Each year the influenza virus infects approximately 10% of the human population, resulting in hundreds of thousands of deaths. Even in North America, nearly 40,000 annual “excess deaths” are attributed to influenza or to secondary bacterial infections. Despite a World Health Organization-monitored vaccine program, the disease remains a significant global health issue, requiring the use of antiviral drugs like oseltamivir (Tamiflu). A significant problem in controlling the spread of influenza is the emergence of oseltamivir-resistant strains.
To address this problem, Dr. Jeremy Wulff is taking a collaborative approach to develop potent new influenza virus inhibitors. With Professor Martin Boulanger's group at the University of Victoria Department of Biochemistry, Dr. Wulff has developed a new class of antiviral agents that function by a similar mechanism to oseltamivir. His research group is working to further improve the efficacy of these agents through structural and kinetic means. Finally, Dr. Wulff will test the potency of the new anti-influenza compounds in collaboration with Dr. Terrence Tumpey, from the U.S. Centers for Disease Control in Atlanta.
Identifying and developing new drugs to fight oseltamivir-resistant influenza is anticipated to have wide-reaching impacts on global health. In addition to creation of new influenza drugs, Dr. Wulff’s research interests include the development of novel methodologies for the synthesis of complex molecules, and the invention of new kinds of inhibitors that specifically block interactions between certain proteins involved in pancreatic cancer and HIV.
Many major chronic diseases, including cancer, Type 2 diabetes, and neurodegenerative disorders, are caused by perturbations in the internal communication network of the cells within the body. Signaling molecules, which are an important part of the intracellular communication network, coordinate different processes by relaying signals to switch on or off the proper sets of cellular machineries at the appropriate time. By understanding how these signaling molecules work, scientists hope to understand the molecular basis of different diseases and how to treat and prevent these diseases.
One important group of signaling molecules are the PIKK kinases. PIKK kinases are responsible for regulating cell growth and initiating responses to DNA damage, processes that are often disrupted or exploited in cancer formation and progression. Although recent research has identified the different proteins and protein complexes that PIKK kinases receive signals from or transmit signals to, exactly how these communication events occur at the molecular level remains poorly defined.
Dr. Calvin Yip's research program aims to understand the role of PIKK kinases in cancer progression. He is characterizing the three-dimensional structural and biochemical details of these molecules using an advanced imaging technique known as single-particle electron microscopy. Dr. Yip has obtained the first information on the 3D shape of a signaling complex formed by TOR, a member of the PIKK kinase family. With this foundation, he will use an interdisciplinary approach to combine cutting-edge electron microscopy technology and other biochemical and molecular biology methods to further determine how the TOR signaling complex receives and integrates information and how it sends signals to its targets.
Dr. Yip hopes that by focusing on how TOR and other PIKK signaling molecules carry out their biological activities, he will gain a deeper understanding of the fundamental processes of cell growth regulation. This will help pave the way for the development of new therapeutic approaches against cancer.
The human gut is a unique environment, simultaneously tolerating an endless variety of food particles and billions of helpful bacteria while retaining the ability to recognize and respond to potentially dangerous infectious diseases. In the developing world, gut infections such as cholera, amoebic dysentery, and parasitic worms are the leading causes of disease and death and are a major burden on development. Gut inflammation is also involved in inflammatory bowel disease and colorectal cancer. More than 200,000 Canadians suffer from inflammatory bowel disease (one of the world's highest incidence rates) and each year more than 22,000 Canadians will be diagnosed with colorectal cancer.
Dr. Colby Zaph studies mouse models of intestinal infection and inflammation in the gut in order to identify and understand the molecules and cells that regulate the balance between immunity and inflammation. His unique approach is to study the immune responses that develop after the gut is infected with a worm parasite called whipworm (Trichuris), which infects more than 800 million people globally.
Dr. Zaph hopes that his work will aid in understanding how the body knows it is infected (sensing), how it kills the invading organisms (inflammation), and how it turns off the response to stop inflammatory diseases from developing (resolution). The results from his research will hopefully identify pathways and targets that can both promote protective immune responses and eliminate inflammatory diseases of the intestine, including infectious diseases, inflammatory bowel diseases, and colorectal cancer.
