We show how an important class of nonlinear feedback controllers can be designed using idealized abstract chemical reactions and implemented via DNA strand displacement (DSD) reactions. Exploiting chemical reaction networks (CRNs) as a programming language for the design of complex circuits and networks, we show how a set of unimolecular and bimolecular reactions can be used to realize input-output dynamics that produce a nonlinear quasi sliding mode (QSM) feedback controller. The kinetics of the required chemical reactions can then be implemented as enzyme-free, enthalpy/entropy driven DNA reactions using a toehold mediated strand displacement mechanism via Watson-Crick base pairing and branch migration. We demonstrate that the closed loop response of the nonlinear QSM controller outperforms a traditional linear controller by facilitating much faster tracking response dynamics without introducing overshoots in the transient response. The resulting controller is highly modular and is less affected by retroactivity effects than standard linear designs.

Many of the most important potential applications of Synthetic Biology will require the ability to design and implement high performance feedback control systems that can accurately regulate the dynamics of multiple molecular species within the cell. Here, we argue that the use of design strategies based on combining ultrasensitive response dynamics with negative feedback represents a natural approach to this problem that fully exploits the strongly nonlinear nature of cellular information processing. We propose that such feedback mechanisms can explain the adaptive responses observed in one of the most widely studied biomolecular feedback systems—the yeast osmoregulatory response network. Based on our analysis of such system, we identify strong links with a well-known branch of mathematical systems theory from the field of Control Engineering, known as Sliding Mode Control. These insights allow us to develop design guidelines that can inform the construction of feedback controllers for synthetic biological systems.

Until the approval of vaccines at the end of 2020, societies relied on non-pharmaceutical interventions (NPIs) in order to control the COVID-19 pandemic. Spontaneous changes in individual behavior might have contributed to or counteracted epidemic control due to NPIs. For example, the population compliance to NPIs may have varied over time as people developed “epidemic fatigue” or altered their perception of the risk and severity of COVID-19. Whereas official measures are well documented, the behavioral response of the citizens is harder to capture. We propose a mathematical model of the societal response, taking into account three main effects: the citizen response dynamics, the authorities’ NPIs, and the occurrence of unpreventable events that significantly alter the virus transmission rate. A key assumption is that a society has a waning memory of the epidemic effects, which reflects on both the severity of the authorities’ NPIs and on the citizens’ compliance to the prescribed rules. This, in turn, feeds back onto the transmission rate of the disease, such that a higher number of hospitalizations decreases the probability of transmission. We show that the model is able to reproduce the COVID-19 dynamics in terms of hospital admissions for several European countries during 2020 over surprisingly long time scales. Also, it is capable of capturing the effects of disturbances (for example the emergence of new virus variants) and can be exploited for implementing control actions to limit such effects. A possible application, illustrated in this letter, consists of exploiting the estimations based on the data of one country, to predict and control the evolution in another country, where the virus spreading is still in an earlier phase.

The general problem of reconstructing a biological interaction network from temporal evolution data is tackled via an approach based on dynamical linear systems identification theory. A novel algorithm, based on linear matrix inequalities, is devised to infer the interaction network. This approach allows to directly taking into account, within the optimisation procedure, the a priori available knowledge of the biological system. The effectiveness of the proposed algorithm is statistically validated, by means of numerical tests, demonstrating how the a priori knowledge positively affects the reconstruction performance. A further validation is performed through an in silico biological experiment, exploiting the well-assessed cell-cycle model of fission yeast developed by Novak and Tyson.