COMPUTATIONAL MODELING AND SIMULATION AS ENABLERS FOR BIOLOGICAL DISCOVERY 161
5.4.4 Organ Physiology,
Sydney Brenner has noted that “genes can only specify the properties of the proteins they code for,
and any integrative properties of the system must be ‘computed’ by their interactions.”^86 In this context,
subcellular behavior and function represents a first level of “computed” interaction; cellular behavior and
function, a second level. Organization of cells into organs provides a context for cellular behavior, and in
the words of Denis Noble, “successful physiological analysis requires an understanding of the functional
interactions between the key components of cells, organs, and systems, as well as how these interactions
change in disease states. This information resides neither in the genome nor even in the individual
proteins that genes code for. It lies at the level of protein interactions within the context of subcellular,
cellular, tissue, organ, and system structures. There is therefore no alternative to copying nature and
computing these interactions to determine the logic of healthy and diseased states. The rapid growth in
biological databases; models of cells, tissues, and organs; and the development of powerful computing
hardware and algorithms have made it possible to explore functionality in a quantitative manner all the
way from the level of genes to the physiological function of whole organs and regulatory systems.”^87
5.4.4.1 Multiscale Physiological Modeling,
Physiological modeling is the modeling of biological units at a level of aggregation larger than that
of an individual cell. Biological units can be successively decomposed into subunits (e.g., an organism
may consist of subsystems for circulatory, pulmonary, digestive, and cognitive function; a digestive
FIGURE 5.10 The isoniazid (INH) response network. Red nodes indicate up-regulated genes. Blue nodes indicate
down-regulated genes. SOURCE: Courtesy of Christian Forst, Los Alamos National Laboratories, December 8,
2004.
(^86) S. Brenner, “Biological Computation,” The Limits of Reductionism in Biology. Wiley, Chichester, UK, 1998, pp. 106-116.
(^87) D. Noble, “Modeling the Heart—from Genes to Cells to the Whole Organ,” Science 295(5560):1678-1682, 2002.
(^88) Much of the material in Section 5.4.4.1 is based on excerpts from A.D. McCulloch and G. Huber, “Integrative Biological
Modelling in Silico,” Novartis Foundation Symposium 247:4-19, 2002.