Cell size control and homeostasis is a long-standing subject in biology. Recent experimental work provides extensive evidence for a simple, quantitative size homeostasis principle coined adder (as opposed to sizer or timer). The adder principle provides unexpected insights into how bacteria maintain their size without employing a feedback mechanism. We review the genesis of adder and recent cell size homeostasis study on evolutionarily divergent bacterial organisms and beyond. We propose new coarse-grained approaches to understand the underlying mechanisms of cell size control at the whole cell level.
Highlights d Purification of biologically functional human IGF-1R in fulllength d Cryo-EM structures of insulin or IGF-1 bound human IGF-1R d Hormone induces the formation of active IGF-1R assembly
We examine five quantitative models of the cell-cycle and cell-size control in Escherichia coli and Bacillus subtilis that have been proposed over the last decade to explain single-cell experimental data generated with high-throughput methods. After presenting the statistical properties of these models, we test their predictions against experimental data. Based on simple calculations of the defining correlations in each model, we first dismiss the stochastic Helmstetter-Cooper model and the Initiation Adder model, and show that both the Replication Double Adder (RDA) and the Independent Double Adder (IDA) model are more consistent with the data than the other models. We then apply a recently proposed statistical analysis method and obtain that the IDA model is the most likely model of the cell cycle. By showing that the RDA model is fundamentally inconsistent with size convergence by the adder principle, we conclude that the IDA model is most consistent with the data and the biology of bacterial cell-cycle and cell-size control. Mechanistically, the Independent Adder Model is equivalent to two biological principles: (i) balanced biosynthesis of the cell-cycle proteins, and (ii) their accumulation to a respective threshold number to trigger initiation and division.
The reference point for cell-size control in the cell cycle is a fundamental biological question. We previously reported that we were unable to reproduce the conclusions of Witz et al.’s eLife paper (Witz, van Nimwegen, and Julou 2019) entitled, “Initiation of chromosome replication controls both division and replication cycles in E. coli through a double-adder mechanism”, despite extensive efforts. In this ‘replication double adder’ (RDA) model, both replication and division cycles are determined via replication initiation as the sole implementation point of size control. Witz et al. justified the RDA model using a type of correlation analysis (the “I-value analysis”) that they developed. By contrast, we previously showed that, in both Escherichia coli and Bacillus subtilis, replication initiation and cell division are determined by balanced biosynthesis of key cell cycle proteins (e.g., DnaA for initiation and FtsZ for cell division) and their accumulation to their respective threshold numbers, which Witz et al. coined the ‘independent double adder’ (IDA) model. The adder phenotype is a natural quantitative consequence of these mechanistic principles. In a recent bioRxiv response to our report, Witz and colleagues explicitly confirmed two important limitations of the I-value analysis: (1) it is only applicable to non-overlapping cell cycles, wherein E. coli is known to deviate from the adder principle, and (2) it is only applicable to select biological models and, for example, cannot evaluate the IDA model. These limitations of the I-value analysis were not explained in the original eLife paper and were overlooked during the review process. In this report, we show using data analysis, mathematical modeling, and experiments why the I-value analysis - in its current implementation - cannot compare different biological models. Furthermore, the RDA model is incompatible with the adder principle and is not broadly supported by experimental data. For completeness, we also provide a detailed point-by-point response to Witz et al.’s response (Witz, Julou, and van Nimwegen 2020) in the Supplemental Information.
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