Vaccines and immunization programs are the best way to prevent infectious diseases, improve child health, and save lives. According to the Public Health Agency of Canada, vaccines have saved the lives of more babies and children than any other medical intervention in the past 50 years. Through immunization, we have eliminated smallpox and have nearly eliminated eight other deadly diseases of childhood, including chickenpox and some kinds of pneumonia and meningitis. We need to continue to immunize all children so that we maintain high levels of protection throughout communities, which will prevent these diseases from re-emerging. Despite having province-wide immunization programs in place, not everyone gets vaccinated, as shown by several disease outbreaks in the past few years.
Dr. Julie Bettinger is working to address key questions about vaccines and immunization programs to ensure optimal disease protection in the population. Her research assesses the effectiveness of existing vaccination programs, evaluates the effectiveness of new vaccines, and also studies the best way to deliver them to children, adults and communities. Her approach uses quantitative and qualitative methods and includes collecting and analyzing surveillance data on select vaccine-preventable diseases and vaccine-adverse events from the Canadian Immunization Monitoring Program Active, an active surveillance network in 12 pediatric centers across Canada.
Dr. Bettinger’s research also focuses on evaluating the safety and effectiveness of vaccines through grant-funded clinical trials and observational studies and promoting improved immunization uptake through qualitative studies that assess the factors affecting vaccine use. Her work is used by local, provincial, and national public health decision makers, other research scientists, health care providers, and the public. This work, which is conducted at the Vaccine Evaluation Center at the Child and Family Research Institute and BC Children's Hospital, will create a centre for applied, population-based immunization research unique to BC and Canada.
Pre-term babies, those born before week 37 weeks of gestation, are more susceptible to invasive infections than full-term babies. The smallest babies born “extremely” premature (those born before 32 weeks, or approximately 1,500 grams or less of birth weight) suffer the greatest burden of infection among all age patient age groups in BC and other developed countries in general. About one in four “extremely” pre-term babies suffers from an invasive infection, which adds up to more than 8,760 new invasive infections in North America each year. In addition to the immediate health risks, such as a major loss of cardiorespiratory function or death, these infections may lead to long-term physical and intellectual handicaps in these children.
The work of Dr. Pascal Lavoie aims to understand why pre-term babies are so vulnerable to infections caused by common micro-organisms. Dr. Lavoie and his team are examining the way that babies’ immune cells work early in life to determine if this differs from the function of mature immune systems. In order to do this in a way that is completely safe to babies, he takes advantage of scavenged blood samples (he uses, for example, placental blood normally discarded at birth) analyzed using sophisticated technologies to extract detailed information about the human immune system.
Dr. Lavoie also aims to understand why the immune system of pre-term babies appears underdeveloped and what impact therapeutic manipulation of the latter may have on diseases such as bronchopulmonary dysplasia: a chronic form of neonatal inflammatory lung disease which appears to be caused by excessive activation of the immune system during infection. Ultimately, Dr. Lavoie hopes that a better understanding of the immune systems of pre-term infants will help researchers and doctors develop better treatments to boost immune defenses and prevent the dreadful consequences of infections in vulnerable newborns.
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.
Diabetes mellitus is a chronic disease that affects over 180 million people worldwide. At least two million Canadians currently live with the condition, a figure expected to double in the next 10 years. Type 2 diabetes accounts for 90 percent of cases and has been recognized by the World Health Organization as a global epidemic. Thus, urgent action is needed to reduce the economic and social burden of the disease and its complications. Diabetes is characterized by insufficient production of insulin, a hormone released by the pancreas that regulates blood glucose levels. Type 1 diabetes is an autoimmune disease caused by destruction of insulin-producing beta-cells within the pancreatic islets. Type 2 diabetes is characterized both by resistance to insulin action and by impaired beta-cell insulin production. Inflammation, an immune response to tissue damage, is important in both conditions. Islets from patients with Type 2 diabetes exhibit increased levels of pro-inflammatory cells and proteins. These contribute to beta-cell damage and impaired insulin production, representing a potential target for therapeutic intervention. High circulating levels of glucose and fatty acids, in addition to toxic deposits of a small protein called islet amyloid polypeptide (IAPP), may signal via pattern recognition receptors on cells within the islet to promote an inflammatory state. However, a better understanding of the causes of islet inflammation is required for effective development of targeted therapies. Clara Westwell-Roper’s research focuses on the role of pattern recognition receptor signalling in islet inflammation induced by metabolic stimuli and IAPP. Her research will enhance our knowledge of the mechanisms that contribute to beta-cell death and impaired insulin secretion in patients with Type 2 diabetes. An understanding of the causes of islet inflammation may facilitate the development of new medications that improve pancreatic islet function.
