Sidney Brenner and Caenorhabditis elegans | Advantages of C. elegans for genetic analysis
Following his pioneering work in molecular genetics with Francis Crick, Sidney Brenner shifted his research focus to more complex biological questions in the early 1960's. In particular, he was interested in the molecular mechanisms of development and behavior.
Brenner realized that the remarkable success of early molecular geneticists was due in large part to their selection of appropriate model organisms, most notably the bacterium E. coli. Consequently, Brenner carefully searched for a simple animal exhibiting development and behavior that could be studied exhaustively. He eventually selected Caenorhabditis elegans, because it had just the right combination of complexity and simplicity. For example, like more complex animals, this small (less than 1 mm in length) roundworm develops from a single cell to generate a multicellular adult with specialized structures. Yet C. elegans is so simple (for example, the adult is composed of only about a thousand cells) that the idea of completely characterizing the animal at the cellular and genetic level is potentially achievable. In addition to its simplicity, C. elegans has a number of features that make this unique animal particularly amenable to detailed genetic analysis.
In his original paper, Mendel cited several features of an experimental organism that are especially useful or even necessary for performing genetic analysis; C. elegans possesses all of these features. First, contrasting traits must be available that are easily distinguished and stably inherited. While the number of highly visible structures in C. elegans is somewhat limited, there are several readily observable features that do vary, including locomotion, body shape, and sensitivity to touch. Second, one must be able to set up crosses between genetic variants. C. elegans exists as two sexes, males and hermaphrodites. The males can cross-fertilize hermaphrodites, allowing genetic crosses to be conducted. In addition to cross-fertilization with males, hermaphrodites are able to self-fertilize, because they produce both sperm and eggs. As we'll see later, this ability to self-fertilize (not shared by any other animal commonly used for genetic analysis) is particularly advantageous for the isolation of novel recessive mutations: Unlike other animals which require several generations to achieve homozygosity, a newly-induced mutation in a C. elegans hermaphrodite will be homozygous in one-fourth of the resulting self-progeny.
Realizing the importance of large sample sizes, Mendel also noted the importance of being able to grow large numbers of offspring quickly and easily. C. elegans develops extremely rapidly: Under optimal conditions, a fertilized egg can traverse embryogenesis and the four larval stages to become a reproductive adult in just three days. An adult hermaphrodite is then fertile for about four days during which time it typically produces about 300 eggs. Additionally, C. elegans is easily cultivated in the laboratory on nutrient agar plates. Because of its small size, several hundred worms can easily be accommodated on a small plate. A dissecting microscope and a "worm pick" (a platinum wire implement with a flattened end) are all the tools needed for conveniently observing and manipulating C. elegans.
In summary, C. elegans is an excellent organism for genetic analysis. Many mutants have been isolated in the worm, hastened in large part by the power of hermaphrodite genetics. In addition, the ability of males to mate with hermaphrodites allows genetic crosses to be made between genetic variants. Finally, the short life cycle and large brood sizes allow large numbers of offspring to be quickly generated, as required for detailed genetic analysis, while the small size and easy cultivation of the worm allows these large numbers to be conveniently handled.
William R. Morgan wmorgan@acs.wooster.edu