BlenX-based compositional modeling of complex reaction mechanisms

Molecular interactions are wired in a fascinating way resulting in complex behavior of biological systems. Theoretical modeling provides a useful framework for understanding the dynamics and the function of such networks. The complexity of the biological networks calls for conceptual tools that manage the combinatorial explosion of the set of possible interactions. A suitable conceptual tool to attack complexity is compositionality, already successfully used in the process algebra field to model computer systems. We rely on the BlenX programming language, originated by the beta-binders process calculus, to specify and simulate high-level descriptions of biological circuits. The Gillespie's stochastic framework of BlenX requires the decomposition of phenomenological functions into basic elementary reactions. Systematic unpacking of complex reaction mechanisms into BlenX templates is shown in this study. The estimation/derivation of missing parameters and the challenges emerging from compositional model building in stochastic process algebras are discussed. A biological example on circadian clock is presented as a case study of BlenX compositionality

Quantifying the implicit process flow abstraction in SBGN-PD diagrams with Bio-PEPA

For a long time biologists have used visual representations of biochemical networks to gain a quick overview of important structural properties. Recently SBGN, the Systems Biology Graphical Notation, has been developed to standardise the way in which such graphical maps are drawn in order to facilitate the exchange of information. Its qualitative Process Diagrams (SBGN-PD) are based on an implicit Process Flow Abstraction (PFA) that can also be used to construct quantitative representations, which can be used for automated analyses of the system. Here we explicitly describe the PFA that underpins SBGN-PD and define attributes for SBGN-PD glyphs that make it possible to capture the quantitative details of a biochemical reaction network. We implemented SBGNtext2BioPEPA, a tool that demonstrates how such quantitative details can be used to automatically generate working Bio-PEPA code from a textual representation of SBGN-PD that we developed. Bio-PEPA is a process algebra that was designed for implementing quantitative models of concurrent biochemical reaction systems. We use this approach to compute the expected delay between input and output using deterministic and stochastic simulations of the MAPK signal transduction cascade. The scheme developed here is general and can be easily adapted to other output formalisms

Studying the effects of adding spatiality to a process algebra model

We use NetLogo to create simulations of two models of disease transmission originally expressed in WSCCS. This allows us to introduce spatiality into the models and explore the consequences of having different contact structures among the agents. In previous work, mean field equations were derived from the WSCCS models, giving a description of the aggregate behaviour of the overall population of agents. These results turned out to differ from results obtained by another team using cellular automata models, which differ from process algebra by being inherently spatial. By using NetLogo we are able to explore whether spatiality, and resulting differences in the contact structures in the two kinds of models, are the reason for this different results. Our tentative conclusions, based at this point on informal observations of simulation results, are that space does indeed make a big difference. If space is ignored and individuals are allowed to mix randomly, then the simulations yield results that closely match the mean field equations, and consequently also match the associated global transmission terms (explained below). At the opposite extreme, if individuals can only contact their immediate neighbours, the simulation results are very different from the mean field equations (and also do not match the global transmission terms). These results are not surprising, and are consistent with other cellular automata-based approaches. We found that it was easy and convenient to implement and simulate the WSCCS models within NetLogo, and we recommend this approach to anyone wishing to explore the effects of introducing spatiality into a process algebra model

Continuous-time temporal logic specification and verification for nonlinear biological systems in uncertain contexts

