“The Physiome: Genes to organism, modeling toward human health”

The Physiome is the quantitative description of the structure and function of the intact organism. The Physiome Project is a multi-centric program to archive and disseminate quantitative information on all aspects of physiological systems, and to develop and disseminate integrative models of functional behavior from regulation of transcription and protein-protein interactions to cell biology and to the normal and pathologic behavior of tissues, organs, and the organism. Complex systems tend to have emergent properties not evident on the parts, only in the whole. Systems viewpoints are necessarily hierarchical: a human body operates organ systems, tissues and cells. Models develop in stages: (a) collections of objects, (b) diagrams of connectivity, (c) descriptions of causation and kinetics of the connections, (d) physico-chemical mechanistic equations for the integrated system, and (e), for practical utility, reduced-form versions describing limited aspects of system behavior. At each level, the model must account realistically for or be in tune with the observations made at the next level down. Physical models (circulatory or skeletal mechanics, or protein dynamics) can be well based upon a combination of theory and observation. Biochemical systems models can be based on thermodynamics and experimentally observed chemical reactions. Higher level models summarize a broad diversity of experimental data comprehensively. Bioinformatics models are attempts to bring together meaningful diagrams of connectivity through “inference engines”, even while cause and effect is often unknown; this is still a long way from stage (c), and is very difficult. The current state is that there are few validated models of protein-protein interaction. For cell electrophysiology and metabolism there is a century of observation and integration leading to numerous level (d) models; these are gaining reliability and therefore utility in prediction, but to remain reliable over a wide range of conditions such models have several internal levels and tend to be computationally costly. They are used in the development of pharmaceuticals. Advanced but computationally and operationally simplified models have value in clinical practice. Modern science is facilitated by open standard and rapid dissemination of knowledge. Component modules developed by independent investigators can be brought together through adherence to standards of quality, use of common ontologies, programming in common languages, archiving in standard forms with complete descriptions. The automated construction of large model from validated modules is beginning, and will allow putting together models from several different laboratories. A fundamental and major feature of the Physiome Project is the databasing of the basic observations and for evaluation of the modeling. When the models integrate the observations from many laboratories into quantitative, self-consistent, comprehensive descriptions they will provide to the community of scientists, physicians, teachers, and to medical health professional and industrial communities, functional descriptions of human biological systems in health and disease.