Fundamental limitation of the instantaneous approximation in fold-change detection models

The phenomenon of fold-change detection, or scale-invariance, is exhibited by a variety of sensory systems, in both bacterial and eukaryotic signalling pathways. It has been often remarked in the systems biology literature that certain systems whose output variables respond at a faster time scale than internal components give rise to an approximate scale-invariant behaviour, allowing approximate fold-change detection in stimuli. This study establishes a fundamental limitation of such a mechanism, showing that there is a minimal fold-change detection error that cannot be overcome, no matter how large the separation of time scales is. To illustrate this theoretically predicted limitation, the authors discuss two common biomolecular network motifs, an incoherent feedforward loop and a feedback system, as well as a published model of the chemotaxis signalling pathway of Dictyostelium discoideum.