Irene Otero-Muras

• PhD
• Researcher at Spanish National Research Council

Engineering biology requires precise control of biomolecular circuits, and Cybergenetics is the field dedicated to achieving this goal. A significant challenge in developing controllers for cellular functions is designing systems that can effectively manage molecular noise. To address this, there has been increasing effort to develop model-based co...

In this paper, a finite volume discretization scheme for partial integro-differential equations (PIDEs) describing the temporal evolution of protein distribution in gene regulatory networks is proposed. It is shown that the obtained set of ODEs can be formally represented as a compartmental kinetic system with a strongly connected reaction graph. T...

Motivation One of the main causes hampering predictability during the model identification and automated design of gene circuits in synthetic biology is the effect of molecular noise. Stochasticity may significantly impact the dynamics and function of gene circuits, specially in bacteria and yeast due to low mRNA copy numbers. Standard stochastic s...

Microorganisms (mainly bacteria and yeast) are frequently used as hosts for genetic constructs in synthetic biology applications. Molecular noise might have a significant effect on the dynamics of gene regulation in microbial cells, mainly attributed to the low copy numbers of mRNA species involved. However, the inclusion of molecular noise in the...

Recent advances in synthetic biology are enabling exciting technologies, including the next generation of biosensors, the rational design of cell memory, modulated synthetic cell differentiation, and generic multifunctional biocircuits. These novel applications require the design of gene circuits leading to sophisticated behaviors and functionaliti...

Mechanistic dynamic models have become an essential tool for understanding biomolecular networks and other biological systems. Biochemical stochasticity can be extremely important in some situations, e.g. at the single-cell level where there is a low copy number of the species involved. In these scenarios, deterministic models are not suitable to c...

In this work, we present an optimization-based design strategy for gene regulatory networks (GRNs) in the stochastic regime (i.e., in the presence of molecular noise). The approach exploits a recently developed framework for the efficient simulation of stochastic GRNs based on a Partial Integro Differential Equations (PIDE) model formulation, which...

In the context of phenotype switching and cell fate determination, numerousexperimental studies report hysteresis, despite the fact that the (forward) Chemical Master Equation governing the inherently stochastic underlying gene regulatory networks has a unique steady state (precluding memory effects and hysteresis). In previous works, we demonstrat...

Achieving control of gene regulatory circuits is one of the goals of synthetic biology, as a way to regulate cellular functions for useful purposes (in biomedical, environmental or industrial applications). The inherent stochastic nature of gene expression makes it challenging to control the behavior of gene regulatory networks, and increasing effo...

The level of unpredictability of the COVID-19 pandemics poses a challenge to effectively model its dynamic evolution. In this study we incorporate the inherent stochasticity of the SARS-CoV-2 virus spread by reinterpreting the classical compartmental models of infectious diseases (SIR type) as chemical reaction systems modelled via the Chemical Mas...

Recent advances in synthetic biology are enabling exciting technologies, including the next generation of biosensors, the rational design of cell memory, modulated synthetic cell differentiation and generic multi-functional bio-circuits. These novel applications require the design of gene circuits leading to sophisticated behaviours and functionali...

Computational tools have been widely adopted for strain optimization in metabolic engineering, contributing to numerous success stories of producing industrially relevant biochemicals. However, most of these tools focus on single metabolic intervention strategies (either gene/reaction knockout or amplification alone) and rely on hypothetical optima...

This study presents the results of SARS-CoV-2 surveillance in sewage water of 11 municipalities and marine bioindicators in Galicia (NW of Spain) from May 2020 to May 2021. An integrated pipeline was developed including sampling, pre-treatment and biomarker quantification, RNA detection, SARS-CoV-2 sequencing, mechanistic mathematical modeling and...

Biofoundries are highly automated facilities that enable the rapid and efficient design, build, test, and learn cycle of biomanufacturing and engineering biology, which is applicable to both research and industrial production. However, developing a biofoundry platform can be expensive and time consuming. A biofoundry should grow organically, starti...

Background Theoretical analysis of signaling pathways can provide a substantial amount of insight into their function. One particular area of research considers signaling pathways capable of assuming two or more stable states given the same amount of signaling ligand. This phenomenon of bistability can give rise to switch-like behavior, a mechanism...

SYNBADm is a Matlab toolbox for the automated design of biocircuits using a model-based optimization approach. It enables the design of biocircuits with pre-defined functions starting from libraries of biological parts. SYNBADm makes use of mixed integer global optimization and allows both single and multi-objective design problems. Here we describ...

