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.

Molecular Tools for Monitoring and Controlling the Mechanobiology of Diseases

Cells in our body are constantly engaged in physical interactions. They stick together, squeeze through each other, and each possesses a primitive sense of touch. These physical interactions are crucial in processes that control how we grew from a single cell into a complex organism and how they function. In diseases from cancer to neurodegeneration to chronic inflammation, these mechanical regulatory mechanisms are interrupted or impaired, causing cells to lose control and wreak havoc in our body.

The research proposed here aims to understand the changes to mechanical interactions in diseases down to the molecular scale. To do so, we need to develop tiny molecular tools that will allow us to look at these mechanical interactions through a microscope and control them with drugs.

We will build these tools using the latest DNA nanotechnology, which gives us predictable control over the shape and function of these molecules. We will apply these tools to understand how cancer metastasize to a new place in the body and how neurons break connections in neurodegeneration. This will help us identify drug targets towards a cure to two major diseases with high impact to the health of people in our society.

Advancing Health Equity Action

The trajectories of people's lives are often shaped by things that fall outside of their control, having more to do with unearned disadvantages than with their own behaviours or biology. Despite solid evidence and practical policy solutions, systematic differences in health and health outcomes persist both within and between countries. Evidence shows the distribution of power, resources, and wealth along social gradients are causes of these inequities. Many people working in health and health research, and particularly in public and global health, describe their work as reducing health inequities or advancing health equity; but research shows their efforts are often poorly aligned the evidence, focusing on symptoms and not causes. 

This program of knowledge translation science supports researchers, students, and professionals in different settings (e.g., rural communities, municipalities, health systems) to align their equity intentions with evidence about causes of health inequities. By supporting people to integrate evidence-informed strategies and principles, efforts to improve population health can move toward more productive health equity action that focuses on addressing the causes, rather than symptoms, of inequities.

Novel bioengineered probiotics increase colonization and persistence in the gut enhancing bioavailability and their therapeutic potential for inflammatory bowel disease

Inflammatory bowel disease (IBD) is a major global health burden and the rapid surge in pediatric cases in Canada over the past decade is raising alarm bells. Current pharmaceutical therapies are risky or ineffective, cost and health-wise, especially for long-term use and are associated with severe side effects. Therefore, new alternative therapies for IBD are needed urgently. Probiotic therapy, which is the ingestion of non-pathogenic microorganisms to provide health benefits, is considered a potential treatment option. However, clinical trials using probiotics for IBD treatment have yielded very inconsistent and difficult to interpret data.

Specific to IBD, the gut environment is highly inflamed and oxidized; these properties may interfere with the growth and therefore beneficial effects of probiotics. As such, current probiotics are ineffective at persisting in the hostile gut of IBD patients. A novel therapeutic approach is to engineer designer probiotics that strategically target these limitations. The present invention relates to bioavailable and optimized genetically-engineered recombinant probiotic bacteria with enhanced therapeutic potential, for use in treating IBD.

Here we propose that our novel patented next generation microtechnology is an alternative to traditional probiotics to enhance bioavailability and is a potential alternative therapeutic option for IBD. This proposal aims to test how the designer probiotics enrich gut health in pre-clinical
models.

Impact of Hypertension on Lung-Heart Interaction in Patients with Chronic Obstructive Pulmonary Disease

Over 2.5 million Canadians have chronic obstructive pulmonary disease (COPD), which is a progressive lung condition that blocks the airways and makes it difficult to breathe. These patients experience worsening shortness of breath, increasing exercise limitation, and reduced quality of life. Patients must work harder to breathe, and the lungs can over-inflate, which can squeeze the heart and affect how it functions. Further, more than 1-in-4 patients also have high blood pressure, which might amplify the negative effects of lung over-inflation on the heart. This is important because cardiovascular issues contribute to exercise limitation and account for 25% of deaths in COPD.

This study will use non-invasive imaging and monitoring to measure heart function and blood pressure. First, to understand the direct effects of lung volume and blood pressure on the heart, we will study how lung over-inflation can affect heart function when blood pressure is normal or high in healthy adults by using temporary experimental increases in lung volume and blood pressure. Second, we will perform a similar study in patients with COPD, which will allow us to better understand why patients who have COPD are more affected by cardiovascular disease.

Can Blending Western and Traditional Knowledge Improve Diabetes and Obesity Health in Urban Indigenous Communities?

