The goal of the CBR is to improve the health and well-being of patients by performing innovative research in blood and blood-related processes. Since impairments in blood and the circulation of the blood are a feature of all diseases, the impact of the CBR is far-reaching.
The CBR is committed to and embraces solution-driven and curiosity-driven research, as history reveals that both approaches lead to profound advances in human knowledge and to major clinical and commercial advances. The following represent key areas of research at the CBR that extend, in a cyclical manner, to the bench and the bedside.
Each of these themes provides a focus for interaction and promotes research that addresses fundamental and urgent clinical problems.
Blood Transfusion Products: Solving the Problem of Increased Demand and Limited Supply
The demand for blood products continues to increase, while the supply remains limited. Major objectives of the CBR are to utilize innovative approaches to prolong the “shelf-life” of current blood components, to optimize the use of available supplies, and to develop safe and effective blood substitutes. Major inroads have been made in i) discovering the mechanisms by which platelets lose their function during storage, ii) predicting which donors might have “better” platelets, iii) characterizing the proteins in cells (“cytoskeleton”) that are crucial to maintain their integrity and function, iv) synthesizing functional human serum albumin and artificial platelets, v) improving fractionation of blood components, vi) developing biomaterials for storage of blood components over longer periods of time, vii) creating biocompatible, biodegradable polymers to more effectively carry blood components in the circulation, viii) exploring the biology of stem cells and the mechanisms that regulate hematopoiesis to enhance endogenous production of blood, thereby obviating the need for transfusion, and ix) recombinantly producing blood coagulation components for safe administration.
All patients who have a disease for which they receive many red blood cell transfusions can develop iron overload. Too much iron from the red cells causes liver disease, heart disease, skin changes, and endocrine disturbances such as diabetes and hypothyroidism. Excess iron has also recently been implicated in contributing to the neurologic disorder, multiple sclerosis, although further confirmatory research is required. Thus, children who have been treated for leukemia or other cancers or chronic illnesses, children with abnormal hemoglobins (thalassemia), and adults with bone marrow failure syndromes or so-called myelodysplastic syndrome (MDS) require treatment to prevent iron overload. We have a poor understanding of how iron levels are controlled, how to monitor how much iron is present, and why too much of it causes disease. CBR scientists and clinicians are working together to better understand the chemical pathways that control iron levels in the body, so that optimal therapies can be designed to improve quality of health. With the aim of providing better treatments and thereby reducing the need for transfusion, CBR investigators are also studying the molecular mechanisms underlying bone marrow failure syndromes, identifying and characterizing relevant molecular defects in patients with these disorders, and making major advances in our understanding of stem cell biology and hematopoiesis.
Restoring Hemostatic Balance: Clotting Too Much or Clotting Too Little
Over 200,000 people in Canada develop blood clots (deep vein thrombosis, DVT) each year. The risk of DVT is increased in patients with cancer, inflammatory diseases, serious infections, after surgery or trauma, and during childbirth. When the clots travel to the lungs, they are a common cause of death. Over 30,000 Canadians suffer from excessive bleeding that ranges in severity from mild to life-threatening. Treatments for clotting system abnormalities are often inadequate, difficult to administer or associated with side-effects.
The CBR is committed to identifying blood-borne, blood vessel wall, genetic and environmental factors that are altered in clotting or bleeding disorders, with the aim of designing, producing and testing safer and more effective preventative, diagnostic and therapeutic strategies. Multiple lines of investigation are leading to promising advances, using basic biochemical approaches, proteomics and functional genomics, transgenic animal models of disease, and studies in stem cell biology. The molecular mechanisms that link the hemostatic system with cancer, metabolic and immune disorders, such as diabetes, inflammatory bowel disease and arthritis, are revealing entirely novel therapeutic targets.
Reducing Inflammation and Infection, and Promoting Tissue Repair
Inflammation is a normal response to injury or infecton, and under normal circumstance is short-lived and followed by healing. Problems arise when the inflammatory response is too exuberant or healing is hindered, in which case, organ damage and disease occur. Examples of common chronic inflammatory diseases include rheumatoid arthritis, colitis, allergic asthma, atherosclerosis and Alzheimer’s disease, but there are many others. In spite of medical advances, inflammatory and immune diseases continue to be major causes of disability and death. The cells and the molecules that cause much of the damage in these disorders often circulate in the blood or their production is controlled by blood-borne factors. It is the goal of CBR scientists and clinicians to gain new knowledge so as to be able to suppress inflammation and promote healing. For example, CBR investigators are identifying novel compounds to interfere with tissue-damaging enzymes that are increased in arthritis and atherosclerosis. They are using proteomics techniques to uncover mechanisms by which white blood cells and platelets become activated to promote tissue injury. Novel biochemical pathways involved in innate immune responses are being delineated that will lead to new therapeutic strategies. Modulating the function of a recently discovered new type of progenitor cell that participates in wound healing and tissue repair holds major promise for many inflammatory diseases.
HIV, blood borne infections and so-called “superbugs” are challenging the efficacy of current antibiotics. CBR scientists are tackling this problem via several sophisticated approaches. For example, CBR scientists are attempting to modulate the immune system to enhance the ability of patients to fight infections. For HIV, CBR investigators are sequencing the genome of the AIDS-causing virus that infects each patient, and then correlating the results with drug response and resistance. This allows for appropriate drug selection and the development of novel therapies. The 3-D “crystal” structures of superbugs are being delineated, providing insights into how they become resistant, and allowing the strategic design of new drugs and antimicrobial peptides. With the knowledge to be to able to synthesize next-generation therapeutic agents, CBR engineers and basic scientists are utilizing innovative polymer chemistry techniques to develop technologies to synthesize and purify large quantities of these drugs for clinical use. These integrated advances are crucial, as infections remain a major cause of death in patients with AIDS, cystic fibrosis, chronic lung disease, diabetes, kidney disease, cancer and immune deficiencies.