The emergence of broad-spectrum antibiotic resistance is leading to the appearance of an increasing number of multi-resistant pathogenic bacteria, or “”superbugs.”” During the past decade, the superbug Methicillin-Resistant Staphylococcus Aureus (MRSA) has become a major cause of drug-resistant infectious disease. MRSA strains are resistant to all beta-lactam antibiotics, including the commonly prescribed penicillins and cephalosporins. The rapid emergence of community-acquired MRSA strains affecting previously healthy individuals outside the healthcare environment is particularly distressing, as it presents an urgent public health threat. The objective of Dr. Solmaz Sobhanifar’s research project is to investigate antibiotic resistance mechanisms in MRSA. Dr. Sobhanifar is specifically studying beta-lactam sensor/signal transducer proteins, BlaR1 and MecR1, which sense beta-lactam antibiotic levels. Understanding the structures of BlaR1 and MecR1 and how their mechanisms of action permit survival of MRSA during antibiotic treatment would considerably assist drug-design efforts. Dr. Sobhanifar is using x-ray crystallography and NMR spectroscopy to conduct the first detailed molecular structural analysis of these important drug resistance signaling proteins. Obtaining the necessary quantity of materials for structural investigation has proven notoriously challenging, so a “”cell-free”” protein expression approach will be used to obtain sufficient levels of BlaR1 and MecR1 for structural studies. This approach also facilitates selective amino acid labeling, which is important for x-ray- and NMR-based investigations. In partnership with the Centre for Drug Research and Development at UBC, the acquired structural and biochemical data will be used, in conjunction with unique small molecule and natural product chemical libraries, to screen and optimize novel lead inhibitors against BlaR1/MecR1-induced antibiotic resistance in MRSA. This will hopefully provide new therapeutic approaches to manage MRSA in the future.
Chronic myelogenous leukemia (CML) is a cancer of the white blood cells. The disease starts when genetic changes in blood stem cells (hematopoietic stem cells, or HSCs) cause them to become malignant (leukemic stem cells) and grow uncontrollably. Normally, HSCs make all the white and red blood cells that function to protect our bodies from infections and to carry oxygen and nutrients to other cells in the body. In CML, leukemic stem cells crowd out all other cells in the bone marrow, leading to illness and eventually, if uncontrolled, death in the patient.
Dr. Kevin Lin's research group recently discovered that the Ahi-1 gene plays an important role in CML. The gene contributes to leukemic stem cell activity and can influence how these cells become resistant to current drug therapy. The goal of Dr. Lin’s research is to understand exactly how Ahi-1 contributes to CML disease development in HSCs and leukemic stem cells. Using a new mouse model that is deficient in this gene, he will examine what happens to the development and function of HSCs when Ahi-1 is absent. The findings from this project will contribute to our understanding of the biology of normal hematopoietic stem cells and malignant leukemia stem cells. This new knowledge will then be applied to develop better diagnostics and eventually better treatments for patients suffering from CML.
Vaccines are important in protecting our bodies against potentially deadly infectious diseases. The vaccines developed in the past 200 years have clearly had a great impact on human health by preventing many infectious diseases and eradicating others, such as smallpox. Despite this success, strategies for developing new and better vaccines are urgently needed. Current vaccine technologies are still inadequate to counter persistent infectious disease threats like human immunodeficiency virus (HIV), tuberculosis, and malaria. This is partly due to the limited ability of our body to mount a robust immune response to these vaccines, particularly for immuno-compromised individuals such as children, elders, and individuals on immunosuppressive treatments such as post-transplant patients or patients with autoimmune diseases. Further, during epidemics, vaccine production capacity is often limited. Dr. Jacqueline Lai will be developing/optimizing strategies that will deliver safer, more stable and effective vaccines painlessly through the skin. Dr. Lai will be exploring the use of novel vaccine formulations and delivery technologies. The laboratory in which she will train has previously shown that a DNA adjuvant – a chemical that can modulate the response to a vaccine – enhances vaccination responses when rubbed onto the skin at the time of vaccination. The use of adjuvants may increase the efficacy of small vaccine doses, resulting in the immunization of more individuals with existing vaccine production capacity. As part of her research, she will be developing new DNA adjuvant formulations and administration strategies to explore the possibility of further enhancing vaccine responses. The second part of Dr. Lai’s research involves the evaluation of new vaccine delivery technologies. As the skin serves to protect us from the environment, the outer-most layer of the skin forms a tight barrier that prevents the penetration of most substances, including DNA adjuvants. To circumvent the limited penetration of adjuvants and vaccines through the skin, she will test new hollow microneedles, designed by collaborating material engineers, which allow for the painless delivery of vaccines directly into the skin. In addition, she will evaluate vaccines encapsulated in biodegradable materials to increase the stability and efficacy of the vaccine formulations and to obviate the need for refrigeration of the vaccine during distribution.
Beyond playing an important role in nutrition, carbohydrate building blocks and their biochemistry have been described as the "last frontier of cell and molecular biology." It is easy to see why their study has remained a great challenge: even a simple chain with only six sugar links has over a trillion possible arrangements. This vast structural diversity is reflected in the role of polysaccharides (sugar chains) as the "language of the cell," in that specific arrangements of carbohydrate messages act like dual receivers and transmitters of cell-signaling events. These signals may contribute to friendly cell-cell interactions, lead immune responses, or help to disguise human pathogens from immune detection. Because of the central importance of polysaccharides in signaling events, characterizing the cellular mechanisms responsible for the synthesis, breakdown, and recognition of cell-surface polysaccharides are of vast importance in understanding how the cell works.
