Once organisms are fully developed, stem cells are the basis for replenishing cells that wear out or are otherwise destroyed in the normal course of living. Researchers are now looking for ways of identifying and manipulating stem cells to regenerate organs or tissues such as heart muscle, liver, brain or the surface of the lung and digestive tract that have degenerated due to disease. The most well studied stem cells to date, are hematopoietic stem cells, which are produced in the bone marrow and are the precursors from which all blood cells develop. Dr. Kelly McNagny’s laboratory discovered MEP21, a molecule that appears to have a close connection to stem cells since its activation correlates closely with the appearance of stem cells in tissues. This suggests that the molecule may be involved in stem cell production and the processes by which stem cells grow differentially to become a specific type of tissue. Dr. McNagny’s research has shown that MEP21 is required for survival – i.e., mice lacking the molecule die shortly after birth. He is now studying its role in activating adult stem cells, with the goal of finding new ways of purifying and using stem cells to regenerate tissues.
Program: Scholar
Appropriate uses of genetic information in the diagnosis, treatment and prevention of autosomal dominant polycystic kidney disease and rheumatoid arthritis
Genetic testing confirms the presence or absence of genes associated with the development of various diseases. Early detection of these genes sometimes enables physicians to recommend interventions that can help to delay onset of disease or prevent the most serious symptoms. The downside, however, is that many of the diseases that are detectable through genetic testing have no treatments or cures. This creates serious ethical and other considerations about when and how such tests should be administered. Dr. Susan Cox is studying the potential benefits and harms of using genetic information to diagnose, treat and prevent two common and devastating chronic diseases: autosomal dominant polycystic kidney disease (ADPKD) and rheumatoid arthritis (RA). Increased availability of genetic screening for ADPKD may have implications for routine screening of people at risk for the disease and for assessing potential kidney donors. The discovery of a gene influencing the severity of some forms of RA may prove to be clinically useful in tailoring drug therapies to persons diagnosed with the condition. Dr. Cox is documenting and comparing perspectives on these developments from patients, families, health care professionals and non-profit agencies. She will use this information to develop criteria for the appropriate use of genetic information in the diagnosis, treatment and prevention of ADPKD and RA. Results from the study will also be relevant to other genetic and hereditary diseases.
Cell therapies for the treatment of hematopoietic malignancies
Though small in numbers, stem cells are responsible for the continued production of blood cells throughout a person’s life. They are also responsible for regenerating the blood-forming system following a bone marrow transplant in people with leukemia and other blood diseases. While blood stem cell transplantation is a promising therapy, its use is currently restricted because researchers have not yet found a way to reproduce these cells in large enough numbers for effective transplantation. Dr. Clayton Smith’s research is devoted to developing a better understanding of blood-forming stem cells so they can be effectively isolated and manipulated. Using leading-edge bioengineering and computer-based technologies, he is systematically exploring how the body’s environment affects stem cell growth, to see if these conditions can be replicated outside the body. He is also studying the function of certain genes that may be important to stem cell growth. Ultimately, he hopes to learn enough about stem cells to be able to grow them in large numbers outside the body for use in blood stem cell transplantation.
The demand for hereditary cancer services
The Hereditary Cancer Program at the BC Cancer Agency provides genetic testing and counseling services. The demand for these services in BC depends on many factors, each of which is subject to change. Factors include the growing knowledge in basic, applied and social sciences relating to hereditary cancer; the size of BC’s population and its characteristics in terms of age, ethnicity and family size; the evolving criteria by which people are deemed eligible for services; and people’s desire for these services. Through his research, Dr. Chris Bajdik is determining the demand for hereditary cancer services in BC and predicting how this demand may change in the future. He has created a computerized simulation model of the BC population, based on information about demography, cancer epidemiology and etiology, genetics, genetic technology, and human behaviour. The results from this model will help the BC Cancer Agency plan its services and assess the health benefits and costs of its Hereditary Cancer Program.
Structural analysis of the bacterial Sec-dependent protein secretion system
Cells have compartments separated by membranes. Many proteins are made in one compartment but actually function in another. The ability of proteins to travel across membranes within cells is essential to cell life. Malfunctions in this process can lead to a variety of inherited and autoimmune diseases in humans. Dr. Mark Paetzel’s research focuses on the mechanisms by which proteins travel across cell membranes, a process called protein targeting and translocation. Using the technique of X-ray crystallography, Dr. Paetzel is uncovering the three-dimensional structures of the protein complexes that make up the molecular machines involved in bacterial protein targeting and translocation. A better understanding of the functions and mechanisms of these protein complexes may yield insights about how the process works in human cells. In addition, learning how the process differs between bacteria and human cells could lead to a novel class of antibiotics that can shut down protein targeting and translocation activities in bacteria, but leaves human cells unaffected.
