Pertussis (whooping cough) continues to be a problem despite high vaccination coverage against Bordetella pertussis, the bacterium that causes the disease. Annually, there are 24 million cases of pertussis and ~160,700 deaths worldwide. Pertussis is a respiratory disease that is transmitted from person to person through airborne droplets and poses a threat to unvaccinated infants and children whose immunity has dropped. Currently, there are two forms of the vaccine in use. The first is the killed whole-cell vaccine (wP), which is effective, but has side-effects such as swelling at the site of injection and fever. These adverse effects have diminished its acceptance in high-income countries and led to its replacement by the acellular vaccine (aP) that only contains purified components of the organism. While the aP vaccine protects against getting pertussis, it does not prevent transmission of the disease and fails to provide long-term immunity.
We aim to develop two new vaccine candidates: a revised wP and a novel aP to control the re-emergence of pertussis. This will be done through modifying some of the structural components of the bacteria to either alleviate the side effects or overcome the deficiencies of the wP and aP vaccines.
Research Location: University of British Columbia
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.
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.
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.
Molecular mechanisms of sensing and repairing dysfunctional mitochondria
Mitochondria are factories in our cells that produce energy and building blocks. Constant delivery of proteins, the factory “workers”, to mitochondria from other parts of the cell is important for proper function of these factories. Defects in delivery occurs in many diseases, including diseases involving nerve cell death (neurodegenerative) like Alzheimer’s. It is thus extremely important and timely to gain more knowledge on how cell health is maintained when protein delivery into mitochondria is damaged.
I discovered a new mechanism, the mitochondrial compromised protein import response (mitoCPR), which protects mitochondria and cells when protein delivery is damaged. I showed that such damage leads to proteins getting stuck and clogging entry sites into mitochondria. My research aims to gain a deeper understanding of how the mitoCPR unclogs mitochondria entry sites and helps them recover under disease and physiological conditions. Using molecular biology and advanced technologies such as gene editing, proteomics, and microscopy, my lab will reveal how the cell keeps mitochondria healthy. This research may uncover new treatment strategies for neurodegenerative and other diseases, caused by improper mitochondrial function.
A program of social epidemiology and metabolic outcomes research (SEMOR) to support healthy aging
Obesity is one of many chronic conditions that are rising in Canada, with heart disease as the top killer for women. Social inequalities exist in these conditions, but few studies focus on the social causes of obesity in women versus men, or on how social causes reinforce each other.
My research program aims to fill these knowledge gaps so that interventions to prevent and manage chronic conditions can be better designed and more effective. One of my projects is focused on co-developing novel ways to promote heart health among Indigenous women because of the profound burden of CVD in one of Canada’s most marginalised group. A key program goal is to produce strong research evidence to inform public health strategies and interventions for preventive action on obesity, and to build capacity of the next generation of researchers and healthcare providers to further improve health and health equity in Canada, especially BC.
Antibody therapies encoded in self-amplifying RNA
Antibody therapies have revolutionized modern medicine: they offer highly specific and effective treatments, with applications in oncology and rare diseases. The drawback of current antibody therapies is that they are expensive and must be administered intravenously, which limits widespread use. RNA-based gene therapy is a potential way to encode antibodies to make these treatments more universally affordable and accessible. For example, RNA-based gene therapy is used in the leading COVID-19 vaccines because it is easy to produce rapidly and cost-effectively at large scales. While RNA vaccines or protein replacement therapies have been widely investigated, the application to RNA-encoded antibodies is still in the early development phase. The main challenge is delivering sufficient amounts of RNA to target cells and ensuring the duration of antibody expression is therapeutically relevant. We aim to use self-amplifying RNA (saRNA), a type of RNA that replicates itself in cells, to encode antibodies. saRNA results in higher protein expression than normal RNA using a lower dose of RNA. We hypothesize that by optimizing the formulation saRNA will enable a low-cost, easily administered approach to antibody therapy.