Program: Scholar

BRIDGE-MTB: Bringing Integrated Data, Genomics, and Evaluation to Mycobacteria and Tuberculosis

Tuberculosis (TB) and non-tuberculous mycobacterial infections (NTMs) are bacterial infections that create serious problems in BC. Treating TB costs the health system nearly $13 million per year, and NTMs are emerging as a new and poorly-understood threat, especially in BC’s seniors.

My previous work has shown that we can get faster and cheaper information by replacing standard TB/NTM lab tests with a single genome sequence test on the bacteria. It has also shown that comparing the mutations in the genomes of bacteria from different patients allowed us to reconstruct the timeline of an outbreak, deducing who infected whom and when.

BRIDGE-MTB is a five-year province-wide program that will expand my previous work to explore three key areas:

  1. If we use genomics to diagnose and phenotype every single mycobacterial isolate coming into our provincial lab, will it still prove better and faster than traditional laboratory methods? How will it improve our health delivery systems? How will it improve patient outcomes?
  2. By looking for shared mutations in TB and NTM genomes, can we discover where, why and how TB and NTMs are spreading in BC? Can we use this technique of genomic epidemiology to control outbreaks?
  3. The genomic data is complex. Can we design a clinical report that summarizes it in an intuitive, interpretable way for our doctors and nurses?    

BRIDGE-MTB seeks to improve BC's practice and policy on testing, treating, controlling and understanding TB and NTMs.

Detecting neuroplasticity after spinal cord injury: Implications for neuropathic pain

Current interventions for neuropathic pain after spinal cord injury (SCI) have proven largely ineffective, an unfavorable outcome that can be partly attributed to poor understanding of mechanisms.

Through his research program, Dr. Kramer aims to shed light on this problem, focusing specifically on the hypothesis that changes in supraspinal (above the spine) structures contribute to neuropathic pain symptoms (e.g., burning sensation in the legs). In experiments using functional magnetic resonance imaging (MRI) and electroencephalography, a technique for measuring electrical activity in the brain, the brain activities following afferent stimulation in individuals with SCI will be investigated.

In an initial experiment, Dr. Kramer will explore how descending control of nociception, the neural processes of encoding and processing noxious stimuli, is affected by SCI. This will be done using behavioral manipulations to control awareness to noxious stimuli (e.g. placebo-analgesia, the inability to feel pain).

In the second experiment, Dr. Kramer will build on preliminary results, which indicate that neuropathic pain is associated with prominent changes in cortical functioning in brain areas involved in processing noxious stimuli. Beyond cortical functioning, he will also examine the role of plasticity in the brainstem in the maintenance of neuropathic pain.

In a final experiment, Dr. Kramer will delve further into the role of cortical and brainstem plasticity, determining the time course for when these changes occur. In proposed imaging experiments, the extent by which structural changes in the central nervous system accompany sensory deficits will be examined using quantitative anatomical MRI techniques.

As part of Dr. Kramer’s ongoing research program, quantitative approaches to objectively assess sensory function will continue to be developed. The focus of this work will be on validating novel neurophysiological and neuroimaging techniques to examine discrete elements of sensory impairments. Additionally, Dr. Kramer will continue to investigate the inter-relationship between neuropathic pain, other secondary complications (e.g., cardiovascular disease), and neurological recovery by analyzing large epidemiological SCI databases.

Overall, the research program will provide a clearer picture of the impact of neuropathic pain on neurological function, methods to improve objective measurement, and will enable implementation of novel interventions aimed at improving outcomes and quality of life for people with SCI.

Molecular detection of known and novel cancer predisposition genes

Diagnosis of inherited cancer susceptibility has implications for both the patient and their family, as certain drugs may be more effective in cancers caused by a patient’s inherited cancer risk. Carrier testing can also determine whether family members are at risk of cancer. Both the patient and at-risk family members may benefit from increased screening, surveillance and/or prophylactic cancer prevention measures. However, current gene-by-gene testing strategies are costly and time consuming.

