arXiv subjects

Domitilla Del Vecchio

Publications and source records attributed to Domitilla Del Vecchio.

18 recordsLinked to original sources

arXiv2026

Learning Genetic Circuit Modules with Neural Networks: Full Version

In several applications, including in synthetic biology, one often has input/output data on a system composed of many modules, and although the modules' input/output functions and signals may be unknown, knowledge of the composition architecture can significantly reduce the amount of training data required to learn the system's input/output mapping. Learning the modules' input/output functions is also necessary for designing new systems from different composition architectures. Here, we propose a modular learning framework, which incorporates prior knowledge of the system's compositional structure to (a) identify the composing modules' input/output functions from the system's input/output data and (b) achieve this by using a reduced amount of data compared to what would be required without knowledge of the compositional structure. To achieve this, we introduce the notion of modular identifiability, which allows recovery of modules' input/output functions from a subset of the system's input/output data, and provide theoretical guarantees on a class of systems motivated by genetic circuits. We demonstrate the theory on computational studies showing that a neural network (NNET) that accounts for the compositional structure can learn the composing modules' input/output functions and predict the system's output on inputs outside of the training set distribution. By contrast, a neural network that is agnostic of the structure is unable to predict on inputs that fall outside of the training set distribution. By reducing the need for experimental data and allowing module identification, this framework offers the potential to ease the design of synthetic biological circuits and of multi-module systems more generally.

cs.LG↗

arXiv2026

Control systems for synthetic biology and a case-study in cell fate reprogramming

This paper gives an overview of the use of control systems engineering in synthetic biology, motivated by applications such as cell therapy and cell fate reprogramming for regenerative medicine. A ubiquitous problem in these and other applications is the ability to control the concentration of specific regulatory factors in the cell accurately despite environmental uncertainty and perturbations. The paper describes the origin of these perturbations and how they affect the dynamics of the biomolecular ``plant'' to be controlled. A variety of biomolecular control implementations are then introduced to achieve robustness of the plant's output to perturbations and are grouped into feedback and feedforward control architectures. Although sophisticated control laws can be implemented in a computer today, they cannot be necessarily implemented inside the cell via biomolecular processes. This fact constraints the set of feasible control laws to those realizable through biomolecular processes that can be engineered with synthetic biology. After reviewing biomolecular feedback and feedforward control implementations, mostly focusing on the author's own work, the paper illustrates the application of such control strategies to cell fate reprogramming. Within this context, a master regulatory factor needs to be controlled at a specific level inside the cell in order to reprogram skin cells to pluripotent stem cells. The article closes by highlighting on-going challenges and directions of future research for biomolecular control design.

eess.SY↗

arXiv2025

Coclique level structure for stochastic chemical reaction networks

Continuous time Markov chains are commonly used as models for the stochastic behavior of chemical reaction networks. More precisely, these Stochastic Chemical Reaction Networks (SCRNs) are frequently used to gain a mechanistic understanding of how chemical reaction rate parameters impact the stochastic behavior of these systems. One property of interest is mean first passage times (MFPTs) between states. However, deriving explicit formulas for MFPTs can be highly complex. In order to address this problem, we first introduce the concept of coclique level structure and develop theorems to determine whether certain SCRNs have this feature by studying associated graphs. Additionally, we develop an algorithm to identify, under specific assumptions, all possible coclique level structures associated with a given SCRN. Finally, we demonstrate how the presence of such a structure in a SCRN allows us to derive closed form formulas for both upper and lower bounds for the MFPTs. Our methods can be applied to SCRNs taking values in a generic finite state space and can also be applied to models with non-mass-action kinetics. We illustrate our results with examples from the biological areas of epigenetics, neurobiology and ecology.

