Shaping Pulses to Control Bistable Biological Systems

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.Comment: 14 pages, contains material from the paper in Proc Amer Control Conf 2015, (pp. 3138-3143) and "Shaping pulses to control bistable systems analysis, computation and counterexamples", which is due to appear in Automatic

Shaping Pulses to Control Bistable Monotone Systems Using Koopman Operator

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.Comment: 7 page

Geometric Properties of Isostables and Basins of Attraction of Monotone Systems

In this paper, we study geometric properties of basins of attraction of monotone systems. Our results are based on a combination of monotone systems theory and spectral operator theory. We exploit the framework of the Koopman operator, which provides a linear infinite-dimensional description of nonlinear dynamical systems and spectral operator-theoretic notions such as eigenvalues and eigenfunctions. The sublevel sets of the dominant eigenfunction form a family of nested forward-invariant sets and the basin of attraction is the largest of these sets. The boundaries of these sets, called isostables, allow studying temporal properties of the system. Our first observation is that the dominant eigenfunction is increasing in every variable in the case of monotone systems. This is a strong geometric property which simplifies the computation of isostables. We also show how variations in basins of attraction can be bounded under parametric uncertainty in the vector field of monotone systems. Finally, we study the properties of the parameter set for which a monotone system is multistable. Our results are illustrated on several systems of two to four dimensions.Comment: 12 pages, to appear in IEEE Transaction on Automatic Contro

An Optimal Control Formulation of Pulse-Based Control Using Koopman Operator

In many applications, and in systems/synthetic biology, in particular, it is desirable to compute control policies that force the trajectory of a bistable system from one equilibrium (the initial point) to another equilibrium (the target point), or in other words to solve the switching problem. 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 this problem can be solved using a static optimization problem in the case of monotone systems. Changing the initial point to an arbitrary state allows to build 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. One of the main advantages of using the Koopman operator is the powerful computational tools developed for this framework. Besides the presence of numerical solutions, the switching/convergence problem can also serve as a building block for solving more complicated control problems and can potentially be applied to non-monotone systems. We illustrate this argument on the problem of synchronizing cardiac cells by defibrillation. Potentially, our approach can be extended to problems with different parametrizations of control signals since the only fundamental limitation is the finite time application of the control signal.Comment: corrected typo

Effects of cell cycle noise on excitable gene circuits

We assess the impact of cell cycle noise on gene circuit dynamics. For bistable genetic switches and excitable circuits, we find that transitions between metastable states most likely occur just after cell division and that this concentration effect intensifies in the presence of transcriptional delay. We explain this concentration effect with a 3-states stochastic model. For genetic oscillators, we quantify the temporal correlations between daughter cells induced by cell division. Temporal correlations must be captured properly in order to accurately quantify noise sources within gene networks.Comment: 15 pages, 8 figure

Evaluation of bistable systems versus matched filters in detecting bipolar pulse signals

This paper presents a thorough evaluation of a bistable system versus a matched filter in detecting bipolar pulse signals. The detectability of the bistable system can be optimized by adding noise, i.e. the stochastic resonance (SR) phenomenon. This SR effect is also demonstrated by approximate statistical detection theory of the bistable system and corresponding numerical simulations. Furthermore, the performance comparison results between the bistable system and the matched filter show that (a) the bistable system is more robust than the matched filter in detecting signals with disturbed pulse rates, and (b) the bistable system approaches the performance of the matched filter in detecting unknown arrival times of received signals, with an especially better computational efficiency. These significant results verify the potential applicability of the bistable system in signal detection field.Comment: 15 pages, 9 figures, MikTex v2.

Bursting through interconnection of excitable circuits

We outline the methodology for designing a bursting circuit with robustness and control properties reminiscent of those encountered in biological bursting neurons. We propose that this design question is tractable when addressed through the interconnection theory of two excitable circuits, realized solely with first-order filters and sigmoidal I-V elements. The circuit can be designed and controlled by shaping its I-V curves in the relevant timescales, giving a novel and intuitive methodology for implementing single neuron behaviors in hardware.The research leading to these results has received funding from the European Research Council under the Advanced ERC Grant Agreement Switchlet n.670645