To try to speed diagnosis, Dr. Schrader will use cutting-edge DNA sequencing technologies to identify the inherited basis of cancers that run in families or occur multiple times in a single individual. Dr. Schrader will also test the patient’s tumor DNA alongside their normal DNA to look for candidate genes altered in both samples that are most likely to be the basis of the patient’s inherited cancer.

As part of her five-year research program, Dr. Schrader also proposes using these same sequencing technologies to test whether we can improve upon current cancer detection strategies in individuals with known cancer susceptibilities. By screening body fluids for free DNA released from early tumors with secondary mutations, it may be possible to detect evidence of early tumors. A positive screen may alert physicians to undertake more targeted diagnostic strategies to find and treat cancers at an early stage. Furthermore, if these technologies are successful in detecting early cancer in these high-risk patient groups, similar strategies could also be considered for screening for common types of cancer in the general population. Finally, genome-wide sequencing also has the potential to reveal information regarding non-cancer related genetic disease risks. Arguably, the clinical uptake of genome-wide sequencing has been the fastest in oncology, where tumor sequencing is undertaken to identify drug-targetable mutations. Clinical and research practices regarding the management of potentially clinically significant incidental genomic findings are evolving. As a medical geneticist in the BC Cancer Agency, Dr. Schrader will research both the cancer and non-cancer related incidental findings revealed through the course of clinical and research tumor sequencing.

Understanding of the scope of potential incidental findings will be critical as the policy and practice moves forward with this regard.

Ion channels: Molecular determinants of health and disease in the head and heart

Though vastly different, both the brain and the heart rely on large complicated proteins called ion channels in order to function properly. These proteins facilitate the controlled flow of ions in and out of cells by forming pores that stud cellular membranes. Specialized brain cells called neurons utilize ion channels and the electrical signals they generate to communicate with one another. A repertoire of different ion channels also shapes the birth, growth and development of neurons. During brain injury, ion channel activity can render populations of neurons vulnerable to damage. However, following injury, ion channels can also sensitize surviving neurons and modify their structure and function in ways that allow them to respond, adapt and promote repair. Similarly, the electrical activity underlying the coordinated beating of heart muscle cells is generated by the concerted actions of a cohort of ion channels. It follows that mutations in the proteins that form ion channels can manifest in a spectrum of clinical neurological and heart conditions.

In a series of coordinated projects, Dr. Swayne is working to shed light on how ion channels impact on brain and heart health. Dr. Swayne has been examining the cell biology of pannexin ion channels and their role in neuronal development and injury-triggered plasticity. In collaboration with a group at the University of Ottawa, Dr. Swayne’s team is also studying how probenecid, a drug that stops the function of pannexins, impacts stroke recovery. In parallel, to identify novel ion channel regulators of developmental and injury-triggered neuronal plasticity, her lab is combining basic biochemistry with cutting edge expertise at the UVIC Genome BC Proteomics Centre. Finally, in partnership with the UBC Community Genetics Research Program, Dr. Swayne is also investigating the cell biological underpinnings of clinically relevant cardiac ion channel mutations affecting certain BC First Nations communities.

Overall, Dr. Swayne’s research will bridge critical knowledge gaps in the understanding of ion channel function and dysfunction in the brain and heart.

Pharmacoepidemiologic and pharmaceutical outcomes research to improve medication use, adherence, and outcomes in patients with arthritis

Arthritis consists of more than 100 types of conditions and is the most common cause of severe chronic pain and disability in Canada, affecting 4.4 million Canadians. People living with arthritis rely on medications to relieve symptoms, prevent their disease from worsening, and allow them to participate in daily activities. However, there are still many unanswered questions regarding these medications. For example: are patients agreeing with doctor recommendations and adhering to treatment;  how can health care providers support and educate arthritis patients about taking arthritis medications; what are the impacts of arthritis medications when taken during pregnancy?

The theme of Dr. De Vera’s research program is “Medication Matters” and her goal is to improve outcomes of medication taking in arthritis patients. In her research, Dr. De Vera will use a variety of methods including clinical trials conducted with pharmacists in the community to evaluate ways in which patients with arthritis, starting with gout, can be supported by so that they better take their medications. She will also use databases in British Columbia on health care visits and drug prescriptions to study how arthritis medications are being used by women with arthritis who are pregnant and how these medications affect the health of the mother and her baby.