math.PR↗

arXiv2025

Contraction Dynamics in Heterogeneous Spatial Environments

Understanding the asymptotic behavior of reaction-diffusion (RD) systems is crucial for modeling processes ranging from species coexistence in ecology to biochemical interactions within cells. In this work, we analyze RD systems in which diffusion is modeled using the $θ$-diffusion framework, while the reaction dynamics are spatially varying. We demonstrate that spatial heterogeneity affects the asymptotic behavior of such systems. Using contraction theory, we derive conditions that guarantee the exponential convergence of system trajectories, regardless of initial conditions. These conditions explicitly account for the influence of spatial heterogeneity in both the diffusion and reaction terms. As an application, we study a biochemical system and derive the quasi-steady-state (QSS) approximation, illustrating how spatial heterogeneity modulates the effective binding rates of biomolecular species.

math.DS↗

arXiv2024

Competition for binding targets results in paradoxical effects for simultaneous activator and repressor action -- Extended Version

In the context of epigenetic transformations in cancer metastasis, a puzzling effect was recently discovered, in which the elimination (knock-out) of an activating regulatory element leads to increased (rather than decreased) activity of the element being regulated. It has been postulated that this paradoxical behavior can be explained by activating and repressing transcription factors competing for binding to other possible targets. It is very difficult to prove this hypothesis in mammalian cells, due to the large number of potential players and the complexity of endogenous intracellular regulatory networks. Instead, this paper analyzes this issue through an analogous synthetic biology construct which aims to reproduce the paradoxical behavior using standard bacterial gene expression networks. The paper first reviews the motivating cancer biology work, and then describes a proposed synthetic construct. A mathematical model is formulated, and basic properties of uniqueness of steady states and convergence to equilibria are established, as well as an identification of parameter regimes which should lead to observing such paradoxical phenomena (more activator leads to less activity at steady state). A proof is also given to show that this is a steady-state property, and for initial transients the phenomenon will not be observed. This work adds to the general line of work of resource competition in synthetic circuits.

q-bio.MN↗

arXiv2024

Multi-variable control to mitigate loads in CRISPRa networks: Extended Version

The discovery of CRISPR-mediated gene activation (CRISPRa) has transformed the way in which we perform genetic screening, bioproduction and therapeutics through its ability to scale and multiplex. However, the emergence of loads on the key molecular resources constituting CRISPRa by the orthogonal short RNA that guide such resources to gene targets, couple theoretically independent CRISPRa modules. This coupling negates the ability of CRISPRa systems to concurrently regulate multiple genes independent of one another. In this paper, we propose to reduce this coupling by mitigating the loads on the molecular resources that constitute CRISPRa. In particular, we design a multi-variable controller that makes the concentration of these molecular resources robust to variations in the level of the short RNA loads. This work serves as a foundation to design and implement CRISPRa controllers for practical applications.

q-bio.BM↗

arXiv2024

Analysis of singularly perturbed stochastic chemical reaction networks motivated by applications to epigenetic cell memory

Epigenetic cell memory, the inheritance of gene expression patterns across subsequent cell divisions, is a critical property of multi-cellular organisms. In recent work [10], a subset of the authors observed in a simulation study how the stochastic dynamics and time-scale differences between establishment and erasure processes in chromatin modifications (such as histone modifications and DNA methylation) can have a critical effect on epigenetic cell memory. In this paper, we provide a mathematical framework to rigorously validate and extend beyond these computational findings. Viewing our stochastic model of a chromatin modification circuit as a singularly perturbed, finite state, continuous time Markov chain, we extend beyond existing theory in order to characterize the leading coefficients in the series expansions of stationary distributions and mean first passage times. In particular, we characterize the limiting stationary distribution in terms of a reduced Markov chain, provide an algorithm to determine the orders of the poles of mean first passage times, and determine how changing erasure rates affects system behavior. The theoretical tools developed in this paper not only allow us to set a rigorous mathematical basis for the computational findings of our prior work, highlighting the effect of chromatin modification dynamics on epigenetic cell memory, but they can also be applied to other singularly perturbed Markov chains beyond the applications in this paper, especially those associated with chemical reaction networks.

