127 research outputs found

    Novel modeling formalisms and simulation tools in computational biosystems

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    Tese de doutoramento em BioengenhariaThe goal of Systems Biology is to understand the complex behavior that emerges from the interaction among the cellular components. Industrial biotechnology is one of the areas of application, where new approaches for metabolic engineering are developed, through the creation of new models and tools for simulation and optimization of the microbial metabolism. Although whole-cell modeling is one of the goals of Systems Biology, so far most models address only one kind of biological network independently. This work explores the integration of di erent kinds of biological networks with a focus on the improvement of simulation of cellular metabolism. The bacterium Escherichia coli is the most well characterized model organism and is used as our case-study. An extensive review of modeling formalisms that have been used in Systems Biology is presented in this work. It includes several formalisms, including Boolean networks, Bayesian networks, Petri nets, process algebras, constraint-based models, di erential equations, rule-based models, interacting state machines, cellular automata and agent-based models. We compare the features provided by these formalisms and classify the most suitable ones for the creation of a common framework for modeling, analysis and simulation of integrated biological networks. Currently, there is a separation between dynamic and constraint-based modeling of metabolism. Dynamic models are based on detailed kinetic reconstructions of central metabolic pathways, whereas constraint-based models are based on genome-scale stoichiometric reconstructions. Here, we explore the gap between both formulations and evaluate how dynamic models can be used to reduce the solution space of constraint-based models in order to eliminate kinetically infeasible solutions. The limitations of both kinds of models are leading to new approaches to build kinetic models at the genome-scale. The generation of kinetic models from stoichiometric reconstructions can be performed within the same framework as a transformation from discrete to continuous Petri nets. However, the size of these networks results in models with a large number of parameters. In this scope, we develop and implement structural reduction methods that adjust the level of detail of metabolic networks without loss of information, which can be applied prior to the kinetic inference to build dynamic models with a smaller number of parameters. In order to account for enzymatic regulation, which is not present in constraint-based models, we propose the utilization of Extended Petri nets. This results in a better sca old for the kinetic inference process. We evaluate the impact of accounting for enzymatic regulation in the simulation of the steady-state phenotype of mutant strains by performing knockouts and adjustment of enzyme expression levels. It can be observed that in some cases the impact is signi cant and may reveal new targets for rational strain design. In summary, we have created a solid framework with a common formalism and methods for metabolic modeling. This will facilitate the integration with gene regulatory networks, as we have already addressed many issues also associated with these networks, such as the trade-o between size and detail, and the representation of regulatory interactions.O objectivo da Biologia de Sistemas é compreender os comportamentos que resultam das complexas interacções entre todos os componentes celulares. A biotecnologia industrial é uma das áreas de aplicação, onde novas abordagens para a engenharia metabólica são desenvolvidas através da criação de novos modelos e ferramentas de simulação e optimização do metabolismo microbiano. Apesar de um dos principais objectivos da Biologia de Sistemas ser a criação de um modelo completo de uma célula, até ao momento a maioria dos modelos desenvolvidos incorpora de forma separada cada tipo de rede biológica. Este trabalho explora a integração de diferentes tipos de redes biológicas, focando melhorar a simulação do metabolismo celular. A bactéria Escherichia coli é o organismo modelo que estáa melhor caracterizado e é usado como caso de estudo. Neste trabalho é elaborada uma extensa revisão dos formalismos de modela ção que têm sido utilizados em Biologia de Sistemas. São considerados vários formalismos tais como, redes Booleanas, redes Bayesianas, redes de Petri, álgebras de processos, modelos baseados em restrições, equações diferenciais, modelos baseados em regras, máquinas de interacção de estados, autómatos celulares e modelos baseados em agentes. As funcionalidades inerentes a estes formalismos são analisadas de forma a classificar os mesmos pelo seu potencial em servir de base à criação de uma plataforma para modela ção, análise e simulação de redes biológicas integradas. Actualmente, existe uma separação entre modelação dinâmica e modelação baseada em restrições para o metabolismo celular. Os modelos dinâmicos consistem em reconstruções cinéticas detalhadas de vias centrais do metabolismo, enquanto que os modelos baseados em restrições são construídos à escala genómica com base apenas na estequiometria das reacçõoes. Neste trabalho explora-se a separação entre os dois tipos de formulação e é avaliada a forma como os modelos dinâmicos podem ser utilizados para reduzir o espaço de soluções de modelos baseados em restrições de forma a eliminar soluções inalcançáveis. As limitações impostas por ambos os tipos de modelos estão a conduzir à criação de novas abordagens para a construção de modelos cinéticos à escala genómica. A geração de modelos cinéticos a partir de reconstruções estequiométricas pode ser feita dentro de um mesmo formalismo através da transformação de redes de Petri discretas em redes de Petri contínuas. No entanto, devido ao tamanho destas redes, os modelos resultantes incluem um número extremamente grande de parâmetros. Neste trabalho são implementados métodos para a redução estrutural de redes metabólicas sem perda de informação, que permitem ajustar o nível de detalhe das redes. Estes métodos podem ser aplicados à inferência de cinéticas, de forma a gerar modelos dinâmicos com um menor número de parâmetros. De forma a considerar efeitos de regulação enzimática, os quais não são representados em modelos baseados em restrições, propõe-se a utilização de redes de Petri complementadas com arcos regulatórios. Este formalismo é utilizado como base para o processo de inferência cinética. A influência da regulação enzimática na determinação do estado estacionário de estirpes mutantes é avaliada através da análise da remoção de reacções e da variação dos níveis de expressão enzimática. Observa-se que em alguns casos esta influência é significativa e pode ser utilizada para obter novas estratégias de manipulação de estirpes. Em suma, neste trabalho foi criada uma plataforma sólida para modelação do metabolismo baseada num formalismo comum. Esta plataforma facilitará a integração com redes de regulação genética, pois foram abordados vários problemas que também se colocam nestas redes, tais como o ajuste entre o tamanho da rede e o seu nível de detalhe, bem como a representação de interacções regulatórias entre componentes da rede

