Model Organisms in Drug Discovery

252 SATURATION SCREENING OF DRUGGABLE MAMMALIAN GENOME
to identify genes involved in organization of the body plan during
development (Nusslein-Volhard and Wieschaus, 1980) and screens in
Caenorhabditis elegans to identify genes involved in producing the invariant
cell lineage pattern (Horvitz and Sulston, 1980; Chalfie et al., 1981; Hedgecock
et al., 1983). These screens relied on saturation mutagenesis to interrogate the
genome for the set of genes involved in these processes and led to the discovery
of genes such as the homeobox genes and apoptosis regulators involved in
development across all invertebrate and vertebrate species examined. Since
these early screens, a tremendous number of additional genetic screens have
been carried out in the fly and worm, further demonstrating the power of
genetics for the dissection of pathways and processes. These screens require
only a method for creating large numbers of tractable mutations in genes and
a phenotype that can be measured.
More recently, genetic screening has been adapted for the vertebrate model
organisms of zebrafish and mice. In zebrafish, both chemical mutagenesis
(Mullins et al., 1994; Haffter et al., 1996) and gene trapping (Golling et al.,
2002) have been combined with phenotypic screens to identify mutations
affecting development of the neural crest, pigmentation, jaw, branchial arches,
visual system, heart and other internal organs, ear, retina, brain, midline,
shape and movement (Brockerhoff et al., 1995; Abdelilah et al., 1996; Baier et
al., 1996; Brand et al., 1996; Chen et al., 1996; Granato et al., 1996; Kelsh et
al., 1996; Malicki et al., 1996a,b; Neuhauss et al., 1996; Odenthal et al., 1996;
Piotrowski et al., 1996; Schier et al., 1996; Solnica-Krezel et al., 1996; Stemple
et al., 1996). These screens take advantage of the large number of offspring,
oviparous development and transparent nature of the zebrafish embryo that
make it an excellent system for the study of vertebrate development. These
studies undoubtedly will result in the identification of a large number of genes
required for vertebrate development. For the purpose of drug discovery,
effective genetic screens in mammals would allow one to dissect mammalian
physiology to identify key genes with therapeutic relevance as potential drug
targets. Some might consider genetic screens in mammals to be impossible
logistically, but recent advances in mutagenesis and screening methods in mice
are facilitating functional dissection of the mammalian genome. Advances in
the scale and speed of gene targeting (Walke et al., 2001; Abuin et al., 2002)
and the development of genome-wide gene trapping (Zambrowicz et al., 1998;
Wiles et al., 2000; Leighton et al., 2001; Mitchell et al., 2001) in mouse
embryonic stem cells have resulted in saturation of the mammalian genome
with tractable mutations in large numbers of genes. This has been combined
with the recent miniaturization of a broad array of medical technologies and
the transfer of many disease challenge assays to the mouse model to enable
detailed diagnostic analysis of mice. The mouse is a model organism that is
ideal for studying many aspects of mammalian physiology with direct medical
relevance. Screens are currently being used to identify genes involved in insulin