Synthetic biology aims at engineering synthetic circuits with pre-defined target functions. From a systems (model-based) perspective, the following problems are of central importance: (1) given the model of a biomolecular circuit, elucidate whether it is capable of a certain behavior/functionality; and (2) starting from a pre-defined required funct...

Background Theoretical analysis of signaling pathways can provide a substantial amount of insight into their function. One particular area of research considers signaling pathways capable of assuming two or more stable states given the same amount of signaling ligand. This phenomenon of bistability can give rise to switch-like behavior, a mechanism...

Motivation: Multi-steady state behaviour, and in particular multi-stability, provides biological systems with the capacity to take reliable decisions (such as cell fate determination). A problem arising frequently in systems biology is to elucidate whether a signal transduction mechanism or a gene regulatory network has the capacity for multi-stea...

Cell fate determination, the process through which cells commit to differentiated states is commonly mediated by gene regulatory motifs with mutually exclusive expression states. The classical deterministic picture for cell fate determination includes bistability and hysteresis, which enables the persistence of the acquired cellular state after wit...

Metabolic engineering has enabled the production of a wealth of chemicals with microorganisms. Classic strategies for pathway engineering rely on the expression of heterologous enzymes in a host that convert native intermediates into target products. Although traditional implementations are based on open-loop control, recent advances in gene circui...

A major challenge in model-based design of synthetic biochemical circuits is how to address uncertainty in the parameters. A circuit whose behavior is robust to variations in the parameters will have more chances to behave as predicted when implemented in practice, and also to function reliably in presence of fluctuations and noise. Here, we extend...

Metabolic engineering has enabled the production of a wealth of chemicals with microorganisms. Classic strategies for pathway engineering rely on the expression of heterologous enzymes in a host that convert native intermediates into target products. Although traditional implementations are based on open-loop control, recent advances in gene circui...

In this work we explore two potential mechanisms inducing multiple equilibria for weakly reversible networks with mass-action kinetics. The study is performed on a class of polynomial dynamic systems that, under some mild assumptions, are able to accommodate in their state-space form weakly reversible mass-action kinetic networks. The contribution...

Cell fate determination, the process through which cells commit to differentiated states, has been shown to be mediated by gene regulatory motifs with mutually exclusive expression states. The classical picture for deterministic cell decision making includes bistability and hysteresis. Despite numerous experimental works supporting evidence of hyst...

Gene expression is inherently stochastic, and the dynamics of gene regulatory networks (GRNs) is governed by the Chemical Master Equation (CME). In most cases, the solution of the CME is not available, and the stochastic simulation algorithm (SSA) requires a high computational effort. In this work we illustrate the performance of a method recently...

In this work we tackle a number of computational challenges in systems and synthetic biology exploiting optimization based approaches. Our framework combines three important capabilities: multiple optimization objectives (taking into account trade-offs between conflicting goals), simultaneous exploration of topology and parameter spaces (through a...

Aggregation of misfolded proteins has been implicated in a number of neurodegenerative disorders including prion disease. In spite of intensive research, the detailed mechanisms of protein misfolding leading to protein aggregation remain unsolved. Here, we explore the capacity for bistability of several classes of mechanisms proposed in the literat...

A complex nonlinear system might exhibit a rich variety of dynamics. Detecting and classifying these dynamics is crucial to understand and ultimately control the system. Starting from an ODE model, this analysis can be done using standard bifurcation/continuation methods. However, when we start from measured data to infer the equations governing th...

Motivation: Gene regulation is inherently stochastic. In many applications concerning Systems and Synthetic Biology such as the reverse engineering and the de novo design of genetic circuits, stochastic effects (yet potentially crucial) are often neglected due to the high computational cost of stochastic simulations. With advances in these fields...

The second law imposes a number of constraints on the set of feasible reaction rate coefficients that a chemical network can accept, known in the literature on CRNT (Chemical Reaction Network Theory) as Wegscheider's condition. One main consequence is that any closed chemical reaction system operating at isothermal conditions, if compatible with th...

Gene expression is inherently stochastic. Advanced single-cell microscopy techniques together with mathematical models for single gene expression led to important insights in elucidating the sources of intrinsic noise in prokaryotic and eukaryotic cells. In addition to the finite size effects due to low copy numbers, translational bursting is a dom...

