title: A population-based temporal logic gate for timing and recording chemical events.
abstract: Engineered bacterial sensors have potential applications in human health monitoring, environmental chemical detection, and materials biosynthesis. While such bacterial devices have long been engineered to differentiate between combinations of inputs, their potential to process signal timing and duration has been overlooked. In this work, we present a two-input temporal logic gate that can sense and record the order of the inputs, the timing between inputs, and the duration of input pulses. Our temporal logic gate design relies on unidirectional DNA recombination mediated by bacteriophage integrases to detect and encode sequences of input events. For an E. coli strain engineered to contain our temporal logic gate, we compare predictions of Markov model simulations with laboratory measurements of final population distributions for both step and pulse inputs. Although single cells were engineered to have digital outputs, stochastic noise created heterogeneous single-cell responses that translated into analog population responses. Furthermore, when single-cell genetic states were aggregated into population-level distributions, these distributions contained unique information not encoded in individual cells. Thus, final differentiated sub-populations could be used to deduce order, timing, and duration of transient chemical events.
authors.affiliation: Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA vhsiao@caltech.edu.
authors.forename: Victoria
authors.identifier: 0000-0001-9297-1522
authors.initials: V
authors.lastname: Hsiao
authors.affiliation: Applied Physics and Physico-Informatics, Keio University, Yokohama, Kanagawa, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hori
authors.affiliation: Computation & Neural Systems, California Institute of Technology, Pasadena, CA, USA.
authors.forename: Paul Wk
authors.initials: PW
authors.lastname: Rothemund
authors.affiliation: Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Murray
mesh_terms: D001435:Bacteriophages / Q000201:enzymology; D015374:Biosensing Techniques / Q000379:methods*; D004926:Escherichia coli / Q000235:genetics*; D005818:Genetic Engineering; D006801:Humans; D019426:Integrases / Q000378:metabolism; D008390:Markov Chains; D011995:Recombination, Genetic; D058615:Synthetic Biology
chemical_list: D019426:Integrases
keywords: DNA memory; event detectors; integrases; population analysis; stochastic biomolecular models