Growth Mechanics and the emergence of metabolic oscillations in growing cells

Abstract

Unicellular organisms exhibit oscillations in metabolic activity and gene expression, even when growing in static media with no external dynamic stimuli. The cause and possible function of these endogenous oscillations are still not fully understood, with different hypotheses including its origin as a byproduct of misguided regulatory processes. To investigate whether such oscillations could be functional rather than incidental, we introduce Growth Mechanics (GM) as a general mathematical framework to study the dynamic resource allocation in models of whole self-replicating cells, built exclusively on the first principles of fitness maximization, mass conservation, nonlinear reaction kinetics, and constant cell density. Inspired by the physical theory of classical mechanics, we first find the simplest mathematical description the problem in terms of generalized coordinates, and then solve the optimal dynamical resource allocation for cells growing in any given medium using the Euler-Lagrange equation, resulting in analytical "equations of optimal motion" (EOM) that apply for growing cells in general. We then solve these equations numerically for simple growing cell models and show that, in general, oscillations are necessary to maximize cell fitness by getting more saturated reactions at the time they are most needed. We also show how the EOM predict the emergence of quasi-linear dependencies of the metabolic oscillation frequency and the ribosome protein allocation with the cell growth rate at different growth media, in line with the "growth laws" observed experimentally in microbes. This work contributes to the foundations of theoretical cell biology with general quantitative principles and a bridge to theoretical tools of physics.