A Synthetic Operational Amplifier

Several electronic circuit motifs and devices including oscillators, latches, logic gates, logarithmically linear circuits, and load drivers have been designed and ported to biological systems and applications. However, the operational amplifier, which is a fundamental and the most popular electronic device in negative-feedback and regulatory loops, has never been ported to biology.

An Operational amplifier (OpAmp) implements a simple circuit building block wherein the voltage difference of its two control inputs are amplified with a large gain, and reported at its output terminal. This simple circuit becomes very powerful when connected to passive components and negative feedback loops, which makes it competent in all mathematical calculations including weighted summer, differentiator, integrator, etc. This versatility makes the operational amplifier incredibly important in making analog electronics and analog computation scalable, and context independent from an input-output point of view. Hence, operational amplifiers are as ubiquitous in integrated analog circuits as logic gates are in integrated digital circuits. Not surprisingly, currently nearly 10M operational amplifiers are sold every day.

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 3-stage inducer-input operational amplifier with a differential transcription-factor stage, a CRISPR-based push-pull stage, and an enzymatic output stage with just 5 proteins including dCas9. Our ‘Bio-OpAmp’ expands the toolkit of fundamental circuits available to bioengineers or biologists, and may shed insight into biological systems that require robust and precise molecular homeostasisand regulation.