    Tropical Abstraction of Biochemical Reaction Networks with Guarantees

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    International audienceBiochemical molecules interact through modification and binding reactions, giving raise to a combinatorial number of possible biochemical species. The time-dependent evolution of concentrations of the species is commonly described by a system of coupled ordinary differential equations (ODEs). However, the analysis of such high-dimensional, non-linear system of equations is often computationally expensive and even prohibitive in practice. The major challenge towards reducing such models is providing the guarantees as to how the solution of the reduced model relates to that of the original model, while avoiding to solve the original model. In this paper, we have designed and tested an approximation method for ODE models of biochemical reaction systems, in which the guarantees are our major requirement. Borrowing from tropical analysis techniques, we look at the dominance relations among terms of each species' ODE. These dominance relations can be exploited to simplify the original model, by neglecting the dominated terms. As the dominant subsystems can change during the system's dynamics, depending on which species dominate the others, several possible modes exist. Thus, simpler models consisting of only the dominant subsystems can be assembled into hybrid, piecewise smooth models, which approximate the behavior of the initial system. By combining the detection of dominated terms with symbolic bounds propagation, we show how to approximate the original model by an assembly of simpler models, consisting in ordinary differential equations that provide time-dependent lower and upper bounds for the concentrations of the initial models species. The utility of our method is twofold. On the one hand, it provides a reduction heuristics that performs without any prior knowledge of the initial system's behavior (i.e., no simulation of the initial system is needed in order to reduce it). On the other hand, our method provides sound interval bounds for each species, and hence can serve to evaluate the faithfulness of tropicalization reduction heuristics for ODE models of biochemical reduction systems. The method is tested on several case studies

    Discrepancies between extinction events and boundary equilibria in reaction networks