Huntington disease (HD), is an adult-onset progressive, degenerative disease affecting the neurons of a particular area of the brain called the striatum. The striatum is partially responsible for regulating movement, and HD affects the part of the striatum responsible for inhibiting unwanted movement. The primary symptom of HD is chorea, or involuntary “”dance-like”” movements. Currently, no effective treatment or cures exist, and death occurs on average 15 years after disease onset. HD is caused by a mutation in the Huntington gene where a short sequence at the beginning of the gene is multiplied, resulting in more than 36 repetitions. The mutation is inherited, so that people with HD have a 50 percent chance of passing it onto their children. The mutation has many effects on the function of the Huntington protein (htt), including interfering with how it interacts with other proteins, such as Huntington Interacting Protein 14 (HIP14). HIP14 is a “”PAT”” enzyme, which is a type of enzyme involved in a process called palmitoylation. There is a growing body of evidence to suggest that palmitoylation plays an important role in HD. Shaun Sanders’ research into HD involves the development of a new, genetically modified “conditional knockout” mouse model. Using this model, Sanders can “”turn off”” HIP14 when and where wanted, in a particular organ or area of an organ, like turning a light off in one room but not in another. He will then look for the symptoms of HD in the mouse model. His research will provide more evidence for the role of HIP14 in HD and further validate the model of palmitoylation in HD. The results will also improve our knowledge regarding “”PAT”” enzymes and palmitoylation which will expand the understanding of other neurological diseases, such as Schizophrenia and mental retardation.
The trend towards delayed childbearing has accelerated in recent decades, and as a result more women find it difficult to become pregnant. Consequently, the use of fertility drugs and assisted reproductive techniques, such as in-vitro-fertilization, has increased. The most profound population effect of these fertility treatments is an increase in multiple births (twins, triplets and higher order multiples), and recent data from Statistics Canada show a continued increase in these types of births. Unfortunately, this unintended increase in multiple births carries a considerably higher risk of pregnancy complications and adverse outcomes in newborns, and therefore carries implications for public health. While evidence suggests that use of fertility drugs is the most significant contributor to multiple pregnancies, identifying the proportion of births that result from the use of fertility drugs alone remains challenging. Further, there is little current information in Canada regarding the temporal trend in fertility drug use and the number of women who currently use these treatments. And, little is known about the impact of fertility drugs alone (without any invasive procedure). Dr. Sarka Lisonkova’s research will provide much needed information on pregnancy and perinatal outcomes including multiple pregnancies, congenital anomalies, miscarriages and pregnancy terminations, stillbirths, preterm births and neonatal deaths among women who did and did not use fertility drugs. By utilizing systematically collected population-based pharmaceutical and health related data available in BC she can identify the trend in fertility drug use among BC women between 1996 and 2006, as well as the maternal age distribution and demographic characteristics of those women. This information is important and timely, and the results will not only inform the women who have difficulty becoming pregnant about potential risks associated with fertility drugs, but also provide useful information to health services planners and administrators.
Brain cancer is an extremely aggressive disease that remains difficult to cure and carries a high mortality rate. Every year, more than 3,500 children in North America are diagnosed with this disease. Brain tumours are the most common solid tumours and the second leading cause (after leukemia), of cancer-related deaths in children. The majority of patients (80 percent), with the more aggressive forms of brain tumours will survive less than two years. Surgical removal of brain tumours is challenging for a number of reasons, and complete removal of cancer cells is virtually impossible. The chemotherapeutic agent Temozolomide (TMZ), is used in patients with aggressive brain cancers however, in a subgroup of patients this drug does not work effectively because they are resistant to it. Furthermore, recent research shows that TMZ is not generally very effective at eliminating pediatric brain tumour cells. Consequently, certain ‘survivor’ tumour cells become ‘seeds’, generating more cells that subsequently form a new tumour. Cathy Lee’s research focuses on a protein called PLK1, which is essential to the cell division process in cancer cells. Many researchers have shown that PLK1 levels are higher in cancer cells than in normal cells and that tumour cells require this protein for survival. When this protein is eliminated, cancer cells either die or their growth is suppressed. Importantly, normal cells do not seem to be greatly affected by PLK1. Ms. Lee’s research will provide a deeper understanding of this protein. In related research, Lee will examine the ‘seeds’ of brain tumours, called ‘brain tumour initiating cells’, with a view to determining a way to prevent their expansion and induce cell death. The results of her research will improve our understanding of pediatric brain cancers and allow future design of novel, alternative therapeutic strategies that benefit patients’ health and improve the way we currently treat this devastating disease.
