I am studying protein folding, a poorly understood but fundamental cellular process by which proteins made in cells fold to attain their correct three-dimensional structures (shapes) and become active. When proteins in a cell do not become active, the result is abnormal function, which often leads to disease. Amino acids are the basic component of proteins, with hundreds of amino acids in each protein. The sequence of amino acids in proteins dictates how a protein folds into its proper shape and achieves its specific function. In some instances, proteins called molecular chaperones have been shown to help newly-made proteins fold properly. My research focuses on understanding how molecular chaperones function at the biochemical and cellular levels, and determining what goes wrong when certain proteins don’t fold properly. For example, one protein called von Hippel-Lindau relies on a particular molecular chaperone to fold correctly. The protein’s loss of function is often caused by protein misfolding, and leads to the major cause of renal cancer. Other diseases, such as Huntington’s and Alzheimer’s, are also associated with the improper folding of proteins. My basic biomedical work on molecular chaperones helps us understand a fundamental process (protein folding) required for good health. Ultimately, such studies may also provide valuable clues regarding how to tackle some diseases that arise from protein misfolding.
Research Pillar: Biomedical
Encapsulation based in vitro selection of RNA catalysts
Naturally occurring cellular components such as enzymes are often the only tools available to perform biological research, a limitation that slows the pace of research and hinders the search for cures to human disease. The situation is similar to having your car break down in the middle of the street and having to make repairs using parts scavenged from neighbouring automobiles. A proper toolbox would greatly decrease the time required to perform the repair. My research examines the potential functions of ribonucleic acid (RNA), a cellular component which is vital for the development and functioning of all living things. I am examining the ability of RNA to replicate itself, without the help of protein, because RNA may be capable of important metabolic functions that are currently performed by protein enzymes. I am developing in vitro (in the test tube) techniques to isolate new RNA catalytic molecules. Because these artificially manufactured catalysts perform specific functions, they can be used as tools for conducting medical research. Ultimately, I will examine whether artificial RNA sequences can interact with existing cellular components. Such experiments give us a better understanding of natural processes within cells, perhaps leading to potent new genetic therapies for the treatment of disease.
Environment-sensing ribozymes and DNA-based sensors for biomedical utility
DNA and RNA (the genetic matter in the cells of all living organisms) have properties beyond their function as storehouses of genetic information. I am examining ways we can exploit these other properties to develop new biomedical applications to combat disease. For example, DNA has a slight tendency to conduct electricity. I am investigating how to harness this conductivity to generate sensors that can detect and monitor hormones, metabolites (substances essential to metabolism), toxins, enzymes, drugs, proteins and other molecules in the blood or other body fluids. DNA has potential as an electrical tool to manipulate products at the molecular level. A major interest of mine is based on the discovery that synthetic enzymes made out of DNA and RNA can sometimes function as efficiently as naturally occurring enzymes. Enzymes act as catalysts to accelerate chemical reactions and cellular processes in the body, such as breaking down food during the digestive process. With huge, synthetic DNA and RNA libraries available, we have endless opportunities to create enzymes that perform specific therapeutic functions. Ultimately, we hope to synthesize nucleic acid enzymes to help counteract cancers and viral infections.
Angiogenesis in ischemia
I am examining angiogenesis – the process of how blood vessels grow – to learn how to make more blood vessels grow and discover ways to stop their growth. New blood vessels sprout from existing blood vessels. In addition, stem cells from bone marrow go to areas that require new blood vessels and differentiate into blood vessel-lining cells called endothelial cells. Endothelial cells line the inside of every blood vessel. My research lab has confirmed that when we turn on a protein receptor on the surface of the endothelial cells, we can block blood vessels from growing. We are also studying whether blocking this receptor will have the opposite effect of increasing blood vessel growth. All tissue needs blood to deliver nutrients to survive and grow. In heart disease, blood vessels are blocked by hardening of the arteries. When not enough blood gets to the heart, tissue dies, causing a heart attack. If we can make new blood vessels grow and bypass the blockage, heart tissue could potentially survive without surgery. Cancer tumours also require blood vessels to grow, and will only grow to 1-2 millimetres without a blood supply. If we can stop the growth of blood vessels to this tissue, tumour growth could be blocked. Stopping blood vessel growth could also stop tumours from spreading. Blood vessel growth also promotes chronic inflammatory conditions such as rheumatoid arthritis and psoriasis, so blocking growth may ultimately help treat these conditions as well.
Molecular and genetic mechanisms of obstructive lung disease
Asthma and chronic obstructive pulmonary disease (COPD), also known as emphysema, are major causes of disease and death worldwide. The prevalence of asthma is increasing, and in some Canadian communities, up to 20 per cent of children are affected. Globally, emphysema ranks twelfth as a cause of lost quantity and quality of life, and is projected to rank fifth by the year 2020 as smoking and air pollution increase around the world. Significant gaps exist in our understanding of these disorders, and while limited therapies are available, none is universally effective or without side effects. I am examining genetic susceptibility for asthma and COPD. Many people smoke and are exposed to allergens, but only a small percentage develop asthma or COPD. For example, cigarette smoking is the major risk factor for COPD, but only 10-20 per cent of smokers develop the disease. Similarly allergy is common, but only some individuals develop asthma. The evidence suggests that susceptibility runs in families, but few genetic risk factors have been identified. My research team is using a registry of lung tissue from patients who have had lung surgery, as well as DNA from large groups of individuals who have these conditions, to identify the genes that account for this susceptibility. We want to discover the molecular mechanisms that cause asthma and COPD, and to predict if an individual’s genetic makeup puts them at increased risk for these disorders. Ultimately, this research should increase understanding of these disorders and contribute to the development of new diagnostic tests, preventative strategies and therapies.
