Model Organisms in Drug Discovery

44 C. ELEGANS FUNCTIONAL GENOMICS IN DRUG DISCOVERY
Figure 3.1 Caenorhabditis elegans in drug discovery. Target identification and validation
are the initial steps in genomics-based drug discovery and C. elegans plays an important
role during this phase (dark grey). Caenorhabditis elegans assay development and in vivo
high-throughput screening capacities are used for hit generation (dark grey). As soon as
vertebrate studies and clinical trials are required, the utility of C. elegans diminishes (light
grey). However, the drug discovery process is no longer linear and feedback loops are
possible between the various phases. For example, an alternative ‘route B’ is screening in
animal and insect models to obtain in vivo hits of high quality. The caveat of this approach
is that often the molecular target will be unknown. Caenorhabditis elegans can be used for
mode-of-action studies to identify molecular targets as needed for lead development and
registration (dark grey). Obviously, in the case where a novel target is identified, route B
would be merged into route A
Consortium, 1998). These methods have become the basis for other highthroughput
genome sequencing projects, particularly the human genome
project. Comparison of the human and C. elegans genomes revealed that
many disease genes and disease pathways are present in C. elegans. This has
stimulated many studies to establish C. elegans as a model for the study of a
range of human disorders. For example, mutations in the human presenilin-1
gene are associated with early-onset familial Alzheimer’s disease. Mutations in
the corresponding C. elegans ortholog sel-12 cause defects in neurons as well.
Experiments in which these defects have been restored by transgenic
expression of human presenilin-1 demonstrated a remarkable functional
conservation between C. elegans and humans (Levitan et al., 1996; Wittenburg
et al., 2000). Another well-conserved pathway, the Ras pathway, provides the
possibility to use C. elegans in the discovery of anticancer therapeutics. A
compelling example is given by the analysis of the effects of farnesyl
transferase inhibitors on activated Ras in C. elegans mutants. Farnesyl
transferase inhibitors inhibit the requisite processing of a number of proteins,
including the proto-oncogene Ras, and have been shown to afford good
antitumor efficacy (Karp et al., 2001). These inhibitors specifically revert the