Modelling bacterial regulatory networks with Petri nets

To exploit the vast data obtained from high throughput molecular biology, a variety of modelling and analysis techniques must be fully utilised. In this thesis, Petri nets are investigated within the context of computational systems biology, with the specific focus of facilitating the creation and analysis of models of biological pathways. The analysis of qualitative models of genetic networks using safe Petri net techniques was investigated with particular reference to model checking. To exploit existing model repositories a mapping was presented for the automatic translation of models encoded in the Systems Biology Markup Language (SBML) into the Petri Net framework. The mapping is demonstrated via the conversion and invariant analysis of two published models of the glycolysis pathway. Dynamic stochastic simulations of biological systems suffer from two problems: computational cost; and lack of kinetic parameters. A new stochastic Petri net simulation tool, NASTY was developed which addresses the prohibitive real-time computational costs of simulations by using distributed job scheduling. In order to manage and maximise the usefulness of simulation results a new data standard, TSML was presented. The computational power of NASTY provided the basis for the development of a genetic algorithm for the automatic parameterisation of stochastic models. This parameter estimation technique was evaluated on a published model of the general stress response of E. coli. An attempt to enhance the parameter estimation process using sensitivity analysis was then investigated. To explore the scope and limits of applying the Petri net techniques presented, a realistic case study investigated how the Pho and aB regulons interact to mitigate phosphate stress in Bacillus subtilis. This study made use of a combination of qualitative and quantitative Petri net techniques and was able to confirm an existing experimental hypothesis.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Modelling bacterial regulatory networks with Petri nets

To exploit the vast data obtained from high throughput molecular biology, a variety of modelling and analysis techniques must be fully utilised. In this thesis, Petri nets are investigated within the context of computational systems biology, with the specific focus of facilitating the creation and analysis of models of biological pathways. The analysis of qualitative models of genetic networks using safe Petri net techniques was investigated with particular reference to model checking. To exploit existing model repositories a mapping was presented for the automatic translation of models encoded in the Systems Biology Markup Language (SBML) into the Petri Net framework. The mapping is demonstrated via the conversion and invariant analysis of two published models of the glycolysis pathway. Dynamic stochastic simulations of biological systems suffer from two problems: computational cost; and lack of kinetic parameters. A new stochastic Petri net simulation tool, NASTY was developed which addresses the prohibitive real-time computational costs of simulations by using distributed job scheduling. In order to manage and maximise the usefulness of simulation results a new data standard, TSML was presented. The computational power of NASTY provided the basis for the development of a genetic algorithm for the automatic parameterisation of stochastic models. This parameter estimation technique was evaluated on a published model of the general stress response of E. coli. An attempt to enhance the parameter estimation process using sensitivity analysis was then investigated. To explore the scope and limits of applying the Petri net techniques presented, a realistic case study investigated how the Pho and aB regulons interact to mitigate phosphate stress in Bacillus subtilis. This study made use of a combination of qualitative and quantitative Petri net techniques and was able to confirm an existing experimental hypothesis.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Petri nets for systems and synthetic biology

We give a description of a Petri net-based framework for modelling and analysing biochemical pathways, which uni¯es the qualita- tive, stochastic and continuous paradigms. Each perspective adds its con- tribution to the understanding of the system, thus the three approaches do not compete, but complement each other. We illustrate our approach by applying it to an extended model of the three stage cascade, which forms the core of the ERK signal transduction pathway. Consequently our focus is on transient behaviour analysis. We demonstrate how quali- tative descriptions are abstractions over stochastic or continuous descrip- tions, and show that the stochastic and continuous models approximate each other. Although our framework is based on Petri nets, it can be applied more widely to other formalisms which are used to model and analyse biochemical networks

Hybrid performance modelling of opportunistic networks

We demonstrate the modelling of opportunistic networks using the process algebra stochastic HYPE. Network traffic is modelled as continuous flows, contact between nodes in the network is modelled stochastically, and instantaneous decisions are modelled as discrete events. Our model describes a network of stationary video sensors with a mobile ferry which collects data from the sensors and delivers it to the base station. We consider different mobility models and different buffer sizes for the ferries. This case study illustrates the flexibility and expressive power of stochastic HYPE. We also discuss the software that enables us to describe stochastic HYPE models and simulate them.Comment: In Proceedings QAPL 2012, arXiv:1207.055

Setting the basis of best practices and standards for curation and annotation of logical models in biology

International audienceThe fast accumulation of biological data calls for their integration, analysis and exploitation through more systematic approaches. The generation of novel, relevant hypotheses from this enormous quantity of data remains challenging. Logical models have long been used to answer a variety of questions regarding the dynamical behaviours of regulatory networks. As the number of published logical models increases, there is a pressing need for systematic model annotation, referencing and curation in community-supported and standardised formats. This article summarises the key topics and future directions of a meeting entitled ‘Annotation and curation of computational models in biology’, organised as part of the 2019 [BC]2 conference. The purpose of the meeting was to develop and drive forward a plan towards the standardised annotation of logical models, review and connect various ongoing projects of experts from different communities involved in the modelling and annotation of molecular biological entities, interactions, pathways and models. This article defines a roadmap towards the annotation and curation of logical models, including milestones for best practices and minimum standard requirements

