Quantifying Host-Circuit Interactions with a Mechanistic Chassis Model

Cells have finite resources. Committing resources to one task thus reduces the amount of resource available to other tasks. Intracellular processes consequently do not work in isolation but continually interact with the rest of the cell.

If we aim to design complex synthetic circuits with predictable functions then we need to understand how these circuits compete for resources with their hosts. We thus need a comprehensive and quantitative understanding of these interactions. Host-circuit interactions can alter the designed function of a circuit, reduce the fitness of the host, and ultimately impose a negative selection pressure on cells with functioning synthetic circuits. Although mathematical modelling is an integral part of synthetic biology's design cycle, most models do not include explicit interactions with the host. These models cannot predict the impact of host-circuit interactions, resulting in an inefficient design process and lengthy trial-and-error iterations to appropriately tune circuit expression.

Here we consider three trade-offs that because of limitations in levels of cellular energy, free ribosomes, and proteins are faced by all living cells and construct a mathematical model that comprises these trade-offs. Our model describes the mechanisms of protein synthesis and how cells extract resources from their environment. It further couples gene expression with growth rate and growth rate with a growing population of cells. We show that the model recovers Monod's law for the growth of microbes and two other empirical relationships connecting growth rate to the mass fraction of ribosomes.

Our model can be used as a tool to quantify host-circuit interactions for the 'host-aware' design of synthetic gene circuits. It predicts the reallocation of proteome to accommodate the extra resource demand by a circuit, the resulting drop in growth rate and the quality of the circuit's functionality in response to environmental factors. The interplay between a circuit, its host, and the host's environment can be directly incorporated into the design to minimize the impact of cellular trade-offs and resource competition on the circuit function.