Revisiting the Krogh Principle in the post-genome era:: Caenorhabditis elegans as a model system for integrative physiology research

Molecular biology drove a powerful reductionist or `molecule-centric' approach to biological research in the last half of the 20th century. Reductionism is the attempt to explain complex phenomena by defining the functional properties of the individual components that comprise multi-component systems. Systems biology has emerged in the post-genome era as the successor to reductionism. In my opinion, systems biology and physiology are synonymous. Both disciplines seek to understand multicomponent processes or `systems' and the underlying pathways of information flow from an organism's genes up through increasingly complex levels of organization. The physiologist and Nobel laureate August Krogh believed that there is an ideal organism in which almost every physiological problem could be studied most readily (the `Krogh Principle'). If an investigator's goal were to define a physiological process from the level of genes to the whole animal, the optimal model organism for him/her to utilize would be one that is genetically and molecularly tractable. In other words, an organism in which forward and reverse genetic analyses could be carried out readily, rapidly and economically. Non-mammalian model organisms such as Escherichia coli, Saccharomyces, Caenorhabditis elegans, Drosophila, zebrafish and the plant Arabidopsis are cornerstones of systems biology research. The nematode C. elegans provides a particularly striking example of the experimental utility of non-mammalian model organisms. The aim of this paper is to illustrate how genetic, functional genomic, molecular and physiological methods can be combined in C. elegans to develop a systems biological understanding of fundamental physiological processes common to all animals. I present examples of the experimental tools available for the study of C. elegans and discuss how we have used them to gain new insights into osmotic stress signaling in animal cells.