A multidisciplinary survey of modeling techniques for biochemical networks

All processes of life are dominated by networks of interacting biochemical components. The purpose of modeling these networks is manifold. From a theoretical point of view it allows the exploration of network structures and dynamics, to find emergent properties or to explain the organization and evolution of networks. From a practical point of view, in silico experiments can be performed that would be very expensive or impossible to achieve in the laboratory, such as hypothesis-testing with regard to knockout experiments or overexpression, or checking the validity of a proposed molecular mechanism. The literature on modeling biochemical networks is growing rapidly and the motivations behind different modeling techniques are sometimes quite distant from each other. To clarify the current context, we present a systematic overview of the different philosophies to model biochemical networks. We put particular emphasis on three main domains which have been playing a major role in the past, namely: mathematics with ordinary and partial differential equations, statistics with stochastic simulation algorithms, Bayesian networks and Markov chains, and the field of computer science with process calculi, term rewriting systems and state based systems. For each school, we evaluate advantages and disadvantages such as the granularity of representation, scalability, accessibility or availability of analysis tools. Following this, we describe how one can combine some of those techniques and thus take advantages of several techniques through the use of bridging tools. Finally, we propose a next step for modeling biochemical networks by using artificial chemistries and evolutionary computation. This work was funded by ESIGNET (Evolving Cell Signaling Networks in Silico), an European Integrated Project in the EU FP6 NEST Initiative (contract no. 12789)

40 Years Theory and Model at Wageningen UR

"Theorie en model" zo luidde de titel van de inaugurele rede van CT de Wit (1968). Reden genoeg voor een (theoretische) terugblik op zijn wer

Approaches to in vitro tissue regeneration with application for human disease modeling and drug development

Reliable in vitro human disease models that capture the complexity of in vivo tissue behaviors are crucial to gain mechanistic insights into human disease and enable the development of treatments that are effective across broad patient populations. The integration of stem cell technologies, tissue engineering, emerging biomaterials strategies and microfabrication processes, as well as computational and systems biology approaches, is enabling new tools to generate reliable in vitro systems to study the molecular basis of human disease and facilitate drug development. In this review, we discuss these recently developed tools and emphasize opportunities and challenges involved in combining these technologies toward regenerative science.National Institute for Biomedical Imaging and Bioengineering (U.S.) (Grant 5R01EB010246-02)National Center for Advancing Translational Sciences (U.S.) (Grant 1UH2TR000496)United States. Defense Advanced Research Projects Agency (Cooperative Agreement W911NF-12-2-0039

Modelling and simulating in systems biology: an approach based on multi-agent systems

Systems Biology is an innovative way of doing biology recently raised in bio-informatics contexts, characterised by the study of biological systems as complex systems with a strong focus on the system level and on the interaction dimension. In other words, the objective is to understand biological systems as a whole, putting on the foreground not only the study of the individual parts as standalone parts, but also of their interaction and of the global properties that emerge at the system level by means of the interaction among the parts. This thesis focuses on the adoption of multi-agent systems (MAS) as a suitable paradigm for Systems Biology, for developing models and simulation of complex biological systems. Multi-agent system have been recently introduced in informatics context as a suitabe paradigm for modelling and engineering complex systems. Roughly speaking, a MAS can be conceived as a set of autonomous and interacting entities, called agents, situated in some kind of nvironment, where they fruitfully interact and coordinate so as to obtain a coherent global system behaviour. The claim of this work is that the general properties of MAS make them an effective approach for modelling and building simulations of complex biological systems, following the methodological principles identified by Systems Biology. In particular, the thesis focuses on cell populations as biological systems. In order to support the claim, the thesis introduces and describes (i) a MAS-based model conceived for modelling the dynamics of systems of cells interacting inside cell environment called niches. (ii) a computational tool, developed for implementing the models and executing the simulations. The tool is meant to work as a kind of virtual laboratory, on top of which kinds of virtual experiments can be performed, characterised by the definition and execution of specific models implemented as MASs, so as to support the validation, falsification and improvement of the models through the observation and analysis of the simulations. A hematopoietic stem cell system is taken as reference case study for formulating a specific model and executing virtual experiments

