In this paper we study how to shape temporal pulses to switch a bistable system between its stable steady states. Our motivation for pulse-based control comes from applications in synthetic biology, where it is generally difficult to implement real-time feedback control systems due to technical limitations in sensors and actuators. We show that for monotone bistable systems, the estimation of the set of all pulses that switch the system reduces to the computation of one non-increasing curve. We provide an efficient algorithm to compute this curve and illustrate the results with a genetic bistable system commonly used in synthetic biology. We also extend these results to models with parametric uncertainty and provide a number of examples and counterexamples that demonstrate the power and limitations of the current theory. In order to show the full potential of the framework, we consider the problem of inducing oscillations in a monotone biochemical system using a combination of temporal pulses and event-based control. Our results provide an insight into the dynamics of bistable systems under external inputs and open up numerous directions for future investigation.
a b s t r a c tIn many applications, and in systems/synthetic biology, in particular, it is desirable to solve the switching problem, i.e., to compute control policies that force the trajectory of a bistable system from one equilibrium (the initial point) to another equilibrium (the target point). It was recently shown that for monotone bistable systems, this problem admits easy-to-implement open-loop solutions in terms of temporal pulses (i.e., step functions of fixed length and fixed magnitude). In this paper, we develop this idea further and formulate a problem of convergence to an equilibrium from an arbitrary initial point. We show that the convergence problem can be solved using a static optimization problem in the case of monotone systems. Changing the initial point to an arbitrary state allows building closed-loop, event-based or open-loop policies for the switching/convergence problems. In our derivations, we exploit the Koopman operator, which offers a linear infinite-dimensional representation of an autonomous nonlinear system and powerful computational tools for their analysis. Our solutions to the switching/convergence problems can serve as building blocks for other control problems and can potentially be applied to non-monotone systems. We illustrate this argument on the problem of synchronizing cardiac cells by defibrillation.
In this paper, we investigate geometric properties of monotone systems by studying their isostables and basins of attraction. Isostables are boundaries of specific forward-invariant sets defined by the so-called Koopman operator, which provides a linear infinite-dimensional description of a nonlinear system. First, we study the spectral properties of the Koopman operator and the associated semigroup in the context of monotone systems. Our results generalize the celebrated Perron-Frobenius theorem to the nonlinear case and allow us to derive geometric properties of isostables and basins of attraction. Additionally, we show that under certain conditions we can characterize the bounds on the basins of attraction under parametric uncertainty in the vector field. We discuss computational approaches to estimate isostables and basins of attraction and illustrate the results on two and four state monotone systems.
In this paper, we further develop a recently proposed control method to switch a bistable system between its steady states using temporal pulses. The motivation for using pulses comes from biomedical and biological applications (e.g. synthetic biology), where it is generally difficult to build feedback control systems due to technical limitations in sensing and actuation. The original framework was derived for monotone systems and all the extensions relied on monotone systems theory. In contrast, we introduce the concept of switching function which is related to eigenfunctions of the so-called Koopman operator subject to a fixed control pulse. Using the level sets of the switching function we can (i) compute the set of all pulses that drive the system toward the steady state in a synchronous way and (ii) estimate the time needed by the flow to reach an epsilon neighborhood of the target steady state. Additionally, we show that for monotone systems the switching function is also monotone in some sense, a property that can yield efficient algorithms to compute it. This observation recovers and further extends the results of the original framework, which we illustrate on numerical examples inspired by biological applications.
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