The question of “What is essential for life?” is one of the most fundamental questions we face. The complete reconstruction of a minimal cell in silico is key to fully understanding and identifying underlying regulatory and organizational concepts central to life. The success of whole organism genome sequencing and high-throughput measurements provides an opportunity for system-level analysis of whole organisms, or what has been termed “systems biology”. Systems biology investigates the behavior of all of the elements in a biological system while it is functioning. As a systems biology approach, the Minimal Cell Model (MCM) depicts the total functionality of a minimal cell and its explicit response to perturbations in its environment.
We propose a framework for establishing the minimum number of genes necessary to accomplish a given metabolic function by drawing on the genetic repertoire of a range of bacterial species. These gene sets can be integrated with our existing models of bacteria to form “hybrid” bacterial cell models. An initial step in this approach was the development of a whole-cell coarse-grained model which explicitly links DNA replication, metabolism, and cell geometry with the external environment. A hybrid model can then be constructed from chemically-detailed and genome-specific subsystems, called modules, inserted into the original coarse-grained model. The project proposed here includes two main parts: 1) Establishing a minimal gene set, and 2) Development of novel algorithms that facilitate rapid addition of chemically and genetically detailed modules to the hybrid cell models.