Genetic programs can be compressed and autonomously decompressed in live cells

Abstract

Fundamental computer science concepts have inspired novel information-processing molecular systems in test tubes1,2,3,4,5,6,7,8,9,10,11,12,13 and genetically encoded circuits in live cells14,15,16,17,18,19,20,21. Recent research has shown that digital information storage in DNA, implemented using deep sequencing and conventional software, can approach the maximum Shannon information capacity22 of two bits per nucleotide23. In nature, DNA is used to store genetic programs, but the information content of the encoding rarely approaches this maximum24. We hypothesize that the biological function of a genetic program can be preserved while reducing the length of its DNA encoding and increasing the information content per nucleotide. 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 circuit25 that comprises redundant DNA sequences and is therefore amenable for compression, as are many other complex gene circuits15,18,26,27,28. 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.

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Fig. 1: Mechanism of compression and decompression of a multi-input miRNA logic circuit.
Fig. 2: Optimization of the decompression process.
Fig. 3: Compression of three-input AND gate circuits.
Fig. 4: Compression of four-input AND gate circuits.

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Acknowledgements

The research was funded by the National Institutes of Health award 5R01CA155320 and by ETH Zürich. We thank B. Angelici for discussions and E. Shapiro for commenting on the manuscript.

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N.L. conceived research, performed experiments, analysed data, and wrote the paper. Y.B. conceived research, analysed data, supervised the project, and wrote the paper.

Corresponding author

Correspondence to Yaakov Benenson.

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Competing interests

The original miRNA circuit technology is protected by patents awarded to Y.B. and co-inventors (US patent no. 9458509). The output delay technology is pending, with N.L. and Y.B. listed as co-inventors.

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Lapique, N., Benenson, Y. Genetic programs can be compressed and autonomously decompressed in live cells. Nature Nanotech 13, 309–315 (2018). https://doi.org/10.1038/s41565-017-0004-z

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