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In the last few decades, scientists have learned how to manipulate the basic components of life, how to design biomolecular networks, how to evolve biomolecules with unique characteristics and how to direct and control cellular processes at the molecular level. Using this knowledge as a foundation, it is theoretically possible to conceive of designing biological constructs, which we refer to as cell-like entities (CLEs), that use custom engineered biological machinery to accomplish specified tasks. The practical challenge is: Can we fabricate biological constructs for specific purposes using the same principles and components found in natural biological systems? For example, can CLEs be designed to detect very low levels of specific chemicals and fluoresce to indicate their presence; can they be designed to synthesize functional chemicals on demand, or can they use engineered metabolic pathways to detoxify environmental pollutants? The building of CLEs that could accomplish these goals would result in fundamental breakthroughs in exploiting our understanding of cellular control systems and biochemical information processing. The concept of the CLE is based on understanding how the biochemical reactions network that we call a living cell functions, how is it controlled and what are the key processes and components that will provide unique functions when integrated. The goal is not to create a living organism, but to create a biological construct that utilizes the essence of living systems to provide a wide array of solutions to current technological and medical challenges., Prepared in cooperation with Wright State Univ. and URES, Inc., Dayton, OH.

This project under the DARPA BIOCOMP program integrated fundamental scientific investigations in the field of molecular systems biology, algorithm development for biomolecular modeling, and open source, object based software implementation. Major accomplishments were 1) experimental gene knockout strain investigations of the V.fisheri quorum sensing system that yielded a mathematical model of its regulatory proteins, 2) a model of stringent response in E.coli and M.tuberculosis describing the role of enzyme RelMtb, 3) a first example of reachability analysis applied to a biomolecular system (lactose induction), 4) a model of tetracycline resistance that discriminates between two possible mechanisms for tetracycline diffusion through the cell membrane, and 5) a new method for investigating the producibility of a metabolite by a network of chemical reactions from an available set of nutrients using sets of gene knockouts. Accomplishments in algorithm/implementation were 1) reachability and other metabolic analysis tools for non-linear biomolecular networks aiding construction of a hybrid systems-based abstraction, 2) a Systems Biology Markup Language compatible reachability algorithm using a piecewise multi-affine hybrid system method, and 3) a metabolic network producibility analysis algorithm for large scale metabolic networks predicting the possibility of producing a set of metabolites from a set of available nutrients, complementing biomass flux optimization., The original document contains color images.