Dr. Michael Suits is working to understand how infection by Streptococcus pneumoniae, a human pathogen that is one of the world's leading causes of death, causes infection by recognizing and manipulating the carbohydrate building blocks present on many of our cell surfaces. Certain strains of S. pneumoniae have evolved resistance to antibiotics, are not recognized by human immune defenses even following vaccination, and have the capacity to act in lethal synergy with the Influenza virus. As part of a concerted attack, S. pneumoniae releases proteins, which help the microbe to attach to host cells and short circuit the carbohydrate messages being transmitted. Dr. Suits is directing his research attention towards a pair of carbohydrate-modifying enzymes produced by S. pneumoniae.
Using powerful X-rays to investigate these key enzymes in very precise detail, Dr. Suits hopes to determine how these enzymes interact with an important type of carbohydrate found on the surface of human cells. Additionally, he will use molecular biology tools to "knock out" S. pneumoniae genes encoding important carbohydrate modifying enzymes and then examine how this influences bacterial growth and the ability to cause infection. These research results will help identify potential targets for therapeutic intervention, and provide a platform to develop compounds to inhibit carbohydrate-modifying enzymes.
Most simply, biomaterials are materials that interact with biological systems to perform, augment, or replace a function that has been lost through disease or injury. Biomaterials have played a critical role in the advancement of modern medical treatments and are key components in medical devices, equipment, and processes. As some examples, biomaterials are essential for the manufacture of artificial hearts, contact lenses, artificial hips, dental materials, stents, and are involved in drug delivery systems and blood storage bags. While biomaterials based on synthetic polymers are extremely versatile, they also come with significant problems. Most materials were not specifically designed for medical use, and, as a result, issues such as biocompatibility and biodegradation can create serious side-effects such as inflammation, immune reactions, local tissue damage, and ultimately the device rejection. Dr. Jayachandran Kizhakkedathu is working to address these challenges by creating new biomaterials designed specifically for use in biological systems. His research group integrates advanced polymer design and chemistry, biological analyses, and animal models to address this important problem. The knowledge and technologies developed in this program will significantly improve our understanding of how synthetic materials interact with human body. Importantly Dr. Kizhakkedathu hopes that the development of new biomaterials will help to advance medical science by inspiring innovative new treatments for cardiovascular diseases and blood disorders and by creating new diagnostic tools and devices.
The Human Genome Project, which had the goal of sequencing the entire human genome, took more than 10 years, involved the work of thousands of people and cost more than $1 billion. Today, this same amount of work can be accomplished on a single machine in 10 days at a cost of $10,000, which halves every 18 months. The emergence of this "Next Generation Sequencing" (NGS) technology can reveal the precise genetic mutations that underlie how cancers develop, how they become more aggressive and how they acquire resistance to chemotherapy. A challenge of this technology is the data generated can be voluminous, complex and error prone; a single genome can produce over a terabyte of data.
Dr. Sohrab Shah is developing a new generation of computational tools using machine-learning approaches to improve accuracy and best interpret the large scale NGS data sets. With his clinically focused collaborators, he will then apply these technologies to sequence the tumour genomes from patients with triple negative breast cancer, ovarian clear cell carcinoma, and childhood osteosarcoma tumours — three cancer subtypes that do not respond to standard therapies. They hope to identify and profile unknown mutation patterns — or "mutation landscapes” — in each of these diseases.
These mutation landscapes will help Dr. Shah’s team further understand the biology of these tumours and provide a rational basis for the design of novel therapies to improve patient outcomes. His work will also include studying small populations of cancer cells to determine how they influence patients’ responses to treatment and how they become resistant to chemotherapy — two of the major issues facing oncologists today.
Cancer is one of the leading causes of death among Canadians, and therefore the identification of new cancer therapies is of great importance. To that end, researchers have found that the structurally diverse defence chemicals provided by sessile marine organisms offer great potential in the fight against cancer. In fact, in the past decade more than 30 natural products isolated from marine sources have entered preclinical and clinical trials as potential treatments for cancer. However, it is rarely ecologically or economically feasible to obtain the active ingredient by harvesting the natural source. Fortunately, synthetic organic chemistry – where molecules are fabricated in the laboratory through a series of chemical transformations – can serve as an alternative source of these compounds. Eleutherobin was originally isolated from a rare soft coral located of the coast of Western Australia in 1997, and in preliminary tests it has shown many promising anti-cancer properties. In fact, taxol, a member of the same class of agents, has already been used to treat more than one million patients suffering from advanced breast and ovarian cancers. Over the past two years, Jeffrey Mowat has spearheaded research centered on the development of a concise synthesis of eleutherobin and analogues of this substance as candidates for cancer treatment. However, so far, eleutherobin's preclinical evaluation has been hampered by lack of material from the natural source or chemical synthesis. Mr. Mowat's current research project addresses this situation through the development of a synthetic strategy that would significantly reduce the number of steps required to access eleutherobin and facilitate its preclinical evaluation. His research also provides a venue for the construction of analogues of eleutherobin, the biological evaluation of which may well lead to the discovery of new, improved antimitotic drugs for cancer therapy.
