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A multiplexed, automated evolution pipeline enables scalable discovery and characterization of biosensors

Author

Listed:
  • Brent Townshend

    (Stanford University)

  • Joy S. Xiang

    (Stanford University)

  • Gabriel Manzanarez

    (Stanford University)

  • Eric J. Hayden

    (Stanford University
    Boise State University)

  • Christina D. Smolke

    (Stanford University
    Chan Zuckerberg Biohub)

Abstract

Biosensors are key components in engineered biological systems, providing a means of measuring and acting upon the large biochemical space in living cells. However, generating small molecule sensing elements and integrating them into in vivo biosensors have been challenging. Here, using aptamer-coupled ribozyme libraries and a ribozyme regeneration method, de novo rapid in vitro evolution of RNA biosensors (DRIVER) enables multiplexed discovery of biosensors. With DRIVER and high-throughput characterization (CleaveSeq) fully automated on liquid-handling systems, we identify and validate biosensors against six small molecules, including five for which no aptamers were previously found. DRIVER-evolved biosensors are applied directly to regulate gene expression in yeast, displaying activation ratios up to 33-fold. DRIVER biosensors are also applied in detecting metabolite production from a multi-enzyme biosynthetic pathway. This work demonstrates DRIVER as a scalable pipeline for engineering de novo biosensors with wide-ranging applications in biomanufacturing, diagnostics, therapeutics, and synthetic biology.

Suggested Citation

  • Brent Townshend & Joy S. Xiang & Gabriel Manzanarez & Eric J. Hayden & Christina D. Smolke, 2021. "A multiplexed, automated evolution pipeline enables scalable discovery and characterization of biosensors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21716-0
    DOI: 10.1038/s41467-021-21716-0
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    Cited by:

    1. Shodai Komatsu & Hirohisa Ohno & Hirohide Saito, 2023. "Target-dependent RNA polymerase as universal platform for gene expression control in response to intracellular molecules," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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