Model Organisms in Drug Discovery

178 MECHANISM OF ACTION IN MODEL ORGANISMS
to alter the function of a single gene product within the context of a complex
cellular environment. Once hooked into a pathway, many new genomics tools
can be brought to bear on any given problem. Advances in Drosophila and C.
elegans research allow the combination of genome sequence information,
genome-wide cDNAs, mapping protein interactions, gene expression profiles
and genome-wide mutations in an unprecedented dissection of a complex
organism. In general, the challenge of a model system biology group in an
industrial setting is to balance throughput with quality biological information.
There is a significant amount of potential to enhance all target validation
methodologies, including model systems. Improvement in automation,
miniaturization and visualization of biological processes offers the most
promise.
Studies with compounds can be integrated with many of the evolving
genomics and proteomics tools. This chapter summarized the advantages of
C. elegans and Drosophila as model systems in understanding a broad
spectrum of MOA and lead compound identification issues. However, model
organism approaches when combined with other methods, in parallel or
circuit, can produce a complete biochemical and genetic profile of the drug
target protein(s). There are many evolving approaches in chemical genomics,
such as protein profiling and cell-based chemical screenings, that were beyond
the scope of this review chapter (Zheng and Chan, 2002). The technologies
developed for work in S. cerevisiae remain the model of researchers in the
multicellular world (see Chapter 2).
6.11 Acknowledgments
Lisa Moore carried out the fly experiments shown in Figure 6.2. The authors
would like to thank Jenny Kopczynski, Ross Francis, Garth McGrath, Steve
Doberstein, Dan Curtis, Mark Cockett and Petra Ross-MacDonald for ideas
and input, and Ben Burley for technical assistance. Hong Xiao, Bo Guan,
Libeng Chen and Tiffany Vora conducted experiments in the S2 cell system.
The authors would like to thank Becket Feierbach for her thoughtful
manuscript review and helpful ideas.
6.12 References
Abraham, R. T., Acquarone, M., Andersen, A., Asensi, A., Belle, R., Berger, F.,
Bergounioux, C., et al. (1995). Cellular effects of olomoucine, an inhibitor of cyclindependent
kinases. Biol. Cell 83, 105–120.
Arbeitman, M. N., Furlong, E. E., Imam, F., Johnson, E., Null, B. H., Baker, B. S.,
Krasnow, M. A., et al. (2002). Gene expression during the life cycle of Drosophila
melanogaster. Science 297, 2270–2275.