Small-molecule regulation of gene expression is intrinsic to cellular function and indispensable to the construction of new biological sensing, control and expression systems. However, there are currently only a handful of strategies for engineering such regulatory components and fewer still that can give rise to an arbitrarily large set of inducible systems whose members respond to different small molecules, display uniformity and modularity in their mechanisms of regulation, and combine to actuate universal logics.

In a Nature Biotechnology paper, researchers in the Arkin Lab describe an approach for small-molecule regulation of transcription based on the combination of cis-regulatory leader-peptide elements with genetically encoded unnatural amino acids. In their system, any genetically encoded unnatural amino acid (UAA) can be used as a small-molecule attenuator or activator of gene transcription, and the logics intrinsic to the network defined by expanded genetic codes can be actuated.

In a related commentary, Erika Pastrana notes that "one of the exciting capabilities of this system is its modularity and the possibility of making combinatorial logics with it." Lead author Chang Liu of the Arkin Lab describes it like a train set: “it works as if we are building railroad switches; you can add an arbitrary number of individual switches that respond to a given unnatural amino acid, each of which controls whether the train continues moving in one direction or not, and the movement of the train integrates the decisions made at each switch,” he explains. A second advantage is that this system relies on components engineered for expanded genetic codes and as such, the number of unnatural amino acid–induced switches that could be made is large and quickly expanding.

Pastrana notes that this type of research teaches us how the knowledge obtained from basic science studies—here aimed at understanding how microbes control transcription to survive in the world—can be imaginatively put into practice for the building of tools that will one day be of practical value to humans.