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    Reaction networks are mathematical models of interacting chemical species that are primarily used in biochemistry. There are two modeling regimes that are typically used, one of which is deterministic and one that is stochastic. In particular, the deterministic model consists of an autonomous system of differential equations, whereas the stochastic system is a continuous-time Markov chain. Connections between the two modeling regimes have been studied since the seminal paper by Kurtz (J Chem Phys 57(7):2976–2978, 1972), where the deterministic model is shown to be a limit of a properly rescaled stochastic model over compact time intervals. Further, more recent studies have connected the long-term behaviors of the two models when the reaction network satisfies certain graphical properties, such as weak reversibility and a deficiency of zero. These connections have led some to conjecture a link between the long-term behavior of the two models exists, in some sense. In particular, one is tempted to believe that positive recurrence of all states for the stochastic model implies the existence of positive equilibria in the deterministic setting, and that boundary equilibria of the deterministic model imply the occurrence of an extinction event in the stochastic setting. We prove in this paper that these implications do not hold in general, even if restricting the analysis to networks that are bimolecular and that conserve the total mass. In particular, we disprove the implications in the special case of models that have absolute concentration robustness, thus answering in the negative a conjecture stated in the literature in 2014

    Second Generation General System Theory: Perspectives in Philosophy and Approaches in Complex Systems

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    Following the classical work of Norbert Wiener, Ross Ashby, Ludwig von Bertalanffy and many others, the concept of System has been elaborated in different disciplinary fields, allowing interdisciplinary approaches in areas such as Physics, Biology, Chemistry, Cognitive Science, Economics, Engineering, Social Sciences, Mathematics, Medicine, Artificial Intelligence, and Philosophy. The new challenge of Complexity and Emergence has made the concept of System even more relevant to the study of problems with high contextuality. This Special Issue focuses on the nature of new problems arising from the study and modelling of complexity, their eventual common aspects, properties and approaches—already partially considered by different disciplines—as well as focusing on new, possibly unitary, theoretical frameworks. This Special Issue aims to introduce fresh impetus into systems research when the possible detection and correction of mistakes require the development of new knowledge. This book contains contributions presenting new approaches and results, problems and proposals. The context is an interdisciplinary framework dealing, in order, with electronic engineering problems; the problem of the observer; transdisciplinarity; problems of organised complexity; theoretical incompleteness; design of digital systems in a user-centred way; reaction networks as a framework for systems modelling; emergence of a stable system in reaction networks; emergence at the fundamental systems level; behavioural realization of memoryless functions

    Tools and Algorithms for the Construction and Analysis of Systems

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    This open access two-volume set constitutes the proceedings of the 27th International Conference on Tools and Algorithms for the Construction and Analysis of Systems, TACAS 2021, which was held during March 27 – April 1, 2021, as part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2021. The conference was planned to take place in Luxembourg and changed to an online format due to the COVID-19 pandemic. The total of 41 full papers presented in the proceedings was carefully reviewed and selected from 141 submissions. The volume also contains 7 tool papers; 6 Tool Demo papers, 9 SV-Comp Competition Papers. The papers are organized in topical sections as follows: Part I: Game Theory; SMT Verification; Probabilities; Timed Systems; Neural Networks; Analysis of Network Communication. Part II: Verification Techniques (not SMT); Case Studies; Proof Generation/Validation; Tool Papers; Tool Demo Papers; SV-Comp Tool Competition Papers