math.PR↗

arXiv2024

A Stein's Method Approach to the Linear Noise Approximation for Stationary Distributions of Chemical Reaction Networks

Stochastic Chemical Reaction Networks are continuous time Markov chain models that describe the time evolution of the molecular counts of species interacting stochastically via discrete reactions. Such models are ubiquitous in systems and synthetic biology, but often have a large or infinite number of states, and thus are not amenable to computation and analysis. Due to this, approximations that rely on the molecular counts and the volume being large are commonly used, with the most common being the Reaction Rate Equations and the Linear Noise Approximation. For finite time intervals, Kurtz established the validity of the Reaction Rate Equations and Linear Noise Approximation, by proving law of large numbers and central limit theorem results respectively. However, the analogous question for the stationary distribution of the Markov chain model has remained mostly unanswered, except for chemical reaction networks with special structures or bounded molecular counts. In this work, we use Stein's Method to obtain sufficient conditions for the stationary distribution of an appropriately scaled Stochastic Chemical Reaction Network to converge to the Linear Noise Approximation as the system size goes to infinity. Our results give non asymptotic bounds on the error in the Reaction Rate Equations and in the Linear Noise Approximation as applied to the stationary distribution. As a special case, we give conditions under which the global exponential stability of an equilibrium point of the Reaction Rate Equations is sufficient to obtain our error bounds, thus permitting one to obtain conclusions about the Markov chain by analyzing the deterministic Reaction Rate Equations.

q-bio.QM↗

arXiv2023

Comparison Theorems for Stochastic Chemical Reaction Networks

Continuous-time Markov chains are frequently used as stochastic models for chemical reaction networks, especially in the growing field of systems biology. A fundamental problem for these Stochastic Chemical Reaction Networks (SCRNs) is to understand the dependence of the stochastic behavior of these systems on the chemical reaction rate parameters. Towards solving this problem, in this paper we develop theoretical tools called comparison theorems that provide stochastic ordering results for SCRNs. These theorems give sufficient conditions for monotonic dependence on parameters in these network models, which allow us to obtain, under suitable conditions, information about transient and steady state behavior. These theorems exploit structural properties of SCRNs, beyond those of general continuous-time Markov chains. Furthermore, we derive two theorems to compare stationary distributions and mean first passage times for SCRNs with different parameter values, or with the same parameters and different initial conditions. These tools are developed for SCRNs taking values in a generic (finite or countably infinite) state space and can also be applied for non-mass-action kinetics models. When propensity functions are bounded, our method of proof gives an explicit method for coupling two comparable SCRNs, which can be used to simultaneously simulate their sample paths in a comparable manner. We illustrate our results with applications to models of enzymatic kinetics and epigenetic regulation by chromatin modifications.

math.PR↗

arXiv2022

Identifiability of Chemical Reaction Networks with Intrinsic and Extrinsic Noise from Stationary Distributions

Many biological systems can be modeled as a chemical reaction network with unknown parameters. Data available to identify these parameters are often in the form of a stationary distribution, such as that obtained from measurements of a cell population. In this work, we introduce a framework for analyzing the identifiability of the reaction rate coefficients of chemical reaction networks from stationary distribution data. Working with the linear noise approximation, which is a diffusive approximation to the chemical master equation, we give a computational procedure to certify global identifiability based on Hilbert's Nullstellensatz. We present a variety of examples that show the applicability of our method to chemical reaction networks of interest in systems and synthetic biology, including discrimination between possible molecular mechanisms for the interaction between biochemical species.

eess.SY↗

arXiv2021

What Is the Trait d'Union between Retroactivity and Molecular Communication Performance Limits?

