Combining high throughput metabolomics with real-time biosensors to study the oxidative state in cell culture producing recombinant proteins.

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From basic chemicals to complex pharmaceuticals, many of today's products are created with the help of cells. Similar to the use of yeast in alcoholic fermentation, a large number of different cell types allow us to make products that would be too difficult or costly to manufacture through purely chemical means. While the goal of cell culture is to take advantage of cellular complexity for chemical or pharmaceutical production, the same complexity also poses a challenge - how can we improve on the production process to make new products at lower cost if we don't know what the cells are doing? The goal of the proposed research program is to improve on the current methods of cell culture monitoring and gain a deeper insight into cellular complexity with a particular focus on pharmaceutical production. First, it is necessary to identify and measure the chemicals (or metabolites) that the cells are using and determine how they are being used. In much the same way as a cow's feed will influence the quality and quantity of milk, the cell culture "feed" has a profound influence on what it is able to make. Second, it is necessary to get the cells to "talk" to the researchers. As it stands, many important cellular functions are completely invisible to both the naked eye and to analytical instruments. For this research, we will modify the cells so that they light up depending on their state - distinguishing between healthy and stressed cells as well as the conditions that are causing them problems. Combining a cost effective and rapid measurement of cellular metabolites with a quick and easy readout for cellular state will allow rapid development of improved feeding strategies for new and existing products. Although the final cost of pharmaceuticals or chemicals is dictated by many different factors, the collection of useful data that can build on existing knowledge is a considerable barrier to the development of new products and improvement of existing ones. In today's competitive environment, reducing the cost of research and development as well as manufacturing will be passed down to the consumer. This will be particularly important to spur the development of "generic" pharmaceuticals (referred to as "biosimilars" in cell culture production) as important pharmaceutical patents begin to expire. Canada stands to gain from this research on two different fronts. As the 10th largest world market for pharmaceuticals, reducing the cost of existing pharmaceutical products and the development of new ones will have a tangible effect on the everyday Canadian. As Canada is also home to a number of pharmaceutical companies that make use of cell culture production processes - including Eli Lilly, Merck, and Roche - reducing the material cost of research and development can also promote further investments into research activity, potentially generating more high skilled jobs.