Research
Cellular Simulations
Given detailed information on lists of cellular components, their interactions and behaviour it is now becoming possible to construct models which attempt to realistically simulate experimental observations. Previous attempts to generate such models have tended to rely on the use of ordinary- and partial-differential equations. Such systems of equations are notoriously difficult to solve and tend to neglect potentially important spatial and organisational factors. To surmount these problems, we have created a novel simulation environment termed Cell++, which is able to account for the influence of spatial and temporal factors. In a typical system, discrete elements representing individual proteins or complexes are allowed to move and interact within a 3D environmment where behaviour is determined by a set of predefined rules (laws of 'physics'). We are currently focussed on three systems of interest:
- Metabolic pathways
- Lipid raft mediated signalling
- Kinase mediated signalling cascades
Evolution of diversity
Comparative genomics offers the possibility of using genomes from different species to gain a better understanding of how species have evolved and to help determine the function of those genes for which no experimental evidence currently exists. For example, much information on the function of human genes may be gleaned by examining their counterparts in simpler model organisms such as yeast and the worm. For eukaryotes, only a limited number of full genome sequences have so far been generated. However there is an enormous amount of sequence data in the form of expressed sequence tags which may be utilised to create so called 'partial genomes'. We have developed a novel database PartiGeneDB which collates and presents these data within a genomic context. In our lab, we are exploiting this resource to compare available genome data of parasitic organisms, to help identify parasite specific traits which may form the basis for novel therapeutics.
Cellular and extra-cellular architecture
The extra-cellular matrix (ECM) represents an intricate network of structural proteins responsible for imparting biomechanical properties to associated cells and tissues. Despite decades of study, the role of network connectivity and organisation in the biomechanical properties of structural protein networks still remain poorly understood. Furthermore, while we have witnessed the growth in databases concerned with metabolic proteins, kinases or other signalling elements, very little attention has been devoted to structural proteins. In collaboration with Dr Fred Keeley and Dr Regis Pomes, we are currently studying the organization and structure of the ECM with a particularly emphasis on understanding the role of elastin.
Network Biology
In this emerging “systems biology” era, studies examining interaction networks – in particular genome scale analyses of protein-protein interactions (PPI) (e.g. yeast two hybrid screens and mass spectrometry based analyses of isolated protein complexes), transcriptional regulatory networks (e.g. ChIP-ChIP, DNA microarrays), genetic (gene-gene) interactions (e.g. though genome-wide phenotypic screens of gene knockouts, double mutants, RNA interference (RNAi) mediated knockdowns, haploinsufficiency, and population genomics), and large-scale evolutionary perspectives (pan-species sequence conservation) – are rapidly accumulating, especially for such tractable model systems like the budding yeast Saccharomyces cerevisiae. The availability of these complementary resources not only enhances functional insight into individual genes and protein families, but is also paving the way for an exciting new era of Integrative Biology wherein, for the first time, entire systems of interacting biomolecular components can be comprehensively studied at multiple levels of biological abstraction. For example, combining genomic, microarray and protein-protein interaction (PPI) data will allow for the identification of not only which proteins interact, but also their overall functional organization, abundance and evolutionary relationships
Parasite Genomics
Parasites inflict devastation and misery on the lives of their victims, leaving millions of people debilitated and incapacitated. For example, malaria affects over 300 million people worldwide, while almost one fifth of the population of North America is chronically infected with a related parasite - Toxoplasma (the causative agent of toxoplasmosis). The high prevalence of Toxoplasma has severe implications for those whose immune systems have been compromised (e.g. individuals affected by HIV/AIDS). Roughly 30-50% of HIV/AIDS patients who test positive for Toxoplasma infection develop potentially lethal toxoplasmic encephalitis. Despite the terrifying impact of these parasites, relatively few effective treatments and vaccines are currently available. The recent availability of DNA sequence data generated from many of these organisms offers opportunities to derive insights into the molecular basis of parasitism. By adopting an integrated datamining approach, we are analysing these data to identify genes essential for the survival of Toxoplasma within the host. Those which show promise as amenable drug targets will be subsequently characterised through a series of experimental assays. This program of research promises to deliver a host of new candidate drug targets that may be exploited through existing drug development pipelines.
International Genetically Engineered Machine (iGEM) Competition
iGEM is the premiere undergraduate Synthetic Biology competition. Student teams are given a kit of biological parts at the beginning of the summer from the Registry of Standard Biological Parts. They use these parts and new parts of their own design to build biological systems and operate them in living cells. This project design and competition format is an exceptionally motivating and effective teaching method. Past iGEM projects ranged from banana and wintergreen smelling bacteria, to an arsenic biosensor, to Bactoblood, and buoyant bacteria. The University of Toronto team has, in the past, contributed temperature sensing bacteria and designed a bacterial neural network! This year over 120 teams with over 1200 participants from >20 countries are expected to participate in the competition. Teams will present their projects at the iGEM Championship Jamboree in November. The Parkinson lab hosted the Toronto MaRS Discovery team for iGEM 2009 and 2010.
