RT Journal Article
SR Electronic
T1 Programmable Mixed-Signal Biocomputers in Mammalian Cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.07.495130
DO 10.1101/2022.06.07.495130
A1 Justin H. Letendre
A1 Benjamin H. Weinberg
A1 Marisa Mendes
A1 Jeffery M. Marano
A1 K. J. William Benman
A1 Rachel Petherbridge
A1 Kamila Drezek
A1 Samantha E. Koplik
A1 Alexandra Piñeiro
A1 Wilson W. Wong
YR 2022
UL http://biorxiv.org/content/early/2022/06/07/2022.06.07.495130.abstract
AB Living cells perform sophisticated computations that guide them toward discrete states. Synthetic genetic circuits are powerful tools for programing these computations, where transcription-regulatory networks and DNA recombination are the two dominant paradigms for implementing these systems. While each strategy exhibits unique strengths and weaknesses, integrating both into one seamless design framework would enable advanced gene circuit designs intractable with either approach alone. Here, we present Computation via Recombinase Assisted Transcriptional Effectors (CREATE), which leverages site-specific recombination to perform robust logic on discreet computational layers and programmable transcription factors that connect these layers, allowing individual calculations to contribute toward larger operations. We demonstrate the functionality of CREATE by producing sophisticated circuits using a simple plug- and-play framework, including 189 2-input-3-output circuits, modular digital-to-analog signal converters, a 2-bit multiplier circuit, and a digital and analog mixed-signal generator. This work establishes CREATE as a versatile platform for programming complex signal processing systems capable of high-fidelity logic computation and tunable control over circuit output levels.One-Sentence Summary We present a minimal and robust genetic circuit platform for programming cells with sophisticated signal processing capabilities.Competing Interest StatementWWW is a co-founder and shareholder of Senti Biosciences. BHW is a current employee of Tessera Therapeutics. JHL is a current employee of Strand Therapeutics. All other authors declare no competing interests.