Multicellular PI control for gene regulation in microbial consortia

Martinelli, Vittoria; Salzano, Davide; Fiore, Davide; Bernardo, Mario di

doi:10.1101/2022.03.21.485171

Cited by 3 publications

(2 citation statements)

References 23 publications

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“…The efficacy of this biomolecular mechanism has also been demonstrated experimentally in living cells, at both the cell population and the single-cell level, and in cell-free environments using either external (in silico) or embedded single-output control schemes [33,39,40,43,[55][56][57][58][59][60][61]. Furthermore, in recent years, considerable attention has been given to topologies combining the antithetic integral controller with proportional and derivative control action or biomolecular buffering [39,40,43,60,[62][63][64][65][66]. Such efforts seek to resolve commonly encountered issues associated with the standalone antithetic integral controller, such as instability, poor transient dynamics including overshoots, and long-lasting oscillations or increased variance.…”

Section: Introductionmentioning

confidence: 99%

Regulation strategies for two-output biomolecular networks

Alexis,

Schulte,

Cardelli

et al. 2023

J. R. Soc. Interface.

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Feedback control theory facilitates the development of self-regulating systems with desired performance which are predictable and insensitive to disturbances. Feedback regulatory topologies are found in many natural systems and have been of key importance in the design of reliable synthetic bio-devices operating in complex biological environments. Here, we study control schemes for biomolecular processes with two outputs of interest, expanding previously described concepts based on single-output systems. Regulation of such processes may unlock new design possibilities but can be challenging due to coupling interactions; also potential disturbances applied on one of the outputs may affect both. We therefore propose architectures for robustly manipulating the ratio/product and linear combinations of the outputs as well as each of the outputs independently. To demonstrate their characteristics, we apply these architectures to a simple process of two mutually activated biomolecular species. We also highlight the potential for experimental implementation by exploring synthetic realizations both in vivo and in vitro . This work presents an important step forward in building bio-devices capable of sophisticated functions.

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Section: Introductionmentioning

confidence: 99%

Regulation strategies for two-output biomolecular networks

Alexis,

Schulte,

Cardelli

et al. 2023

J. R. Soc. Interface.

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“…In fact, Integral (I) controllers are typically augmented with Proportional (P) and/or Derivative (D) controllers to obtain PI/PID controllers that offer more flexibility in enhancing the dynamic performance while maintaining the RPA property. Recently, more advanced molecular controllers such as PI/PID controllers found their way to molecular biology (7,(37)(38)(39)(40)(41)(42). Ideally, pure proportional control is achieved via instantaneous negative feedback from the output XL to the input species X1 and it is shown that it is not only capable of enhancing the transient dynamic performance, but also reducing cell-to-cell variability (37,40).…”

mentioning

confidence: 99%

Inteins in the Loop: A Framework for Engineering Advanced Biomolecular Controllers for Robust Perfect Adaptation

Anastassov

Filo

Chang

et al. 2022

Preprint

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Homeostasis is one of the cornerstones of life shaped by billions of years of evolution. A notion that is similar to homeostasis, but yet more stringent, is Robust Perfect Adaptation (RPA). A system is endowed with RPA if it is capable of driving a variable of interest to a prescribed level despite the presence of disturbances and uncertainties in the environment. Designing and building biomolecular controllers capable of achieving RPA have been identified as an important task which has immediate implications for various disciplines. Here, we develop systematic theoretical and experimental frameworks for custom-built proteins that exploit split inteins --- short amino acid sequences capable of performing protein-splicing reactions --- to design, genetically build and analyze a wide class of RPA-achieving integral feedback controllers. We first lay down a theoretical foundation that facilitates the screening of intein-based controller networks for RPA, and then usher an easy-to-use recipe to simplify their, otherwise complex, underlying mathematical models. Furthermore, we genetically engineer and test various controller circuits based on commonly used transcription factors in mammalian cells. We experimentally and theoretically demonstrate their ability of robustly rejecting external disturbances (that is achieving RPA) over an exquisitely broad dynamic range. Due to their small size, flexibility, modularity, lack of side effects and applicability across various forms of life, inteins serve as promising genetic parts to implement RPA-achieving controllers. To this end, we believe "inteins in the control loop" will leave a significant impact on various disciplines spanning synthetic biology, biofuel production, metabolic engineering and cell therapy among others.

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A cybergenetic framework for engineering intein-mediated integral feedback control systems

et al. 2023

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The ability of biological systems to tightly regulate targeted variables, despite external and internal disturbances, is known as Robust Perfect Adaptation (RPA). Achieved frequently through biomolecular integral feedback controllers at the cellular level, RPA has important implications for biotechnology and its various applications. In this study, we identify inteins as a versatile class of genetic components suitable for implementing these controllers and present a systematic approach for their design. We develop a theoretical foundation for screening intein-based RPA-achieving controllers and a simplified approach for modeling them. We then genetically engineer and test intein-based controllers using commonly used transcription factors in mammalian cells and demonstrate their exceptional adaptation properties over a wide dynamic range. The small size, flexibility, and applicability of inteins across life forms allow us to create a diversity of genetic RPA-achieving integral feedback control systems that can be used in various applications, including metabolic engineering and cell-based therapy.

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Multicellular PI control for gene regulation in microbial consortia

Cited by 3 publications

References 23 publications

Regulation strategies for two-output biomolecular networks

Regulation strategies for two-output biomolecular networks

Inteins in the Loop: A Framework for Engineering Advanced Biomolecular Controllers for Robust Perfect Adaptation

A cybergenetic framework for engineering intein-mediated integral feedback control systems

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