Biophysical Control of Cellular Programming and Tissue Patterning

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Cells contain a genome equivalent to 3 billion lines of instructional code, storing information that directs everything from protein synthesis to long-range communication amongst other cells to form complex shape. Both embryos and tumors use this same information to achieve very different ends; however, genes and their regulatory networks alone, do not explain how millions, or even billions of cells coordinate to achieve functional multicellularity within patterned tissues. To construct an entire organism from a single cell - one that expresses segmented limbs and digits comprised of interwoven vasculature, nerve, muscle, bone, and connective tissue - is to orchestrate an unfathomably complex yet delicate set of simultaneous inter- and intra-cellular events. While it is clear that specialized biomolecules called morphogens are integral to the acquisition of form (morphogenesis), in recent years it has become increasingly evident that electrical signals are of equal importance. Indeed, depolarizing calcium waves are known to initiate proliferation, migration, and apoptosis among other key developmental processes. And bioelectric gradients regulate tissue boundaries, organ size, and identity. Dysfunctions of cellular bioelectricity - particularly, resting membrane potential (Vmem) - can prompt mispatterning of cells to induce birth defects and cancers. What remains unknown is the contribution of spatio-temporal patterns of Vmem to specifying cell fate independently and how these dynamics interplay with genetic, biochemical and microenvironmental factors to direct large-scale tissue patterning. My long-term goal of my research program is to address this knowledge gap and reveal the complementary role of bioelectricity in tissue patterning, I have designed a 5-year NSERC Discovery Grant funded research program with short-term objectives to determine cell mechanisms and functions of bioelectric control that drive three fundamental features of tissue patterning: cell fate, tissue geometry, and microenvironment patterning. My interdisciplinary approach will combine cutting-edge techniques in stem cell biology, bioprinting, tissue engineering, and bioelectric modulation to translate the electrical language of cell fate and behaviour, a biophysical `Rosetta Stone', with transformative implications for developmental biology, regenerative medicine, and biomedical engineering. The proposed research program will significantly impact the field of biology, allowing researchers to read and write cellular bioelectric codes to pattern and control tissue growth. My team of HQP will benefit from world-class mentorship and acquire highly marketable skills in biomedical engineering and stem cell biology that will allow them to be a part of the next generation of leading international academic and industry scientists.