    Computational Approaches to Address the Next-Generation Sequencing Era

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    In this thesis, I propose new algorithms and models to address biological problems. Computer science in fact plays a key role in proteomics and genetics research due to the advent of big datasets. In the context of protein study, I developed new methods for protein function prediction based on information retrieval principles. By using heterogeneous source of knowledge, like graph search and sequence similarity, I designed a tool called INGA that can be used to annotate entire genomes. It has been benchmarked during the Critical Assessment of Function Annotation challenge, and it proved to be one of the most effective approach for function inference. To better characterize proteins from the structural point of view, I proposed a protein conformers detection strategy based on residue interaction network (RIN) data. RIN graphs were extended to deal with the time-dependent protein coordinate fluctuations, and were generated by clustering algorithms. An implementation called RING MD highlighted effectively the key amino acids known to be functionally relevant in Ubiquitin. These amino acids in fact are very important to explain the protein three-dimensional dynamics. With the same rationale, RIN graphs were used also to predict the impact of mutations within a protein structure. By combining information about a mutant node in the network and its features, an artificial neural network was trained to estimate the free Gibbs energy change of a protein. Extreme changes in the internal energy might lead to the protein unfolding, and possibly to disease. The reduction of a protein flexibility may hamper its function as well. As an example, the extreme fluctuations observed in intrinsically disordered proteins (IDPs) are fundamental for their activities. To better understand IDPs, I contributed in the collection of the largest dataset of disordered regions. In the following analysis, it was shown what are the typical functions of these sequences and the biological processes where they are involved. Due to the importance of their detection, a comprehensive assessment of disorder predictors was performed to show what are the state-of-the-art methods and their limitations. In the context of genetics, I focused on phenotype prediction. During the Critical Assessment of Genome Interpretation (CAGI), I proposed new approaches for the analysis of exome data to prioritize the risk of Crohn's disease and abnormal cholesterol levels. These are often defined as complex disease, since the mechanism behind their insurgence is still unknown. In my study, human samples with an enrichment of mutations in critical genes were predicted to have an high genetic risk. In addition to disease associated genes, protein interaction networks were considered to better account for variants accumulation in biological pathways. Such strategy was shown to be among the best approaches by CAGI organizers. In the simpler case of Mendelian traits, with BOOGIE I designed a method for human blood groups prediction based on exome data. It uses a specialized version of nearest neighbor algorithm in order to match the gene variants in an unannotated exome with the ones available in a reference knowledge base. The most similar hit is used to transfer the blood group. With an accuracy above 90%, BOOGIE is a proof-of-concept that shows the potential applications of genetic prediction, and can be easily extended to any Mendelian trait. To summarize, this thesis is a partial answer to the exponential growth of sequences available that need further experiments. By integrating heterogeneous information and designing new predictive models based on machine learning, I developed novel tools for biological data analysis and classification. All implementations are freely available for the community and might be helpful during future investigations like in drug design and disease studies

    Infobiotics : computer-aided synthetic systems biology

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    Until very recently Systems Biology has, despite its stated goals, been too reductive in terms of the models being constructed and the methods used have been, on the one hand, unsuited for large scale adoption or integration of knowledge across scales, and on the other hand, too fragmented. The thesis of this dissertation is that better computational languages and seamlessly integrated tools are required by systems and synthetic biologists to enable them to meet the significant challenges involved in understanding life as it is, and by designing, modelling and manufacturing novel organisms, to understand life as it could be. We call this goal, where everything necessary to conduct model-driven investigations of cellular circuitry and emergent effects in populations of cells is available without significant context-switching, “one-pot” in silico synthetic systems biology in analogy to “one-pot” chemistry and “one-pot” biology. Our strategy is to increase the understandability and reusability of models and experiments, thereby avoiding unnecessary duplication of effort, with practical gains in the efficiency of delivering usable prototype models and systems. Key to this endeavour are graphical interfaces that assists novice users by hiding complexity of the underlying tools and limiting choices to only what is appropriate and useful, thus ensuring that the results of in silico experiments are consistent, comparable and reproducible. This dissertation describes the conception, software engineering and use of two novel software platforms for systems and synthetic biology: the Infobiotics Workbench for modelling, in silico experimentation and analysis of multi-cellular biological systems; and DNA Library Designer with the DNALD language for the compact programmatic specification of combinatorial DNA libraries, as the first stage of a DNA synthesis pipeline, enabling methodical exploration biological problem spaces. Infobiotics models are formalised as Lattice Population P systems, a novel framework for the specification of spatially-discrete and multi-compartmental rule-based models, imbued with a stochastic execution semantics. This framework was developed to meet the needs of real systems biology problems: hormone transport and signalling in the root of Arabidopsis thaliana, and quorum sensing in the pathogenic bacterium Pseudomonas aeruginosa. Our tools have also been used to prototype a novel synthetic biological system for pattern formation, that has been successfully implemented in vitro. Taken together these novel software platforms provide a complete toolchain, from design to wet-lab implementation, of synthetic biological circuits, enabling a step change in the scale of biological investigations that is orders of magnitude greater than could previously be performed in one in silico “pot”
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