Ultrasensitive molecular controllers for quasi-integral feedback

Samaniego, Christian Cuba; Franco, Elisa

doi:10.1016/j.cels.2021.01.001

Cited by 41 publications

(26 citation statements)

References 100 publications

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“…In particular, the ability to easily tune signaling pathway activity through phosphatase expression and the ability to robustly control downstream gene expression processes will facilitate the creation of synthetic signaling systems that can operate across diverse cellular contexts. In the future, our circuits can form the basis for advanced cellular computing 66 and feedback control 67 architectures. In addition, connecting signaling pathway activity to endogenous gene regulation, such as through miRNA regulation of pathway components, will facilitate applications in guiding differentiation or programming custom signaling for different cellular states.…”

Section: Discussionmentioning

confidence: 99%

Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles

Qian

Ilia

Wang

et al. 2021

Preprint

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Rewiring signaling networks imparts cells with new functionalities that are useful for engineering cell therapies and directing cell development. While much effort has gone into connecting extracellular inputs to desired outputs, less has been done to control the signal processing steps in-between. Here, we develop synthetic signal processing circuits in mammalian cells using proteins derived from bacterial two-component signaling pathways. First, we isolate kinase and phosphatase activities from the bifunctional histidine kinase EnvZ and demonstrate tunable phosphorylation control of the response regulator OmpR via simultaneous phosphoregulation by an EnvZ kinase and phosphatase. We show that modulation of phosphatase expression at the mRNA and protein levels via miRNAs and small molecule-regulated degradation domains, respectively, can effectively tune kinase-to-output responses. Further, we implement a novel phosphorylation-based miRNA sensor that effectively classifies cell types and enables cell type-specific kinase-output signaling responses. Finally, we implement a tunable negative feedback controller by co-expressing the kinase-driven output gene with the small molecule-tunable phosphatase, substantially reducing both gene expression noise and sensitivity to perturbations at the transcriptional and translational level. Our work lays the foundation for establishing tunable, precise, and robust control over cell behavior with synthetic signaling networks.

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Section: Discussionmentioning

confidence: 99%

Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles

Qian

Ilia

Wang

et al. 2021

Preprint

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“…A number of works have sought to find alternative circuits that provide adaptation properties similar to antithetic control. For example, several authors have shown that ultrasensitive feedback can display some of the features of perfect adaptation 25,28 , and the idea was recently extended in great detail for synthetic gene circuits 30 . Other works have sought to devise molecular implementations of Proportional-Integral-Derivative control 9 , as this is a widely adopted strategy for perfect adaptation in engineered control systems.…”

Section: Discussionmentioning

confidence: 99%

“…Our main goal in this paper was to show that molecular sequestration can improve perfect adaptation in the antithetic control motif. Since buffering is known to stabilise a much wider range of molecular networks 16 , it also has the potential to improve other circuits implementing perfect adaptation, e. g. those that rely on ultrasensitive behaviour 30 . Another promising line of inquiry is investigating production feedback mechanisms with similar kinetic effects to degradation 16 , which may enable topology 3 type buffers to stabilise the systems without an increase in burden.…”

Section: Sugarsmentioning

confidence: 99%

Stabilisation of Antithetic Control via Molecular Buffering

Hancock

Oyarzún

2021

Preprint

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A key goal in synthetic biology is the construction of molecular circuits that robustly adapt to perturbations. Although many natural systems display perfect adaptation, whereby stationary molecular concentrations are insensitive to perturbations, its de novo engineering has proven elusive. The discovery of the antithetic control motif was a significant step toward a universal mechanism for engineering perfect adaptation. Antithetic control provides perfect adaptation in a wide range of systems, but it can lead to oscillatory dynamics due to loss of stability, and moreover, it can lose perfect adaptation in fast growing cultures. Here, we introduce an extended antithetic control motif that resolves these limitations. We show that molecular buffering, a widely conserved mechanism for homeostatic control in nature, stabilises oscillations and allows for near-perfect adaptation during rapid growth. We study multiple buffering topologies and compare their performance in terms of their stability and adaptation properties. We illustrate the benefits of our proposed strategy in exemplar models for biofuel production and growth rate control in bacterial cultures. Our results provide an improved circuit for robust control of biomolecular systems.

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“…Furthermore, the dynamics of biochemical reactions are inherently nonlinear. To achieve RPA, BCRN realizations of standalone Integral (I) controllers initially received the widest attention [24][25][26][27][28][29]. In previous work [26], the Antithetic Integral (aI) feedback controller was introduced to realize integral action that ensures RPA.…”

mentioning

confidence: 99%

“…A detailed mathematical analysis of the performance tradeoffs that may arise in the aI controller is presented in [30,31], and optimal tuning is treated in [32]. Furthermore, practical design aspects, particularly the dilution effect of controller species, are addressed in [28,29]. Biological implementations of various biomolecular integral controllers appeared in bacteria in vivo [7,9,10] and in vitro [14], and more recently in mammalian cells [15].…”

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confidence: 99%

A Hierarchy of Biomolecular Proportional-Integral-Derivative Feedback Controllers for Robust Perfect Adaptation and Dynamic Performance

Filo

Khammash

2021

Preprint

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Proportional-Integral-Derivative (PID) feedback controllers have been the most widely used controllers in the industry for almost a century. This is mainly due to their simplicity and intuitive operation. Recently, motivated by their success in various engineering disciplines, PID controllers found their way into molecular biology. In this paper, we consider the mathematical realization of (nonlinear) PID controllers via biomolecular interactions in both the deterministic and stochastic settings. We propose several simple biomolecular PID control architectures that take into consideration the biological implementation aspect. We verify the underlying PID control structures by performing a linear perturbation analysis and examine their effects on the (deterministic and stochastic) performance and stability. In fact, we demonstrate that different proportional controllers exhibit different capabilities of enhancing the dynamics and reducing variance (cell-to-cell variability). Furthermore, we propose a simple derivative controller that is mathematically realized by cascading the antithetic integral controller with an incoherent feedforward loop without adding any additional species. We demonstrate that the derivative component is capable of enhancing the transient dynamics at the cost of boosting the variance, which agrees with the well known vulnerability of the derivative controller to noise. We also show that this can be mitigated by carefully designing the inhibition pathway of the incoherent feedforward loop. Throughout the paper, the stochastic analysis is carried out based on a tailored moment-closure technique and is also backed up by simulations.

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Ultrasensitive molecular controllers for quasi-integral feedback

Cited by 41 publications

References 100 publications

Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles

Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles

Stabilisation of Antithetic Control via Molecular Buffering

A Hierarchy of Biomolecular Proportional-Integral-Derivative Feedback Controllers for Robust Perfect Adaptation and Dynamic Performance

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