Engineering simulations for cancer systems biology

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions

GPU-powered Simulation Methodologies for Biological Systems

The study of biological systems witnessed a pervasive cross-fertilization between experimental investigation and computational methods. This gave rise to the development of new methodologies, able to tackle the complexity of biological systems in a quantitative manner. Computer algorithms allow to faithfully reproduce the dynamics of the corresponding biological system, and, at the price of a large number of simulations, it is possible to extensively investigate the system functioning across a wide spectrum of natural conditions. To enable multiple analysis in parallel, using cheap, diffused and highly efficient multi-core devices we developed GPU-powered simulation algorithms for stochastic, deterministic and hybrid modeling approaches, so that also users with no knowledge of GPUs hardware and programming can easily access the computing power of graphics engines.Comment: In Proceedings Wivace 2013, arXiv:1309.712

Modelling the cAMP pathway using BioNessie, and the use of BVP techniques for solving ODEs (Poster Presentation)

Copyright @ 2007 Gu et al; licensee BioMed Central LtdBiochemists often conduct experiments in-vivo in order to explore observable behaviours and understand the dynamics of many intercellular and intracellular processes. However an intuitive understanding of their dynamics is hard to obtain because most pathways of interest involve components connected via interlocking loops. Formal methods for modelling and analysis of biochemical pathways are therefore indispensable. To this end, ODEs (ordinary differential equations) have been widely adopted as a method to model biochemical pathways because they have an unambiguous mathematical format and are amenable to rigorous quantitative analysis. BioNessie http://www.bionessie.com webcite is a workbench for the composition, simulation and analysis of biochemical networks which is being developed in by the Systems Biology team at the Bioinformatics Research Centre as a part of a large DTI funded project 'BPS: A Software Tool for the Simulation and Analysis of Biochemical Networks' http://www.brc.dcs.gla.ac.uk/projects/dti_beacon webcite. BioNessie is written in Java using NetBeans Platform libraries that makes it platform independent. The software employs specialised differential equations solvers for stiff and non-stiff systems to produce model simulation traces. BioNessie provides a user-friendly interfact that comes up with an intuitive tree-based graphical layout, an edition function to SBML-compatible models and feature of data output

An integrative top-down and bottom-up qualitative model construction framework for exploration of biochemical systems

The authors would like to thank the support on this research by the CRISP project (Combinatorial Responses In Stress Pathways) funded by the BBSRC (BB/F00513X/1) under the Systems Approaches to Biological Research (SABR) Initiative.Peer reviewedPublisher PD

The role of Computer Aided Process Engineering in physiology and clinical medicine

This paper discusses the potential role for Computer Aided Process Engineering (CAPE) in developing engineering analysis and design approaches to biological systems across multiple levels—cell signalling networks, gene, protein and metabolic networks, cellular systems, through to physiological systems. The 21st Century challenge in the Life Sciences is to bring together widely dispersed models and knowledge in order to enable a system-wide understanding of these complex systems. This systems level understanding should have broad clinical benefits. Computer Aided Process Engineering can bring systems approaches to (i) improving understanding of these complex chemical and physical (particularly molecular transport in complex flow regimes) interactions at multiple scales in living systems, (ii) analysis of these models to help to identify critical missing information and to explore the consequences on major output variables resulting from disturbances to the system, and (iii) ‘design’ potential interventions in in vivo systems which can have significant beneficial, or potentially harmful, effects which need to be understood. This paper develops these three themes drawing on recent projects at UCL. The first project has modeled the effects of blood flow on endothelial cells lining arteries, taking into account cell shape change resulting in changes in the cell skeleton which cause consequent chemical changes. A second is a project which is building an in silico model of the human liver, tieing together models from the molecular level to the liver. The composite model models glucose regulation in the liver and associated organs. Both projects involve molecular transport, chemical reactions, and complex multiscale systems, tackled by approaches from CAPE. Chemical Engineers solve multiple scale problems in manufacturing processes – from molecular scale through unit operations scale to plant-wide and enterprise wide systems – so have an appropriate skill set for tackling problems in physiology and clinical medicine, in collaboration with life and clinical scientists

A SystemC-based Platform for Assertion-based Verification and Mutation Analysis in Systems Biology

