Model Organisms in Drug Discovery

multivulva phenotype of Ras gain-of-function C. elegans mutants (Hara and
Han, 1995). The long list of human diseases studied in C. elegans also includes
metabolic disorders (e.g. diabetes), central nervous system (CNS) disorders
(e.g. depression) and several congenital disorders such as Duchenne muscular
dystrophy and polycystic kidney disease (Bessou et al., 1998; Barr and
Sternberg, 1999; Habeos and Papavassiliou, 2001).
The above attributes have prompted the entry of C. elegans into the drug
discovery industry in recent years. It is amenable to high-throughput
compound screening, mode-of-action analysis and large-scale target validation
(Figure 3.1). Millions of animals can be grown daily for screening
campaigns, either in liquid or on plates. Conservation of disease pathways,
considerable transferability of human drug action into C. elegans and drug
uptake through the gut membrane allow large-scale in vivo pharmacology. A
short 3-day life cycle and amenability to molecular, genetic, biochemical and
physiological analyses speed up the dissection of entire pathways and target
validation programs. Finally, and importantly, the growth and maintenance
requirements of C. elegans are of relatively low cost.
In the following pages we will describe how to apply C. elegans technologies
to drug discovery. As an example, we will describe the successful use of C.
elegans within a CNS disease project. This example will serve as a guide
throughout the following chapters.
3.2 From disease to target
Hunt for validated targets
FROM DISEASE TO TARGET 45
Many diseases are caused by heritable disturbances in gene function whereby
the disease is manifested during gestation or shortly after birth. However, the
majority of human diseases such as cancer, stroke and diabetes, although also
linked to malfunctions in genes, are manifested only later in life. The causes of
the malfunctions are case dependent and may involve acquired point
mutations, pathogenic mis-expression of genes or may be related to other
specific perturbations of cell biology. Importantly, the most common human
diseases are often characterized by uncontrolled signaling within several
biological pathways. An understanding of the molecular mechanism of
diseases opens many opportunities to develop new therapies, including those
tailored to the genetic profiles of individual patients.
In this chapter we describe an efficient route leading from the molecular
analysis of human disease in the model organism C. elegans to the discovery of
validated therapeutic targets (Figure 3.2). The process starts with the
development of a C. elegans disease model, exemplified here via a discussion
of a C. elegans unipolar depression model. Caenorhabditis elegans disease