Harnessing the power of Nature’s for the production of High-Value Natural Products: Opiates, anti-cancer drugs, anti-addictive agents and the future access to natural products.
Dr. Scott Farrow
Director of Biological Discoveries,
The use of natural products by humans’ pre-dates written history, and while synthetic organic chemistry has produced new commercially relevant compounds, the organisms found in nature are the master chemists. These organisms have evolved an inexhaustible array of natural product scaffolds that are used directly in medicine (i.e. morphine from opium poppy), exploited for drug development (i.e. salicylic acid for acetylsalicylic acid or Aspirin), and used across industries including but not limited to food (i.e. health products such as green foods), cosmetic (i.e. scents in perfumes) and fuel (biofuel, specialty fuels). While the utilization of natural products has helped address the needs of a growing human population, challenges remain that threaten our well-being. In this context, nature remains a rich source of solutions to these challenges. For example, the utility of natural products as the source for food and medicine is still significant. In this seminar I will discuss my work on the elucidation of several key medicinal plant biochemical pathways (morphine, vinblastine and ibogaine) and outline traditional and modern approaches for accessing known and novel high-value natural products. I will also discuss my new role as director of biological discovery at Noblegen and some of the work we are conducting to access sustainable foods and medicines.
Dr. Timothy Healy
Scripps Institute of Oceanography, Marine Biology
University of California, San Diego
Tuesday, November 19 10:30am – 11:30am Humphrey Auditorium
Fitness-related physiological traits play key roles in both the adaptive responses of organisms to environmental change, and the formation of reproductive barriers between locally adapted populations. Therefore, identifying the mechanistic basis for variation in these traits is a critical aspect of understanding local adaptation and early-stage reproductive isolation. My research addresses this need by integrating comparative physiology, genetics and genomics to provide novel insights into the mechanisms that underlie intraspecific variation in tolerance limits, metabolic rate and oxidative phosphorylation. In this talk, I demonstrate these approaches using my graduate work on adaptive responses to anthropogenic climate change in the Atlantic killifish (Fundulus heteroclitus), and my postdoctoral work on hybrid breakdown, mitochondrial performance and mitonuclear compatibility in Californian tiger copepods (Tigriopus californicus). Taken together, these studies reveal the immense complexity and polygenic nature of the physiological and genetic mechanisms that underlie population divergence and local adaptation, and illustrate the power of my integrative approach for studying the evolution of physiological systems. My research not only highlights the pivotal role that physiological traits play in adaptive processes, but also addresses a fundamental goal of modern biology: mechanistically linking genotype to phenotype.
Tues Nov 12 // From mechanisms to populations: Assessing the ecological consequences of emerging pollutants for aquatic organisms
Dr. Erin McCallum
Department of Wildlife, Fish & Environmental Studies
Swedish University of Agricultural Sciences
Tues. Nov 12 10:30AM – 11:30AM, in Biosciences 1102
Human use of synthetic chemical compounds, such as pharmaceuticals and personal care products, is on the rise in developed countries. Many of these chemicals are discharged into freshwater ecosystems via, for example, municipal wastewater effluents. While the concentrations in surface waters are often unlikely to cause direct mortality, there is rising concern about how chronic exposure to sub-lethal amounts of these pollutants may directly or indirectly affect animal fitness. I will discuss a series of experiments I conducted addressing how pharmaceuticals and municipal wastewater effluents impact wild fish across scales of biological organization, from physiology to behaviour to changes in fish community composition. I will compare my results from controlled laboratory studies with findings from in situ field exposures and from studies using animal tracking technologies. Our current understanding of how chemical contaminants affect aquatic organisms is largely based on individual-level responses. Yet, understanding and mitigating the impacts of anthropogenic pollution requires knowledge of how pollutants affect animals in their natural social environment and habitats. I will therefore highlight how my research program is closing these knowledge gaps by focusing on complex inter- and intra-specific interactions (e.g., predator-prey, social dominance) in realistic environments.
Tues Nov 5 // Shaping physiological phenotypes: The influence of genomic, developmental, and environmental inputs on salt and water balance in freshwater fishes
Dr. Alex Zimmer
Department of Biology, University of Alberta
10:30AM – 11:30AM, in Biosciences 1102
Ecological and evolutionary success of animals depends on the expression of phenotypes that are compatible with their environment. In order to understand how specific physiological phenotypes arise, and the degree of plasticity or flexibility of these phenotypes, it is critical that we integrate the study of physiology across different levels of biological organisation. In my research, I have used ionoregulatory systems (salt and water balance) of freshwater fishes as a model to demonstrate how the genome and environment interact to influence phenotypes and how these interactions change over life history to shape physiological systems. In particular, I have studied how fishes sustain Na+ absorption, a process critical to maintaining internal ion and water balance, over development and in response to a range of environmental conditions (ionic strength, pH, contaminant exposure). In this presentation, I will discuss the molecular mechanisms of Na+ absorption by rainbow trout, how they change over development, and the implications that this has in understanding how fish at different stages of life history respond to changes in environmental conditions. I will also discuss the use of CRISPR/Cas9 gene editing as a tool to knock out genes that regulate Na+ absorption in zebrafish and explore how the resulting reduction in genetic complexity influences the expression and plasticity of phenotypes. This research highlights the importance of integrating molecular, organismal, and environmental physiology to understand how fishes occupy different environmental niches and how they respond to environmental change.
