Model Organisms in Drug Discovery

50 C. ELEGANS FUNCTIONAL GENOMICS IN DRUG DISCOVERY
served as important tools to study human disease-relevant neurological
signaling in C. elegans (Figure 3.4).
We have mentioned earlier several disease pathways that could be studied in
C. elegans. It is impossible to discuss all C. elegans disease models in sufficient
detail but we have outlined in Figure 3.4 three entry points for the
development of a C. elegans disease model. A certain biological process
such as drinking can be chosen as a genetically tractable phenotype to model
synapse function. A thorough knowledge of neurotransmitter signaling in
C. elegans and the availability of drugs has been used to develop this
phenotype into a disease-relevant model of serotonergic signaling. A more
common approach is the use of gene knock-downs to create disease models.
A disease gene such as Ras can be knocked down or overexpressed to create
genetically tractable phenotypes (Hara and Han, 1995). It is also possible to
express the human gene in C. elegans to induce a phenotype. The modeling of
a disease in C. elegans immediately raises the question: how many genes are
actually conserved between humans and C. elegans? Depending on the
bioinformatics approach, a C. elegans homolog has been identified for 65–
78% of human genes (Sonnhammer and Durbin, 1997; Kuwabara and O’Neil,
2001). A more rigorous prediction of the number of C. elegans homologs that
are putative disease gene orthologs has been made based on a comparison of
C. elegans sequences with genes of the OMIM database (the OMIM database
is a catalogue of human genes and genetic disorders, http://www.ncbi.nlm.
nih.gov/omim). A C. elegans homolog has been found for about 85% of 100
analyzed disease genes. When blasting these C. elegans homologs against the
human genome, the human disease gene was the closest human gene to the
C. elegans gene for 42% of the tested genes (Culetto and Sattelle, 2000).
Developing a functional assay
A successful exploitation of model organisms such as C. elegans as tools to
study human diseases is dependent upon the availability of reliable assays to
study gene and pathway function. The primary challenge is to develop an
assay that models a disease at the molecular level in a format appropriate for
large-scale genetics and compound screening. Regarding the serotonin
pathway, the question is how to convert the measurement of a serotoninrelated
C. elegans behavioral phenotype into an assay that can identify genes
or compounds that increase activity at the serotonergic synapse. As described
previously, pharynx contraction in C. elegans is regulated by serotonin. The
measurement of pharynx contractions is too laborious for use on a large scale
but the eating and drinking behavior of C. elegans can be used as an indirect
measure of pharynx contraction. Devgen, a drug discovery company based in
Belgium, uses a dye that fluoresces only when taken up into the gut of