Model Organisms in Drug Discovery

64 C. ELEGANS FUNCTIONAL GENOMICS IN DRUG DISCOVERY
only through the interaction of hits with targets that the biological activity of
compounds is revealed. Thus, the prediction of biological activity based on a
compound’s chemical structure remains largely an art. We will revisit this
issue when discussing the value of a hit derived from a C. elegans screen.
Caenorhabditis elegans is amenable to high-throughput screening
High-throughput screening (HTS) is the complement to combinatorial
chemistry and genome-wide target identification. It allows the screening of
chemical libraries containing several hundreds of thousands of compounds
against a wide range of novel targets in a robust and timely manner. If a nonmammalian
model system is to have a significant impact on drug discovery in
a time-effective way, it must be amenable to HTS. Caenorhabditis elegans can
be grown in liquid and handled efficiently in 96-well or 384-well plates and is
the only multicellular model organism whereby a population of hundreds of
animals can fit into a single well. Inter-animal variations between members of
a C. elegans population commonly used in laboratory settings are low, which
is an advantage over mammalian animal populations. This low variability
leads to the high reproducibility of assays and allows the application of
statistical analyses such as the z-factor calculation of assay variability.
Because most C. elegans biology has been established from the analysis of
mutants that have been identified through genetic screening, appropriate
assays to screen tens of thousands of animals are available. Thus, highthroughput
rates and miniaturization can be readily achieved with C. elegans
assays. Another important prerequisite for high-throughput library screening
is a low compound concentration format. Caenorhabditis elegans takes up
considerable amounts of compound through normal drinking processes,
which allows compound screens to be performed at concentrations of
1–30 mM (Devgen, personal communication).
Assay design
The design of a C. elegans assay depends naturally on the selected target and
the biological process of interest. The challenge for assay design is to ensure
the relevance of an assay for a particular disease, therefore we will classify
C. elegans assays by the type of genetically engineered animal used. The easiest
assay type employs wild-type animals but, as with all C. elegans in vivo assays,
a sufficient specific phenotype or pathway endpoint to track or measure the
biology of interest is required. In our example of the C. elegans depression
model, enhanced pharynx pumping is strongly correlated to increased
serotonergic tonus at the synapse of the C. elegans pharynx. As shown in a