University of Saskatchewan
10:30AM - 11:30AM, in BioSci 1103
We live in a contaminated world, with approximately 23,000 chemicals registered for use in Canada, in addition to numerous contaminants that are unintentionally released in industrial processes. There are many challenges to deciphering the effects of these contaminants on wildlife populations. Laboratory assessments often lack ecological relevance, and conversely the majority of field assessments are correlative in nature. I use a combination of laboratory and field approaches and integrate methods from multiple disciplines (molecular biology, physiology, neurobiology, behaviour) to make causal linkages between contaminant exposure and effects in birds. I will present two case studies from this research. The first demonstrates the use of predictive genotyping, field manipulations, and molecular diagnostics to verify that 2 wild bird species (European starlings and gray catbirds), like the domestic chicken, are highly sensitive to dioxin-like compounds – results that can directly inform risk assessment without extensive toxicity testing on wild birds. In the second example, I used a combination of captive behavioral trials, controlled exposures in the field, and automated telemetry to demonstrate that field-realistic concentrations of a neonicotinoid insecticide cause appetite suppression, body mass loss and migratory delays in migrating white-crowned sparrows. These results link neonicotinoid exposure to population-level consequences, as the timing of migration is critical and delays are known to affect survival and reproduction. This research highlights how we can increase our capacity to answer fundamental and applied questions in animal biology and ecotoxicology by Integrating methods across levels of biological organization, and merging field studies with captive studies and laboratory analysis in novel ways.
Special time and place, Room 3110 at 10:30 - 11:30
University of Sherbrooke
RNA silencing is a major mechanism of constitutive antiviral defense in plants. Arabidopsis encodes four Dicer-like (DCL) proteins and ten different Argonaute (AGO) proteins that are specialized to function in different RNA silencing-related mechanisms. We have previously shown that AGO2 plays an important role in protecting plants against viruses, including Potato virus X (PVX) in Arabidopsis. However, despite having a functional AGO2 protein, Nicotiana benthiana is highly susceptible to PVX. Using a transient expression system in N. benthamiana leaves, we found that Arabidopsis AGO2 (AtAGO2), but not N. benthamiana (NbAGO2), possesses antiviral activity against PVX. Consistent with this, we find that activity of NbAGO2, but not AtAGO2, is supressed by the PVX suppressor of RNA silencing, P25. Therefore, we generated transgenic tomato and N. benthamiana plants containing AtAGO2 and NbAGO2 constructs. These transgenic lines were inoculated with PVX and viral accumulation levels were assessed. Recent results of these assays will be discussed. In addition, we have observed natural variation in AtAGO2 in naturally occurring Iberian Arabidopsis wild accessions and found that certain polymorphisms correlate with the degree of susceptibility to PVX and to Turnip mosaic virus (TuMV) but not with susceptibility to Cucumber mosaic virus (CMV). Our results indicate that natural variation in AGO2 can have important effects on infection for some, but not all viruses.
Christian Danve M. Castroverde
Department of Biology, Wilfrid Laurier University
Climate change combined with plant diseases pose serious threats to global agriculture and food security. Because the molecular mechanisms by which environmental factors affect plant immunity and disease are poorly understood, my research program aims to address this critical knowledge gap. We have recently reported that salicylic acid (SA) production is a temperature-sensitive pathway in the plant immune system (Nature Communications 2017 vol 8:1808). SA is an important plant hormone mediating immune responses against a broad range of pathogens.
How elevated temperature intercepts the SA pathway is currently unclear, and strategies to counter temperature-mediated suppression of SA production are also lacking. My continued research into this central biological question has shown that elevated temperature has a profound effect on gene expression of a calmodulin-binding master transcription factor (TF) controlling various immune regulators in plants. Remarkably, constitutive gene expression of this master TF was sufficient to recover SA production and immunity at elevated temperature. Global transcriptome analyses revealed that a significant suite of defense-related target genes were downregulated at elevated temperature. My research has identified a crucial temperature-regulated component of the plant immune system.
The upstream mechanisms involved in temperature regulation of this master TF are unknown. Whether temperature-sensitive immunity observed in the model plant Arabidopsis thaliana occurs in other plant species is also unclear. These are important next-level questions that I am currently investigating. By integrating molecular, genetic and biochemical approaches, my research program aims to understand plant-pathogen interactions in a dynamically changing environment, in order to shed light on plant resilience mechanisms.
Special time and place, Room 3110 at 3:30 PM.
