Using stochastic cell division and death to probe minimal units of cellular replication

The invariant cell initiation mass measured in bacterial growth experiments has been interpreted asa minimal unit of cellular replication. Here we argue that the existence of such minimal unitsinduces a coupling between the rates of stochastic cell division and death. To probe this couplingwe tracked live and dead cells in Escherichia coli populations treated with a ribosome-targetingantibiotic. We find that the growth exponent from macroscopic cell growth or decay measurements canbe represented as the difference of microscopic first-order cell division and death rates. Theboundary between cell growth and decay, at which the number of live cells remains constant overtime, occurs at the minimal inhibitory concentration (MIC) of the antibiotic. This state appearsmacroscopically static but is microscopically dynamic: division and death rates exactly cancel atMIC but each is remarkably high, reaching 60% of the antibiotic-free division rate. A stochasticmodel of cells as collections of minimal replicating units we term ‘widgets’ reproduces bothsteady-state and transient features of our experiments. Sub-cellular fluctuations of widget numbersstochastically drive each new daughter cell to one of two alternate fates, division or death.First-order division or death rates emerge as eigenvalues of a stationary Markov process, and can beexpressed in terms of the widget’s molecular properties. High division and death rates at MIC arisedue to low mean and high relative fluctuations of widget number. Isolating cells at the threshold ofirreversible death might allow molecular characterization of this minimal replication unit.