Precision control by protein counting (not concentration sensing)*

Balanced biosynthesis is the hallmark of bacterial cell physiology, where the protein concentrations remain steady during cell elongation. This presents a challenge when attempting to model bacterial cell-cycle and cell-size controls, as the concentration-based models used for eukaryotes do not directly apply. In this seminar, I will delve into the initiator-titration model, a concept introduced three decades ago, which elucidates how bacteria can precisely and robustly control replication initiation by sensing the number of protein copies. At its heart, this model proposes a two-step Poisson process for initiation: first, the titration of initiator proteins by high-affinity chromosome sites, and then their accumulation at the replication origin in a manner akin to a first-passage-time process. This results in profoundly enhanced initiation synchrony, with a CV scaling of approximately 1/N, contrasting with the typical 1/√N scaling in the Poisson process, where N represents the total initiator proteins. The mechanism presented in this work provides a satisfying general solution to how the cell can achieve precision control without sensing protein concentrations, with broad implications from evolution to the design of synthetic cells.