BacSim, a simulator for individual-based modelling of bacterial colony growth

Abstract

The generic, quantitative, spatially explicit, individual-based model BacSim was developed to simulate growth and behaviour of bacteria. The potential of this approach is in relating the properties of microscopic entities - cells - to the properties of macroscopic, complex systems such as biofilms. Here, the growth of a single Escherichia coli cell into a colony was studied. The object-oriented program BacSim is an extension of Gecko, an ecosystem dynamics model which uses the Swarm toolkit for multi-agent simulations. The model describes bacterial properties including substrate uptake, metabolism, maintenance, cell division and death at the individual cell level. With the aim of making the model easily applicable to various bacteria under different conditions, the model uses as few as eight readily obtainable parameters which can be randomly varied. For substrate diffusion, a two-dimensional diffusion lattice is used. For growth-rate-dependent cell size variation, a conceptual model of cell division proposed by Donachie was examined. A mechanistic version of the Donachie model led to unbalanced growth at higher growth rates, whereas including a minimum period between subsequent replication initiations ensured balanced growth only if this period was unphysiologically long. Only a descriptive version of the Donachie model predicted cell sizes correctly. For maintenance, the Herbert model (constant specific rate of biomass consumption) and for substrate uptake, the Michaelis-Menten or the Best equations were implemented. The simulator output faithfully reproduced all input parameters. Growth characteristics when maintenance and uptake rates were proportional to either cell mass or surface area are compared. The authors propose a new generic measure of growth synchrony to quantify the loss of synchrony due to random variation of cell parameters or spatial heterogeneity. Variation of the maximal uptake rate completely desynchronizes the simulated culture but variation of the volume-at-division does not. A new measure for spatial heterogeneity is introduced: the standard deviation of substrate concentrations as experienced by the cells. Spatial heterogeneity desynchronizes population growth by subdividing the population into parts synchronously growing at different rates. At a high enough spatial heterogeneity, the population appears to grow completely asynchronously.