We argue that quantized signaling may be a powerful strategy for cells. From ensuring reliable messaging, even in changing and noisy environments, to something akin to a molecular Morse code, where time-domain messages communicate complex environmental cues.

2. Once the receptor turns on it’s all the same: Regardless of species, each activated complex recruits a quantized number of kinases with the same dynamics. i.e., the “on” signal is stereotyped, suggesting each activated complex delivers a digital packet of signaling information into the cell.

1. Affinity shapes sensitivity: Species-specific affinity, or how tightly the receptor and IL-1β variant binds the human receptor, affects how sensitive the cells are to the cytokine in terms of the number and timing of receptor activation. This matches expectations from classical signaling.

We then used purified IL-1β from across a range of species and exposed human cells (engineered to express an endogenous reporter for activated signaling complexes) to each. By pairing live-cell imaging with computational models and single particle tracking we found two critical insights.

Using a mixture of phylogenetic and structural analysis, we found that IL-1β – a key inflammatory cytokine - from a panel of species is likely to engage productively with human receptors, albeit with different affinities.

In our preprint, we present results from what we call our “zoo experiment”. Here, @cmupittcompbio.bsky.social Ph.D. students Annie Kim and Benjamin Krummenacher explore whether naturally occurring variation between species could test whether cytokines follow the rules of classical signaling.

In classical cell signaling, the strength of a signal depends on how long a ligand interacts with its receptor – for a high affinity interaction the duration is longer, and so is the resulting signal. What happens then, when the ligand comes from a different species? Does the signal go through?