A Synthetic Microbial Operational Amplifier.

Synthetic biology has created oscillators, latches, logic gates, logarithmically linear circuits, and load drivers that have electronic analogs in living cells. The ubiquitous operational amplifier, which allows circuits to operate robustly and precisely has not been built with biomolecular parts. As in electronics, a biological operational-amplifier could greatly improve the predictability of circuits despite noise and variability, a problem that all cellular circuits face. Here, we show how to create a synthetic three-stage inducer-input operational amplifier with a fast CRISPR-based differential-input push-pull stage, a slow transcription-and-translation amplification stage, and a fast-enzymatic output stage. Our "Bio-OpAmp" uses only 5 proteins including dCas9. It expands the toolkit of fundamental analog circuits in synthetic biology and provides a simple circuit motif for robust and precise molecular homeostasis.