Respiratory Syncytial Virus (RSV) is the number one cause of hospitalizations and death for severe respiratory infections in young infants across the world. Antibodies made by our immune system are important to help fight viruses like RSV. Newborns lack their own antibodies at birth and rather obtain them from their mothers during pregnancy. To increase antibody levels at birth in babies, researchers have proposed to vaccinate mothers against RSV during pregnancy. We do not completely understand how much antibodies are critical for protection against RSV infection in early life. We also do not know which function(s) of RSV antibodies are associated with protection from RSV disease in young infants. Infants’ samples obtained at delivery will be tested for levels and different functions of RSV antibodies and this will be correlated with the risk of infection in infants. Data from these projects will inform RSV vaccine design and development, especially in pregnancy as the levels and functions of RSV antibodies after vaccination should be similar to the levels and functions that protects from RSV disease.
Program: Trainee
Development of a non-invasive diagnostic to detect bacterial pulmonary infections in patients with cystic fibrosis
Cystic fibrosis (CF), once known as an untreatable fatal disease in early childhood, is now recognized as a fairly manageable disease but with a primary morbidity dominated by persistent lung infections. Our team and others have shown that bacterial volatile molecules in human breath represent a substantive diagnostic potential for lung infections. The focus of almost all breath research in CF, including ours, has been on two bacterial pathogens (Pseudomonas aeruginosa and Staphylococcus aureus). Here, we propose to target three additional pathogens (Haemophilus influenza, Stenotrophomonas maltophilia, and Burkholderia cepacia complex) that are common for patients with CF and are also broadly relevant to pneumonia in children. My scientific approach spans the careful testing of the molecules produced by bacterial cultures as well as breath of patients with CF. The expected outcomes (biomarker signatures) will provide clinical utility in the diagnosis of these pathogens as well as monitoring antimicrobial therapy efficacy. In addition, the signatures will likely provide a greater understanding of pathogen metabolism.
Counteracting the “Jumping to Conclusion” bias in schizophrenia with a combination of neuromodulation and metacognitive training
In Canada around 1% of the population is diagnosed with schizophrenia, roughly corresponding to 40 000 people in British Columbia. One typical feature of Schizophrenia is making hasty decisions without weighing evidence; this is known as the “Jumping to Conclusion” (JTC) bias. The bias can be understood as a tendency of quickly committing a final decision based only on the first available evidence. One of the most successful forms of treating the bias in schizophrenia is Metacognitive Training. During this therapy, patients try to question the logic of their own decisions. The goal of this project is to enhance the beneficial effect of this treatment and establish methods for objective monitoring of successful therapy. The previous research of Prof. Woodward lab showed that is possible to track neural connections of brain regions involved in the JTC bias. Here, we plan to identify these networks in each of our patients. Next, using a new technology for safe electric modulation of neural connectivity, we will strengthen connections in the network. Through multiple testing sessions we will monitor changes in the brains of patients and thus the progress of therapy. This project can help us improve the treatment of schizophrenia.
Investigating what matters to youth: A mixed-methods study of youth-centred opioid treatments and their outcomes
Since 2016, approximately 1,200 youth in British Columbia (BC) between the ages of 15 and 24 have died from opioid-related overdoses. This has left families and communities to mourn the loss of their loved ones.
These overdose deaths can be avoided by getting youth the help they need, as early as possible. However, most of the currently available help has focused on adults, under the assumption that what works for adults will also work for youth. Unfortunately, research in BC has recently found that this is not the case. Instead, existing options for help do not meet youths’ opioid treatment needs.
The main goal of this study is to determine how to best help youth who use opioids. To meet this objective, we will engage youth, parents/caregivers and service providers in a research study. This study will explore priorities for opioid use treatment delivery. It will also determine how to best define the benefits of opioid use treatment for youth.
The findings of this study will help service providers and policy makers to deliver opioid treatments in a way that will better meet youths’ unique needs. The findings will also help future researchers to make sure that they are studying what matters most to youth.
Portable MRI for multiple sclerosis: Feasibility establishment and technical development for clinical and research applications
Magnetic resonance imaging (MRI) is an important tool for diagnosing and monitoring multiple sclerosis (MS), a disease which affects millions of people. Unfortunately, current clinical MRI scanners are expensive to purchase and operate, have long wait times, and are often inaccessible for people in remote areas or with mobility issues. Recently, the world’s first portable and easy-to-use MRI scanner was developed by a commercial company (Hyperfine), and it will be available at the UBC MRI Research Centre in early 2021. Because this portable MRI scanner has a very low magnetic field and a small size, it has few safety concerns and can be easily brought to people anywhere. This platform will vastly improve MRI accessibility for clinical use, and make large-scale MS research possible. However, the portable MRI scanner’s ability to detect MS lesions in the brain needs to be tested. My project will compare the portable MRI scans with standard clinical MRI scans in terms of image quality for MS brains, and come up with a guideline for the use of portable MRI in MS. This work will be the first application of portable MRI to MS clinical care and research, and the ultimate goal is to bring MRI technology to everyone with equal opportunity.