Function and mechanism of genomic imprinting on mouse chromosome 6
Along with the completion of the Human Genome Project have come new insights and tools to understand complex gene interactions. Dr. Louis Lefebvre’s work focuses on genomic imprinting, an inheritance process that works counter to the traditional genetic rules. Genes are inherited in two copies – one from the father and one from the mother. Usually, the outcome in the offspring will depend on whether genes are dominant or recessive. With certain genes, however, the inheritance is parent-of-origin-specific: the gene will always be inherited by either the mother or father, with the corresponding gene from the other parent maintained in a silent state. This type of inheritance is thought to be especially important for the development of the embryo and in adult tissues. Defects in imprinting are associated with a variety of disease syndromes. Dr. Lefebvre is studying the mechanisms of genomic imprinting. He hopes to identify new genes required for normal development and better understand the origins and causes of human syndromes that are associated with abnormal imprinting.
Pain in preterm infants
Dr. Ruth Grunau is a world expert on the measurement and long-term consequences of pain in newborns and premature infants in neonatal intensive care units. From the late 1980s, when she conducted landmark research on measures for assessing pain in infants, she has continuously added to the body of research concerning how early pain experiences in very low birthweight infants may affect their clinical and developmental outcomes. Dr. Grunau is conducting several studies on pain and stress in fragile premature infants whose medical care involves repeated exposure to invasive procedures. She is studying how to distinguish pain from stress in very premature infants, and how pain, sedation and analgesia may affect their neurobehavioural development. She is investigating the effects of repetitive pain on attention, behavioural organization and development in very premature infants and toddlers. Finally, she is studying whether positive maternal interaction may moderate the potentially negative effects of neonatal intensive care unit experiences. By learning the most effective ways to minimize any detrimental consequences caused by early repetitive pain and stress, Dr. Grunau’s goal is to help clinicians improve the short- and long-term outcomes of very premature infants.
Airway epithelial injury as a result of corticosteroid-induced apoptosis
In people living with asthma, the cells lining the airway are more sensitive to injury from allergens and other irritants. Researchers have found that these cells have an impaired ability to repair themselves following injury. Dr. Delbert Dorscheid is studying how the inhaled corticosteroids that asthmatics use to control their symptoms may actually contribute to ongoing breathing problems. While corticosteroid benefit asthmatics by suppressing the inflammation of the airway, Dr. Dorscheid’s research has shown that corticosteroid use also causes the death of cells lining the airway. In severe asthmatics, this may create a cycle of repeated injury and incomplete repair that results in permanent damage. Dr. Dorscheid’s is assessing the extent to which corticosteroids may cause permanent damage to airways and also clarifying the mechanisms by which these drugs cause cell death. His goal: the development of treatment options that will have fewer damaging side effects.
Secondary prevention – the gap between evidence and practice
Cardiac disease remains the leading cause of death in Canada. A significant portion of cardiac health care resources are expended on acute interventions such as clot-busting drugs, angioplasty and bypass surgery. However, there is a lack of research on the use of proven strategies – known as secondary prevention – to prevent patients from experiencing subsequent coronary events such as a heart attack. Dr. Karin Humphries is a leading investigator in the area of cardiac health outcomes and the epidemiology of cardiovascular disease. Dr. Humphries is studying how BC patients with heart disease are monitored and how many are using aspirin, beta-blockers and cholesterol-lowering drugs as part of their efforts to reduce their risk of further coronary events. Eventually, she hopes to design a clinical trial to assess new approaches to increase the use of secondary prevention strategies.
Central pathways mediating testosterone effects on hypothalamic responses to stress
The hypothalamic-pituitary-adrenal (HPA) axis is a brain-hormone system that plays an important role in the body’s reaction to stress. The HPA axis controls the secretion of glucocorticoids – steroid hormones that are released from the adrenal glands during stressful episodes. In the short term, acute elevations in circulating glucocorticoids are beneficial, serving to meet the metabolic demands of stress by mobilizing energy stores. In the long term, however, chronic stress-induced elevations in glucocorticoids are implicated in several forms of systemic, neurodegenerative and affective disorders, including depression. Dr. Viau is working to determine the sites and mechanisms by which testosterone acts in the brain to regulate the HPA axis. Given the association of chronic stress with depression and the potency by which testosterone inhibits stress-HPA function, Dr. Viau is investigating where stress, testosterone, and depression intersect in the brain. Dr. Viau hopes his discoveries will be taken from the bench to the bedside, towards implementing sex steroid replacement as an adjunct to antidepressant therapy.