Development and Application of Next Generation Synthetic Biology Tools

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A variety of micro-organisms including E. coli and S. cerevisiae (baker's yeast), are used in commercial bio-production processes to manufacture a number of products, ranging from high-value low-volume products, such bio-therapeutics (e.g. recombinant insulin), to mid-value products, (e.g. biocatalysts and specialised chemicals), to low-value bulk commodity products (e.g. succinic acid and biofuels). In addition, the same biotechnologies used in these production processes are commonly used in basic life science research. As such, the development of new gene control systems would be of great benefit in a number of applied and fundamental areas of biological and biomedical R&D. In particular, the research here seeks to develop novel protein production and metabolic engineering tools, and to demonstrate the applications of these novel synthetic biology tools in the context of the bioprocessing industry. Within the pharmaceutical sector, biopharmaceuticals constitute 7 out of the 10 bestselling products. The global protein-based biopharmaceutical market had sales worth $70b in 2010, and this figure is set to increase to $110b by 2015. The reasons for the increase in projected global sales are thus: i) many of the targets of these therapeutic proteins are deemed 'undruggable' by traditional small molecule approaches, ii) therapeutic proteins often have superior safety and efficacy profiles, iii) the development times on average are shorter for therapeutic proteins than traditional therapies, iv) there is often limited or absent competition. However, although biopharmaceuticals offer many health benefits along with substantial commercial opportunities, their production remains a significant technical challenge. Through this current study, I shall develop and demonstrate four important flavours of a novel gene co-expression technology, to allow multimeric protein products to be produced more effectively, along with the potential to provide a simpler and more efficient manufacturing process. Additionally, these co-expression technologies will be used to optimise a number of multivariate co-expression challenges, helping to guide metabolic engineering efforts. The outputs from this fellowship will lead to improved bioprocess efficiencies, with the potential to reduce both drug development times and manufacturing costs, and therefore the financial burden upon national healthcare providers. This research project will also generate technology and knowledge that will help maintain the UK's competitive edge, and will produce highly trained and skilled research personnel.