Combined mechanistic modeling and machine-learning approaches in systems biology - A systematic literature review

Background and objective: Mechanistic-based Model simulations (MM) are an effective approach commonly employed, for research and learning purposes, to better investigate and understand the inherent behavior of biological systems. Recent advancements in modern technologies and the large availability of omics data allowed the application of Machine Learning (ML) techniques to different research fields, including systems biology. However, the availability of information regarding the analyzed biological context, sufficient experimental data, as well as the degree of computational complexity, represent some of the issues that both MMs and ML techniques could present individually. For this reason, recently, several studies suggest overcoming or significantly reducing these drawbacks by combining the above-mentioned two methods. In the wake of the growing interest in this hybrid analysis approach, with the present review, we want to systematically investigate the studies available in the scientific literature in which both MMs and ML have been combined to explain biological processes at genomics, proteomics, and metabolomics levels, or the behavior of entire cellular populations. Methods: Elsevier Scopus®, Clarivate Web of Science™ and National Library of Medicine PubMed® databases were enquired using the queries reported in Table 1, resulting in 350 scientific articles. Results: Only 14 of the 350 documents returned by the comprehensive search conducted on the three major online databases met our search criteria, i.e. present a hybrid approach consisting of the synergistic combination of MMs and ML to treat a particular aspect of systems biology. Conclusions: Despite the recent interest in this methodology, from a careful analysis of the selected papers, it emerged how examples of integration between MMs and ML are already present in systems biology, highlighting the great potential of this hybrid approach to both at micro and macro biological scales

Modelling and multiobjective optimization for simulation of cyanobacterial metabolism

