Computational physiology and the physiome project

Abstract

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.

Acidosis in models of cardiac ventricular myocytes

“…To investigate these and other issues in pH regulation and acidosis, the challenge for the development of an integrated cellular model, coupled to existing models of electrophysiology Hund et al 2001), is to construct detailed, biophysically based schemes for each of the model components (Crampin et al 2004). For example, while experimental evidence indicates that the acid equivalent transporters are largely influenced by intracellular pH, justifying pH i as the sole variable required to determine these fluxes, a higher level of detail will be needed to distinguish between the response to metabolic acidosis (during ischaemia, for example), where there is increased intracellular production of protons, and the changes due to CO 2 build-up in respiratory acidosis, as examined in this study.…”

Graphical simulation environments for modelling and simulation of integrative physiology

“…The necessity of such integrated implementation needs to be assessed taking into consideration the computational intensity, and purpose of the model, and the aptness of carrying a large complexity if it is not necessary. An example of model implementation at the 'macro' (computational physiology [49], systems physiology, organ systems) level has been shown by Cabrera [50], who looks at the dynamics of lactate production during exercise. The model is in a block diagram form and at the 'Organ systems' (or interorgan) level in Fig.…”

SAPHIR: a physiome core model of body fluid homeostasis and blood pressure regulation

“…Specifically, biomedical ontologies are the subject of a recently created National Centre for Biomedical Ontology (Rubin et al 2006). A helpful discussion of ontologies in the physiome can be found in Crampin et al (2004).…”