Genetic programs can be compressed and autonomously decompressed in live cells

Abstract

Fundamental computer science concepts inspired novel information-processing molecular systems in test tubes ^{1– 13} and genetically-encoded circuits in live cells ^{14– 21} . Recent research showed that digital information storage in DNA, implemented using deep sequencing and conventional software, can approach the maximum Shannon information capacity ²² of 2 bits per nucleotide ²³ . DNA is used in nature to store genetic programs, but the information content of natural encoding rarely approaches this maximum ²⁴ . We hypothesize that the biological function of a genetic program can be preserved while reducing the length and increasing the information content of its DNA encoding. Here we support this hypothesis by describing an experimental procedure for compressing a genetic program and its subsequent autonomous decompression and execution in human cells. As a test-bed we choose an RNAi cell classifier circuit ²⁵ that comprises redundant DNA sequence and is therefore amenable for compression, as are many other complex gene circuits ^{15, 18, 26– 28} . In one example, we implement a compressed encoding of a ten-gene four-input AND gate circuit using only four genetic constructs. The compression principles applied to gene circuits can enable fitting complex genetic programs into DNA delivery vehicles with limited cargo capacity, and storing compressed and biologically inert programs in vivo for on-demand activation.