Design of Modular Cell Systems for Biocatalysis with Multi-Objective Optimization

Modular design has been the cornerstone of contemporary engineering, enabling efficient production of exchangeable parts that interact in a reproducible manner to constitute functional systems. In this thesis, we transfer engineering modular design principles to the emerging fields of synthetic biology and metabolic engineering, that have promising applications to address problems related to health, energy, security, and the environment.We focus on microbial biocatalysis which can become a renewable and lower-cost replacement of traditional chemical synthesis processes. This thesis begins with an interdisciplinary review and perspective of the concepts, methodology, and applications of modular design. Then, we develop a conceptual, mathematical, and algorithmic framework based on multi-objective optimization theory to design modular cell biocatalysts. The proposed framework is used to design modular cell systems for renewable production of diverse biofuels and biochemicals, using genome-scale metabolic models of the organisms Escherichia coli and Clostridium thermocellum to simulate metabolic phenotypes. Overall, this thesis addresses the current modular design interest in synthetic biology through development of novel design principles and quantitative tools. We anticipate this modular cell design approach will not only bring whole-cell biocatalysis closer to being an industrially competitive technology, but also provide tools to understand the natural modular architectures of metabolic networks designed by evolution for billions of years under biological constraints.