Stepping both forward, and back: How cells might sense right from abundant wrong

Cells adapt to varying environments by recognizing specific biochemical signals among a sea of similar but spurious molecules. Growing evidence attests that cells accomplish this exquisite molecular recognition by investing energy along molecular binding and discrimination steps to amplify the affinity differences between correct and incorrect signals. The performance of such discriminatory strategies depends critically on both the relative affinities of these signals and their abundances. While insightful analyses have studied how affinities shape sensory performance, much more demands to be discovered about how significantly unequal abundances of correct and incorrect signals transform sensory tradeoffs. Here, we explore how simple sensory cascades unify a class of classical and nontraditional discriminatory networks. We learn how the resulting generalized tradeoffs between speed, fidelity, and dissipation change dramatically across biophysical and architectural parameters. Viewing these networks in light of differential signal abundances reveals fundamental differences between networks that otherwise appear to perform competitively. Next, we discuss simple, biologically-inspired and synthetically-realizable mechanisms that can make discrimination indifferent to signal concentrations. These findings clarify design principles for general discrimination networks, whether natural or synthetic.