The primary route of infection for human immunodeficiency virus (HIV), in infants is from mother to child. Following the introduction of ‘Prevention of Mother To Child Transmission’ (PMTCT), programs, HIV infection rates in newborns from mother to child (vertical transmission), have been reduced from 30 percent to less than five percent. As a result, the number of ‘HIV Exposed but Uninfected’ infants (HEU) has steadily risen. In South Africa, where 30 percent of all women of childbearing age are HIV infected, 300,000 HEU births occur per year. Recently, infection and death rates among HEU infants have been determined to be much higher than those in HIV unexposed (UE) infants. Consequently, there is an urgent need to understand why HEU infants are so vulnerable to infections. Briefly, when a person is exposed to an infecting microbe, two major arms of the immune system respond: innate immunity, which keeps the microbe at bay, and adaptive immunity, which eventually clears the infection. While it is now known that alterations in the adaptive immune system of HEU infants do take place, there is little known about how the innate immune system of HEU compared to that of the UE infant. Mr. Brian Reikie, working in collaboration with Stellenbosch University, South Africa, is conducting a pilot study to determine whether exposure to HIV, in the womb or around birth, activates the innate immune system, which then causes damage to the adaptive immune system. As well, he will explore the HIV-innate-adaptive interaction to help explain why HEU infants are so susceptible to infections. Beyond the study of HEU, this will be the first demonstration of how innate immune responsiveness correlates with development of either normal or altered adaptive vaccine immune responses over time. The findings from this project will provide the essential groundwork for urgently needed guidelines for appropriate treatment and clinical follow-up of this vulnerable population.
Predictive testing for Huntington disease (HD) has been available since 1986. This genetic test has the ability to ‘predict’ whether individuals will develop HD in their lifetime and possibly pass the disease onto their children. Some individuals who undergo predictive testing receive an unusual test result, called an ‘intermediate allele’ (IA), which differs from a gene positive or negative result. While individuals with an IA will never develop HD themselves, there remains a risk that their children or grandchildren could subsequently develop the disorder. Currently, knowledge gaps exist with respect to IA for HD. Specifically, the current International Predictive Testing Guidelines do not address the possibility of this result, nor are the complexities surrounding this result acknowledged in the literature. Alicia Semaka’s research, which is the largest empirical study on HD IAs to date, will not only address these gaps, but also inform the development of clinical standards of care for communicating IA results during predictive testing. The specific objectives of Ms. Semaka’s research are to determine the prevalence of IAs in British Columbia’s general population; determine quantified risk estimates for the likelihood that an individual with an IA will have a child who will develop the disease in their lifetime; and lastly, describe the psychological and social impact of receiving an IA result. Collectively, the three objectives of this unique, multidisciplinary study will provide the foundation for the development of clinical standards and practice recommendations for IA predictive test results. These standards will help ensure that this subset of patients receive appropriate information, support, education and counselling throughout the predictive testing process.
While completing medical training in clinical genetics, Dr. Cornelius Boerkoel was consulted on two patients with a rare disease called Schimke immuno-osseous dysplasia (SIOD). At the time, there was little known about the disease, other than that it involved kidney failure and abnormal bone growth causing short height. Dr. Boerkoel’s early research in this area highlighted several previously unknown features of this disease, including the cause of SIOD: mutations (alterations) in both copies of a gene named SMARCAL1. He has also shown that SIOD arises from abnormal activity across most genes. Working with fly and mouse models that he developed to study SIOD, Dr. Boerkoel has created a model for studying how many small alterations in gene expression can cause disease.
Since common diseases such as atherosclerosis, stroke, endocrine dysfunction, immunodeficiency, and poor growth are all features of SIOD, this research is relevant to a better understanding of various unstudied mechanisms underlying these common diseases in the general population. To continue this work, Dr. Boerkoel will complete characterization of the function of SMARCAL1 using biochemical, fruit fly and mouse studies. He will test whether hormone supplementation might be an effective treatment for SIOD. Dr. Boerkoel will also determine whether the gene expression changes observed in SIOD are a feature in other patient populations affected with diseases also found in SIOD. This research will develop a new and unique model for understanding how changes in gene expression can predispose individuals to disease.
