Integrated solutions for functional genomics and proteomics at the Network Biology Collaborative Centre

May 16, 2018

The Network Biology Collaborative Centre (NBCC) at the Lunenfeld-Tanenbaum Research Institute assists scientists with connecting information on genomic and phenotypic variation in health and disease with a functional understanding of how gene products convey biological information and how their alterations drive disease. The Centre provides critical added value to Canada’s genomics enterprise by offering an integrated suite of resources that support the discovery and validation of targets and disease mechanisms. To fulfill this mandate, the NBCC incorporates key proteomics technologies that allow users to map dynamic physical interactions between proteins on either a small or large scale in either cell lines or tissues. This is a powerful strategy to gain insight into the biological function of poorly studied proteins, so-called “guilt-by-association”. Protein networks can then be functionally interrogated by systematically depleting specific nodes from a cell or tissue system, for instance by RNA interference or by CRISPR gene editing, and the impact on a myriad of cell behaviours can then be assessed by end-point assays, sophisticated automated microscopy, super-resolution microscopy (to provide for detailed analysis of tissue and subcellular structures) or by evaluating impact on transcriptomes. Extensive resources to perturb networks using targeted chemical probes are also utilized to provide another powerful dimension to understanding how biological networks control cell function. NBCC resources thus allow users to rapidly reveal new disease gene functions, uncover novel pathways driving disease pathology and establish rational bases for the design of therapeutic strategies in the clinic.

The NBCC traces its roots back to 1999 with the establishment of one of the first proteomics mass spectrometry facilities in Canada and the development of one of the first academic screening centres. In 2014, these facilities were amalgamated into the Network Biology Collaborative Centre to provide Canadian scientists with integrated services in functional genomics, chemical genetics and proteomics. The NBCC subsequently expanded with new offerings in high spatio-temporal resolution imaging and next-generation sequencing. The Centre is directed by Drs. Jeff Wrana and Anne-Claude Gingras with expert input from co-investigators Drs. Laurence Pelletier and Daniel Durocher. Together, they provide unparalleled expertise in genetic and chemical screens, protein interactions and networks, advanced imaging, and transcriptomics.  Since its amalgamation, the NBCC has contributed to >100 publications with over 25% being in prestigious journals (Cell, Molecular Cell, Science, Nature family journals). These publications have resulted from collaborations with >175 Principal Investigators across Canada and internationally.

The NBCC operates through multiple complementary nodes: proteomics, high-throughput screening, next-generation sequencing, and high-content to high-resolution imaging. Each of these nodes is managed by an experience technical expert with oversight provided by Centre Manager Dr. Karen Colwill. The proteomics node has unique expertise in functional proteomics, particularly protein-protein interactions, where validated experimental approaches are combined with a unique and robust computational platform. This pipeline dovetails with the high-throughput screening (HTS) node, which incorporates sophisticated automated robotics and sample management. This enables the physical and functional interrogation of mammalian systems through application of an extensive collection of cDNA libraries, RNA interference resources and small molecule libraries. Complementing these two nodes, a suite of high-content, automated imaging and high spatial-temporal resolution instruments permit various screening modalities. Lastly, our next-generation sequencing node specializes in transcriptomics and CRISPR pooled screening support. The NBCC provides not only its extensive expertise in the design and application of sophisticated screening strategies through these nodes, but also its ability to integrate these screens with each other to drive biological insights. Customers often enter the NBCC through one node, e.g. HTS that identifies genes with interesting phenotypes, then move to imaging to obtain detailed phenotypical readouts and proteomics to identify interaction partners; this enables rapid transition from target identification to functional insight; a unique strength of the NBCC.

The NBCC has been funded as a technology platform by Genome Canada, through Ontario Genomics, since 2015, with a recent investment of $5 million in 2017 for operation support and technology development.   With this funding, the Centre is incorporating new capabilities into the Centre to better model health and disease states. The NBCC will establish next generation screening modalities by pairing CRISPR-based screening with more complex readouts including single cell sequencing and imaging-based phenotyping. Chemical screening capabilities will be extended by adding a chemical proteomics pipeline to identify proteins targeted by compounds of interest. Finally, data management and analytics across all the NBCC nodes will be expanded and strengthened to allow users to rapidly extract mechanistic insight into their biological and disease models. These improvements will help ensure that future NBCC users remain internationally competitive and drive their science to realize the greatest benefit.