摘要：SummaryIn balanced exponential growth, bacteria maintain many properties statistically stable for a long time: cell size, cell cycle time, and more. As these are strongly coupled variables, it is nota-prioriobvious which are directly regulated and which are stabilized through interactions. Here, we address this problem by separating timescales in bacterial single-cell dynamics. Disentangling homeostatic set points from fluctuations around them reveals that some variables, such as growth-rate, cell size and cycle time, are “sloppy” with highly volatile set points. Quantifying the relative contribution of environmental and internal sources, we find that sloppiness is primarily driven by the environment. Other variables such as fold-change define “stiff” combinations of coupled variables with robust set points. These results are manifested geometrically as a control manifold in the space of variables: set points span a wide range of values within the manifold, whereas out-of-manifold deviations are constrained. Our work offers a generalizable data-driven approach for identifying control variables in a multidimensional system.Graphical abstractDisplay OmittedHighlights•Temporal averaging over lineages disentangles homeostatic set points from noise•The environment is revealed as the dominant source of set point variability•Cellular variable set points exhibit a range of behaviors from sloppy to stiff•Geometry of homeostatic control manifold is identified in cellular variable spaceMicrobiology; Systems biology