Understanding the link between lung genomics, transcriptomics, and sex differences in COPD
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease that causes respiratory symptoms such as shortness of breath and is the fourth leading cause of death worldwide. While COPD affects both males and females, females, in general, have worse symptoms and more COPD complications compared to males. We still do not have a good understanding as to why COPD behaves differently in females versus males. COPD was thought to mainly affect elderly males who were cigarette smokers; thus, most of the research have focused on males rather than females. To shrink this gap in knowledge, it is necessary to include females in biomedical and clinical studies and investigate the biological reasons behind why sex might affect how COPD develops. We hypothesise that some of the genes associated with COPD have different effects on males and females. In this project we will use a patient’s genetic code and how their genes behave to determine sex-specific signatures in their lungs and airways, and then measure how these signatures can predict the development of future COPD. This project can potentially contribute to the improvement of COPD treatment (particularly in females) and to identify new therapeutic targets for COPD.
Movement and young minds: Co-designing and integrating physical activity programming into health services for young people experiencing mental health and substance use challenges
In Canada, mental health and substance use (MHSU) disorders affect 25 percent of young people aged 12 to 24 years. Foundry is an organization in British Columbia (BC) made up of a number of centres across the province that offer a variety of services to young people with MHSU disorders. A service not yet offered is physical activity, which can be used to manage mental and physical health. An ideal time to help people develop healthy habits, including being physically active, is while they are still teenagers or young adults.
This study will explore how physical activity programming can be included as a service offered through Foundry centres. This will be done by using photographs to understand youth needs; development of a working group to consider how to add a service; and, co-creation of a physical activity program. This work will be done collaboratively with diverse youth, service providers, and researchers. The long-term goal is to improve the quality of care, and the health of young people with MHSU disorders living in BC, Canada and across the world.
The impact of the loss-of-function ankyrin-B p.S646F variant on cardiomyocyte and neuronal excitability: Implications for diagnosis and treatment of heart disease
The electrical rhythms underlying heart and brain function are sustained by proteins that form pores in cellular membranes that flux ions like calcium and sodium. These pores are anchored in place by a molecule called ankyrin-B (ANKB). We discovered a genetic change in the Gitxsan Nation of Norther BC that results in a version of ANKB (ANKB p.S646F) associated with heart defects at birth, arrhythmias, sudden death, seizures, and cerebral aneurysms. We showed that this version of the ANKB molecule is mishandled by immature heart cells; however, we do not fully understand how this ANKB version contributes to clinical manifestations. As a clinician-scientist and expert in microscopy-based measurement of cellular excitability, I am well-positioned to bridge this important knowledge gap. By imaging calcium and voltage changes in living cells, I will study the impact of partial loss of ANKB and expression of disease-associated ANKB p.S646F versions on heart and brain cell excitability. I will also compare heart cell excitability data with patient electrocardiograms to help understand the connections between fundamental laboratory and clinical observations.
Ventilation heterogeneity in asthma, COPD and asthma-COPD overlap: oscillometry and pulmonary MRI
Airways disease is a hallmark finding in both asthma and chronic obstructive pulmonary disease (COPD). Although tobacco cigarette smoking is the largest known cause of COPD, recent studies have revealed that 10% of patients with life-long asthma may develop COPD later in life without ever smoking. The mechanisms underlying asthma transition to COPD are unknown. To better understand this transition, this proposal will use 129Xe magnetic resonance imaging (MRI), computed tomography (CT) imaging and oscillometry to measure airway abnormalities in patients with asthma, COPD, and asthma-COPD overlap. These measurements will provide a better understanding of airway abnormalities that contribute to development of COPD in these patients with asthma. COPD is the most common cause of hospital admission in Canada and treatment costs in BC alone are estimated to be over $600M/year. The results generated from this proposal may identify new ways to treat COPD or halt its development in patient with asthma, contributing to reduced hospital admissions and costs related to COPD.
End of Award Update – March 2024
Results
With the emergence of long COVID, we pivoted our novel lung imaging methods to investigate the lungs of people who experienced COVID-19 infection with persisting, long term symptoms over 1-year after infection. In collaboration with colleagues at the University of Kansas Medical Center and Duke University, we created a multi-centre dataset of patients with long COVID to better understand how long COVID may differ across different patients. We used xenon gas magnetic resonance imaging (MRI) to measure how effectively the lungs of patients with long COVID were performing gas exchange (the main function of the lungs). Our results showed that there are 4 different sub-types of long COVID that have different lung abnormalities. We anticipate that the xenon MRI results can be used to help determine appropriate treatment for patients experiencing long COVID.