Key signaling pathways controlling survival and death of hemopoietic cells
All cells are programmed to die eventually. If cells don’t die normally, they can become harmful. For example, cancer can result when cells that should die keep growing instead. Each cell produces 10 to 15,000 proteins, with approximately 25 to 50 per cent of these involved in transmitting signals from the outside to the inside of the cell. My research is investigating how signals are sent within individual cells during the process of cell death. Signalling proteins bind to receptors on the cell surface to regulate growth and determine whether a cell lives or dies. The function of many signal proteins is to keep cells from undergoing apoptosis (cell suicide). My research team has deciphered the function of some key proteins and is continuing to study how proteins determine whether cells live or die. Our goal is to find ways to stimulate or block cell growth or death, which could lead, for example, to the ability to force cancer cells to die. We are also examining macrophages, scavenger cells that clean up debris and are important in the development of atherosclerosis (narrowing of the arteries), and the function of inflammatory cells in the immune system that respond to infection. This research will increase understanding of cell death and may lead to the development of new drug therapies for cancer, cardiovascular disease or inflammatory conditions such as asthma.
The Genome Sciences Centre: a platform for large-scale high-throughput genomics in British Columbia
Our genes play a major role in our health and in our susceptibility to disease. In fact, the course of every disease is thought to be influenced to some extent by genetic factors. Confounding researchers’ attempts to understand the genetic basis of health and disease are the very large number of human genes (estimated at between 30,000 and 40,000) and the limitations in technology that, up until recently, allowed researchers to study only one or a few genes at a time. At the BC Cancer Agency Genome Sciences Centre, a new laboratory unique in Canada, we are developing and using state-of-the-art technology to examine thousands of genes simultaneously, searching for those that play a role in cancer. These genes will ultimately provide new tools for early diagnosis, improved treatment strategies and discovering cures to a disease that has touched the lives of almost all of us.
Primary deafferetation of the spinal cord: consequences and repair strategies
Excessive force on the brachial plexus – the network of nerves in the shoulder that carry information to and from the arm and hand – can tear sensory nerve roots from the spinal cord. Traffic accidents, complications during childbirth and other situations can cause this common condition. As a result, people lose sensation and, paradoxically, develop a severe and untreatable condition called deafferentation pain. Sensation loss is permanent because sensory nerve fibres cannot regenerate into the spinal cord. However, recent studies have shown that groups of naturally occurring proteins called neurotrophic factors have the potential to promote re-growth of damaged sensory neurons, the nerve cells that carry information about touch and pain from sense organs like the skin to the cord. Some of these proteins can also prevent or reverse the deafferentation pain that results from the interruption of sensory input to the spinal cord. My research will examine the therapeutic potential of neurotrophins on regeneration in spinal cord injury and deafferentation pain. We will also assess the consequences of brachial plexus injury in the spinal cord and develop methods for assessing the resulting pain. This work will help explain why regeneration fails, and identify new therapies for treating brachial plexus and other spinal cord injuries.
Expanding and exploiting the catalytic repertoire of combinatorial nucleic acid selections for medical applications
Synthetic DNA can potentially be used to develop new drugs that target infectious diseases and cancer. I am studying how to create new molecules based on DNA. My research team is examining billions of molecules at a time and selecting synthetic DNA that may have therapeutic properties or act as catalysts. Part of developing new catalysts involves developing building blocks of synthetic DNA with particular properties that regular DNA doesn’t have. For example, we have been able to modify synthetic DNA to enhance its catalytic activity. I am examining whether the catalytic activity can be used to target the RNA sequence involved in the development of cancer. I am also studying a DNA catalyst with the potential to cut viral RNA sequences in HIV. In addition, we are screening molecules to find DNA that can stimulate or inhibit activity on a cell surface or in proteins. In particular, I am examining the proteins involved in cancer. Our goal for this research is to support the development of potent anti-viral and anti-cancer therapies.
Cell adhesion and signaling in oncogenesis
The main objective of my research is to understand the molecular basis of how cancer progresses and to use the knowledge to identify new cancer therapies. To achieve this, my research team is studying receptors found on the surface of most cells that cause them to attach to other cells. We want to determine how the receptors communicate information they detect on the outside of the cell to the inside of the cell. We have identified proteins that interact with these receptors on the inside of the cell and are responsible for transmitting information to other parts of the cell to control cell division, cell death, cell differentiation and cell movement. We are focusing on one protein – Integrin Linked Kinase (ILK) – whose function is tightly regulated in normal cells, where its activity rapidly turns on and off. But in cancer cells, ILK is on all the time, leading to increased cell division, decreased cell death and increased cell movement. We have determined that ILK is at least partly responsible for the abnormal behaviour of cancer cells, and ILK activity is considerably elevated in many types of cancer. We have also identified specific chemical inhibitors of ILK activity, which are currently being evaluated in pre-clinical trials. The results to date show these inhibitors are effective in blocking growth and spread of tumours. ILK is present in many tissue types, and it is likely that it plays a critical role in the development and function of these tissues, and in other diseases of chronic inflammation such as arthritis, asthma, kidney disease and heart disease. To investigate this further we are using genetic techniques to alter ILK expression and function in a tissue-specific manner. Such studies will lead to a better understanding of the role of ILK and related proteins in nomal and diseased tissues.