31 research outputs found
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An introduction to Biomodel engineering, illustrated for signal transduction pathways
BioModel Engineering is the science of designing, constructing
and analyzing computational models of biological systems. It is inspired
by concepts from software engineering and computing science.
This paper illustrates a major theme in BioModel Engineering, namely
that identifying a quantitative model of a dynamic system means building
the structure, finding an initial state, and parameter fitting. In our
approach, the structure is obtained by piecewise construction of models
from modular parts, the initial state is obtained by analysis of the structure
and parameter fitting comprises determining the rate parameters of
the kinetic equations. We illustrate this with an example in the area of
intracellular signalling pathways
Speeding up systems biology simulations of biochemical pathways using condor
This is the accepted version of the following article: Speeding up Systems Biology Simulations of Biochemical Pathways using Condor". Concurrency and Computation: Practice and Experience Volume 26, Issue 17, pages 2727â2742, 10 December 2014 which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/cpe.3161/abstractSystems biology is a scientific field that uses computational modelling to study biological and biochemical systems. The simulation and analysis of models of these systems typically explore behaviour over a wide range of parameter values; as such, they are usually characterised by the need for nontrivial amounts of computing power. Grid computing provides access to such computational resources. In previous research, we created the grid-enabled biochemical networks simulation environment to attempt to speed up system biology simulations over a grid (the UK National Grid Service and ScotGrid). Following on from this work, we have created the simulation modelling of the epidermal growth factor receptor microtubule-associated protein kinase pathway utility, a standalone simulation tool dedicated to the modelling and analysis of the epidermal growth factor receptor microtubule-associated protein kinase pathway. This builds on experiences from biochemical networks simulation environment by decoupling the simulation modelling elements from the Grid middleware. This new utility enables us to interface with different grid technologies. This paper therefore describes the new SIMAP utility and an empirical investigation of its performance when deployed over a desktop grid based on the high throughput computing middleware Condor. We present our results based on a case study with a model of the mammalian ErbB signalling pathway, a pathway strongly linked to cance
Designing Predictive Mathematical Models for the Metabolic Pathways Associated with Polyhydroxybutyrate Synthesis in \u3ci\u3eEscherichia coli\u3c/i\u3e
Polyhydroxybutyrate (PHB) is a polyhydroxyalkanoate that has been extensively studied as a potential biodegradable replacement for petrochemically derived plastics. The synthesis pathway of PHB is native to Ralstonia eutropha, but the genes for the PHB pathway have successfully been introduced into Escherichia coli through plasmids such as the pBHR68 plasmid. However, the production of PHB needs to be more cost-effective before it can be commercially produced.
A mathematical model for PHB synthesis was developed to identify target genes that could be genetically engineered to increase PHB production. The major metabolic pathways included in the model were glycolysis, acetyl coenzyme A (acetyl-CoA) synthesis, tricarboxylic acid (TCA) cycle, glyoxylate bypass, and PHB synthesis. Each reaction in the selected metabolic pathways was modeled using the kinetic mechanism identified for the associated enzyme. The promoters and transcription factors for each enzyme were incorporated into the model. The model was validated through comparison with other published models and experimental PHB production data. The predictive model identified 16 enzymes as having no effect on PHB production, 5 enzymes with a slight effect on PHB production, and 9 enzymes with large effects on PHB production. Decreasing the substrate affinity of the enzyme citrate synthase resulted in the largest increase in PHB synthesis. The second largest increase was observed from lowering the substrate affinity of glyceraldehyde-3-phosphate dehydrogenase. The predictive model also indicated that increasing the activity of the lac promoter in the pBHR68 plasmid resulted in the largest increase in the rate of PHB production.
