Model Organisms in Drug Discovery

198 GENETICS AND GENOMICS IN THE ZEBRAFISH
Here, the steps of assembling a physical contiguity is often rate limiting,
however, with a fully annotated genome sequence well on its way this will
become much less of an issue.
The versatility of zebrafish will undoubtedly continue to excite scientists.
There will be more forward genetic screens using increasingly sophisticated
assays and endpoints that will allow the identification of novel gene functions
in increasingly complex assay systems (e.g. Farber et al., 2001). There will be
large-scale reverse genetic screens in which whole classes of proteins will be
scanned for their role in a biological process of interest. Targeted mutagenesis
will be used to generate stable mutant lines that do not exhibit a lethal
phenotype on their own and can therefore be used as the basis for screens in
genetically sensitized backgrounds. The number of transgenic lines that
express fluorescent proteins under the control of a cell-type specific promoter
will increase, and some of these will constitute the basis for screens utilizing
cameras instead of the human eye as a first filter. Sensitized genetic
backgrounds and the possibility for semi-automated readouts can be
combined with compound screens, where thousands of chemicals are being
tested for their effect on a whole organism level. Although this technology is
unlikely to reach ultrahigh-throughput screening levels where millions of
compounds are being tested, compound screens in fish could be useful to test
those compounds that stem from a cell-based high-throughput screen and that
need to be screened for further efficacy, toxicity or teratogenic side-effects
(Nagel, 2002).
Finally, for those whose foremost interest is studying human diseases, it will
be an interesting challenge to create human disease models that can be utilized
in combination with the technologies listed above. One recent interesting
example of this has been reported by Langenau et al. (2003), who described
the induction of clonally derived T-cell acute lymphoblastic leukemia in
zebrafish transgenic for the mouse c-myc gene. Suppressor screens using
disease models such as this offer an exciting avenue for understanding better
the genes contributing to human disease states, thereby defining future
potential drug targets. Here, and in other areas of developmental,
physiological and medical relevance, the zebrafish system will continue to
make valuable contributions.
7.8 Acknowledgments
I would like to thank P. Beeckmann, T. Kidd, U. Langheinrich, N. Scheer and
G. Stott for discussions and reading of the manuscript. H. Habeck provided
the figure. Owing to space limitations, in many cases reviews are cited rather
than original publications and I apologize to those whose original work I was
not able to cite.