On proving the absence of oscillations in models of genetic circuits

International audienceUsing computer algebra methods to prove that gene regulatory networks cannot oscillate appears to be easier than expected. We illustrate this claim on a family of models related to historical examples

The Dynamics of Hybrid Metabolic-Genetic Oscillators

The synthetic construction of intracellular circuits is frequently hindered by a poor knowledge of appropriate kinetics and precise rate parameters. Here, we use generalized modeling (GM) to study the dynamical behavior of topological models of a family of hybrid metabolic-genetic circuits known as "metabolators." Under mild assumptions on the kinetics, we use GM to analytically prove that all explicit kinetic models which are topologically analogous to one such circuit, the "core metabolator," cannot undergo Hopf bifurcations. Then, we examine more detailed models of the metabolator. Inspired by the experimental observation of a Hopf bifurcation in a synthetically constructed circuit related to the core metabolator, we apply GM to identify the critical components of the synthetically constructed metabolator which must be reintroduced in order to recover the Hopf bifurcation. Next, we study the dynamics of a re-wired version of the core metabolator, dubbed the "reverse" metabolator, and show that it exhibits a substantially richer set of dynamical behaviors, including both local and global oscillations. Prompted by the observation of relaxation oscillations in the reverse metabolator, we study the role that a separation of genetic and metabolic time scales may play in its dynamics, and find that widely separated time scales promote stability in the circuit. Our results illustrate a generic pipeline for vetting the potential success of a potential circuit design, simply by studying the dynamics of the corresponding generalized model

Negative circuits and sustained oscillations in asynchronous automata networks

The biologist Ren\'e Thomas conjectured, twenty years ago, that the presence of a negative feedback circuit in the interaction graph of a dynamical system is a necessary condition for this system to produce sustained oscillations. In this paper, we state and prove this conjecture for asynchronous automata networks, a class of discrete dynamical systems extensively used to model the behaviors of gene networks. As a corollary, we obtain the following fixed point theorem: given a product $X$ of $n$ finite intervals of integers, and a map $F$ from $X$ to itself, if the interaction graph associated with $F$ has no negative circuit, then $F$ has at least one fixed point

On the role of differential algebra in biological modeling

Extended abstract of an invited talk at Differential Algebra and related Computer Algebra (Catania, Italy, March 28th, 2008)International audienceDifferential algebra is an algebraic theory for studying systems of polynomial ordinary differential equations (ODE). Among all the methods developed for system modeling in cellular biology, it is particularly related to the well-established approach based on nonlinear ODE. A subtheory of the differential algebra, the differential elimination, has proved to be useful in the parameters estimation problem. It seems however still more promising in the quasi-steady state approximation theory, recent results show

Population Dynamics of Globally Coupled Degrade-and-Fire Oscillators

This paper reports the analysis of the dynamics of a model of pulse-coupled oscillators with global inhibitory coupling. The model is inspired by experiments on colonies of bacteria-embedded synthetic genetic circuits. The total population can be either of finite (arbitrary) size or infinite, and is represented by a one-dimensional profile. Profiles can be discontinuous, possibly with infinitely many jumps. Their time evolution is governed by a singular differential equation. We address the corresponding initial value problem and characterize the dynamics' main features. In particular, we prove that trajectory behaviors are asymptotically periodic, with period only depending on the profile (and on the model parameters). A criterion is obtained for the existence of the corresponding periodic orbits, which reveals the existence of a sharp transition as the coupling parameter is increased. The transition separates a regime where any profile can be obtained in the limit of large times, to a situation where only trajectories with sufficiently large groups of synchronized oscillators perdure

A passivity-based stability criterion for a class of interconnected systems and applications to biochemical reaction networks

This paper presents a stability test for a class of interconnected nonlinear systems motivated by biochemical reaction networks. One of the main results determines global asymptotic stability of the network from the diagonal stability of a "dissipativity matrix" which incorporates information about the passivity properties of the subsystems, the interconnection structure of the network, and the signs of the interconnection terms. This stability test encompasses the "secant criterion" for cyclic networks presented in our previous paper, and extends it to a general interconnection structure represented by a graph. A second main result allows one to accommodate state products. This extension makes the new stability criterion applicable to a broader class of models, even in the case of cyclic systems. The new stability test is illustrated on a mitogen activated protein kinase (MAPK) cascade model, and on a branched interconnection structure motivated by metabolic networks. Finally, another result addresses the robustness of stability in the presence of diffusion terms in a compartmental system made out of identical systems.Comment: See http://www.math.rutgers.edu/~sontag/PUBDIR/index.html for related (p)reprint