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In vitro implementation of robust gene regulation in a synthetic biomolecular integral controller

Author

Listed:
  • Deepak K. Agrawal

    (Northeastern University
    Northeastern University)

  • Ryan Marshall

    (University of Minnesota)

  • Vincent Noireaux

    (University of Minnesota)

  • Eduardo D Sontag

    (Northeastern University
    Northeastern University
    Laboratory of Systems Pharmacology, Program in Therapeutic Science, Harvard Medical School)

Abstract

Feedback mechanisms play a critical role in the maintenance of cell homeostasis in the presence of disturbances and uncertainties. Motivated by the need to tune the dynamics and improve the robustness of gene circuits, biological engineers have proposed various designs that mimic natural molecular feedback control mechanisms. However, practical and predictable implementations have proved challenging because of the complexity of synthesis and analysis of complex biomolecular networks. Here, we analyze and experimentally validate a synthetic biomolecular controller executed in vitro. The controller ensures that gene expression rate tracks an externally imposed reference level, and achieves this goal even in the presence of certain kinds of disturbances. Our design relies upon an analog of the well-known principle of integral feedback in control theory. We implement the controller in an Escherichia coli cell-free transcription-translation system, which allows rapid prototyping and implementation. Modeling and theory guide experimental implementation with well-defined operational predictability.

Suggested Citation

  • Deepak K. Agrawal & Ryan Marshall & Vincent Noireaux & Eduardo D Sontag, 2019. "In vitro implementation of robust gene regulation in a synthetic biomolecular integral controller," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13626-z
    DOI: 10.1038/s41467-019-13626-z
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    Cited by:

    1. Maurice Filo & Sant Kumar & Mustafa Khammash, 2022. "A hierarchy of biomolecular proportional-integral-derivative feedback controllers for robust perfect adaptation and dynamic performance," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Ankit Gupta & Mustafa Khammash, 2022. "Frequency spectra and the color of cellular noise," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Stanislav Anastassov & Maurice Filo & Ching-Hsiang Chang & Mustafa Khammash, 2023. "A cybergenetic framework for engineering intein-mediated integral feedback control systems," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Chelsea Y. Hu & Richard M. Murray, 2022. "Layered feedback control overcomes performance trade-off in synthetic biomolecular networks," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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