The present thesis is devoted to the development of models and algorithms to improve metabolic simulations of cyanobacterial metabolism. Cyanobacteria are photosynthetic bacteria of great biotechnological interest to the development of sustainable bio-based manufacturing processes. For this purpose, it is fundamental to understand metabolic behaviour of these organisms, and constraint-based metabolic modelling techniques offer a platform for analysis and assessment of cell's metabolic functionality. Reliable simulations are needed to enhance the applicability of the results, and this is the main goal of this thesis. This dissertation has been structured in three parts. The first part is devoted to introduce needed fundamentals of the disciplines that are combined in this work: metabolic modelling, cyanobacterial metabolism and multi-objective optimisation. In the second part the reconstruction and update of metabolic models of two cyanobacterial strains is addressed. These models are then used to perform metabolic simulations with the application of the classic Flux Balance Analysis (FBA) methodology. The studies conducted in this part are useful to illustrate the uses and applications of metabolic simulations for the analysis of living organisms. And at the same time they serve to identify important limitations of classic simulation techniques based on mono-objective linear optimisation that motivate the search of new strategies. Finally, in the third part a novel approach is defined based on the application of multi-objective optimisation procedures to metabolic modelling. Main steps in the definition of multi-objective problem and the description of an optimisation algorithm that ensure the applicability of the obtained results, as well as the multi-criteria analysis of the solutions are covered. The resulting tool allows the definition of non-linear objective functions and constraints, as well as the analysis of multiple Pareto-optimal solutions. It avoids some of the main drawbacks of classic methodologies, leading to more flexible simulations and more realistic results. Overall this thesis contributes to the advance in the study of cyanobacterial metabolism by means of definition of models and strategies that improve plasticity and predictive capacities of metabolic simulations.La presente tesis está dedicada al desarrollo de modelos y algoritmos para mejorar las simulaciones metabólicas de cianobacterias. Las cianobacterias son bacterias fotosintéticas de gran interés biotecnológico para el desarrollo de bioprocesos productivos sostenibles. Para este propósito, es fundamental entender el comportamiento metabólico de estos organismos, y el modelado metabólico basado en restricciones ofrece una plataforma para el análisis y la evaluación de las funcionalidades metabólicas de las células. Se necesitan simulaciones fidedignas para aumentar la aplicabilidad de los resultados, y este es el objetivo principal de esta tesis. Esta disertación se ha estructurado en tres partes. La primera parte está dedicada a introducir los fundamentos necesarios de las disciplinas que se combinan en este trabajo: el modelado metabólico, el metabolismo de cianobacterias, y la optimización multiobjetivo. En la segunda parte, se encara la reconstrucción y la actualización de los modelos metabólicos de dos cepas de cianobacterias. Estos modelos se usan después para llevar a cabo simulaciones metabólicas con la aplicación de la metodología clásica Flux Balance Analysis (FBA). Los estudios realizados en esta parte son útiles para ilustrar los usos y aplicaciones de las simulaciones metabólicas para el análisis de los organismos vivos. Y al mismo tiempo sirven para identificar importantes limitaciones de las técnicas clásicas de simulación basadas en optimización lineal mono-objetivo que motivan la búsqueda de nuevas estrategias. Finalmente, en la tercera parte, se define una nueva aproximación basada en la aplicación al modelado metabólico de procedimientos de optimización multiobjetivo. Se cubren los principales pasos en la definición de un problema multiobjetivo y la descripción de un algoritmo de optimización que aseguren la aplicabilidad de los resultados obtenidos, así como el análisis multi-criterio de las soluciones. La herramienta resultante permite la definición de funciones objetivo y restricciones no lineales, así como el análisis de múltiples soluciones en el sentido de Pareto. Esta herramienta evita algunos de los principales inconvenientes de las metodologías clásicas, lo que lleva a obtener simulaciones más flexibles y resultados más realistas. En conjunto, esta tesis contribuye al avance en el estudio del metabolismo de cianobacterias por medio de la definición de modelos y estrategias que mejoran la plasticidad y las capacidades predictivas de las simulaciones metabólicas.La present tesi està dedicada al desenvolupament de models i algorismes per a millorar les simulacions metabòliques de cianobacteris. Els cianobacteris són bacteris fotosintètics de gran interés biotecnològic per al desenvolupament de bioprocessos productius sostenibles. Per a aquest propòsit, és fonamental entendre el comportament metabòlic d'aquests organismes, i el modelatge metabòlic basat en restriccions ofereix una plataforma per a l'anàlisi i l'avaluació de les funcionalitats metabòliques de les cèl·lules. Es necessiten simulacions fidedignes per a augmentar l'aplicabilitat dels resultats, i aquest és l'objectiu principal d'aquesta tesi. Aquesta dissertació s'ha estructurat en tres parts. La primera part està dedicada a introduir els fonaments necessaris de les disciplines que es combinen en aquest treball: el modelatge metabòlic, el metabolisme de cianobacteris i l'optimització multiobjectiu. En la segona part, s'adreça la reconstrucció i l'actualització dels models metabòlics de dos soques de cianobacteris. Aquests models s'empren després per a portar a terme simulacions metabòliques amb l'aplicació de la metodologia clàssica Flux Balance Analysis (FBA). Els estudis realitzats en aquesta part són útils per a il·lustrar els usos i aplicacions de les simulacions metabòliques per a l'anàlisi dels organismes vius. I al mateix temps serveixen per a identificar importants limitacions de les tècniques clàssiques de simulació basades en optimització lineal mono-objectiu que motiven la cerca de noves estratègies. Finalment, en la tercera part, es defineix una nova aproximació basada en l'aplicació al modelatge metabòlic de procediments d'optimització multiobjectiu. Es cobreixen els principals passos en la definició d'un problema multiobjectiu i la descripció d'un algorisme d'optimització que asseguren l'aplicabilitat dels resultats obtinguts, així com l'anàlisi multi-criteri de les solucions. La ferramenta resultant permet la definició de funcions objectiu i restriccions no lineals, així com l'anàlisi de múltiples solucions òptimes en el sentit de Pareto. Aquesta ferramenta evita alguns dels principals inconvenients de les metodologies clàssiques, el que porta a obtenir simulacions més flexibles i resultats més realistes. En conjunt, aquesta tesi contribueix a l'avanç en l'estudi del metabolisme de cianobacteris per mitjà de la definició de models i estratègies que milloren la plasticitat i les capacitats predictives de les simulacions metabòliques.Siurana Paula, M. (2017). Modelling and multiobjective optimization for simulation of cyanobacterial metabolism [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/9057

Systems Biology in ELIXIR: modelling in the spotlight

info:eu-repo/semantics/publishedVersio