Systematic stem cell bioprocess engineering

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Bioprocess engineering of cell based manufacturing represents a next wave in the development of biologic treatments. Whether or not these products ever reach the market depends upon technologies to manufacture cells in a robust and cost effective manner. Stem cells play an important role as the `raw material' in manufacturing cells, however the fact that the product is living cells brings forward a unique set of manufacturing and control challenges. Stem cells must be directed down the appropriate path to generate the cell types needed. Pluripotent stem cells (PSC) are a powerful system as they can be expanded in culture indefinitely while retaining the potential to differentiate into almost any mature cell type when placed under the right conditions. They offer immense promise as a `universal source' for cell manufacturing. To realize this promise, bioengineering fundamentals including bioreactor design, process control, and computational modelling must be combined with knowledge of developmental biology and 3D tissue organisation. These factors instruct our long-term goal of this research program which is to develop innovative cell based technologies to promote self-organized functional behaviour from PSC for manufacturing blood cell products. We will focus on developing microfabrication, bioreactor, and other bioengineering technologies to robustly control spatial temporal organization of cell differentiation in 3D systems. Understanding the spatial and temporal signaling events leading to asymmetric cell fate decisions will allow us to identify bioprocess control points that we can use to promote desirable differentiation trajectories to go from PSC to differentiated cells in vitro. This will ultimately enable scaled-up cell production, however, often that involves heterogeneous cell populations where competing growth rates and culture requirements yield continuously changing and unstable cultures, necessitating control strategies. We will engineer synthetic biology circuits in PSC to integrate multiple inputs and drive complex gene expression programs to direct cell fate during blood induction and differentiation, toward our desired end point in a scalable way. This represents a novel layer of bioprocess control, beyond standard approaches of soluble factor addition. Real-time, dynamic, and dose-control of signaling factors will create a more homogeneous culture microenvironment, thereby improving our ability to direct differentiation, ensure target cell expansion, and reduce output variability. The proposed research program will develop technologies that enable the emerging Canadian cell manufacturing industry, and will support the training of a diverse group of >6 qualified researchers, using equitable and inclusive recruitment and mentoring practices. These personnel will be ideally suited to contribute to high value next-generation industrial biotechnology manufacturing processes.