Indigenous peoples in Canada suffer from significantly higher rates of diabetes and obesity, resulting in reduced quality of life. There is often a lack of Traditional knowledge and community leadership within health, government, and community organizations. The impact of Western care services on improving health are often limited, whereas inclusion of Indigenous community-led care services has shown to improve health. Our current study will co-develop, co-implement, and co-evaluate locally-informed, culturally relevant diabetes and obesity programs in six urban/rural Indigenous Centres. The aim of the study is to blend Traditional and Western knowledge to improve diabetes and obesity services in urban/rural Indigenous communities.

Throughout the project, Community members and Advisory teams will identify needs and solutions for community specific interventions. The proposed will explore the effects of community programs on participant clinical diabetes and obesity measures. Knowledge translation activities will include community gatherings, presentations, publications, and adaptable program platforms. Knowledge gained from this will inform health policy, research, and practice for urban Indigenous communities.

Understanding service use decision-making and improving engagement among youth and young adults with mental health disorders

This program of research will seek to understand how youth and young adults (YYA) with mental health (MH) disorders make decisions about seeking MH services at YYA centres such as Foundry BC. Foundry BC provides health and wellness services to YYAs through integrated service care in communities across BC. Nearly 75% of MH disorders develop before the age of 25, yet less than 20 percent of Canadian YYAs receive appropriate treatment. This can cause serious problems such as relapse, rehospitalisation, increased suicide risk, and can interrupt critical identity development. Currently, there is little to no research that understands how Canadian YYAs making decision about accessing and staying engaged MH services.

This program of research will work closely with Foundry BC to:

  1. To develop a theoretical framework of service use decision-making and engagement among Canadian YYAs living with MH disorders using mixed-method approaches; and
  2. Explore barriers that marginalized YYAs with MH disorders face when accessing digital information using mixed method approaches. Ultimately, this research will lead to the development of a YYA MH service use lab in BC that uses mixed-method approaches and an innovative decision-making framework to develop interventions to increase service use among this vulnerable group in BC. This research will work closely with YYAs and parent knowledge users as part of the research team, and mentor highly qualified students to become MH leaders.

Changing cognitions to change behaviour change: Reframing biased thinking to improve exercise adherence in individuals with prediabetes

Pre-diabetic individuals exercise less than their non-diabetic counterparts, with less than 15 percent meeting Canada’s physical activity guidelines. Behaviour change techniques (BCTs) such as self-monitoring and provision of goal feedback are key components of interventions for cardiovascular risk factor reduction. However, patients in such programs may not accurately interpret risk information and fail to act in ways that reduce or prevent risk. Individuals at risk for type 2 diabetes (T2D) who exhibit biased thinking (e.g. all-or-nothing thinking; “Going for walks is not going to prevent me from getting T2D”) may not be ready to engage in risk-reducing behaviours. For this reason, reframing biased thoughts may offer a critical pre-intervention (pre-IV) step that prepares them for future attempts at behaviour change.

The purpose of this study is to examine cognitive reframing as a pre-IV strategy for individuals at risk of T2D about to embark on a brief exercise counselling intervention. The main hypothesis is pre-IV cognitive reframing will increase:

  • Individuals’ self-regulatory efficacy
  • Compliance with brief exercise counselling
  • Independent exercise adherence

Cognitive reframing is an evidence-based strategy for reducing biased thinking in health contexts whereby individuals are taught to identify and challenge biased thinking caused by cognitive errors. This study will employ a randomized experimental design (intervention VS control group) to examine the effectiveness of pre-IV reframing for individuals at risk of T2D who experience biased exercise thoughts. The proposed research will be embedded within Dr. Mary Jung’s ongoing randomized control trials examining brief behavioural change IVs for people living with prediabetes in the community.

Results will partly be disseminated by coordinating a community-based prediabetes exercise clinic within Kelowna, and by working directly with Interior Health, the Kelowna Diabetes Program, and the Central Okanagan Division of Family Practitioners.

This novel research program seeks to triage individuals at risk of T2D with biased exercise thoughts. Findings may better prepare individuals with prediabetes struggling with a lifestyle change to be more receptive to receiving BCTs and attempt risk-reducing behaviour.

Central mechanisms of cerebral blood flow regulation

In healthy humans, blood flow to the brain is regulated such that appropriate amounts of oxygen and glucose are delivered to brain tissue. Even when blood pressure changes or when a region of the brain becomes more active, brain blood vessels react in order to provide sufficient blood to their respective area of tissue. When these processes fail, disease states develop. For example, too little blood flow to the brain for even a few seconds causes fainting and too much blood flow can cause a stroke.

Our understanding of these processes is currently lacking, particularly with respect to the relationships between the sympathetic nervous system (associated with the "fight-or-flight" response), brain metabolism, and regulation of brain blood flow.

This project aims to develop a better understanding of the relationships between these processes.