Understanding how the genotype results in the phenotype that scientists observe is one of the biggest challenges facing comparative physiologists. Asking which animals are the best to test this relationship in, Kevin Strange(p. 1622) revisits the Krogh principle: `for many problems there is an animal in which it can be most conveniently studied'. The ideal genetic model organism in which to answer the question of how the parts of a biological system work individually, and with each other, must be easy to manipulate genetically but still complex enough to be interesting. Strange highlights why the nematode C. elegans is an ideal animal to study: its well-developed muscular and nervous systems are of interest to physiologists, while it is also easy to manipulate genetically and its development is well categorised.

Julian Dow continues the discussion of how scientists can understand how phenotypes are created from genotypes, and how they can use model organisms to answer physiological questions(p. 1632). Dow argues that integrative physiology benefits from the investigation of gene function in the context of the intact animal. This implies that researchers need to use a genetically tractable model organism to answer physiological questions on the `general principles of function,' he says, and can extend the Krogh principle a little further by choosing organisms on the basis of how easy they are to study experimentally. Drosophila is such a model organism, and studies on these flies have, for example, increased our understanding of circadian clocks through the scrutiny of emergence times and their genetic control.

How animals are adapted to their environment is a fascinating question, but Michael Berenbrink wants to answer the question `how did it come to work as it does?' (p. 1641). By using a method of evolutionary reconstruction, Berenbrink discusses how molecular phylogenetic trees can be used to piece together the evolutionary steps of a system's development and thus offer another route for understanding physiological diversity. Focussing on the evolution of the swimbladder in fishes, Berenbrink relates how changes in the pH dependence of the oxygen-binding ability of haemoglobin and its specific buffer ability facilitated the evolutionary development in some fish of an inflatable swimbladder to achieve neutral buoyancy at great depths.

Continuing with the evolutionary theme, Martin Feder(p. 1653) concludes the issue by discussing how mutation influences gene function, which in turn influences how adaptations arise. While a lot of focus has been on single nucleotide mutations, which can have a large impact, they only affect existing genes. Other mechanisms at work include gene duplication, lateral gene transfer, or hybridisation, and other processes that can scramble and reassemble a nucleotide sequence. Understanding these mechanisms will allow researchers to detail the evolution of complex physiological and biochemical traits.