This INSPIRE award is partially funded by the Systems and Synthetic Biology Program and the Cellular Dynamics and Function Program in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Science; and the Biophotonics Program and Biomedical Engineering Program in the Division of Chemical, Bioengineering, Environmental, and Transport System in the Directorate for Engineering. Intellectual Merit: In this INSPIRE project, unique concepts from several disciplines are combined in a novel way to give a consistent theoretical framework for the analysis, design, construction and evolution of metabolic networks. First, the proposed work builds on the premise that metabolic networks can be discretized into fundamental pathways or elementary modes. Cells function only according to these elementary modes or combinations of modes in compliance with the mass conservation law. These unique, discrete metabolic states of a network can be rigorously evaluated with computational tools to reveal all the possibilities that a cell can perform. Because the entire property space of a cell is known, the design of a metabolic network can be carried out on a completely rational basis and then implemented with molecular biology techniques. Second, the Maximum Entropy Production principle (MEP) predicts that the most probable metabolic state is reached when the usage of the individual, discrete elementary modes is distributed according to the Boltzmann distribution law. Third, when the predictable most probable state, which is computed from the distributed usage of elementary modes, is compared with the current measurable state of the network, it is possible to predict what reaction will be altered during the course of evolution. Thus, this research has far reaching implications and, therefore, requires careful investigation to prove its general validity. If proven to be valid, this represents a design principle in synthetic biology that needs to be followed in order to engineer robust, stable systems that do not evolve further in time. Broader Impacts: This research has the potential to transform the field of metabolic engineering in several significant ways. For example, biotechnology processes that produce valuable chemicals, including pharmaceuticals or biofuels, may be enhanced. The proposed study could also provide a platform for the sequestration and transformation of carbon dioxide into isobutanol, the production of carotenoids and bioethanol from biomass. It would further impact society by providing advanced training to the next generation of scientists, including high school, undergraduates, graduate, and post-graduate students. Most importantly, the project would lay the foundation for the scientific community to further advance and apply these groundbreaking principles in novel ways.
