Model Organisms in Drug Discovery

should soon be possible to carry out experiments in Drosophila using a larger
number of experimental variables than previously feasible, such as large-scale
compound screen and large-scale study of interactions between gene function,
metabolism, physiology and environment variables (e.g. diet and stress).
Cell culture
RESEARCH TOOLS IN DROSOPHILA STUDIES 109
Drosophila-cultured cells have been studied extensively for the last 50 years
(Echalier, 1997; Cherbas and Cherbas, 1998). Many different permanent cell
lines and extensive primary cell culture methods have been developed. The
most widely used permanent cell lines are the Kc cells and S2 cells, both
derived from embryos. The Kc cells are considered to be like larval lymph
gland cells and hemocytes (Cherbas and Cherbas, 1998). From the drug
discovery standpoint, one of the most important usages of Drosophila cell
culture is for high-throughput LOF genetic screens. This approach is feasible
because of the demonstrated specificity, dose-dependency and perdurance of
dsRNAi effects by low-cost long dsRNA (Worby et al., 2001). Doublestranded
RNA molecules against most of the fly genes can be synthesized
through in vitro transcription using the full-length cDNA clones in the
Drosophila Gene Collection (DGC) (Stapleton et al., 2002). There is great
potential in combining in vivo cell-specific markers, mass isolation of the
marked cells, short-term primary cell culture and genome-wide dsRNAi to
identify genes involved in disease-relevant pathways. As mentioned above,
Drosophila cells may be useful also for MOA studies and compound screens.
A major advantage of using Drosophila cell lines is that in each case the
identified candidate genes can be introduced rapidly back into transgenic flies
and studied further using the advanced genetic approaches available in
Drosophila.
High-throughput tools to be developed
To meet the high demands of the functional genomics era, as well as the
demand for shortening the drug development cycle, it is important to develop
high-throughput technology in many areas of Drosophila research:
1. Fast and reliable methods are needed to maintain mutant stocks. A simple
calculation of 14 000 genes with one LOF mutant allele and one GOF allele
per gene would result in a stock of 28 000 mutants. (13 000 if genes without
human homologs are excluded.)
2. Controlled and highly parallel genetic cross-technology is necessary (such
as in 96-well format) if many modifier screens are to be performed against a