Structural exploration of locked nucleic acids (LNAs) for incorporation into anticancer oligonucleotides

Antisense oligonucleotides (AON) are short lengths of RNA or DNA molecules which are used to change gene expression to treat diseases like cancer and Parkinson’s disease. Like DNA, AONs are made up of chains of nucleotide units, but to make them useful as drugs, these nucleotides have to be structurally changed. Locked nucleic acids (LNAs) are a very useful type of altered nucleotide unit, since they are not broken down as quickly in the body, and attach strongly to the gene they are targeting. The problem with LNAs is that they are very difficult to make, so it is hard for chemists to make a lot of different changes to the structure of LNAs in order to find the best one to use in AONs.
The Britton research team recently discovered a new way to make LNAs very quickly and easily, in large amounts, from simple compounds. Using this new technology, we want to make a large number of structurally unique LNAs and, test them to find the best ones to use in AONs for the treatment of cancer.

Examination of Long QT Syndrome causing variants in induced pluripotent stem cell-derived cardiomyocytes to evaluate novel therapeutic treatments

The rhythmic beating of the heart requires coordinated electrical activity that causes the heart to contract and relax. The electrical activity is controlled by proteins in the membranes of heart cells that form ion channels. Failure of channels to work properly is associated with abnormal heart rhythm, heart attack and sudden death. Long QT Syndrome (LQTS) is a condition that affects 1:2000 people and often results from inherited mutations in one of the heart channels. However, determining whether a mutation will cause the individual serious heart problems is still a major challenge. By using cutting edge technology, like induced pluripotent stem cells and CRISPR, we can recreate patient mutations in cells in the lab and turn them into beating heart cells. Specific techniques can be used to look at individual heart cells, as well as heart cells in a layer that beat together. The properties of the cells can be measured so that the effects of the mutations can be understood, and so that newer specific drugs can be tested to see if they are effective against different mutation types. The results from this research will help inform clinicians on how to better help patients with LQTS and potentially identify new, better treatments.

Investigating the role of sleep disruption in the progressive memory loss associated with Alzheimer’s disease

Alzheimer’s disease is the most common cause of dementia and a leading cause of death in Canada. Unfortunately, there are currently limited treatments available for this devastating disease. Recently sleep has been shown to regulate important aspects of Alzheimer’s disease pathology and is emerging as a promising target for novel interventions to prevent and slow disease progression.

To identify how changes in sleep and the body’s biological clock contribute to the cognitive deficits associated with Alzheimer’s disease, we will conduct a combination of preclinical experiments to evaluate causal mechanisms and clinical studies to evaluate the same processes in patients diagnosed with Alzheimer’s disease.

The ultimate goal is to determine whether treating specific aspects of sleep disruption is an effective therapy for Alzheimer’s disease, which will help identify new treatments to prevent the progressive memory loss, improve the health and quality of life of patients and their families, and reduce the economic burden of the disease.

Informing the future of primary care: Virtual care, workforce optimization and the learning health system

Primary care is the foundation of strong health systems, ensuring people stay healthy and get care when needed. However, timely access to high-quality primary care is an ongoing problem in British Columbia and other provinces.

My program of research aims to ensure that all British Columbians can access quality primary care how and when they need it. The central project I lead uses information from interviews with health professionals (physicians, nurse practitioners and nurses) and patients; data from the health system; and provincial policy documents to study access to, experiences with, and outcomes from virtual primary care. Complementary research will inform modernization of the primary care workforce and informing ideal deployment of providers in team-based models in the context of COVID-19 and beyond. Finally, I lead work about implementation of “learning health systems” to support continuous improvement and innovation in primary care and across the health system more broadly.

My work follows an integrated knowledge translation model; I work with a team of researchers, policy makers, clinicians and patient partners to co-produce knowledge and address important and relevant questions that are driven by their combined input.

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:

  1. General-purpose software for annotating the genome.
  2. Easy-to-use reference data sets.
  3. Insights into the link between genetic variation and chronic obstructive pulmonary disease (COPD).

Healthy Children, Healthy Communities: Co-Benefits of Children’s Action on Climate Change and Mental Health

Problem: British Columbia is being increasingly impacted by climate change and therefore the health and wellbeing of children in this region are at risk, and will be throughout their lives unless action is taken.

Overview: Conducted for, by and with children, this research will answer 2 questions: How is children’s health being impacted by climate change? Can taking action on climate change through community projects, strengthen and build resilience in children, even in the age of climate change? A central focus of this work will be on mental health and wellbeing.

Outcomes: After filling a significant scientific knowledge gap about the public health impacts of climate change on children in BC, evidence gathered will be used to help develop community projects that tackle a local impact of climate change. 

Impacts: This research will identify why and how certain community projects on climate change protect, and even improve, the mental health and wellbeing of children and make recommendations for how other communities can use this information to build their own healthy children, healthy community projects. These successes will be shared with decision makers to support the choices they make around climate change and health.

Real-time Combined Genomic and Epidemiological Monitoring of COVID-19 in British Columbia

Viruses accrue small amounts of genetic variation over time. By sequencing the virus, we can see this variation and use it to understand where an individual virus likely came from and how it is moving through a population. This helps public health teams to estimate how many cases are due to local transmission as opposed to imported cases. In this proposal, we will establish ways to use virus sequences to understand transmission in a high-resolution way that is not possible with epidemiological or virus sequence data alone. To do this, we will combine viral sequences with epidemiological data in new ways, establishing high-resolution pictures of transmission. We will operationalize the use of these combined datasets for real-time COVID19 public health use in BC.

“Blind Spots”: People in Prison and Precarious Housing During COVID-19

Prisons and substandard housing pose serious risks to individuals and communities during the COVID-19 pandemic. Limits on physical distancing are associated with disease outbreaks in shelters, camps, and prisons. The high prevalence of pre-existing illness in the settings places people at risk for medical complications. This project will generate evidence of ways to reduce the spread and impact of COVID-19 by analysing hospitalizations among people who were in custody or inadequate housing during the first wave of COVID-19 in BC. The project will also develop recommendations on the use of mandatory testing. The project team is drawn from established networks of researchers, decision-makers, service providers, and people who have experienced homelessness and time in custody.

Role of ciliary proteins in vision and obesity

The cilium is an extension on most cells and tissues that works similarly to a television antenna, in that it receives signals from the environment. When a mutation disrupts the function of cilia, cells no longer receive the proper environmental input. Mutations in cilia proteins have been identified in patients with clinical ailments such as blindness, obesity, diabetes and polycystic kidney disease; some are also found in syndromes encompassing all or most of these disorders. Although some of these syndromes affect entire families, the molecular and cellular causes of these disorders have not been identified or characterized; for this reason there are no therapies available. Dr. Victor Jensen aims to study and identify novel cilia genes that are associated with multiple disorders, including blindness and obesity. These results will provide essential information about the association between disease and different genes, as well as the function of cilia. This unique approach to gene discovery and characterization was developed in the laboratory of Dr. Leroux, and has already led to the discovery and understanding of numerous disease genes, including those associated with the multi-systemic Bardet-Biedl syndrome. Dr. Jensen’s research work is therefore aimed at providing novel insights into the nature and function of disease genes, a step that will eventually lead to improved treatments or prevention of common human medical ailments.