In this thesis we introduce a complete framework for modelling and verification of biological systems in uncertain contexts based on the bond-calculus process algebra and the LBUC spatio-temporal logic. The bond-calculus is a biological process algebra which captures complex patterns of interaction based on affinity patterns, a novel communication mechanism using pattern matching to express multiway interaction affinities and general kinetic laws, whilst retaining an agent-centric modelling style for biomolecular species. The bond-calculus is equipped with a novel continuous semantics which maps models to systems of Ordinary Differential Equations (ODEs) in a compositional way. We then extend the bond-calculus to handle uncertain models, featuring interval uncertainties in their species concentrations and reaction rate parameters. Our semantics is also extended to handle uncertainty in every aspect of a model, producing non-deterministic continuous systems whose behaviour depends either on time-independent uncertain parameters and initial conditions, corresponding to our partial knowledge of the system at hand, or time-varying uncertain inputs, corresponding to genuine variability in a system’s behaviour based on environmental factors. This language is then coupled with the LBUC spatio-temporal logic which combines Signal Temporal Logic (STL) temporal operators with an uncertain context operator which quantifies over an uncertain context model describing the range of environments over which a property must hold. We develop model-checking procedures for STL and LBUC properties based on verified signal monitoring over flowpipes produced by the Flow* verified integrator, including the technique of masking which directs monitoring for atomic propositions to time regions relevant to the overall verification problem at hand. This allows us to monitor many interesting nested contextual properties and frequently reduces monitoring costs by an order of magnitude. Finally, we explore the technique of contextual signal monitoring which can use a single Flow* flowpipe representing a functional dependency to complete a whole tree of signals corresponding to different uncertain contexts. This allows us to produce refined monitoring results over the whole space and to explore the variation in system behaviour in different contexts

Formal computational framework for the study of molecular evolution

Over the past 10 years, multiple executable modelling formalisms for molecular biology have been developed in order to address the growing need for a system-level understanding of complex biological phenomena. An important class of these formalisms are biology-inspired process algebras, which offer-among other desirable properties - an almost complete separation of model specification (syntax) from model dynamics (semantics). In this thesis, the similarity between this separation and the genotype-phenotype duality in evolutionary biology is exploited to develop a process-algebraic approach to the study of evolution of biochemical systems. The main technical contribution of this thesis is the continuous π-calculus (cπ), a novel process algebra based on the classical π-calculus of Milner et. al. Its two defining characteristics are: continuous, compositional, computationally inexpensive semantics, and a exible interaction structure of processes (molecules). Both these features are conductive to evolutionary analysis of biochemical systems by, respectively, enabling many variants of a given model to be evaluated, and facilitating in silico evolution of new functional connections. A further major contribution is a collection of variation operators, syntactic model transformation schemes corresponding to common evolutionary events. When applied to a cπ model of a biochemical system, variation operators produce its evolutionary neighbours, yielding insights into the local fitness landscape and neutral neighbourhood. Two well-known biochemical systems are modelled in this dissertation to validate the developed theory. One is the KaiABC circadian clock in the cyanobacterium S. elongatus, the other is a mitogen-activated protein kinase cascade. In each case we study the system itself as well as its predicted evolutionary variants. Simpler examples, particularly that of a generic enzymatic reaction, are used throughout the thesis to illustrate important concepts as they are introduced

A diversity-aware computational framework for systems biology

L'abstract è presente nell'allegato / the abstract is in the attachmen

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”

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”

Spatio-temporal logic for the analysis of biochemical models

Process algebra, formal specification, and model checking are all well studied techniques in the analysis of concurrent computer systems. More recently these techniques have been applied to the analysis of biochemical systems which, at an abstract level, have similar patterns of behaviour to concurrent processes. Process algebraic models and temporal logic specifications, along with their associated model-checking techniques, have been used to analyse biochemical systems. In this thesis we develop a spatio-temporal logic, the Logic of Behaviour in Context (LBC), for the analysis of biochemical models. That is, we define and study the application of a formal specification language which not only expresses temporal properties of biochemical models, but expresses spatial or contextual properties as well. The logic can be used to express, or specify, the behaviour of a model when it is placed into the context of another model. We also explore the types of properties which can be expressed in LBC, various algorithms for model checking LBC - each an improvement on the last, the implementation of the computational tools to support model checking LBC, and a case study on the analysis of models of post-translational biochemical oscillators using LBC. We show that a number of interesting and useful properties can be expressed in LBC and that it is possible to express highly useful properties of real models in the biochemistry domain, with practical application. Statements in LBC can be thought of as expressing computational experiments which can be performed automatically by means of the model checker. Indeed, many of these computational experiments can be higher-order meaning that one succinct and precise specification in LBC can represent a number of experiments which can be automatically executed by the model checker