Stringent Control Over Cytoplasmic and Membrane Densities Defines Cell Geometry In Escherichia coli
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.