Microbial Systems Biology

Michael L. Shuler, Patricia Foley, Jordan Atlas

One important aim of synthetic biology is to develop a self-replicating biological system capable of performing useful tasks. A mathematical model of a synthetic organism would greatly enhance its value by providing a platform in which proposed modifications to the system could be rapidly prototyped and tested. Such a platform would allow the explicit connection of genomic sequence information to physiological predictions. As an initial step toward this aim, a minimal cell model (MCM) has been formulated. The MCM is defined as a model of a hypothetical cell with the minimum number of genes necessary to grow and divide in an optimally supportive culture environment. It is chemically detailed in terms of genes and gene products, as well as physiologically complete in terms of bacterial cell processes (e.g., DNA replication and cell division). A mathematical framework originally developed for modeling Escherichia coli has been used to build the platform MCM. A MCM with 241 product-coding genes (those which produce protein or stable RNA products) is presented. This gene set is genomically complete in that it codes for all the functions that a minimal chemoheterotrophic bacterium would require for sustained growth and division. With this model, the hypotheses behind a minimal gene set can be tested using a chemically detailed, dynamic, whole-cell modeling approach. Furthermore, the MCM can simulate the behavior of a whole cell that depends on the cell's (1) metabolic rates and chemical state, (2) genome in terms of expression of various genes, (3) environment both in terms of direct nutrient starvation and competitive inhibition leading to starvation, and (4) genomic sequence in terms of the chromosomal locations of genes.