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A framework for complex signal processing via synthetic biological operational amplifiers

Author

Listed:
  • Wenjun Cao

    (Hunan University
    Chinese Academy of Sciences
    Hunan Academy of Agricultural Sciences)

  • Lili Liu

    (Chinese Academy of Sciences)

  • Qingxu Sun

    (Chinese Academy of Sciences)

  • Yang Shan

    (Hunan University
    Hunan Academy of Agricultural Sciences)

  • Ye Chen

    (Chinese Academy of Sciences)

Abstract

Engineering genetic circuits to process complex biological signals remains a significant challenge due to non-orthogonal signal responses that limit precise control. In this study, we introduce a framework that integrates orthogonal operational amplifiers (OAs) into standardized biological processes to enable efficient signal decomposition and amplification. By engineering σ/anti-σ pairs, varying ribosome binding site (RBS) strengths, and utilizing both open-loop and closed-loop configurations, we design scalable OAs that enhance the precision, adaptability, and signal-to-noise ratio of genetic circuits. Additionally, we present a prototype whole-cell biosensor capable of detecting transcriptional changes in response to growth conditions, enabling growth-state-responsive induction systems. These systems provide dynamic gene expression control without external inducers, offering significant advantages for metabolic engineering applications. We also apply our framework to mitigate crosstalk in multi-signal systems, ensuring independent control over each signal channel within complex biological networks. Our approach enhances synthetic biology systems by robust signal processing and precise dynamic regulation.

Suggested Citation

  • Wenjun Cao & Lili Liu & Qingxu Sun & Yang Shan & Ye Chen, 2025. "A framework for complex signal processing via synthetic biological operational amplifiers," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62464-9
    DOI: 10.1038/s41467-025-62464-9
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    as
    1. Ximing Li & Luna Rizik & Valeriia Kravchik & Maria Khoury & Netanel Korin & Ramez Daniel, 2021. "Synthetic neural-like computing in microbial consortia for pattern recognition," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Yeqing Zong & Haoqian M. Zhang & Cheng Lyu & Xiangyu Ji & Junran Hou & Xian Guo & Qi Ouyang & Chunbo Lou, 2017. "Insulated transcriptional elements enable precise design of genetic circuits," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    3. Yuanli Gao & Lei Wang & Baojun Wang, 2023. "Customizing cellular signal processing by synthetic multi-level regulatory circuits," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Ye Chen & Joanne M. L. Ho & David L. Shis & Chinmaya Gupta & James Long & Daniel S. Wagner & William Ott & Krešimir Josić & Matthew R. Bennett, 2018. "Tuning the dynamic range of bacterial promoters regulated by ligand-inducible transcription factors," Nature Communications, Nature, vol. 9(1), pages 1-8, December.
    5. Alvin Tamsir & Jeffrey J. Tabor & Christopher A. Voigt, 2011. "Robust multicellular computing using genetically encoded NOR gates and chemical ‘wires’," Nature, Nature, vol. 469(7329), pages 212-215, January.
    6. Alexander A. Green & Jongmin Kim & Duo Ma & Pamela A. Silver & James J. Collins & Peng Yin, 2017. "Complex cellular logic computation using ribocomputing devices," Nature, Nature, vol. 548(7665), pages 117-121, August.
    7. Joseph Bondy-Denomy & Bianca Garcia & Scott Strum & Mingjian Du & MaryClare F. Rollins & Yurima Hidalgo-Reyes & Blake Wiedenheft & Karen L. Maxwell & Alan R. Davidson, 2015. "Multiple mechanisms for CRISPR–Cas inhibition by anti-CRISPR proteins," Nature, Nature, vol. 526(7571), pages 136-139, October.
    8. Amir Pandi & Mathilde Koch & Peter L. Voyvodic & Paul Soudier & Jerome Bonnet & Manish Kushwaha & Jean-Loup Faulon, 2019. "Metabolic perceptrons for neural computing in biological systems," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    9. Ramiz Daniel & Jacob R. Rubens & Rahul Sarpeshkar & Timothy K. Lu, 2013. "Synthetic analog computation in living cells," Nature, Nature, vol. 497(7451), pages 619-623, May.
    10. Timothy S. Gardner & Charles R. Cantor & James J. Collins, 2000. "Construction of a genetic toggle switch in Escherichia coli," Nature, Nature, vol. 403(6767), pages 339-342, January.
    11. Heonjoon Lee & Tian Xie & Byunghwa Kang & Xinjie Yu & Samuel W. Schaffter & Rebecca Schulman, 2024. "Plug-and-play protein biosensors using aptamer-regulated in vitro transcription," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    12. Luna Rizik & Loai Danial & Mouna Habib & Ron Weiss & Ramez Daniel, 2022. "Synthetic neuromorphic computing in living cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    13. Brandon Alexander Holt & Gabriel A. Kwong, 2020. "Protease circuits for processing biological information," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    14. Lingchong You & Robert Sidney Cox & Ron Weiss & Frances H. Arnold, 2004. "Programmed population control by cell–cell communication and regulated killing," Nature, Nature, vol. 428(6985), pages 868-871, April.
    15. Nicolas Kylilis & Zoltan A. Tuza & Guy-Bart Stan & Karen M. Polizzi, 2018. "Tools for engineering coordinated system behaviour in synthetic microbial consortia," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    16. Stephanie K. Aoki & Gabriele Lillacci & Ankit Gupta & Armin Baumschlager & David Schweingruber & Mustafa Khammash, 2019. "A universal biomolecular integral feedback controller for robust perfect adaptation," Nature, Nature, vol. 570(7762), pages 533-537, June.
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