Lecture Series: Engineering next generation mammalian cells for biotherapeutics with systems and synthetic biology

Abstract: Over the past couple decades, biologics have emerged as essential therapeutics. Indeed, the majority of the top selling drugs are recombinant proteins, and growth in gene an cell therapies has been accelerating. Mammalian cells have been particularly important. However, the complexity of these cells and the associated drug products have made it more difficult to control their quality, safety, and affordability. To address this, we have established tools and platforms to engineer Chinese hamster ovary (CHO) cells, the predominant chassis in the biopharmaceutical industry. This has included efforts to sequence and annotate the Chinese hamster genome, map out the cellular pathways driving CHO cell growth, protein secretion and glycosylation, and deploy powerful genome editing tools to engineer gene circuits to enhance cell phenotypes. Using these resources with novel systems biology algorithms, we have successfully deployed complex multi-gene modifications to engineer metabolism and protein synthesis in CHO cells. Through this we have eliminated toxic metabolic byproducts limiting cell growth and protein production, boosted productivity, and demonstrated that the glycosylation of therapeutic glycoproteins can be effectively controlled to obtain higher quality drugs. Thus, systems and synthetic biology tools can be effectively deployed in mammalian cells for diverse discovery and the development and manufacturing of high-value therapeutics.