Model Organisms in Drug Discovery

signaling pathway. The third category of genes includes miscellaneous or
‘bystander’ genes, which would not be of interest to elucidate the biology
under study.
Three basic types of genetic screens have been successfully developed and
applied using C. elegans. The first type of screen, like the screen described
above, isolates genetic mutations that induce a measurable phenotype
associated with a particular area of biology. The second type of screen is an
enhancer/suppressor screen that maps out complete pathways and the third
type is a resistance/sensitivity screen that identifies the mode of action of a
drug. Enhancer/ suppressor screens have been applied successfully to decipher
many C. elegans pathways, such as Ras signaling, apoptosis, Alzheimer’s
disease, transforming growth factor b (TGF-b) and insulin signaling. For
example, a model to study the epidermal growth factor (EGF)/Ras pathway in
C. elegans is the vulva development (Sternberg and Han, 1998; Chang and
Sternberg, 1999). The vulva consists of 22 cells and is located in the middle of
the hermaphrodite. The eight muscles of the vulva mediate egg-laying. We
have already stated that egg-laying is highly regulated by serotonin and
acetylcholine. This EGF/Ras signaling cascade induces three out of six
candidate vulva precursor cells to adopt vulval fates during vulva development.
Mutations in the C. elegans homolog of the EGF receptor, LET-23,
interrupts this signal and inhibits differentiation of precursors into vulval cells,
resulting in a vulva-less phenotype. Gain-of-function mutations in the C.
elegans Ras kinase homolog, LET-60, lead to overactivation of the pathway
whereby all six precursor cells produce vulvae, resulting in a multivulva
phenotype. Genetic studies in C. elegans, based on mutational outcomes
measured via the vulval phenotypes, provided the first indication, in any
organism, that Ras proteins have roles in cell specification and differentiation
as opposed to cell growth and proliferation (Han and Sternberg, 1990). This
work elucidated the cellular function of Ras and established a C. elegans
model for EGF/Ras-related oncogenesis. A nematode-based enhancer/
suppressor screen for genes within the EGF/Ras pathway identified the
C. elegans homolog of the proto-oncogen c-cbl, SLI-1 (Yoon et al., 1995). An
epistatic analysis of SLI-1 was used to study interactions of the gene with
other pathway components to indicate that c-cbl acts as a negative regulator
of the EGF/Ras pathway. This hypothesis has been confirmed in c-cbldeficient
mice, leading to an improved understanding of mammalian c-cbl
function (Murphy et al., 1998).
Mode-of-action studies
FROM DISEASE TO TARGET 53
The third type of genetics screen is often referred to as ‘chemical genetics’
(Alaoui-Ismaili et al., 2002; Zheng and Chan, 2002). The principle is similar to