Faculty Opinions recommendation of A universal biomolecular integral feedback controller for robust perfect adaptation.

AbstractFor control in biomolecular systems, the most basic objective of maintaining a small error in a target variable, say the expression level of some protein, is often difficult due to the presence of both large uncertainty of every type and intrinsic limitations on the controller’s implementation. This paper explores the limits of biochemically plausible controller design for the problem of robust perfect adaptation (RPA), biologists’ term for robust steady state tracking. It is well-known that for a large class of nonlinear systems, a system has RPA iff it has integral feedback control (IFC), which has been used extensively in real control systems to achieve RPA. However, we show that due to intrinsic physical limitations on the dynamics of chemical reaction networks (CRNs), cells cannot implement IFC directly in the concentration of a chemical species. This contrasts with electronic implementations, particularly digital, where it is trivial to implement IFC directly in a single state. Therefore, biomolecular systems have to achieve RPA by encoding the integral control variable into the network architecture of a CRN. We describe a general framework to implement RPA in CRNs and show that well-known network motifs that achieve RPA, such as (negative) integral feedback (IFB) and incoherent feedforward (IFF), are examples of such implementations. We also develop methods to solve the problem of designing integral feedback variables for unknown plants. This standard control notion is surprisingly nontrivial and relatively unstudied in biomolecular control. The methods developed here connect different existing fields and approaches on the problem of biomolecular control, and hold promise for systematic chemical reaction controller synthesis as well as analysis.

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Antithetic Integral Feedback: A new motif for robust perfect adaptation in noisy biomolecular networks

10.1101/024919 ◽

2015 ◽

Author(s):

Corentin Briat ◽

Ankit Gupta ◽

Mustafa Khammash

Keyword(s):

Feedback Regulation ◽

Reaction Rates ◽

Living Cells ◽

Regulatory Function ◽

Regulatory Motif ◽

Analysis And Design ◽

Perfect Adaptation ◽

Integral Feedback ◽

The Stability ◽

And Control

Homeostasis is a running theme in biology. Often achieved through feedback regulation strategies, homeostasis allows living cells to control their internal environment as a means for surviving changing and unfavourable environments. While many endogenous homeostatic motifs have been studied in living cells, some other motifs may remain under-explored or even undiscovered. At the same time, known regulatory motifs have been mostly analyzed at the deterministic level, and the effect of noise on their regulatory function has received low attention. Here we lay the foundation for a regulation theory at the molecular level that explicitly takes into account the noisy nature of biochemical reactions and provides novel tools for the analysis and design of robust homeostatic circuits. Using these ideas, we propose a new regulation motif, which we refer to as antithetic integral feedback, and demonstrate its effectiveness as a strategy for generically regulating a wide class of reaction networks. By combining tools from probability and control theory, we show that the proposed motif preserves the stability of the overall network, steers the population of any regulated species to a desired set point, and achieves robust perfect adaptation -- all with low prior knowledge of reaction rates. Moreover, our proposed regulatory motif can be implemented using a very small number of molecules and hence has a negligible metabolic load. Strikingly, the regulatory motif exploits stochastic noise, leading to enhanced regulation in scenarios where noise-free implementations result in dysregulation. Finally, we discuss the possible manifestation of the proposed antithetic integral feedback motif in endogenous biological circuits and its realization in synthetic circuits.

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A variance-constrained proportional-integral feedback controller that tunes itself

IIE Transactions ◽

10.1080/07408170008963925 ◽

2000 ◽

Vol 32 (6) ◽

pp. 479-491 ◽

Cited By ~ 2

Author(s):

ENRIQUE DEL CASTILLO

Keyword(s):

Feedback Controller ◽

Proportional Integral ◽

Integral Feedback

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

10.1101/2020.12.06.412304 ◽

2020 ◽

Author(s):

T. Frei ◽

C.-H. Chang ◽

M. Filo ◽

M. Khammash

Keyword(s):

Transcription Factor ◽

Negative Feedback ◽

Mammalian Cells ◽

Basic Research ◽

Genetically Engineered ◽

Industrial Biotechnology ◽

Biological Organization ◽

Regulatory Motif ◽

Perfect Adaptation ◽

Integral Feedback

AbstractMammalian cells collectively maintain a consistent internal milieu that supports their host’s survival in varying and uncertain environments. This homeostasis is often achieved through negative feedback loops that act at various levels of biological organization, from the system and organ levels down to gene expression at the molecular scale. Recently, a molecular regulatory motif has been discovered that enables a regulated variable to adapt perfectly (at the steady state) to network and parameter changes and to persistent environmental perturbations. The regulatory motif that achieves this robust perfect adaptation property realizes integral feedback, a control strategy that employs mathematical integration in a negative feedback loop. Here, we present the first synthetic implementation of integral feedback in mammalian cells. We show that this implementation successfully maintains constant levels of a transcription factor, even when its degradation is significantly increased. Furthermore, we establish the structural robustness properties of our controlled system by demonstrating that perturbing the network topology does not affect the transcription factor levels. We believe that the ability to robustly and predictably regulate the expression levels of genes will both become an indispensable tool for basic research as well as lead to substantial advances in the development of industrial biotechnology and cell-based therapies.

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Glycerol is the actuator of integral feedback control in yeast osmotic stress signaling

10.1101/045682 ◽

2016 ◽

Author(s):

Suzannah Rutherford

Keyword(s):

Steady State ◽

Feedback Control ◽

Osmotic Stress ◽

Stress Responses ◽

Turgor Pressure ◽

Metabolic Energy ◽

Stress Signaling ◽

Glycerol Concentration ◽

Perfect Adaptation ◽

Integral Feedback

AbstractIn a 2009 article in Cell van Oudenaarden and colleagues employed elegant experiments and control theory to model perfect adaptation of the yeast osmotic stress response – precise return of turgor pressure to its optimal, steady-state value despite variation in system parameters and the continued presence of osmotic stress. Their data convincingly showed that nuclear signaling and cell volume undergo “robust perfect adaptation” implying that integral feedback must restore their steady state values. However, the authors incorrectly mapped the integrator onto a minimal network that violates assumptions implicit in conventional block diagrams. Using known features of osmotic stress signaling and results presented by the authors, I argue that glycerol concentration – the integral of the rate of glycerol accumulation (synthesis minus leakage) – transforms metabolic energy into an increased osmolarity that drives water influx and restoration of turgor pressure. I show how integral feedback control actuated through glycerol synthesis is logically positioned to provide perfect adaptation and robustness in hyperosmotic stress responses.

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