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A mechanistic first--passage time framework for bacterial cell-division timing

How exponentially growing cells maintain size homeostasis is an important fundamental problem. Recent single-cell studies in prokaryotes have uncovered the adder principle, where cells on average, add a fixed size (volume) from birth to division. Interestingly, this added volume differs considerably among genetically-identical newborn cells with similar sizes suggesting a stochastic component in the timing of cell-division. To mechanistically explain the adder principle, we consider a time-keeper protein that begins to get stochastically expressed after cell birth at a rate proportional to the volume. Cell-division time is formulated as the first-passage time for protein copy numbers to hit a fixed threshold. Consistent with data, the model predicts that while the mean cell-division time decreases with increasing size of newborns, the noise in timing increases with size at birth. Intriguingly, our results show that the distribution of the volume added between successive cell-division events is independent of the newborn cell size. This was dramatically seen in experimental studies, where histograms of the added volume corresponding to different newborn sizes collapsed on top of each other. The model provides further insights consistent with experimental observations: the distributions of the added volume and the cell-division time when scaled by their respective means become invariant of the growth rate. Finally, we discuss various modifications to the proposed model that lead to deviations from the adder principle. In summary, our simple yet elegant model explains key experimental findings and suggests a mechanism for regulating both the mean and fluctuations in cell-division timing for size control.