The predictive model successfully identified two genes and one promoter as targets for genetic engineering to create an optimized strain of E. coli for PHB production. The substrate-binding sites for the genes gltA (citrate synthase) and gapA (glyceraldehyde-3-phosphate dehydrogenase) should be genetically engineered to be less effective at binding the substrates. The lac promoter in the pBHR68 plasmid should be genetically engineered to more closely match the consensus sequence for binding to RNA polymerase. The model predicts that an optimized strain of E. coli for PHB production could be achieved by genetically altering gltA, gapA, and the lac promoter
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A generic approach to behaviour-driven biochemical model construction
This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Modelling of biochemical systems has received considerable attention over the last decade from bioengineering, biochemistry, computer science, and mathematics. This thesis investigates the applications of computational techniques to computational systems biology, for the construction of biochemical models in terms of topology and kinetic rates. Due to the complexity of biochemical systems, it is natural to construct models representing the biochemical systems incrementally in a piecewise manner. Syntax and semantics of two patterns are defined for the instantiation of components which are extendable, reusable and fundamental building blocks for models composition. We propose and implement a set of genetic operators and composition rules to tackle issues of piecewise composing models from scratch. Quantitative Petri nets are evolved by the genetic operators, and evolutionary process of modelling are guided by the composition rules. Metaheuristic algorithms are widely applied in BioModel Engineering to support intelligent and heuristic analysis of biochemical systems in terms of structure and kinetic rates. We illustrate parameters of biochemical models based on Biochemical Systems Theory, and then the topology and kinetic rates of the models are manipulated by employing evolution strategy and simulated annealing respectively. A new hybrid modelling framework is proposed and implemented for the models construction. Two heuristic algorithms are performed on two embedded layers in the hybrid framework: an outer layer for topology mutation and an inner layer for rates optimization. Moreover, variants of the hybrid piecewise modelling framework are investigated. Regarding flexibility of these variants, various combinations of evolutionary operators, evaluation criteria and design principles can be taken into account. We examine performance of five sets of the variants on specific aspects of modelling. The comparison of variants is not to explicitly show that one variant clearly outperforms the others, but it provides an indication of considering important features for various aspects of the modelling. Because of the very heavy computational demands, the process of modelling is paralleled by employing a grid environment, GridGain. Application of the GridGain and heuristic algorithms to analyze biological processes can support modelling of biochemical systems in a computational manner, which can also benefit mathematical modelling in computer science and bioengineering. We apply our proposed modelling framework to model biochemical systems in a hybrid piecewise manner. Modelling variants of the framework are comparatively studied on specific aims of modelling. Simulation results show that our modelling framework can compose synthetic models exhibiting similar species behaviour, generate models with alternative topologies and obtain general knowledge about key modelling features
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A systems biology approach to multi-scale modelling and analysis of planar cell polarity in drosophila melanogaster wing
This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Systems biology aims to describe and understand biology at a global scale where biological systems function as a result of complex mechanisms that happen at several scales. Modelling and simulation are computational tools that are invaluable for description, understanding and prediction these mechanisms in a quantitative and integrative way. Thus multi-scale methods that couple the design, simulation and analysis of models spanning several spatial and temporal scales is becoming a new emerging focus of systems biology. This thesis uses an exemplar â Planar cell polarity (PCP) signalling â to illustrate a generic approach to model biological systems at different spatial scales, using the new concept of Hierarchically Coloured Petri Nets (HCPN). PCP signalling refers to the coordinated polarisation of cells within the plane of various epithelial tissues to generate sub-cellular asymmetry along an axis orthogonal to their apical-basal axes. This polarisation is required for many developmental events in both vertebrates and non-vertebrates. Defects in PCP in vertebrates are responsible for developmental abnormalities in multiple tissues including the neural tube, the kidney and the inner ear. In Drosophila wing, PCP is seen in the parallel orientation of hairs that protrude from each of the approximately 30,000 epithelial cells to robustly point toward the wing tip. This work applies HCPN to model a tissue comprising multiple cells hexagonally packed in a honeycomb formation in order to describe the phenomenon of Planar Cell Polarity (PCP) in Drosophila wing. HCPN facilitate the construction of mathematically tractable, compact and parameterised large-scale models. Different levels of abstraction that can be used in order to simplify such a complex system are first illustrated. The PCP system is first represented at an abstract level without modelling details of the cell. Each cell is then sub-divided into seven virtual compartments with adjacent cells being coupled via the formation of intercellular complexes. A more detailed model is later developed, describing the intra- and inter-cellular signalling mechanisms involved in PCP signalling. The initial model is for a wild-type organism, and then a family of related models, permitting different hypotheses to be explored regarding the mechanisms underlying PCP, are constructed. Among them, the largest model consists of 800 cells which when unfolded yields 164,000 places (each of which is described by an ordinary differential equation). This thesis illustrates the power and validity of the approach by showing how the models can be easily adapted to describe well-documented genetic mutations in the Drosophila wing using the proposed approach including clustering and model checking over time series of primary and secondary data, which can be employed to analyse and check such multi-scale models similar to the case of PCP. The HCPN models support the interpretation of biological observations reported in literature and are able to make sensible predictions. As HCPN model multi-scale systems in a compact, parameterised and scalable way, this modelling approach can be applied to other large-scale or multi-scale systems.This study was funded by Brunel University