Bistability has important implications in signaling pathways, since it indicates a potential cell decision between alternative outcomes. We present two approaches developed in the framework of the Chemical Reaction Network Theory for easy and efficient search of multiple steady state behavior in signaling networks (both with and without mass conser...

Supporting proofs and computations. Pdf file containing supporting definitions, proofs, detailed computations and additional figures. (PDF)

Matlab codes. Zip file containing Matlab codes. (ZIP)

In this work we consider Pareto optimality for automated design in synthetic biology. We present a generalized framework based on a mixed-integer dynamic optimization formulation that, given design specifications, allows the computation of Pareto optimal sets of designs, i.e. the set of best trade-offs for the metrics of interest. We show how this...

One central problem in systems and synthetic biology is to characterize the biological functions of regulatory network motifs. Here we consider recent model-based exploration approaches used to identify motifs capable of performing a specific biological task. In this work, we propose an optimization based strategy where the motivation is twofold: o...

In bridging theory and potential applications of chemical reaction networks, we adopt a geometric perspective to explore equilibrium in mass action law kinetic systems. Such systems are typically employed to model nonlinear dynamics in open and closed chemical reaction networks. As a class nonnegative systems, the range of potential applications ex...

From cyanobacteria to human, sustained oscillations coordinate important biological functions. Although much has been learned concerning the sophisticated molecular mechanisms underlying biological oscillators, design principles linking structure and functional behavior are not yet fully understood. Here we explore design principles of biological o...

Zip file containing Matlab code. (ZIP)

Pdf file containing additional information. (PDF)

We present an efficient method to design synthetic oscillators with optimal robustness against molecular noise.

Motivation: The design of de novo circuits with predefined performance specifications is a challenging problem in Synthetic Biology. Computational models and tools have proved to be crucial for a successful wet lab implementation. Natural gene circuits are complex, subject to evolutionary tradeoffs and playing multiple roles. However, most synthet...

Background: Within cells, stimuli are transduced into cell responses by complex networks of biochemical reactions. In many cell decision processes the underlying networks behave as bistable switches, converting graded stimuli or inputs into all or none cell responses. Observing how systems respond to different perturbations, insight can be gained...

We consider the problem of optimal design of synthetic biological oscillators. Our aim is, given a set of standard biological parts and some pre-specified performance requirements, to automatically find the circuit configuration and its tuning so that self-sustained oscillations meeting the requirements are produced. To solve this design problem, w...

Background One of the challenges in Synthetic Biology is to design circuits with increasing levels of complexity. While circuits in Biology are complex and subject to natural tradeoffs, most synthetic circuits are simple in terms of the number of regulatory regions, and have been designed to meet a single design criterion. Results In this contribu...

Engineering a synthetic oscillator requires an oscillatory model which can be implemented into practice. Some required conditions for a successful practical implementation include the robustness of the oscillation under realistic parameter values and the accessibility to the variables that need to be manipulated. For a particular class of theoretic...

Switch like responses appear as common strategies in the regulation of cellular systems. Here we present a method to characterize bistable regimes in biochemical reaction networks that can be of use to both direct and reverse engineering of biological switches. In the design of a synthetic biological switch, it is important to study the capability...

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Representation of the tangent and secant hyperplanes associated to a nonlinear manifold, in this case a curve, at ; and are unit vectors centered at ; and are two different points of the manifold. (EPS)

In this work, we illustrate the potential of Chemical Reaction Network Theory for model identification of kinetic models, setting up the basis for a novel method of inverse bifurcation analysis of bistable biochemical systems. The method exploits the structural properties of biochemical networks to infer the kinetic parameters from dose response cu...

Chemical Reaction Network theory allows us to decide whether many classes of networks have the capacity for multiple positive equilibria, based on their structural properties. In this way, the deficiency zero theorem asserts that every weakly reversible network of zero deficiency has a unique equilibrium, for any choices of parameter values. We mak...

The global harvesting of marine products has increased from around 17 million tons in the 1950s to a current average amount of 85 million tons. The Food and Agriculture Organization (FAO) estimates that an annual average of 27 million tons of non-targeted species are caught and thrown back into the sea, what means that near third of the fish volume...

Metal bioaccumulation in fish is influenced by factors specific to the chemical and environmental conditions, the exposure route and the species. For a better understanding of the main interactions among these factors, models are needed to capture the basic principles driving the dynamics of metal bioaccumulation in fish, taking into account differ...