By answering these urgent questions, Dr. De Vera’s research will help inform the optimal use of arthritis medications and directly impact people living with these diseases and their health care providers.

Increasing awareness and improving outcomes of children with developmental coordination disorder in British Columbia

Developmental coordination disorder (DCD) is one of the most common conditions in children, affecting five to six percent of the school-age population. In British Columbia, this is about 40,000 children, or one-two children in every classroom. Children who were born prematurely are especially likely to have DCD; nearly half will develop it. Children with DCD find it hard to learn motor skills and perform everyday activities, such as getting dressed, tying shoelaces, using a fork and knife, printing, riding a bicycle, or playing sports. They often feel lonely, depressed or anxious, and may have low self-esteem and problems with peers. It was once believed that children would outgrow DCD, but long-term studies have now confirmed that functional difficulties can persist into adulthood. Despite being a common condition, DCD is under-recognized, under-diagnosed, and under-treated.

The aim of Dr. Zwicker’s research program is to increase awareness of this disorder and improve services and outcomes for these children through four research studies:

(1) examining brain structure and function in children with/without DCD and seeing if we can use treatment to change the brain and improve motor skills of children with DCD; (2) determining brain differences and early risk factors for DCD in children born prematurely; (3) establishing the first research-integrated clinic in BC to diagnose children with DCD and creating a research database of psychosocial functioning, participation, and quality of life of children with the disorder; (4) conducting a survey of pediatric occupational therapists in BC to determine their awareness of DCD, and what, if any, service (assessment and/or intervention) they provide.

These studies will give us a better understanding of how the brain differs in children with/without DCD, and will help us to determine if rehabilitation can change the brain and improve outcomes of these children. Because children born prematurely often develop DCD, identifying predictors of DCD in these children will help us to see if we can modify any factors to prevent the disorder and its life-long consequences. The DCD Clinic will provide a new diagnostic service and create a research database to better understand the needs of these children. The survey of occupational therapists will provide a baseline of current service delivery and outline directions for how to better meet the needs of children with DCD in BC.

Cardiac responses to spinal cord injury and exercise

The prognosis for the 2.5 million North Americans living with spinal cord injury (SCI) is poor. These wheelchair bound individuals are subjected to a number of physical, social, and environmental barriers that compound paralysis and limit daily physical activity. The five-fold increase in risk for heart disease reduces life-expectancy and costs the North American healthcare system $3 billion per annum.

Heart disease is the number one cause of illness and death in the SCI population. On a daily basis, these individuals are tasked with managing abnormal blood pressure control, fatigue, and a host of other bowel and bladder problems. Chronic management of these ‘secondary’ conditions can be poor, owing primarily to a lack of understanding of the underlying mechanisms. In able-bodied individuals, regular physical activity has multiple cardiovascular benefits. Although numerous attempts have been made to engage SCI individuals in regular physical activity, there is limited information available on the cardiovascular benefits of exercise in SCI individuals.

The primary aim of this research project is to investigate the effects of daily physical activity and structured exercise on heart function after SCI.

To improve our understanding of how the heart changes after SCI and the effectiveness of exercise, Dr. West will conduct simultaneous studies in rodents and humans with SCI. The use of a clinically relevant rodent model of SCI will allow Dr. West to answer fundamental questions about cardiac structure and function, and what mechanisms are responsible for the changes that occur after SCI and exercise. The findings will then be translated through conducting assessments of the heart in individuals with SCI.

This project is unique as it will be the first to use ultrasound to make identical measures of heart function in both rodents and humans. Additionally, Dr. West will be able to conduct direct assessments of heart function in the rodent model and follow this up with a detailed examination of the structure of the heart. Finally, he will conduct novel experiments into the effect of lower-limb passive cycling in rodents with SCI and follow this up by assessing how the heart responds to a novel passive leg energetic arm exercise intervention in humans.

Results from this study will yield vital information that can be used to assist in the rehabilitation and management of individuals with SCI.

