Curbing the Emergence of Clonal Drift in Stem Cell Expansion Culture

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Literature and Recent Progress As evolution guided the development of multicellular organisms, single cells adapted their social interactions to co-operate with one another. Nevertheless, remnants of natural selection remain cells with higher fitness eliminate their relatively weak neighbours. Cell competition has been shown to play a significant role in the growth and repair of tissues, impacting organism survival as a whole. Cancer cells are an example of super-competitors, overtaking communal resources and out-competing the body's normal cells. Much as cancer cells emerge as “cheaters” within our tissues, cell populations grown outside the body are often overtaken by abnormal cells that acquire genetic mutations, giving them a fitness advantage. The emergence of abnormally fit cells continues to plague bioprocesses that aim to derive appropriate and relevant quantities of stem cells and their derivatives for downstream applications. Pluripotent stem cells (PSCs) are particularly powerful given their ability to indefinitely expand (make copies of themselves) and differentiate into all cell types in the body. However, owing to their great expansion potential, PSCs are particularly susceptible to mutations. Objectives and Methodology My long-term objective is to use cell competition as a new lens to reverse-engineer multicellular systems, uncovering how the rules that govern interactions between single cells lead to the success or peril of the whole population. My lab will serve as an interdisciplinary hub, providing mentorship to convergent researchers. By leveraging expertise in computational modeling, stem cells, and synthetic biology, we will design a novel pipeline to better maintain the quality and safety of PSC batches. There are two short-term objectives. First, we will apply a synthetic biology approach to develop a cellular “barcoding” platform to tag PSCs and their progeny with unique DNA identifiers, allowing us to manipulate them based on their barcode. Second, we will track the growth dynamics of each PSC as it expands. By applying a mathematical modeling strategy, we will predict the emergence of PSCs with abnormal fitness and use the active barcode to trigger a suicide switch in these cells, recovering the integrity of the cell batch. HQP I intend to train a diverse group of HQP, including 2 graduate and 5 undergraduate trainees. I will be conscious of using equitable and inclusive recruitment and mentoring practices. Impact The recent boom in the cell therapy sector, including the launch of the Centre for Commercialization of Regenerative Medicine and BlueRock Therapeutics in Canada, have increased the need to produce large quantities of cells. This work addresses a major challenge in the cell manufacturing pipeline, with a novel quality control strategy to maintain cell integrity. Our findings will be broadly applicable to bioprocesses, including protein, virus, and biopharmaceutical production.