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Genetically Engineered Proportional-Integral Feedback Controllers for Robust Perfect Adaptation in Mammalian Cells

View ORCID ProfileT. Frei, View ORCID ProfileC.-H. Chang, View ORCID ProfileM. Filo, A. Arampatzis, View ORCID ProfileM. Khammash
doi: https://doi.org/10.1101/2020.12.06.412304
T. Frei
1Department of Biosystems Science and Engineering, ETH Zürich, Switzerland
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C.-H. Chang
1Department of Biosystems Science and Engineering, ETH Zürich, Switzerland
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M. Filo
1Department of Biosystems Science and Engineering, ETH Zürich, Switzerland
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A. Arampatzis
1Department of Biosystems Science and Engineering, ETH Zürich, Switzerland
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M. Khammash
1Department of Biosystems Science and Engineering, ETH Zürich, Switzerland
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  • For correspondence: mustafa.khammash@bsse.ethz.ch
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Abstract

To support their survival, cells adapt to environmental disturbances by maintaining a constant internal milieu. Robust perfect adaptation is a strategy that utilizes integral feedback to promote adaptation by robustly driving regulated physiological variables to their pre-disturbance levels. Present in natural systems, this stringent regulatory strategy promises to enable the engineering of sophisticated genetic programs with diverse applications. Here, we present the first synthetic implementations of integral and proportional-integral feedback controllers in mammalian cells. We show that the integral controller robustly and precisely maintains a desired level of a transcription factor, in spite of induced disturbances and network perturbations. Augmenting proportional feedback reduces stochastic variability while maintaining robust perfect adaptation. We demonstrate the benefits of these controllers in mitigating the impact of resource burden and investigate their use in cell therapy. The synthetic biological realization of robust perfect adaptation holds promise for substantial advances in industrial biotechnology and cell-based therapies.

Competing Interest Statement

ETH Zürich has filed a patent application on behalf of the inventors T.F., C.H.C., M.F. and M.K. on the genetic circuit designs described (application no. EP20206417.6).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 13, 2021.
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Genetically Engineered Proportional-Integral Feedback Controllers for Robust Perfect Adaptation in Mammalian Cells
T. Frei, C.-H. Chang, M. Filo, A. Arampatzis, M. Khammash
bioRxiv 2020.12.06.412304; doi: https://doi.org/10.1101/2020.12.06.412304
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Genetically Engineered Proportional-Integral Feedback Controllers for Robust Perfect Adaptation in Mammalian Cells
T. Frei, C.-H. Chang, M. Filo, A. Arampatzis, M. Khammash
bioRxiv 2020.12.06.412304; doi: https://doi.org/10.1101/2020.12.06.412304

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