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.
Program: Scholar
Organelle signalling in stem cell identity specification
Stem cells offer tremendous potential for tissue regeneration and uncovering causes and treatments for many human diseases. Technologies developed over the past decade now allow us to grow human stem cells in the lab and manipulate them to carry disease-causing gene mutations and turn them into any cell type of interest. My lab’s research uses these powerful tools to identify important regulators of stem cell function, particularly as they develop into cell types relevant to brain disorders. We focus on identifying the biological processes that build our brains, and biomarkers and treatment approaches for diseases.
Though the genes that regulate stem cell function are fairly well know, the impact of cell organelles, which coordinate many biological functions and are potential targets for treatment, is poorly understood. My lab is working to bridge this gap by investigating the impact of vesicle-like organelles called lysosomes on brain stem cells. Our data suggests lysosomes are critical regulators of stem cell function and brain development. Given new imaging-based tools and clinically approved lysosome-targeted drugs, studying the role of lysosomes can transform our potential to understand, diagnose, and treat brain disease.
Understanding human genome regulation through robust and multi-scale reference chromatin state annotations across hundreds of human cell types
Although researchers have identified tens of thousands of disease-associated genetic variants, the mechanisms driving most of these variants remains unknown. Most variants are believed to affect regulatory elements. However, regulatory elements are incompletely annotated and understood. Large-scale projects have recently generated thousands of epigenomic data sets. These data sets measure the regulatory activity of the genome in human cells. However, computational methods are needed to understand the link between genetic variation and disease.
We previously developed a computational method, Segway, that annotates genomic regulatory elements on the basis of epigenomic data sets. Enabled by new epigenetic data sets, this project will annotate the genome in hundreds of human cell types, and use these annotations to understand disease-associated genetic variation.
Additionally, we will develop computational methods that improve our ability to identify genomic elements. This outputs of this project will come in three forms:
- General-purpose software for annotating the genome.
- Easy-to-use reference data sets.
- Insights into the link between genetic variation and chronic obstructive pulmonary disease (COPD).
The role of microglia in neurodevelopmental disorders
Neurodevelopmental disorders (NDDs) impact 7 to 14 percent of all children in developed countries. NDDs are incredibility heterogeneous and are caused by a complex interaction of genetic and environmental risk factors. One of the most consistent findings across NDDs is altered immune function, but it is unclear if neuroinflammation is a cause or consequence of brain pathology. My laboratory will directly test for causality and identify the optimal mechanisms and timepoints for immune based interventions in NDDs. Targets and compounds that impact microglia, the main immune cell in the brain, have immense potential for treating a broad range of NDDs.
Addressing food insecurity and the double burden of malnutrition in a changing climate
Malnutrition is a serious public health concern in Inuit and northern regions of Canada, driven by a complex array of social and ecological determinants, including poverty, food insecurity, and climate change. In northern communities, country foods (wild foods harvested from the lands and waters) often comprise an integral component of food systems and contribute to food security, nutrition, and social and cultural integrity. Yet, many country foods are also high in environmental contaminants (e.g., mercury and persistent organic pollutants), which have negative implications for health. Meanwhile, due to transportation challenges, available retail foods in northern and Inuit communities tend to be pre-packaged, processed, and expensive.
In this research program, I will use existing health survey data to evaluate dietary patterns in Nunavik (northern Quebec) and associated nutritional benefits and health risks. Through interviews and community workshops, I will also identify political, social, geographical, and environmental factors that impact food access, affordability, and desirability. Findings will be shared with decision-makers to generate evidence for sustainable and healthy food systems in northern regions across Canada.
The impact of parasites and microbes on immunity at mammalian mucosal surfaces
Under normal healthy circumstances our intestines are home to hundreds of species of microbes, collectively termed the microbiota. Our intestines can also be colonized by parasites, such as parasitic worms (helminths). Both the microbiota and helminths can affect the functioning of our immune system, which in turn, can influence our susceptibility to a variety of infectious, allergic, and inflammatory diseases. Research in my laboratory is focused on understanding the mechanisms by which helminths and the microbiota affect immune system functioning during normal development and during states of disease.
