@Article{ garcia2019, abstract = {Diversity of cellular metabolism can be harnessed to produce a large space of molecules. However, development of optimal strains with high product titers, rates, and yields required for industrial production is laborious and expensive. To accelerate the strain engineering process, we have recently introduced a modular cell design concept that enables rapid generation of optimal production strains by systematically assembling a modular cell with an exchangeable production module(s) to produce target molecules efficiently. In this study, we formulated the modular cell design concept as a general multiobjective optimization problem with flexible design objectives derived from mass balance. We developed algorithms and an associated software package, named ModCell2, to implement the design. We demonstrated that ModCell2 can systematically identify genetic modifications to design modular cells that can couple with a variety of production modules and exhibit a minimal tradeoff among modularity, performance, and robustness. Analysis of the modular cell designs revealed both intuitive and complex metabolic architectures enabling modular production of these molecules. We envision ModCell2 provides a powerful tool to guide modular cell engineering and sheds light on modular design principles of biological systems.}, author = {Garcia, Sergio and Trinh, Cong T}, doi = {10.1016/j.ymben.2018.09.003}, issn = {10967184}, journal = {Metabolic Engineering}, keywords = {Modular cell,Modular cell engineering,Modular design,Modularity,Multiobjective evolutionary algorithms,Multiobjective optimization,Production modules}, title = {{Multiobjective strain design: A framework for modular cell engineering}}, volume = {51}, year = {2019} } @Article{ garcia2019b, title = "Modular design: Implementing proven engineering principles in biotechnology", journal = "Biotechnology Advances", year = "2019", issn = "0734-9750", doi = "https://doi.org/10.1016/j.biotechadv.2019.06.002", url = "http://www.sciencedirect.com/science/article/pii/S0734975019300928", author = "Sergio Garcia and Cong T. Trinh", keywords = "Modular design, Modularity, Modular cell, Modular cell engineering, ModCell, Systems biology, Metabolic engineering, Synthetic biology, Robustness, Evolvability, Networks, Pareto optimality, Industrialization of biology, Microbial biocatalysis", abstract = "Modular design is at the foundation of contemporary engineering, enabling rapid, efficient, and reproducible construction and maintenance of complex systems across applications. Remarkably, modularity has recently been discovered as a governing principle in natural biological systems from genes to proteins to complex networks within a cell and organism communities. The convergent knowledge of natural and engineered modular systems provides a key to drive modern biotechnology to address emergent challenges associated with health, food, energy, and the environment. Here, we first present the theory and application of modular design in traditional engineering fields. We then discuss the significance and impact of modular architectures on systems biology and biotechnology. Next, we focus on the very recent theoretical and experimental advances in modular cell engineering that seeks to enable rapid and systematic development of microbial catalysts capable of efficiently synthesizing a large space of useful chemicals. We conclude with an outlook towards theoretical and practical opportunities for a more systematic and effective application of modular cell engineering in biotechnology." } @Article{ garcia2019c, author = {Garcia, Sergio and Trinh, Cong T.}, title = {Comparison of Multi-Objective Evolutionary Algorithms to Solve the Modular Cell Design Problem for Novel Biocatalysis}, journal = {Processes}, volume = {7}, year = {2019}, number = {6}, article-number= {361}, url = {https://www.mdpi.com/2227-9717/7/6/361}, issn = {2227-9717}, abstract = {A large space of chemicals with broad industrial and consumer applications could be synthesized by engineered microbial biocatalysts. However, the current strain optimization process is prohibitively laborious and costly to produce one target chemical and often requires new engineering efforts to produce new molecules. To tackle this challenge, modular cell design based on a chassis strain that can be combined with different product synthesis pathway modules has recently been proposed. This approach seeks to minimize unexpected failure and avoid task repetition, leading to a more robust and faster strain engineering process. In our previous study, we mathematically formulated the modular cell design problem based on the multi-objective optimization framework. In this study, we evaluated a library of state-of-the-art multi-objective evolutionary algorithms (MOEAs) to identify the most effective method to solve the modular cell design problem. Using the best MOEA, we found better solutions for modular cells compatible with many product synthesis modules. Furthermore, the best performing algorithm could provide better and more diverse design options that might help increase the likelihood of successful experimental implementation. We identified key parameter configurations to overcome the difficulty associated with multi-objective optimization problems with many competing design objectives. Interestingly, we found that MOEA performance with a real application problem, e.g., the modular strain design problem, does not always correlate with artificial benchmarks. Overall, MOEAs provide powerful tools to solve the modular cell design problem for novel biocatalysis.}, doi = {10.3390/pr7060361} }