Gene function: Getting specific, generally speaking

Much of modern biological research is concerned with identifying genes and the protein products of genes involved in cellular processes: determining how, when, and where they are involved in specific biochemical processes. The tools by which these aims are achieved can be roughly divided into two types: those that are specific to the study of individual or classes of proteins versus those with more general and broad utility. General tools are methods that allow for rapid inference of function of a gene product, either from the mRNA or the proteins it codes for, for any particular molecule or class of molecules. These are increasingly in demand, particularly those that can be applied to entire genomes or large subsets of the genes contained therein. At the same time, generality comes at a cost. By their nature, general tools do not usually provide high-quality information about the function of a gene and may even mislead, particularly when applied across large numbers of genes. Examples include DNA microarrays and multidimensional separation-MS and yeast two-hybrid strategies that detect protein–protein interactions or complexes (1–9). Although these approaches can, respectively, provide information on whether and to what extent a given gene is being transcribed in a defined condition and with which proteins the protein gene product is interacting with, they cannot provide any insight into other crucial questions. For instance, many proteins are enzymes that catalyze biochemical reactions. In the case of novel genes of unknown function it is not easy to definitively determine whether they are enzymes nor what reactions they may catalyze. In this issue of PNAS Baker et al. (10) present a proof-of-principle study on another approach that might fulfill this need, but unlike the approaches described previously, the strategy is applied in intact, living cells. Here we discuss the significance of this …