Research Pillar: Biomedical

A significant breakthrough in diabetes research occurred in 2000, when an Edmonton research group developed a protocol for transplanting insulin-producing cells from human donors into patients with type 1 (insulin-dependent) diabetes. More than 100 successful islet transplantations have been performed worldwide, bringing realistic hope for a cure to diabetes. Since two donors on average are required to acquire sufficient islets to treat one patient, a shortage of donor islets remains a significant obstacle for widespread use of transplantation. There is a great demand for alternative sources of these cells, such as cells derived from adult stem cells produced in the laboratory. Ideally, cells would be taken from a patient. From these, the appropriate stem cells would be isolated then cultivated to produce a supply of islet cells for transplantation back into the patient. Before this can be achieved, however, researchers must optimize techniques for increasing the numbers of pancreatic islet cells that can be produced in this fashion. Corinne Hoesli’s research focuses on duct cells, which are believed to be the precursors of insulin-producing islet cells. She is working both to determine the best ways to grow these cells in-vitro and how to translate these protocols to support larger scale production. As process optimization and scale-up are typical engineering issues, she hopes that applying engineering approaches to this field of health research will help overcome the bottleneck of tissue shortage for islet transplantations.

The selective passage of ions through channels in cellular membranes provides the molecular basis for many cellular processes. This includes control of the initial phase of depolarizations that lead to contraction of the heart. Upon initiation of contraction, sodium ion channels open briefly, and then are inactivated by a portion of the protein that “”plugs”” the channel pore, preventing further ion passage. Recently, a much slower form of channel inactivation has been discovered, which researchers believe is controlled by a separate, co-existing mechanism. One theory suggests that slow inactivation occurs when the protein components responsible for the selective passage of sodium ions constrict, causing complete occlusion of the pore during periods of prolonged or rapid openings. Certain drug classes work by blocking sodium channels, such as local anesthetics and a sub-class of anti-arrhythmic drugs, both of which can be used to treat an irregular heartbeat. There is limited understanding of how these drugs affect, or are affected by, the slow inactivation process.

Although aging is a normal biological process, it is also associated with a host of mental and physical illnesses. Many of these illnesses have their basis in genetic function. A key area of focus for researchers examining age-related health issues is the insulin-like growth factor pathway, which plays an important role in cell growth, uptake of nutrients and aging. Genetic researchers often use a microscopic worm named C. elegans for their studies, because this organism shares many of the essential biological characteristics of human biology. Genes controlled by the insulin pathway in C. elegans, flies and mice have been shown to affect longevity, including a gene discovered by PhD trainee Victor Jensen in his honours thesis. Victor is conducting research to study how this gene activity affects longevity. He is also studying a potential connection between this gene and genes involved in stress response to environmental challenges. By learning more about this gene’s role in longevity and stress response, he hopes to contribute to therapeutic and nutritional strategies to counter the negative effects of aging.

Stem cells are normally located in bone marrow, but when grown in the appropriate environment, they have the unique potential to transform into and generate several different types of cells in the body. Many medical researchers believe stem cells have the potential to revolutionize medicine, enabling doctors to repair specific tissues or to grow organs. However, the processes that control their development are not fully understood at present. Mesenchymal stem cells (MSC) are derived from adult bone marrow and have been shown to specifically differentiate into cells of connective tissues, such as ligament, tendon and bone. Due to the relatively recent identification of MSCs, there is still much debate about the basic mechanisms that underlie MSC physiology. There have been several reports to indicate that MSCs can contribute to bone healing; however whether this effect is sustained through the long-term has yet to be determined. Aaron Joe’s research focus is to further current understanding of MSCs and to explore the potential for MSC-based therapies in clinical regenerative medicine. He is investigating whether combining MSCs with a new biomaterial can create a long-lasting source of bone cells that, when transplanted into diseased bone, will result in complete and sustained healing of bone defects. Aaron hopes his research will provide insight into the contribution of transplanted MSCs to bone healing. Specifically his work may lead to the development of prototypic regenerative therapy for severe bone loss associated with replacement hip surgery.

Neurons (nerve cells) in the brain and central nervous system relay messages to each other by releasing neurotransmitters. For the message to be received, neurotransmitter receptors and associated proteins must be strategically transported to the synapse, the site of contact between neurons. Defects in the transportation of proteins is thought to affect neuronal activity and ultimately may lead to neurological impairments like epilepsy and mental retardation. Marie-France Lise is studying this fundamental process – how the molecules important for normal brain functions are transported throughout the neurons from their site of synthesis to their specific site of action. Her research focuses on a family of neuronal proteins known as Myosin V, thought to be important regulators of protein transport. These proteins act as molecular motors by binding and “walking” cargoes along actin filament highways, leading to different destinations within the cell. By characterizing how the Myosin V family regulates transport of proteins in neurons, Marie-France hopes to gain a better understanding of how synapses are formed during brain development, learning, and memory formation.

The Bordetellae are respiratory pathogens that can cause severe infections in both humans and animals, including whooping cough. In spite of widespread vaccination, whooping cough is undergoing resurgence worldwide, including a peak of 1,800 reported infections in British Columbia in 2000. Autotransporters are the largest class of secreted proteins produced by Bordetella and other Gram-negative bacteria. They possess a characteristic domain that facilitates their export from the cell, which is a factor implicated in microbial virulence (disease causing ability of infectious agents). Recently, a novel autotransporter (BapF) was identified from the genome sequences of Bordetella, and is predicted to be modified by lipids. Although lipid-modified autotransporters are rare, known ones contribute significantly to virulence in their respective organisms, and little is known about their mechanism of secretion. Peter Sims is investigating the role of BapF in the disease-causing properties of Bordetellae. His work will determine whether BapF is expressed (activated) in these bacteria, and how this autotransporter is secreted. Research into BapF may reveal new information regarding protein secretion in bacteria, and provide potential targets for fighting infection.

B lymphocytes (B cells), which develop from stem cells in the bone marrow, are specialized immune cells that produce antibodies to fight infections. After developing they move into the blood stream where their role is to detect pathogens and be activated by the encounter to mount an immune response against infectious microbes. An important cellular process called adhesion is involved with the development and activation of B cells. Adhesion is the process whereby receptors on the surface of the B cells bind to receptors on the surface of other cell types. A protein called Rap acts as a molecular switch that cycles between an “on” or “off” state to regulate cell adhesion. Kevin Lin is studying the mechanisms of how Rap regulates B cell adhesion and cytoskeleton remodeling. In particular, he is investigating Rap’s control of the activation and function of Pyk2 (nonreceptor protein tyrosine kinase), believed to be involved in regulating the form and structure of the cell in response to antigen binding and chemokine signaling. This work will provide new insights into processes that regulate the development and activation of B cells, and may be important for a better understanding of inflammatory responses, autoimmune diseases, cancer of B cells, and other immune related diseases.