue and hair loss. Little is known about how therapeutic antibodies work, including the reasons why they are ineffective in some cancer patients. This lack of knowledge currently makes it hard to adapt or improve the drugs. Jesse Popov is studying trastuzumab, a therapeutic antibody used to treat aggressive breast cancers. Focusing on revolutionary new theories about the way that cellular membranes function, Jesse is working to determine how trastuzumab works in the body, as well as the basis for trastuzumab resistance. With new insights, he hopes to uncover ways to tailor therapeutic antibody-containing pharmaceuticals to make them more effective in treating different forms of cancer. This research is part of the ongoing Breast Cancer Research Program at the BC Cancer Research Centre, an initiative focused on identifying pharmaceutically viable methods for improving the effectiveness of breast cancer treatment.
Role of Amyloid in Failure of Transplanted Human Islets
In Type 1 diabetes, beta cells are destroyed by the immune system, leaving the body unable to produce insulin. Type 1 diabetic patients inject insulin several times a day to normalize their blood glucose levels. Estimating the correct dose of insulin to administer is difficult: too much insulin leads to hypoglycemic shock, while chronic hyperglycemia (a shortage of insulin) can lead to organ damage and related complications such as blindness, kidney failure, neuropathies, vascular damage and pain in the limbs. The transplantation into diabetics of insulin-producing islet cells shows promise for relief from daily insulin injections and the development of diabetic complications. However, islet transplantation is in the early stages, and long-term rates of transplanted islet graft survival and maintained function are low: only 10 per cent of islet transplanted recipients remained free from insulin injections five years post-transplantation. Kathryn Potter is working to better understand the mechanisms underlying graft failure. In particular, she is interested in how stressors unrelated to immunity—such as pre-transplant and post-transplant hyperglycemia and the use of immunosuppressants—may cause dysfunction in transplanted beta cells and lead to graft failure. Her research may lead to modifications to current transplantation protocols that improve long-term islet transplantation success rates.