Metabolism is inherently stochastic at the cellular level. Whether cells actively regulate processes in response to these random internal variations is a fundamental problem that remains unaddressed, yet critical to understanding biological homeostasis. In this preprint, we show that in E. coli cells, expression of the main catabolic enzymes is continuously adjusted in response to metabolic fluctuations under constant external conditions. This noise feedback is performed by the cAMP-CRP system, which controls transcription of the catabolic enzymes by modulating concentrations of the second messenger cAMP upon changes in metabolite abundance. Using time-lapse microscopy, genetic constructs that selectively disable cAMP-CRP noise feedback, and mathematical modelling, we show how fluctuations circulate through this hybrid metabolic-genetic network at sub cell-cycle timescales.

The Interplay between Metabolic Stochasticity and Regulation in Single E. Coli Cells.
Martijn Wehrens*, Laurens H.J. Krah*, Benjamin D. Towbin, Rutger Hermsen, and Sander J. Tans.
BioRxiv, January 1, 2022, 2022.08.29.505271.
https://www.biorxiv.org/content/10.1101/2022.08.29.505271v1

In bacterial cells, gene expression, metabolism, and growth are highly interdependent and tightly coordinated. As a result, stochastic fluctuations in expression levels and instantaneous growth rate show intricate cross-correlations. These correlations are shaped by feedback loops, trade-offs and constraints acting at the cellular level; therefore a quantitative understanding requires an integrated approach. To that end, we have developed a mathematical model describing a cell that contains multiple proteins that are each expressed stochastically and jointly limit the growth rate. Conversely, metabolism and growth affect protein synthesis and dilution. Thus, expression noise originating in one gene propagates to metabolism, growth, and the expression of all other genes. Nevertheless, under a small-noise approximation many statistical quantities can be calculated analytically. We demonstrate that the predicted cross-correlations between gene expression and growth rate are in broad agreement with published measurements.

Noise Propagation in an Integrated Model of Bacterial Gene Expression and Growth.
Istvan T. Kleijn, Laurens H. J. Krah, and Rutger Hermsen. 
PLOS Computational Biology 14, no. 10 (October 5, 2018): e1006386.
https://doi.org/10.1371/journal.pcbi.1006386.

The spatial structure of natural populations is key to many of their evolutionary processes. Formal theories analysing the interplay between natural selection and spatial structure have mostly focused on populations divided into distinct, non-overlapping groups. Most populations, however, are not structured in this way, but rather (self-)organise into dynamic patterns unfolding at various spatial scales. We developed a mathematical framework that quantifies how patterns and processes at different spatial scales contribute to natural selection in such populations. To illustrate the use of this new multiscale selection framework, we have applied it to two simulation models of the evolution of traits known to be affected by spatial population structure: altruism and pathogen transmissibility. In both models, the spatial decomposition of selection reveals that local and interlocal selection can have opposite signs, thus providing a mathematically rigorous underpinning to intuitive explanations of how processes at different spatial scales may compete.

Multiscale Selection in Spatially Structured Populations.
Doekes, Hilje M., and Rutger Hermsen. 
bioRxiv, December 21, 2021.
https://doi.org/10.1101/2021.12.21.473617.

A range of Bacillus-infecting temperate bacteriophages use small-molecule communication to inform their lysis-lysogeny decision. We have developed and studied a mathematical model of the ecological and evolutionary dynamics of such viral communication. We thus showed that a communication strategy in which phages use the lytic cycle early in an outbreak (when susceptible host cells are abundant) but switch to the lysogenic cycle later (when susceptible cells become scarce) is favored over a bet-hedging strategy in which cells are lysogenised with constant probability. However, such phage communication can evolve only if phage-bacteria populations are regularly perturbed away from their equilibrium state, so that acute outbreaks of phage infections in pools of susceptible cells continue to occur.

Repeated outbreaks drive the evolution of bacteriophage communication
Hilje M Doekes, Glenn A Mulder, Rutger Hermsen
eLife 10:e58410 (2021)
https://doi.org/10.7554/eLife.58410