Events

Professor at Harvard & MIT, co-author of 692 papers, 164 patent publications & a book "Regenesis"; developed methods used for the first genome sequence (1994) & million-fold cost reductions since (via fluor-NGS & nanopores), plus barcoding, DNA assembly from chips, genome editing, writing & recoding; co-initiated BRAIN Initiative (2011) & Genome Projects (GP-Read-1984, GP-Write-2016, PGP-2005:world's open-access personal precision medicine datasets); machine learning for protein engineering, tissue reprogramming, organoids, gene therapy, aging reversal, xeno-transplantation, in situ 3D DNA/RNA/protein imaging.

Many prokaryotic microorganisms interact with their environment and hosts owing to surface structures and nanomachines. The type IV filament superfamily of nanomachines is conserved and widespread in archaea and bacteria. These systems assemble dynamic surface fibers that promote a range of cellular functions, from motility, adhesion and biofilm formation to uptake or secretion or macromolecules. My team investigates fiber assembly and function in several bacterial models – the Klebsiella type II secretion system, the Escherichia coli type IV pili and, more recently, the Geobacter systems involved in secretion and assembly of conductive nanowires. To investigate the molecular mechanism of fiber assembly we integrate structural, modeling and biochemical approaches. I will present our current understanding of these nanomachines and discuss some of the open questions, focusing on the type II secretion system

Prof. David Vocadlo completed his PhD at the University of British Columbia in 2002 with Steve Withers. He was a Canadian Institutes of Health Research (CIHR) postdoctoral fellow at the University of California at Berkeley in the Departments of Chemistry and Molecular and Cell Biology with Carolyn Bertozzi. In 2004, he joined Simon Fraser University (SFU), where he is now a professor in the Departments of Chemistry and Molecular Biology & Biochemistry and Distinguished Professor in Chemical Biology. His research focuses on developing chemical biology tools and using these to advance understanding the roles of glycoconjugates in health and disease. He is an inventor on over 30 families of patents and several technologies have been out-licensed from his SFU laboratory. His team pioneered the creation and preclinical validation of OGA inhibitors for neurodegenerative diseases, a strategy now advanced into clinic trials and pursued by several pharmaceutical companies. Prof. Vocadlo and his team have been recognized with various awards including the EWR Steacie Memorial Fellowship, the Horace Isbell Award of the American Chemical Society, and his appointment as an inaugural member of the Royal Society of Canada, College of New Scholars. Prof. Vocadlo is an Associate Editor at ACS Chemical Biology and Co-Founder and Chief Scientific Officer of Alectos Therapeutics.

Dr. Katie Mitchell-Koch (University of Manitoba)

Connections among Solvation Layer and Protein Structure & Dynamics

The solvation layer surrounding proteins plays a crucial role in protein structure-function-dynamics, from folding to molecular recognition processes. Using molecular dynamics, we have mapped the solvation layer around enzymes, observing variations in water structure and dynamics at different regions of proteins. Analysis has uncovered relationships between protein structure and solvation shell dynamics; solvent dynamics and protein dynamics; and solvent shell structure and dynamics.

Dr. Asmahan AbuArish (University of Saskatchewan)

Discovering the nature of the rare cystic fibrosis-causing CFTR mutation S13F by means of visualization and statistical analyses

Cystic fibrosis (CF) is an autosomal recessive disorder resulting from a dysfunction in cystic fibrosis transmembrane conductance regulator (CFTR) channel conductance due to genetic mutations. The F508del is the most common CF-causing mutation that causes CFTR misfolding. This increases CFTR retention in the endoplasmic reticulum (ER) and dramatically reduces its trafficking, stability, and expression level at the plasma membrane of human airway epithelial cells. On the other hand, the S13F is a rare CF-causing mutation that was believed to disrupt the interaction between CFTR and the actin-associated Filamin A scaffold, which results in membrane CFTR instability and reduced expression. Based on this knowledge, Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy, which restores CFTR misfolding, is expected to restore the F508del-CFTR defects, but not the S13F-CFTR. Our work describes a journey of discovery to highlight the power of using quantitative imaging in discovering the true nature of the S13F mutation and its effects on CFTR molecular behaviours. Using a combination of optimized fluorescence confocal imaging, image-based statistical analyses, and electrophysiology measurements, we report that the S13F-CFTR exhibits similar molecular behaviours as the F508del-CFTR before and after ETI therapy. Both mutations cause CFTR ER retention and reduced membrane expression. Following ETI treatment, the molecular behaviours of both mutants are similarly restored to that of the wild-type CFTR. Using electrophysiology measurements, ETI therapy rescues S13F-CFTR function as well. Furthermore, membrane CFTR molecular behaviours are not modulated by Filamin A or the actin cytoskeleton but are critically dependent on membrane lipid order. These results indicate that people living with CF and carrying the S13F mutation can greatly benefit from ETI therapy (clinically known as TRIKAFTA).

Dr. Harley Kurata/Todd (University of Alberta)

High throughput identification of druggable regulatory mechanisms of potassium channels

Dysregulation of potassium channel function or biogenesis underlie a spectrum of diseases related to cellular electrical excitability. We sought to identify cellular pathways that influence maturation of important neuronal Kv channels and disease-associated mutants, using strategic epitope tags and high-content screening. This approach has highlighted multiple mechanisms that influence maturation of Kv1 or Kv7 family potassium channels, several with the potential to be targeted by existing therapeutic drugs. While ion channel-targeted pharmacological development has focused on direct modulators of channels, this strategy helps to identify cellular pathways and mechanisms that indirectly influence cellular excitation.

Dr. Stacey Wetmore

Professor and Tier I Canada Research Chair

Department of Chemistry and Biochemistry, University of Lethbridge

Computer Modeling of the Chemistry Used by Enzymes to Process Nucleic Acids

Many enzymes control the chemistry and biology of nucleic acids in cells. For example, DNA modifications arising as damage must be repaired or bypassed for cell survival. Alternatively, enzymes introduce or remove DNA modifications as part of epigenetic regulation or generate modification cascades to impart diverse RNA structures and functions. However, critical information about molecular reactions (transition structures, barrier heights) is difficult to obtain from experiments alone at least in part because key species along reaction pathways are short lived. Research in my group uses a multipronged computational approach (quantum mechanical (QM) cluster models, molecular dynamics (MD) simulations, and combined quantum mechanics–molecular mechanics (QM/MM) methods) to characterize the molecular details of enzyme-catalyzed reactions that form the basis of nucleic acid chemistry in cells. This talk will provide a survey of recent topics of interest in my lab related to the enzymatic processing of nucleic acids. The information uncovered is vital for the future design of highly selective and potent small molecule inhibitors for disease management and the design of new enzymes that can process modified nucleic acids as biotechnological tools.

Dr. Jonathan Canton (University of Calgary)

Apolipoprotein control of antigen cross-presentation by dendritic cells

Type I conventional dendritic cells (cDC1s) are essential for the generation of protective cytotoxic T lymphocyte (CTL) responses against many types of viruses and tumours. They do so by internalizing antigens from virally infected or tumour cells and presenting them to CD8⁺T cells in a process known as cross-presentation (XP). Despite the obvious biological importance of XP, the molecular mechanism(s) driving this process remain unclear. In this presentation, I will discuss the discovery of dedicated pore-forming apolipoproteins that mediate the delivery of phagocytosed proteins to the cytosol of activated cDC1s to facilitate MHC class I presentation of exogenous antigen and to regulate adaptive immunity.