sions; how intercellular calcium waves coordinate cellular responses over large areas; how tumors grow and respond to chemotherapy; and how the HIV virus is produced and cleared within cells: all are areas where mathematical models have played an important role.

The need for mathematical models has never been greater. Much of the biological investigation of the past can be described as a compilation and categorization of the list of parts, whether as the delineation of genomic sequences, genes, proteins, or species. The past decade has seen an explosion in probing genetic or cellular defects that alter properties and behaviors at the tissue or organ level, thereby identifying the root basis for many diseases. As examples, we know the mutation to a chloride ion channel that results in cystic fibrosis and the mutations to potassium channels that lead to long QT syndrome (an abnormality of the heart’s electrical system). There have also been many striking advances in imaging and measurement of function, some due to mathematical advances that provide insight into the level and extent of functional degradation or guide clinical intervention. For example, the ability to interpret electrocardiograms has led to spectacular advances in the reliability of implantable pacemakers and defibrillators (Kenknight et al., 1996). Missing is the ability to integrate how the various components of organs work together to achieve dynamic function, and how change of specific components or combinations thereof impact function. Thus, the challenge of systems physiology is to provide an understanding of how the interactions of biological entities across spatial and temporal scales lead to observable behavior and function.

Two important organizing principles need emphasis. First, an integrated understanding of systems requires mathematics and the development of theory, supplemented by simulations. One of the important lessons of the past is that there are behaviors and phenomena that are the consequences of interactions of several or many individual components that cannot occur with the components uncoupled, and the principles governing these emergent behaviors require theory for their full explanation. Secondly, theory cannot be relevant if it is not driven and inspired by experimental data. The committee illustrates these with some examples where systems physiology has great promise.

CARDIAC PHYSIOLOGY

Failure of the cardiac system remains the leading cause of death in the Western world. The cardiac cycle consists of two primary events: (1) a contractile, or mechanical, event, controlled by (2) an electrical event, the cardiac action potential. Failure of either of these can lead to death. Either cardiomyopathies, in which the cardiac muscle does not provide enough



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