Information exchange is a critical process in all communication systems, including biological ones. The concept of retroactivity represents the loads that downstream modules apply to their upstream systems in biological circuits. This paper focuses on studying the impact of retroactivity on different biological signaling system models, which present analogies with well-known telecommunication systems. The mathematical analysis is performed both in the high and low molecular counts regime, by mean of the Chemical Master Equation and the Linear Noise Approximation, respectively. The aim is to provide analytical tools to maximize the reliable information exchange for different biomolecular circuit models. Results highlight how, in general, retroactivity harms communication performance. This negative effect can be mitigated by adding to the signaling circuit an independent upstream system that connects with the same pool of downstream systems.

cs.ET↗

arXiv2020

Robustness of networked systems to unintended interactions with application to engineered genetic circuits

A networked dynamical system is composed of subsystems interconnected through prescribed interactions. In many engineering applications, however, one subsystem can also affect others through "unintended" interactions that can significantly hamper the intended network's behavior. Although unintended interactions can be modeled as disturbance inputs to the subsystems, these disturbances depend on the network's states. As a consequence, a disturbance attenuation property of each isolated subsystem is, alone, insufficient to ensure that the network behavior is robust to unintended interactions. In this paper, we provide sufficient conditions on subsystem dynamics and interaction maps, such that the network's behavior is robust to unintended interactions. These conditions require that each subsystem attenuates constant external disturbances, is monotone or "near-monotone", the unintended interaction map is monotone, and the prescribed interaction map does not contain feedback loops. We employ this result to guide the design of resource-limited genetic circuits. More generally, our result provide conditions under which robustness of constituent subsystems is sufficient to guarantee robustness of the network to unintended interactions.

eess.SY↗

arXiv2018

Multi-modality in gene regulatory networks with slow promoter kinetics

Phenotypical variability in the absence of genetic variation often reflects complex energetic landscapes associated with underlying gene regulatory networks (GRNs). In this view, different phenotypes are associated with alternative states of complex nonlinear systems: stable attractors in deterministic models or modes of stationary distributions in stochastic descriptions. We provide theoretical and practical characterizations of these landscapes, specifically focusing on stochastic slow promoter kinetics, a time scale relevant when transcription factor binding and unbinding are affected by epigenetic processes like DNA methylation and chromatin remodeling. In this case, largely unexplored except for numerical simulations, adiabatic approximations of promoter kinetics are not appropriate. In contrast to the existing literature, we provide rigorous analytic characterizations of multiple modes. A general formal approach gives insight into the influence of parameters and the prediction of how changes in GRN wiring, for example through mutations or artificial interventions, impact the possible number, location, and likelihood of alternative states. We adapt tools from the mathematical field of singular perturbation theory to represent stationary distributions of Chemical Master Equations for GRNs as mixtures of Poisson distributions and obtain explicit formulas for the locations and probabilities of metastable states as a function of the parameters describing the system. As illustrations, the theory is used to tease out the role of cooperative binding in stochastic models in comparison to deterministic models, and applications are given to various model systems, such as toggle switches in isolation or in communicating populations, a synthetic oscillator and a trans-differentiation network.

q-bio.MN↗

arXiv2017

Robust Moment Closure Method for the Chemical Master Equation

The Chemical Master Equation (CME) is used to stochastically model biochemical reaction networks, under the Markovian assumption. The low-order statistical moments induced by the CME are often the key quantities that one is interested in. However, in most cases, the moments equation is not closed; in the sense that the first $n$ moments depend on the higher order moments, for any positive integer $n$. In this paper, we develop a moment closure technique in which the higher order moments are approximated by an affine function of the lower order moments. We refer to such functions as the affine Moment Closure Functions (MCF) and prove that they are optimal in the worst-case context, in which no a priori information on the probability distribution is available. Furthermore, we cast the problem of finding the optimal affine MCF as a linear program, which is tractable. We utilize the affine MCFs to derive a finite dimensional linear system that approximates the low-order moments. We quantify the approximation error in terms of the $% l_{\infty }$ induced norm of some linear system. Our results can be effectively used to approximate the low-order moments and characterize the noise properties of the biochemical network under study.