Molecular determinants of small airway obstruction in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major cause of mortality and attributes to increased health care costs in Canada due to its prevalence and a lack of disease-modifying therapies. COPD is characterized by irreversible lung function decline that is caused by destruction of lung elastic tissue and obstruction of the small airways, which allow airflow in and out of the lungs. In COPD, these lesions are produced in response to repetitive inhalational injury inflicted by smoke exposure but the mechanisms are unknown. Dr. Hackett and colleagues recently performed an in silico drug screen, and identified the tripeptide Gly-His-Lys (GHK) as a modulator of lung tissue destruction in COPD.

In her research program, Dr. Hackett will conduct a series of preclinical studies to evaluate GHK as a potential novel daily-use inhaled COPD therapy. The aim is to progress the drug toward FDA- investigational new drug approval.

To understand the molecular determinants of COPD, Dr. Hackett will first use novel micro x-ray computed imaging to determine how small airways are lost in patients with COPD. Secondly, using lung cells derived from patients with COPD she will determine which cells are the primary cells involved in small airway obstruction, and if GHK can modify these defective cells. Thirdly, Dr. Hackett will conduct pre-clinical studies of GHK to determine if it a therapeutic for COPD.

Dr. Hackett trusts that by pinpointing the causal determinants of COPD pathogenesis, these can be modulated to improve the treatment of this common and deadly disease.

Practice experiences of rural GP surgeons in British Columbia

The recruitment and retention of health care professionals is one of the most pressing challenges currently facing the Canadian health care system. In rural communities, the number of obstetricians and general surgeons is diminishing for a number of reasons, including difficulties in recruitment, an aging workforce, resistance to a demanding call schedule, and an increase in sub-specialization resulting in fewer ‘general’ surgeons. In some rural communities, maternity care is provided by general surgeons with enhanced obstetrical skills.

There are approximately 4,000 pregnant women in BC living in rural communities whose maternity care comes from these general practice (GP) surgeons. Despite the important role these practitioners play in sustaining rural maternity care in BC, to date, there has been no systematic research into their current experiences, and no official policy regarding guidelines for the practice, training, and maintenance of skills. Dr. Jude Kornelsen is investigating the role of these practitioners in rural health care in BC and their contribution to sustainable maternity care in these communities from a multi-disciplinary perspective.

Primarily through in-depth interviews, she will detail the experiences of GP surgeons in providing obstetrical care to rural communities including understanding their motivation, the nature of support received, and identifying any barriers to practice. She will describe the relationship between GP surgeons and specialists in their local community and in referral facilities, and determine how they receive ongoing training, mentoring and education. Ultimately, this research will provide a greater understanding of the culture of GP surgeons’ role in rural maternity service delivery in rural BC, and will help to inform policy guidelines regarding the practice, training, and maintenance of skills.

HIV adaptation to immune selection pressures: historic trends and future implications

HIV has tremendous capacity to mutate and evolve due to the body’s immune response. However, the extent to which the virus has adapted to its human hosts over the course of the pandemic remains poorly understood. Repeated cycles of immune selection and transmission may allow the accumulation of key “escape mutations” — changes in the viral genome that help HIV evade the body’s defences. If immune targets in the HIV genome were disappearing over time due to the accumulation of these mutations, our ability to generate natural and vaccine-induced protective immune responses would diminish as the epidemic progresses.

Furthermore, the extent to which immune escape has influenced HIV pathogenesis remains unknown. Studies investigating the evolution of HIV virulence have largely focused on population-level trends in clinical markers over time, but few have addressed this issue using biological assessments of replication capacity or viral protein function.

Dr. Zabrina Brumme’s research team will undertake the first large-scale investigation of immune-driven HIV evolution and its implications over the 30-year history of the epidemic in North America. Host and viral genetic sequences from 1979 to the present will be analyzed to characterize the extent of population-level HIV adaptation over the epidemic’s course. Functional assessments of viral replication capacity and protein function will be performed to determine whether HIV is evolving towards increased virulence, gradual attenuation, or simply adapting to changing host-pathogen pressures over time.

With this study, Brumme is poised to answer two key questions of HIV biomedical research, namely, to what extent the virus has adapted to its hosts since AIDS was first recognized, and what implications this has for the future of the epidemic. Results have the potential to significantly advance HIV vaccine research.