Model Organisms in Drug Discovery

profiles. The C. elegans gene expression topomap contains 44 gene mountains
or functional groups including collagen, metabolic enzymes or germ-linespecific
genes. In one interesting case, members of the C. elegans Wnt family
have been distributed to either the embryonic or larval Wnt signaling
pathway. In this way, mountains or functional groups enrich for genes of a
certain process of interest. For drug research, it would be very useful to create
a ‘pharmaceutically tractable genome chip’ containing all C. elegans orthologs
that are likely to be druggable (Milburn, 2001).
Genome-wide protein interaction mapping
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The elucidation of protein interactions is a key component in understanding
protein function. Protein–protein interactions are an important facet of
biological processes and their characterization can be used to identify the key
modulators of a given gene of interest. A C. elegans genome-wide protein
interaction map project has been launched (Walhout et al., 2000a).
Complementary DNA from open reading frames is cloned into yeast twohybrid
(Y2H) vectors using the Gateway recombinational cloning system
(Walhout et al., 2000b). These vectors (containing DNA binding domains) can
be used as baits to screen a C. elegans cDNA library. The identified proteins
then can be used for new Y2H screens or tested in a matrix (a vector carrying
an activating domain and a vector carrying the DNA binding domain) to
build protein interaction networks. Such an analysis has been conducted on 27
genes required for C. elegans vulva development. The 27 genes have been used
as baits in extensive Y2H screens leading to the isolation of 124 interacting
partners (Walhout et al., 2000a). It is commonly accepted that Y2H activity is
not strongly predictive of physiologically relevant protein–protein interactions.
Confirmation studies are normally required. The utility of a genomewide
Y2H campaign is realized by the combination of Y2H data with knockout
and gene expression data. This combination allows for the description of a
skeleton of genes that form a pathway or network. It is important to examine
the extent to which interactions identified in the C. elegans genome predict for
human protein interactions. As an example, conserved interactions (interologs)
have been used to identify C. elegans DNA damage response genes
(DDR genes) (Boulton et al., 2002). The C. elegans genome has been
compared with the human sequences of DDR genes and 75 putative orthologs
were identified. These were tested in a Y2H matrix. Seventeen of the 33
interactions that are known in humans have been detected, or stated
otherwise; the experimental data indicate that at least 17 protein–protein
interactions are conserved between human and C. elegans. A further eight,
potentially novel, protein–protein interactions of human genes were indicated
by the experimental results.