Infobiotics : computer-aided synthetic systems biology

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”

Modelling and Analysing Genetic Networks: From Boolean Networks to Petri Nets

Abstract. In order to understand complex genetic regulatory networks researchers require automated formal modelling techniques that provide appropriate analysis tools. In this paper we propose a new qualitative model for genetic regulatory networks based on Petri nets and detail a process for automatically constructing these models using logic mini-mization. We take as our starting point the Boolean network approach in which regulatory entities are viewed abstractly as binary switches. The idea is to extract terms representing a Boolean network using logic minimization and to then directly translate these terms into appropri-ate Petri net control structures. The resulting compact Petri net model addresses a number of shortcomings associated with Boolean networks and is particularly suited to analysis using the wide range of Petri net tools. We demonstrate our approach by presenting a detailed case study in which the genetic regulatory network underlying the nutritional stress response in Escherichia coli is modelled and analysed.

Infobiotics : computer-aided synthetic systems biology

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”

Petri nets for modelling metabolic pathways: a survey

In the last 15 years, several research efforts have been directed towards the representation and the analysis of metabolic pathways by using Petri nets. The goal of this paper is twofold. First, we discuss how the knowledge about metabolic pathways can be represented with Petri nets. We point out the main problems that arise in the construction of a Petri net model of a metabolic pathway and we outline some solutions proposed in the literature. Second, we present a comprehensive review of recent research on this topic, in order to assess the maturity of the field and the availability of a methodology for modelling a metabolic pathway by a corresponding Petri net

Applications of Boolean modelling to study and stratify dynamics of a complex disease

Interpretation of omics data is needed to form meaningful hypotheses about disease mechanisms. Pathway databases give an overview of disease-related processes, while mathematical models give qualitative and quantitative insights into their complexity. Similarly to pathway databases, mathematical models are stored and shared on dedicated platforms. Moreover, community-driven initiatives such as disease maps encode disease-specific mechanisms in both computable and diagrammatic form using dedicated tools for diagram biocuration and visualisation. To investigate the dynamic properties of complex disease mechanisms, computationally readable content can be used as a scaffold for building dynamic models in an automated fashion. The dynamic properties of a disease are extremely complex. Therefore, more research is required to better understand the complexity of molecular mechanisms, which may advance personalized medicine in the future. In this study, Parkinson’s disease (PD) is analyzed as an example of a complex disorder. PD is associated with complex genetic, environmental causes and comorbidities that need to be analysed in a systematic way to better understand the progression of different disease subtypes. Studying PD as a multifactorial disease requires deconvoluting the multiple and overlapping changes to identify the driving neurodegenerative mechanisms. Integrated systems analysis and modelling can enable us to study different aspects of a disease such as progression, diagnosis, and response to therapeutics. Therefore, more research is required to better understand the complexity of molecular mechanisms, which may advance personalized medicine in the future. Modelling such complex processes depends on the scope and it may vary depending on the nature of the process (e.g. signalling vs metabolic). Experimental design and the resulting data also influence model structure and analysis. Boolean modelling is proposed to analyse the complexity of PD mechanisms. Boolean models (BMs) are qualitative rather than quantitative and do not require detailed kinetic information such as Petri nets or Ordinary Differential equations (ODEs). Boolean modelling represents a logical formalism where available variables have binary values of one (ON) or zero (OFF), making it a plausible approach in cases where quantitative details and kinetic parameters 9 are not available. Boolean modelling is well validated in clinical and translational medicine research. In this project, the PD map was translated into BMs in an automated fashion using different methods. Therefore, the complexity of disease pathways can be analysed by simulating the effect of genomic burden on omics data. In order to make sure that BMs accurately represent the biological system, validation was performed by simulating models at different scales of complexity. The behaviour of the models was compared with expected behavior based on validated biological knowledge. The TCA cycle was used as an example of a well-studied simple network. Different scales of complex signalling networks were used including the Wnt-PI3k/AKT pathway, and T-cell differentiation models. As a result, matched and mismatched behaviours were identified, allowing the models to be modified to better represent disease mechanisms. The BMs were stratified by integrating omics data from multiple disease cohorts. The miRNA datasets from the Parkinson’s Progression Markers Initiative study (PPMI) were analysed. PPMI provides an important resource for the investigation of potential biomarkers and therapeutic targets for PD. Such stratification allowed studying disease heterogeneity and specific responses to molecular perturbations. The results can support research hypotheses, diagnose a condition, and maximize the benefit of a treatment. Furthermore, the challenges and limitations associated with Boolean modelling in general were discussed, as well as those specific to the current study. Based on the results, there are different ways to improve Boolean modelling applications. Modellers can perform exploratory investigations, gathering the associated information about the model from literature and data resources. The missing details can be inferred by integrating omics data, which identifies missing components and optimises model accuracy. Accurate and computable models improve the efficiency of simulations and the resulting analysis of their controllability. In parallel, the maintenance of model repositories and the sharing of models in easily interoperable formats are also important