Growth control as a central regulator for tuning the cellular context

Abstract The cellular context decisively shapes genetic circuit performance, but the interplay between host and circuit remains difficult to control rationally. To address this challenge, we replaced the native regulatory machinery of RNA polymerase (RNAP) from the bacteria Pseudomonas putida KT2440 with an inducible system, enabling tunable growth regulation. This was achieved by placing the $$\beta$$ and $$\beta$$ ’ subunits under the control of the XylS–Pm inducible system, in a manner that cell growth can be tuned into distinct stable states using the cognate inducer 3-methylbenzoate. We correlated genetic circuit behaviour with the cell’s growth state by observing reporter gene expression and the performance of genetic NOT gates, finding that the modulation of contextual dependencies is specific to the circuit components. Furthermore, a mathematical model classified this modulation into three categories based on how RNAP availability shapes host–circuit interaction. Additionally, growth control was used as an input for a two-input circuit building a NAND gate with the potential for morphological computing, where the cell’s physical body undertakes information processing. Our findings suggest that growth control could be used as an engineering parameter with potential applications in the optimization of biocomputation, microbial consortia, and the development of digital twins.