Research Location: Simon Fraser University

Infectious diseases are responsible for roughly a third of annual deaths worldwide and contribute greatly to productivity loss. Antimicrobial resistance and newly emerging diseases are both cause for significant concern. With the advent of microbial whole-genome sequencing, there has been renewed optimism that computational analyses of microbial genomes will allow for faster identification of promising new therapeutic targets, which can then be further investigated with laboratory studies. At the moment, however, current computational practices are not accurate enough to be truly effective. Dr. Fiona Brinkman is interested in improving computational methods used to identify new potential bacterial vaccine components or drug/diagnostic targets. She is focusing in particular on improving identification methods for two regions: bacterial cell surface and secreted proteins, since they are the most accessible targets; and clusters of genes called genomic islands, which appear to disproportionately contain virulence genes and so could aid investigations of bacterial pathogenicity. Her research group is also studying the evolution of microbial virulence, both from the pathogen and host perspective, using bioinformatic approaches supported by laboratory studies. This work aims to develop methods and insights that may accelerate the identification of promising new targets from pathogen genomes. With the ability to analyze multiple infectious disease-causing microbes in parallel, this research has the potential to have a wide reaching impact on efforts to control multiple infectious diseases.

The human genome contains all the genes, and their regulatory instructions, required to develop the human body and determine how it deals with the outside environment. Now that the genomes of many species have been sequenced, a major focus of genomics is to identify all gene regulatory elements within DNA sequences. How these building blocks of life work together to build a complex human body – with its different organs, tissues, and cell types – is not well understood. Although most human cells carry the entire genome, each cell is functionally different, suggesting that not all genes are equally expressed.

Gene expression – the full use of information in a gene – is regulated in several ways, including by transcription. Specific regulatory proteins called transcription factors bind to targeted DNA sequences in the genome. This kind of activity can control cells by switching gene expression on and off. To better understand transcription regulation in genes, and thereby better understand gene expression, binding sites for transcription factors have to be identified. It is a fundamental step in the analysis of gene expression, which is tightly regulated so that genes are only expressed in specific cells, at specific developmental stages, and at appropriate levels to ensure correct physiological function.

Dr. Jack Chen’s work investigates the properties of transcription factor binding sites (TFBSs) and determines how these properties can assist with effective genome-wide TFBS identification. Using the nematode C. elegans as the model organism, he will combine experimental and computational approaches to characterize the properties of TFBSs that distinguish functional DNA sequences from nonfunctional ones. This study may pave road for a deep understanding of transcription in C. elegans, which will in turn shed light on both healthy and dysfunctional transcription in humans.

Diseases or injuries affecting the brain frequently have devastating consequences for affected individuals. Despite progress in the last decade, many aspects of brain disease and brain development are still not understood with enough detail to develop effective diagnosis and treatment of disease and injury. Connectivity disorders result from defects in the formation of particular neuronal circuits that interfere with normal communication between neurons. They are especially challenging because they are often inherited and are influenced by more than one gene making it even more difficult to trace the underlying defects. It is suspected that connectivity defects are implicated in a variety of disorders including autism, schizophrenia, attention deficit hyperactivity disorder, obsessive–compulsive disorder and certain forms of epilepsy. In most cases, the nature of the circuitry defects is not understood. Dr. Hutter’s research is directed at identifying and describing central aspects of brain development, in particular how the formation of neuronal circuits is controlled and regulated at the molecular level. His research model is the simple invertebrate organism, C. elegans, which has many of the developmental control genes found in humans. By exploring the molecular basis of neuronal circuit formation in a simpler model organism, his work will contribute to a more detailed picture of the more complex circuitry of humans, and potentially to an improved ability to design drugs and other methods of treating connectivity disorders.

The ability for proteins to travel across cell membranes is critical to the life of all cells, yet research shows that bacterial cells differ from human cells in some of the components necessary for this movement to occur. In previous work supported by an MSFHR Scholar award, Dr. Mark Paetzel uncovered the three-dimensional structure of proteins that make up the molecular machinery involved in this movement in bacterial cells. Now a Senior Scholar, Dr. Paetzel will continue this work with the goal of learning more about these structures in order to determine how to inhibit the movement of proteins across cell membranes in bacteria. He will use X-ray crystallography to investigate the proteins involved in protein targeting, translocation, and membrane protein assembly in bacteria. Dr. Paetzel is also investigating a particular enzyme that functions at the membrane surface — one that causes the cleaving of interior peptide bonds in a protein. Understanding how to inhibit this enzyme and its role in bacterial cell movement could lead to the development of a novel class of antibiotics — a strategy that is required to meet the ever-increasing challenge of antibiotic resistance.