Cell-to-Cell Communication Circuits: Quantitative Analysis of Synthetic Logic Gates.

One of the goals in the field of synthetic biology is the construction of cellular computation devices that could function in a manner similar to electronic circuits. To this end, attempts are made to create biological systems that function as logic gates. In this work we present a theoretical quantitative analysis of a synthetic cellular logic-gates system, which has been implemented in cells of the yeast Saccharomyces cerevisiae (Regot et al., 2011). It exploits endogenous MAP kinase signaling pathways. The novelty of the system lies in the compartmentalization of the circuit where all basic logic gates are implemented in independent single cells that can then be cultured together to perform complex logic functions. We have constructed kinetic models of the multicellular IDENTITY, NOT, OR, and IMPLIES logic gates, using both deterministic and stochastic frameworks. All necessary model parameters are taken from literature or estimated based on published kinetic data, in such a way that the resulting models correctly capture important dynamic features of the included mitogen-activated protein kinase pathways. We analyze the models in terms of parameter sensitivity and we discuss possible ways of optimizing the system, e.g., by tuning the culture density. We apply a stochastic modeling approach, which simulates the behavior of whole populations of cells and allows us to investigate the noise generated in the system; we find that the gene expression units are the major sources of noise. Finally, the model is used for the design of system modifications: we show how the current system could be transformed to operate on three discrete values.