Peter Hunter

The systems biology markup language (SBML) : a medium for representation and exchange of biochemical network models

MOTIVATION Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY The specification of SBML Level 1 is freely available from http://www.sbml.org/

Integration from proteins to organs: the Physiome Project.

The Physiome Project will provide a framework for modelling the human body, using computational methods that incorporate biochemical, biophysical and anatomical information on cells, tissues and organs. The main project goals are to use computational modelling to analyse integrative biological function and to provide a system for hypothesis testing.

Modelling the mechanical properties of cardiac muscle.

A model of passive and active cardiac muscle mechanics is presented, suitable for use in continuum mechanics models of the whole heart. The model is based on an extensive review of experimental data from a variety of preparations (intact trabeculae, skinned fibres and myofibrils) and species (mainly rat and ferret) at temperatures from 20 to 27 degrees C. Experimental tests include isometric tension development, isotonic loading, quick-release/restretch, length step and sinusoidal perturbations. We show that all of these experiments can be interpreted with a four state variable model which includes (i) the passive elasticity of myocardial tissue, (ii) the rapid binding of Ca2+ to troponin C and its slower tension-dependent release, (iii) the kinetics of tropomyosin movement and availability of crossbridge binding sites and the length dependence of this process and (iv) the kinetics of crossbridge tension development under perturbations of myofilament length.

Computational Mechanics of the Heart

Finite elasticity theory combined with finite element analysis provides the framework for analysing ventricular mechanics during the filling phase of the cardiac cycle, when cardiac cells are not actively contracting. The orthotropic properties of the passive tissue are described here by a “pole–zero” constitutive law, whose parameters are derived in part from a model of the underlying distributions of collagen fibres. These distributions are based on our observations of the fibrous-sheet laminar architecture of myocardial tissue. We illustrate the use of high order (cubic Hermite) basis functions in solving the Galerkin finite element stress equilibrium equations based on this orthotropic constitutive law and for incorporating the observed regional distributions of fibre and sheet orientations. Pressure–volume relations and 3D principal strains predicted by the model are compared with experimental observations. A model of active tissue properties, based on isolated muscle experiments, is also introduced in order to predict transmural distributions of 3D principal strains at the end of the contraction phase of the cardiac cycle. We end by offering a critique of the current model of ventricular mechanics and propose new challenges for future modellers.

An Anatomically Based Model of Transient Coronary Blood Flow in the Heart

An efficient finite difference model of blood flow through the coronary vessels is developed and applied to a geometric model of the largest six generations of the coronary arterial network. By constraining the form of the velocity profile across the vessel radius, the three-dimensional Navier--Stokes equations are reduced to one-dimensional equations governing conservation of mass and momentum. These equations are coupled to a pressure-radius relationship characterizing the elasticity of the vessel wall to describe the transient blood flow through a vessel segment. The two step Lax--Wendroff finite difference method is used to numerically solve these equations. The flow through bifurcations, where three vessel segments join, is governed by the equations of conservation of mass and momentum. The solution to these simultaneous equations is calculated using the multidimensional Newton--Raphson method. Simulations of blood flow through a geometric model of the coronary network are presented demonstrating phy...

Cardiac Microstructure: Implications for Electrical Propagation and Defibrillation in the Heart

Abstract— Our understanding of the electrophysiological properties of the heart is incomplete. We have investigated two issues that are fundamental to advancing that understanding. First, there has been widespread debate over the mechanisms by which an externally applied shock can influence a sufficient volume of heart tissue to terminate cardiac fibrillation. Second, it has been uncertain whether cardiac tissue should be viewed as an electrically orthotropic structure, or whether its electrical properties are, in fact, isotropic in the plane orthogonal to myofiber direction. In the present study, a computer model that incorporates a detailed three-dimensional representation of cardiac muscular architecture is used to investigate these issues. We describe a bidomain model of electrical propagation solved in a discontinuous domain that accurately represents the microstructure of a transmural block of rat left ventricle. From analysis of the model results, we conclude that (1) the laminar organization of myocytes determines unique electrical properties in three microstructurally defined directions at any point in the ventricular wall of the heart, and (2) interlaminar clefts between layers of cardiomyocytes provide a substrate for bulk activation of the ventricles during defibrillation.

An Overview of CellML 1.1, a Biological Model Description Language

CellML is an XML-based exchange format developed by the University of Auckland in collaboration with Physiome Sciences, Inc. CellML 1.1 has a component-based architecture allowing a modeller to build complex systems of models that expand and reuse previously published models. CellML Metadata is a format for encoding contextual information for a model. CellML 1.1 can be used in conjunction with CellML Metadata to provide a complete description of the structure and underlying mathematics of biological models. A repository of over 200 electrophysiological, mechanical, signal transduction, and metabolic pathway models is available at www.cellml.org.

Computational physiology and the physiome project

Bioengineering analyses of physiological systems use the computational solution of physical conservation laws on anatomically detailed geometric models to understand the physiological function of intact organs in terms of the properties and behaviour of the cells and tissues within the organ. By linking behaviour in a quantitative, mathematically defined sense across multiple scales of biological organization – from proteins to cells, tissues, organs and organ systems – these methods have the potential to link patient‐specific knowledge at the two ends of these spatial scales. A genetic profile linked to cardiac ion channel mutations, for example, can be interpreted in relation to body surface ECG measurements via a mathematical model of the heart and torso, which includes the spatial distribution of cardiac ion channels throughout the myocardium and the individual kinetics for each of the approximately 50 types of ion channel, exchanger or pump known to be present in the heart. Similarly, linking molecular defects such as mutations of chloride ion channels in lung epithelial cells to the integrated function of the intact lung requires models that include the detailed anatomy of the lungs, the physics of air flow, blood flow and gas exchange, together with the large deformation mechanics of breathing. Organizing this large body of knowledge into a coherent framework for modelling requires the development of ontologies, markup languages for encoding models, and web‐accessible distributed databases. In this article we review the state of the field at all the relevant levels, and the tools that are being developed to tackle such complexity. Integrative physiology is central to the interpretation of genomic and proteomic data, and is becoming a highly quantitative, computer‐intensive discipline.

The CellML Model Repository

SUMMARY The CellML Model Repository provides free access to over 330 biological models. The vast majority of these models are derived from published, peer-reviewed papers. Model curation is an important and ongoing process to ensure the CellML model is able to accurately reproduce the published results. As the CellML community grows, and more people add their models to the repository, model annotation will become increasingly important to facilitate data searches and information retrieval. AVAILABILITY The CellML Model Repository is publicly accessible at http://www.cellml.org/models.

The IUPS human physiome project

Abstract. The Physiome Project of the International Union of Physiological Sciences (IUPS) is attempting to provide a comprehensive framework for modelling the human body using computational methods which can incorporate the biochemistry, biophysics and anatomy of cells, tissues and organs. A major goal of the project is to use computational modelling to analyse integrative biological function in terms of underlying structure and molecular mechanisms. To support that goal the project is establishing web-accessible physiological databases dealing with model-related data, including bibliographic information, at the cell, tissue, organ and organ system levels. Here we discuss the background and goals of the project, the problems of modelling across multiple spatial and temporal scales, and the development of model ontologies and markup languages at all levels of biological function.