# Traceless Regulation of Genetic Circuitry

## TL;DR

This paper reviews how physical cues like light and electricity can control genetic circuits without leaving molecular traces, offering precise and flexible regulation for various applications.

## Contribution

The paper provides a comprehensive review of traceless gene switches, highlighting their advantages and challenges in modern synthetic biology.

## Key findings

- Traceless gene switches offer higher specificity and spatiotemporal resolution compared to traditional molecular methods.
- Physical cues like light and electricity are compatible with bioelectronic interfaces, enabling new applications in electrogenetics.
- The review identifies current translational barriers and prospects for traceless switches across multiple disciplines.

## Abstract

The advent of synthetic biology, enabling the construction of synthetic genetic circuitry with designed functionality, has has a revolutionary impact on medicine, agriculture, sustainable energy, and the industrial production of high‐value compounds over the last few decades. Gene switches have an indispensable role as regulators of such systems. Despite the early introduction of chemically inducible switches to regulate genetic circuitry, ‘traceless’ physical cues (e.g., light, heat, sound, magnetism, electricity, and mechanical force) can provide greater specificity, higher spatiotemporal resolution, more flexible switching patterns, and better compatibility with bioelectronic interfaces, which is of particular significance given the rise of electrogenetics. Indeed, traceless gene switches are on a path to become universal biological control ports interfacing physiology with the electronic world. In this review, we discuss the impact, challenges, and prospects of physically inducible, traceless gene switches in the context of recent cutting‐edge applications.

Energy‐based, as opposed to molecular, control offers unprecedented improvements in key circuit parameters. This review summarizes the fundamentals of such traceless switches, categorizes them by trigger modalities, and compares and contrasts distinct advantages as well as shortcomings of each kind. Subsequent sections highlight current translational barriers and outline prospective applications across different disciplines.