Boolean models are gaining an increasing interest for reproducing dynamic behaviours, understanding processes, and predicting emerging properties of cellular signalling networks through in-silico experiments. They are emerging as avalid alternative to the quantitative approaches (i.e., based on ordinary differential equations) for exploratory modelling when little is known about reaction kinetics or equilibrium constants in the context of gene expression or signalling. Even though several approaches and software have been recently proposed for logic modelling of biological systems, they are limited to specific modelling contexts and they lack of automation in analysing biological properties such as complex attractors, molecule vulnerability, dose response. This paper presents a design and verification platform based on SystemC that applies methodologies and tools well established in the electronic-design automation (EDA) fieldsuch as assertion-based verification (ABV) and mutation analysis, which allow complex attractors (i.e., protein oscillations) and robustness/sensitivity of the signalling networks to be simulated and analysed. The paper reports the results obtained by applying such verification techniques for the analysis of the intracellular signalling network controlling integrin activation mediating leukocyte recruitment from the blood into the tissues

Investigating biocomplexity through the agent-based paradigm.

Capturing the dynamism that pervades biological systems requires a computational approach that can accommodate both the continuous features of the system environment as well as the flexible and heterogeneous nature of component interactions. This presents a serious challenge for the more traditional mathematical approaches that assume component homogeneity to relate system observables using mathematical equations. While the homogeneity condition does not lead to loss of accuracy while simulating various continua, it fails to offer detailed solutions when applied to systems with dynamically interacting heterogeneous components. As the functionality and architecture of most biological systems is a product of multi-faceted individual interactions at the sub-system level, continuum models rarely offer much beyond qualitative similarity. Agent-based modelling is a class of algorithmic computational approaches that rely on interactions between Turing-complete finite-state machines--or agents--to simulate, from the bottom-up, macroscopic properties of a system. In recognizing the heterogeneity condition, they offer suitable ontologies to the system components being modelled, thereby succeeding where their continuum counterparts tend to struggle. Furthermore, being inherently hierarchical, they are quite amenable to coupling with other computational paradigms. The integration of any agent-based framework with continuum models is arguably the most elegant and precise way of representing biological systems. Although in its nascence, agent-based modelling has been utilized to model biological complexity across a broad range of biological scales (from cells to societies). In this article, we explore the reasons that make agent-based modelling the most precise approach to model biological systems that tend to be non-linear and complex

Big data analytics:Computational intelligence techniques and application areas

Big Data has significant impact in developing functional smart cities and supporting modern societies. In this paper, we investigate the importance of Big Data in modern life and economy, and discuss challenges arising from Big Data utilization. Different computational intelligence techniques have been considered as tools for Big Data analytics. We also explore the powerful combination of Big Data and Computational Intelligence (CI) and identify a number of areas, where novel applications in real world smart city problems can be developed by utilizing these powerful tools and techniques. We present a case study for intelligent transportation in the context of a smart city, and a novel data modelling methodology based on a biologically inspired universal generative modelling approach called Hierarchical Spatial-Temporal State Machine (HSTSM). We further discuss various implications of policy, protection, valuation and commercialization related to Big Data, its applications and deployment

Modeling and evolving biochemical networks: insights into communication and computation from the biological domain

This paper is concerned with the modeling and evolving of Cell Signaling Networks (CSNs) in silico. CSNs are complex biochemical networks responsible for the coordination of cellular activities. We examine the possibility to computationally evolve and simulate Artificial Cell Signaling Networks (ACSNs) by means of Evolutionary Computation techniques. From a practical point of view, realizing and evolving ACSNs may provide novel computational paradigms for a variety of application areas. For example, understanding some inherent properties of CSNs such as crosstalk may be of interest: A potential benefit of engineering crosstalking systems is that it allows the modification of a specific process according to the state of other processes in the system. This is clearly necessary in order to achieve complex control tasks. This work may also contribute to the biological understanding of the origins and evolution of real CSNs. An introduction to CSNs is first provided, in which we describe the potential applications of modeling and evolving these biochemical networks in silico. We then review the different classes of techniques to model CSNs, this is followed by a presentation of two alternative approaches employed to evolve CSNs within the ESIGNET project. Results obtained with these methods are summarized and discussed