The use of plants to remediate contaminated lands is of growing interest to the scientific community because of its ease of implementation, cost effectiveness and ability to stabilize contaminated soils. A novel Populus tremula x Populus alba mutant named fuzzy with an increased trichome density, an elevated growth rate, enhanced pest resistance and a predicted root phenotype was investigated for its ability to tolerate and accumulate arsenic and cadmium in soil. The chlorophyll, hydrogen peroxide and proline contents of fuzzy tissues were assayed, its tissue metal content was measured using ICP-MS and its wet biomass was quantified. Transgenic Arabidopsis thaliana overexpressing homologous gene of that overexpressed in the fuzzy poplar were grown on gel media and their roots were measured to corroborate the root phenotype of fuzzy poplars. The fuzzy poplar was found to have lower levels of hydrogen peroxide in its tissues after arsenic and cadmium exposure than control poplars, suggesting it has a reduced oxidative stress response when exposed to high levels of arsenic and cadmium. This low hydrogen peroxide content was not due to reduced arsenic and cadmium accumulation in fuzzy trees, as they did not accumulate different amounts of arsenic or cadmium than control plants. Proline and chlorophyll levels were not significantly different between metal treatments, or between fuzzy and control poplars. fuzzy poplars exhibited significantly higher root biomass than control poplars, and transgenic Arabidopsis thaliana overexpressing a homologous gene to the one that causes the fuzzy phenotype had significantly longer roots than control plants. All poplars exposed to arsenic and cadmium in this trial contained the majority of these compounds in their tissues in roots. The root biomass phenotype, low hydrogen peroxide content and root metal accumulation in the fuzzy poplar make it an ideal candidate for bioremediation and soil stabilization of contaminated soils.
Tuesday Sept. 17 // Driving metabolic flux and avoiding carbon loss; lessons from opiate alkaloid biosynthesis
Department of Biological Sciences,
Brock University, St. Catharines, ON
Opium poppy has been in use as a medicinal plant since before the dawn of civilization. Today, it remains the only source for natural opiate analgesics, codeine and morphine, and precursors used to synthesize derivatives such as the overdose antidote, naloxone. Total chemical synthesis of opiates is not commercially feasible due to complex stereochemistry. Engineering microbes with alkaloid biosynthetic machinery from opium poppy has the potential of providing a sustainable global supply of opiate pharmaceuticals. However, microbial bioproduction often suffers from carbon loss to alternative pathways. In the latter stages of opiate biosynthesis, thebaine is converted, via codeine, to morphine. When this pathway is simulated in vitro or in microbial systems, two undesirable isomers accumulate: neopine and neomorphine. We addressed this aberrant pathway in two studies: 1) In the penultimate step of morphine biosynthesis COR reduces codeinone to codeine. However, codeinone exists in an apparent equilibrium with its isomeric form, neopinone. We showed that COR irreversibly reduces neopinone to neopine. Using natural and synthetic protein variation we also identified four residues that can confer COR with higher protein stability and performance, improving metabolic flux. 2) We sought an explanation for why the plant does not accumulate the isomeric byproducts. Using a proteomics approach, we found a novel enzyme, neopinone isomerase (NISO) that catalyzes the assumed spontaneous conversion of neopinone to codeinone. NISO provides the substrate for COR to produce codeine and precludes the formation of neopine. Inclusion of NISO in yeast strains engineered to convert thebaine to natural or semisynthetic opiates dramatically enhances formation of the desired products and avoids carbon loss.
Tues Sept 3rd // Investigating Suberin Biosynthesis in Poplar: Candidate Genes and Chemical Composition
Meghan Rains, PhD student
Algoma University / Queen's University
Pathogens, climate change, and pollution represent important stressors that plants face continuously. To better prepare for a changing terrestrial landscape, we must understand how plants adapt and cope with various environmental stressors. The plant cuticle and suberized cells (cork) are among the critical adaptations that plants developed when they moved from an aqueous environment to land. These cell wall-specific extracellular lipid barriers provide the first line of defense against pathogens and control water exchange. The cuticle covers most aerial plant surfaces and is composed of a polymer of fatty acids and waxes. The periderms of roots, tubers, and tree bark, contain waxes and suberin –an esterified network of glycerol and fatty acid derivatives that is bound to a lignin-like polymer. Although structural models have been inferred from chemical depolymerizations, the insoluble nature of these polymers makes analyses challenging, and consequently, the native structure of suberin remains unclear. Much of the current research on suberin biosynthesis has focused on the model plant Arabidopsis thaliana. However, the complete pathways have not yet been fully characterized, and it is unclear how knowledge derived from Arabidopsis translates to woody tree periderms. This dissertation work used a combination of chemical and molecular approaches to identify candidate genes for suberin biosynthesis and to investigate the structure of the polyester using the model tree, Populus trichocarpa (Poplar). The results from this research further our understanding of suberin structure in tree bark, establish improved methodologies, and generate hypotheses for future targeted studies.