A Strategy for Integrative Computational Physiology
Hunter et al. (2005): A Strategy for Integrative Computational Physiology
This paper describes a "quantitative modeling framework" being developed "under the auspices of the Physiome and Bioengineering Committee (co-chaired by P. Hunter and A. Popel) of the International Union of Physiological Sciences (IUPS)" that can deal with organ function "through knowledge of molecular and cellular processes within the constraints of structure-function relations at the tissue level".
It follows what other authors have called a "top-down approach":
The challenge is to develop mathematical models of structure-function relations appropriate to each (limited) spatial and temporal domain and then to link the parameters of a model at one scale to a more detailed description of structure and function at the level below.
In the authors' opinion, the concept of a "field" as defined by physicists of the 19th century is essential for this endeavour:
The application of continuum field concepts and constitutive laws, whose parameters are derived from separate, finer-scale models, is the key to linking molecular systems biology (with its characterization of molecular processes and pathways) to larger-scale systems physiology (with its characterization of the integrated function of the body’s organ systems).
The authors also write how this branch of science should be called in their opinion:
The appropriate name for this application of physical and engineering principles to physiology is computational physiology. The term systems biology, currently inappropriately limited to the molecular scale, needs to be associated with all spatial scales.
Next, the authors state that computational modeling must be applied "at the scale of whole organs", "at the tissue level" and "even at the protein level".
Good progress is being made on modeling the anatomy and biophysics of the heart, the lungs, the digestive system, and the musculoskeletal system. [...] Linking the organ and organ systems together to yield models that can predict and interpret multiorgan physiological behavior is the focus of systems physiology. [...] The organ-level models [...] are based on finite-element models of the anatomic fields (geometry and tissue structure) encoded in a markup language called FieldML (http://www.physiome.org.nz/fieldml/pages ).
For "modeling cell function", a framework "has been developed over the past five years by the Bioengineering Institute at the University of Auckland". It employs a markup language called CellML. At the URL http://www.cellml.org/examples/repository there are about 300 models in various categories, such as signal transduction or metabolic pathway models.
The next chapter of the paper focuses on models of the heart. The authors explain:
Molecular dynamics (MD) models of the atomic structure of ion channels, pumps, exchangers, etc. are needed that can predict the open-channel permeation of the channels, the voltage dependence of the channel permeability, and the time- and voltage-dependent gating behavior. [...] MD calculations, based on ~100,000 atoms in current models, are very expensive and are typically run for periods of only 10 ns. Sometimes homology modeling is used in combination with MD simulation to generate, test, and refine models of mammalian potassium channels based on bacterial templates. The structures of sodium and calcium channels are also on the horizon, as well as those of key pumps and exchangers.
In their conclusions, the authors appear to be very optimistic:
Anatomically and biophysically based models of 4 of the 12 organ systems in the human body are now quite well developed at the organ and tissue levels (the cardiovascular, respiratory, digestive, and musculoskeletal systems). Others (the lymphatic system, the kidney and urinary system, the skin, the female reproductive system, and the special sense organs) are at an early stage of development, and the remainder (the endocrine, male reproductive, and brain and nervous systems) will be addressed over the next few years.