Model Organisms in Drug Discovery

DROSOPHILA AS A MODEL ORGANISM FOR BIOMEDICAL SCIENCE 89
be obtained through various academic laboratories. Several thousand
transposon-insertion mutations have been made and their genomic insertion
sites determined by the Drosophila Gene Disruption Project. Currently, the
publicly available mutant collection covers as much as 45% of the predicted
genes in the Drosophila genome. Further increases in coverage may come next
from large-scale analysis of specific gene families, such as kinases and
phosphatases, using reverse genetic methods. For drug discovery efforts it
would be sufficient to have mutations only in fly genes with human homologs,
thus eliminating background ‘noise’ in genetic screens and focusing on the
most useful genes.
Genome-scale genetic approaches
Pathway kit analysis
In addition to the initial discovery of modifiers of a particular disease
pathway, it is important to understand the specificity of the modifier genes.
The information will indicate potential uses of the modifier genes in treating
other diseases and also indicate their potential side-effects. One means for
addressing this is the use of a ‘pathway kit’ to obtain the activity spectrum of a
putative target gene in most disease-relevant pathways. The ‘pathway kit’
approach may involve several steps. First, it is necessary to establish a
collection of important Drosophila strains that can be used to test the
involvement of a modifier mutant/gene in the pathways. They can be LOF
and/or GOF mutants of previously characterized core components in each of
the pathways. Second, a limited number of strains that are most diagnostic for
each pathway will be used collectively as the ‘first-pass filter kit’. Third, only if
tests are positive through the strains of the first-pass filter are more test strains
for a particular pathway used as a secondary test to obtain detailed
knowledge. The value of this approach will increase exponentially as the
Drosophila knowledge base expands over the next few years to include more
genetic and protein–protein interaction data, whole-genome RNA interference
analysis and large datasets from transcriptome, proteome and
metabolome analysis.
Whole-genome double-stranded RNA interference method
The development of RNA interference (RNAi) technology has opened up a
number of new possibilities for functional analysis of the Drosophila genome.
Because Drosophila tissue culture cells tolerate long double-stranded (ds)RNA
and take up these molecules without a requirement for transfection, it is
possible to knock down gene expression levels in cultured Drosophila cells at
relatively low cost and high efficiency (Clemens et al., 2000; Worby et al.,