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According to Weber's law, our perception of sensations, such as light or sound, is based not on the absolute level of the stimulus but on the magnitude of the stimulus relative to the background level — explaining why, for example, you might not notice a lit bulb in a bright room but would easily spot the same light after dark. Three papers now present experimental and theoretical evidence that Weber's law also applies to individual cells, by showing that signalling pathways respond to fold-changes in sensor molecules.

Cohen-Saidon and colleagues previously developed a clonal line of human carcinoma cells in which the nuclear translocation of extracellular signal-regulated kinase 2 (ERK2), which can be used as a read-out of epidermal growth factor (EGF) signalling, could be followed by means of an ERK2–YFP reporter gene. In a new paper, they tracked the response of individual cells to EGF over time: basal levels of nuclear ERK2 vary widely among cells (on average by 30%), as does the absolute peak level of nuclear-translocated ERK2 after stimulation by EGF. Nevertheless, the ratio of stimulated to unstimulated nuclear ERK2 is similar among cells, which suggests that cells are responding — although it is unclear precisely how — to the relative levels of background and stimulated ERK2.

In a second paper, Goentoro and Kirschner investigated a similar issue by asking whether cells that are exposed to Wnt respond to the absolute levels of β-catenin that are induced, or to fold-changes in the level of this molecule. The authors modelled several perturbations (such as Axin1 overexpression) that alter the absolute level of β-catenin with or without inducing fold-changes, then verified their effects in a colon-cancer cell line. They subsequently applied these perturbations to Xenopus laevis embryos to assess their developmental response in vivo. Similarly to the ERK2 study, conditions that caused fold-changes in β-catenin caused dorsoventral patterning phenotypes and transcriptional changes in two downstream genes (siamois and xnr3), whereas those that affected only absolute levels did not — at least within a certain range.

What mechanisms might cells use to respond to such fold-changes? That is, how does a cell remember the basal level and compare it with the stimulated one? In their modelling work, Goentoro and colleagues identified a common network motif — the incoherent feedforward loop — that can behave as a fold-change detector: in this motif, an activator controls the expression of a target gene as well as a repressor of that gene. The authors show that the height and duration of target gene expression depends solely on the fold-changes in input, not on its absolute level.

Responding to fold-changes might be a general feature of biological sensors, as it could provide an effective mechanism for filtering out noise. Almost 200 years after Weber formulated his law we are now in a position to investigate its breadth and molecular basis.