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, âone-potâ in silico synthetic systems biology in analogy to âone-potâ chemistry and âone-potâ 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 âpotâ
Rule-based modeling of biochemical systems with BioNetGen
Totowa, NJ. Please cite this article when referencing BioNetGen in future publications. Rule-based modeling involves the representation of molecules as structured objects and molecular interactions as rules for transforming the attributes of these objects. The approach is notable in that it allows one to systematically incorporate site-specific details about proteinprotein interactions into a model for the dynamics of a signal-transduction system, but the method has other applications as well, such as following the fates of individual carbon atoms in metabolic reactions. The consequences of protein-protein interactions are difficult to specify and track with a conventional modeling approach because of the large number of protein phosphoforms and protein complexes that these interactions potentially generate. Here, we focus on how a rule-based model is specified in the BioNetGen language (BNGL) and how a model specification is analyzed using the BioNetGen software tool. We also discuss new developments in rule-based modeling that should enable the construction and analyses of comprehensive models for signal transduction pathways and similarly large-scale models for other biochemical systems. Key Words: Computational systems biology; mathematical modeling; combinatorial complexity; software; formal languages; stochastic simulation; ordinary differential equations; protein-protein interactions; signal transduction; metabolic networks. 1
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, âone-potâ in silico synthetic systems biology in analogy to âone-potâ chemistry and âone-potâ 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 âpotâ
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Coloured Petri nets for multi-level, multiscale, and multi-dimensional modelling of biological systems
Owing to the availability of data of one biological phenomenon at different levels/scales, modelling of biological systems is moving from single level/scale to multiple levels/scales, which introduces a number of challenges. Coloured Petri nets (ColPNs) have been successfully applied to multilevel, multiscale and multidimensional modelling of some biological systems, addressing many of these challenges. In this article, we first review the basics of ColPNs and some popular extensions, and then their applications for multilevel, multiscale and multidimensional modelling of biological systems. This understanding of how to use ColPNs for modelling biological systems will assist readers in selecting appropriate ColPN classes for specific modelling circumstances
Methods for construction and analysis of computational models in systems biology: applications to the modelling of the heat shock response and the self-assembly of intermediate filaments
Systems biology is a new, emerging and rapidly developing, multidisciplinary
research field that aims to study biochemical and biological systems from
a holistic perspective, with the goal of providing a comprehensive, system-
level understanding of cellular behaviour. In this way, it addresses one of
the greatest challenges faced by contemporary biology, which is to compre-
hend the function of complex biological systems. Systems biology combines
various methods that originate from scientific disciplines such as molecu-
lar biology, chemistry, engineering sciences, mathematics, computer science
and systems theory. Systems biology, unlike âtraditionalâ biology, focuses
on high-level concepts such as: network, component, robustness, efficiency,
control, regulation, hierarchical design, synchronization, concurrency, and
many others. The very terminology of systems biology is âforeignâ to âtra-
ditionalâ biology, marks its drastic shift in the research paradigm and it
indicates close linkage of systems biology to computer science.
One of the basic tools utilized in systems biology is the mathematical
modelling of life processes tightly linked to experimental practice. The stud-
ies contained in this thesis revolve around a number of challenges commonly
encountered in the computational modelling in systems biology. The re-
search comprises of the development and application of a broad range of
methods originating in the fields of computer science and mathematics for
construction and analysis of computational models in systems biology. In
particular, the performed research is setup in the context of two biolog-
ical phenomena chosen as modelling case studies: 1) the eukaryotic heat
shock response and 2) the in vitro self-assembly of intermediate filaments,
one of the main constituents of the cytoskeleton. The range of presented
approaches spans from heuristic, through numerical and statistical to ana-
lytical methods applied in the effort to formally describe and analyse the
two biological processes. We notice however, that although applied to cer-
tain case studies, the presented methods are not limited to them and can
be utilized in the analysis of other biological mechanisms as well as com-
plex systems in general. The full range of developed and applied modelling
techniques as well as model analysis methodologies constitutes a rich mod-
elling framework. Moreover, the presentation of the developed methods,
their application to the two case studies and the discussions concerning
their potentials and limitations point to the difficulties and challenges one
encounters in computational modelling of biological systems. The problems
of model identifiability, model comparison, model refinement, model inte-
gration and extension, choice of the proper modelling framework and level
of abstraction, or the choice of the proper scope of the model run through
this thesis