eess.SY↗

arXiv2016

Safety Verification and Control for Collision Avoidance at Road Intersections

This paper presents the design of a supervisory algorithm that monitors safety at road intersections and overrides drivers with a safe input when necessary. The design of the supervisor consists of two parts: safety verification and control design. Safety verification is the problem to determine if vehicles will be able to cross the intersection without colliding with current drivers' inputs. We translate this safety verification problem into a jobshop scheduling problem, which minimizes the maximum lateness and evaluates if the optimal cost is zero. The zero optimal cost corresponds to the case in which all vehicles can cross each conflict area without collisions. Computing the optimal cost requires solving a Mixed Integer Nonlinear Programming (MINLP) problem due to the nonlinear second-order dynamics of the vehicles. We therefore estimate this optimal cost by formulating two related Mixed Integer Linear Programming (MILP) problems that assume simpler vehicle dynamics. We prove that these two MILP problems yield lower and upper bounds of the optimal cost. We also quantify the worst case approximation errors of these MILP problems. We design the supervisor to override the vehicles with a safe control input if the MILP problem that computes the upper bound yields a positive optimal cost. We theoretically demonstrate that the supervisor keeps the intersection safe and is non-blocking. Computer simulations further validate that the algorithms can run in real time for problems of realistic size.

math.OC↗

arXiv2016

Model order reduction for Linear Noise Approximation using time-scale separation (Extended Version)

In this paper, we focus on model reduction of biomolecular systems with multiple time-scales, modeled using the Linear Noise Approximation. Considering systems where the Linear Noise Approximation can be written in singular perturbation form, with $ε$ as the singular perturbation parameter, we obtain a reduced order model that approximates the slow variable dynamics of the original system. In particular, we show that, on a finite time-interval, the first and second moments of the reduced system are within an $O(ε)$-neighborhood of the first and second moments of the slow variable dynamics of the original system. The approach is illustrated on an example of a biomolecular system that exhibits time-scale separation.

math.DS↗

arXiv2016

Robust Supervisors for Intersection Collision Avoidance in the Presence of Uncontrolled Vehicles

We present the design and validation of a centralized controller, called a supervisor, for collision avoidance of multiple human-driven vehicles at a road intersection, considering measurement errors, unmodeled dynamics, and uncontrolled vehicles. We design the supervisor to be least restrictive, that is, to minimize its interferences with human drivers. This performance metric is given a precise mathematical form by splitting the design process into two subproblems: verification problem and supervisor-design problem. The verification problem determines whether an input signal exists that makes controlled vehicles avoid collisions at all future times. The supervisor is designed such that if the verification problem returns yes, it allows the drivers' desired inputs; otherwise, it overrides controlled vehicles to prevent collisions. As a result, we propose exact and efficient supervisors. The exact supervisor solves the verification problem exactly but with combinatorial complexity. In contrast, the efficient supervisor solves the verification problem within a quantified approximation bound in polynomially bounded time with the number of controlled vehicles. We validate the performances of both supervisors through simulation and experimental testing.

eess.SY↗

arXiv2015

Semi-autonomous Intersection Collision Avoidance through Job-shop Scheduling

In this paper, we design a supervisor to prevent vehicle collisions at intersections. An intersection is modeled as an area containing multiple conflict points where vehicle paths cross in the future. At every time step, the supervisor determines whether there will be more than one vehicle in the vicinity of a conflict point at the same time. If there is, then an impending collision is detected, and the supervisor overrides the drivers to avoid collision. A major challenge in the design of a supervisor as opposed to an autonomous vehicle controller is to verify whether future collisions will occur based on the current drivers choices. This verification problem is particularly hard due to the large number of vehicles often involved in intersection collision, to the multitude of conflict points, and to the vehicles dynamics. In order to solve the verification problem, we translate the problem to a job-shop scheduling problem that yields equivalent answers. The job-shop scheduling problem can, in turn, be transformed into a mixed-integer linear program when the vehicle dynamics are first-order dynamics, and can thus be solved by using a commercial solver.

eess.SY↗