The incidence of allergies and inflammatory bowel diseases has increased dramatically in Canada over recent decades, and there is an urgent need both to understand the factors driving disease development and to identify new treatment strategies. My laboratory uses the mouse model system where the molecular mechanisms of interaction between components of the immune system, the microbiota, and helminths can be identified. Understanding the mechanisms by which the microbiota and helminths can influence immune system functioning may reveal new ways to treat or prevent allergic and inflammatory diseases.
Childhood obesity management using innovative digital technology
Childhood obesity is a major public health challenge in Canada. Without intervention, overweight children will likely continue to be overweight during adolescence and adulthood. Family-based lifestyle programs delivered at local communities can be effective. However, many families cannot attend these in-person programs due to travel distances and program availabilities. The current situation has turned increasingly dire in the COVID-19 landscape, where face-to-face, group, and facility-based interventions are no longer viable. With continued improvements in the sophistication and access to digital communication technology (e.g. Internet, wearables, smartphones), delivering tailored lifestyle programs using these tools may be well-suited to meet these challenges.
The goal of this project is to evaluate the long-term efficacy and the cost of delivering a stand-alone web-based and a blended in-person and web-based program in improving health-related outcomes in children who are overweight or obese in British Columbia (B.C), Canada. This project can be incredibly impactful for B.C. residents as this web-based program can improve the access, reach and personalization of family-based childhood obesity management programs.
The neuroscience and molecular genetics of mosquito chemosensation
Mosquitoes are the deadliest animals on the planet. Many species use sophisticated sensory systems, including smell and taste, to locate human beings and other animal hosts in their environment as a source of blood. When they blood-feed, they can transmit microorganisms that cause human diseases including malaria and dengue fever. After converting a blood-meal into eggs, a female mosquito must find an appropriate body of water to lay eggs where her offspring will thrive. Selecting an egg-laying site is an important part of the mosquito lifecycle, since the juvenile larval and pupal stages are aquatic and cannot move from where they hatch. Mosquitoes do not fly far, and so their choice of breeding site strongly influences where they can be found as adults and thus, where they can transmit disease.
The goal of my research is to understand how mosquitoes use their sense of smell and taste to make decisions about who to bite and where to lay eggs. I use techniques to modify their DNA and to look at the activity in their brains under a microscope. Ultimately, this research will help us understand why some mosquitoes are more deadly than others and provide the basis for mosquito control strategies such as traps and repellents.
Systems transformation for health equity: The PHAIRNESS Research Program
There are growing differences in health among population groups due to unfair social conditions that disadvantage some people more than others in British Columbia and beyond. Health systems play a role in holding this problem in place by presenting unnecessary barriers to accessing quality healthcare. Health systems also have a key role in closing these gaps by taking action to change the underlying conditions that shape health and wellbeing. The Population Health Approaches to Implementing Research (k)Nowledge for Equitable Systems & Strategies (PHAIRNESS) Research Program aims to make visible and intervene on systems-level problems in three connected systems: health systems, surveillance systems and research systems. By working closely with health systems, communities and people who are impacted by these issues, research findings will be relevant, useful, and ready to be rapidly applied to improve health systems and support the wellbeing of all people in British Columbia.
Plant based anticancer drugs – from discovery to final products
Plants are endowed with biological catalysts (enzymes) that make natural drugs used to treat various human illnesses. Among these, the Chinese happy tree (Camptotheca acuminata) produces the anticancer drug camptothecin. Although camptothecin is readily convertible to the more potent drugs topotecan (Hycamtin) and irinotecan (Camptosar), this requires chemical synthesis steps which rely on toxic chemicals and petroleum-based resources.
Our research program aims at developing multidisciplinary approaches to discover and modify happy tree’s enzymes that facilitate the production topotecan, irinotecan and new camptothecin-derived analogues. We aim to rapidly generate 25-50 camptothecin-derived analogues by biotechnological means and test these compounds using in vitro and cellular assays to assess potential anti-cancer activity.
Our biosynthetic approach will allow us to explore the untapped medicinal potentials of a whole host of novel camptothecin-related chemicals in addition to topotecan and irinotecan. Long-term efforts, also ongoing in our laboratory, will focus on synthetic biology approaches to scale up production of compounds that show promising bioactivity.