Impact
In our centre, the xenon MRI results have been used to help determine appropriate for different patients with long COVID. Our results uncover the lung-specific abnormalities that are related to long COVID.
Potential Influence
We anticipate these results will help to better understand and classify patients with long COVID, towards appropriate treatment and alleviating patient symptoms.
Next Steps
We are using similar xenon MRI methods to investigate other forms of lung exposures including cigarette smoking, cannabis smoking, and vaping.
Useful Links
https://erj.ersjournals.com/content/early/2024/02/02/13993003.02301-2023
Vitamin C-induced epigenomic remodeling as a preventive therapy for leukemic transformation
Despite the overall improved diagnostics, standard of care and therapeutic options, most acute myeloid leukemia (AML) patients suffer from severe therapy-related side effects and still only 28% of them reach 5-year overall survival. The hypothesis that drives my project is that mutations which affect DNA-modifying enzymes disrupt a methylation-based control mechanism that regulates gene expression in a way that halts the normal cellular differentiation process. The discovery that vitamin C acts as an enzymatic co-factor that is able to revert this methylation defect in affected cells, provides a unique opportunity to transfer this knowledge to the development of novel, less toxic treatment strategies for patients that harbour these mutations. Within the scope of this project, I plan to explore whether and to which extent I can restore the normal DNA methylation signature in patient-derived leukemic cells in mice, either through vitamin C treatment alone or in addition to Health-Canada approved AML drugs. Further, I will explore the potential of vitamin C treatment to delay or prevent the transformation of not yet leukemic cellular states towards myeloid malignancy.
End of Award Update – August 2023
Most significant outputs
The most exciting results are yet to come: two manuscripts are currently in preparation to be submitted to Genome Biology and Leukemia within the year.
Impact
Despite the overall improved diagnostics, standard of care, and therapeutic options, most acute myeloid leukemia (AML) patients suffer from severe therapy-related side effects and only every third patient reaches 5-year overall survival. An observation that formed the foundation for this project is the frequent occurrence of mutations in AML cells which affect enzymes that contribute to a special control mechanism that regulates if and how much of a gene is read from our DNA to produce functional proteins. This control mechanism involves the precise placement and removal of “methylation marks” – either directly on top of the DNA strands or at proteins that help to organize the DNA into the three-dimensional structure we call chromosomes. If the placement or removal of these methylation marks is altered, protein production and cell survival mechanisms are disturbed as a consequence – a characteristic which we often observe in cancer cells. In the past, our lab contributed to the discovery that vitamin C acts as a co-factor that helps to re-activate the enzymes that deposit and remove methylation marks, even despite their mutations. Thus, treating affected AML cells with vitamin C can help to revert their methylation defect, which directs their gene expression to a healthier state and causes cancer cells to die under controlled laboratory conditions. As vitamin C is a non-toxic, well-tolerated, widely available, and cost-effective substance, its potential anti-cancer effect provided us with a unique opportunity to test whether this knowledge could be translated into effective but less toxic alternative treatment strategies for AML patients who harbour these mutations.
Within the scope of this Health Research BC and Lotte and John Hecht Foundation co-funded project, we have created murine leukemia model systems that allowed us to confirm the vitamin C anti-leukemic effect in living organisms. Interestingly, while studying these models more deeply, we observed that not all cells within a pool of leukemia cells responded equally to vitamin C – whereas most cells matured and died, there seemed to be some cells that were able to survive the treatment despite carrying the same disease-initiating mutations. This observation directly impacts the potential to utilize vitamin C in a therapeutic setting, arguing that even among AML cases that display the same disease-driving genetic abnormalities, not all patients will respond to vitamin C. Also, these findings are consistent with clinical observations, where historically, vitamin C was reported to be both highly effective and not effective at all in a series of trials in the 1970’s and 80’s that assessed the activity of vitamin C against terminal stage solid cancers.
Potential Influence
In the remaining months of finalizing this project, we are focusing on identifying what makes some cells sensitive and others tolerant to vitamin C, despite the presence of the same disease-driving mutations. Therefore, we have selected individual cells from a pool of mutation-positive AML cells which display the ability to produce a leukemia-like myeloid cell hierarchy in a culture dish. Through repeated treatment and testing, we could identify both model hierarchies that repeatedly tolerated or succumbed to the presence of vitamin C. As each cell within a model hierarchy stem from a single ancestor cell, we hypothesize that it is the maturation state of the ancestor cell – in combination with the present mutations – that mediates the observed differential vitamin C responsiveness. Further, we argue that we will be able to observe this difference in maturation state in a cell or a hierarchy’s DNA methylation patterns. We are working to confirm this hypothesis to define a diagnostic molecular signature (a so-called biomarker) that might help decide which AML patients can benefit from vitamin C in a clinical setting.
Next Steps
This research will be continued in the Hirst lab; however, I will move on to a new position soon as the time I am allowed to work as a postdoctoral fellow in Canada is coming to an end