T cells are an important component of our body’s adaptive immune system, helping to identify and overcome diverse diseases. An emerging treatment for cancer, viral infections, and other diseases is to engineer patient’s T cells to recognize and respond to diseased cells. However, because of the reliance on patient-derived T cells, such treatments are highly expensive. To lower costs and increase accessibility to T cell therapies, our laboratory is developing methods to generate T cells from an unlimited and readily-available source: human pluripotent stem cells. Pluripotent stem cells give rise to every cell in our bodies, including T cells, and can be grown indefinitely in laboratory settings. Our current process for producing T cells from stem cells has made great progress, but lacks control over key parameters such as whether the T cells will become “helper” cells that stimulate the immune system or “cytotoxic” cells that directly kill diseased cells, and if they will provide long-term memory or have strong, short-term effects. In this project, I will genetically engineer stem cells such that we can produce T cells with these diverse properties on-demand, thereby enabling the next generation of off-the-shelf T cell therapies.
Year: 2021
Engineering Platelets using therapeutic mRNA
Platelet cells are routinely transfused during treatment of a range of conditions, due to their specialized roles in hemostasis. Despite the significant potential to enhance the efficacy and applicability of platelet transfusions, no techniques have yet been developed to engineer modified platelets. mRNA therapeutics is a promising novel class of nanomedicine with broad clinical applicability, capable of enhancing the physiological function of target cells by modifying cellular protein expression. The therapeutic potential of mRNA editing is particularly relevant to transfusion science, where the mechanisms of delivery to patients are well established. By engineering platelets using gold standard mRNA transfection strategies, their therapeutic potential can be maximized for diverse applications.
Engineered platelets will be created using cutting-edge mRNA lipid nanoparticles. Successful mRNA editing will create platelets with enhanced biochemistry and improved hemostatic function. Results generated from this project will address knowledge gaps in platelet translation mechanism, and guide forthcoming research on the next generation of blood products, improving current standards of care in blood transfusion.
Mapping chronic social isolation-induced brain activation in mice with machine learning-based phenotyping of behavioral deficits to pilot translational assessment of psychomotor disturbance
Loneliness is becoming increasingly recognized as a serious threat to mental health. Social isolation is detrimental to adult brain function and behavior across mammalian species. Chronic social isolation in rodents has been found to lead to depression-, anxiety-, and psychosis-like behaviors as well as signs of abnormal locomotor habituation, fear responses and aggression. However, our understanding of how and why social isolation is risky for health — or conversely — how and why social ties and relationships are protective of health, remains quite limited. Our lab makes use of advanced brain imaging and recording techniques to map connections between brain areas. We plan to use these techniques to help us to first understand the neuropsychiatric basis of chronic social isolation in animal models. A machine learning algorithm will be used to classify large behavior datasets automatically and objectively, and potentially uncover new pathological behavioral patterns that have been overlooked by human observers. Mapping large-scale brain functional connectivity associated with social isolation–induced behavioral deficits may shed light on the etiopathogenesis of mental disorders and lead to the identification of therapeutic targets.
The effect of a telehealth chair-based exercise intervention on motor function in stroke survivors with a mobility impairment
Physical activity plays a key role in maintaining a healthy lifestyle. However, approximately 7% of Canadians live with a mobility impairment, decreasing their ability to participate in daily activities and subsequently increasing their time spent in sedentary behaviours (sitting). Living a sedentary lifestyle is associated with poor health and risk of cardiovascular disease, particularly in those with a compromised health.
In the elderly, chair-based exercises are shown to improve mobility function and quality of life, with general compliance shown to be better than standing or dynamic exercises. During the current COVID-19 pandemic, there is limited access to group activities and therapies due to social distancing requirements. Therefore, telehealth (videocall) delivery of exercise interventions is of great importance in helping to maintain a healthy lifestyle. Our project will investigate the effect of delivering a telehealth chair-based exercise intervention on motor function in stroke survivors with a mobility impairment (unable to walk without assistance of one person). Secondary outcomes include balance and quality of life. The results can help develop telehealth interventions that can be delivered in rural communities.
Optimizing protection against Respiratory Syncytial Virus in infancy
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.
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.