Chure, G. D.; de Silva, R. T.; Sharma, R.; Lanz, M.; Cremer, J.

Understanding how cells regulate their growth rate, macromolecular composition, and size have been central topics in the study of microbial physiology for the better part of a century. However, we lack a mechanistic understanding of how cells so tightly coordinate biosynthesis and size control across diverse environments. In this work, we present a biophysical model of cell size control that quantitatively predicts how rod-shaped bacterial cells such as E. coli regulate their surface-to-volume ratio as a function of their composition. Central to this theory is a biochemical constraint that the protein density within the cell membranes and the macromolecular density within the cell cytoplasm are strictly controlled and kept at a constant ratiometric value. Through a reanalysis of more than 30 published data sets coupled with our own experiments, we demonstrate that this theory quantitatively predicts how the surface-to-volume ratio scales with the total RNA-to-protein ratio. We further test and confirm this theory by directly adjusting the RNA-to-protein ratio through genetic control of cellular ppGpp concentrations. This work demonstrates that cellular composition, rather than the growth rate, drives the regulation of cell geometry and provides a candidate biophysical mechanism for how cell size homeostasis is manifest.