In the present work, a set of generic parameters was proposed for a pharmacokinetic model, with the objective of predicting Cd concentration in the tissues of diverse fish species under different environmental conditions. Cd concentrations in a number of tissues of Oncorhynchus mykiss and Cyprinus carpio were estimated by a structurally identifiabl...

In this work, a novel algorithmic approach to detect multiplicity of steady states in enzymatic reaction networks is presented. The method exploits the structural properties of networks derived from the Chemical Reaction Network Theory. In first instance, the space of parameters is divided in different regions according to the qualitative behavior...

In the present work, we combine the concepts and tools from Irreversible Thermodynamics and Control Theory in a contribution to unravel the origin of complex nonlinear behaviour in biochemical networks. Regarding cells as thermodynamic systems, we can consider dynamic evolution of intracellular processes in terms of the combined action of an endoge...

The aim of this work is to develop a visual interface including the most representative processes in the gelatin production from fish skin. Connecting different components from a library implemented in EcosimPro, users can easily configure a virtual plant according to their requirements, and test different scenarios attending to the quantity and qu...

In this work, a model for metal bioaccumulation in fish is presented. The model captures the basic principles driving the dynamics of metal bioaccumulation in fish, taking into account different exposure routes and the distribution among representative organs. The model is demonstrated to be robust and structurally identifiable. The complete set of...

In this letter we show that closed reversible chemical reaction networks with independent elementary reactions admit a global pseudo-Hamiltonian structure which is at least locally dissipative around any equilibrium point. The structure matrix of the Hamiltonian description reflects the graph topology of the reaction network and it is a smooth func...

Biochemical networks are represented by nonlinear systems of ODEs that can often exhibit qualitatively different dynamics depending on the parameter values. In order to ensure the desired response in a controlled biological system, some flows or kinetic constants can be manipulated to maintain the whole set of parameters of the closed loop system w...

15 pages, 23 figures.-- ESCAPE-15 - Selected Papers from the 15th European Symposium on Computer Aided Process Engineering held in Barcelona, Spain, May 29-June 1, 2005.-- Available online 26 December 2006. In this work, a systematic approach to plant-wide control design is proposed. The method combines ingredients from process networks, thermodyna...

Los procesos de la industria química, alimentaria o biotecnológica, así como muchos de los mecanismos propios de la biología de sistemas, pertenecen a la clase de los llamados sistemas de proceso. En esta contribución se hace uso de un conjunto de resultados previos que combinan aspectos de la teoría de sistemas y grafos, con métodos de termodinámi...

Processes in chemical, food or biotechnology industry, as well as many of the mechanisms characteristics of system biology, belong to the so-called process systems class. In this contribution, use is made of a number of previous results that combine aspects from systems and graph theory with methods from thermodynamics and reaction networks to set...

Biochemical networks are represented by nonlinear systems of ODEs that can often exhibit qualitatively different dynamics depending on the parameter values. In order to ensure the desired response in a controlled biological system, some flows or kinetic constants can be manipulated to maintain the whole set of parameters of the closed loop system w...

In this work, we apply the systematic approach to plant-wide control design presented in [1], based on the fundamentals of process networks, thermodynamics and systems theory, to the Tennessee Eastman (TE) Challenge Process, deriving robust decentralized controllers that will ensure the stability of the complete plant. We take one step further in t...

Metabolic or cell signalling pathways are examples of biochemical networks exhibiting possible complex dynamics in the form of steady-state multiplicity, sustained oscillations or even deterministic chaos. The origin of these nonlinear phenomena is not always well understood, nor it can be systematically predicted beyond a case by case basis. Despi...

In this work, we consider the multiobjective design of bioprocesses, i.e., those from the biotechnological, pharmaceutical, and food industries. We present and compare extensions for three solution strategies for multiobjective optimization of this class of problems, which can be a very challenging task due to the frequent nonconvex nature of the a...

In this contribution we present a robust multi-criteria optimisation method for the design of nonlinear bioprocesses. This method is based on the combination of NBI, a recently proposed scheme for generating Pareto sets, and a global optimisation method, SRES, based on evolutionary computation concepts. A bifurcation method is used to further analy...

Resumen En este trabajo se propone un procedimiento sis-temático para el diseño de estructuras de con-trol plant-wide. Esta propuesta combina con-ceptos procedentes de las redes de procesos, la termodinámica y la teoría de sistemas a fin de obtener controladores robustos y descentralizados A lo largo de los años, eí area del control de plan-tas com...