Model Organisms in Drug Discovery

underlying genetic factors, is termed forward genetics. Forward genetics is
driven by phenotypic analysis, and looks for the ‘phenotype first’, and then the
molecular basis of a given trait (Figure 9.1A).
In contrast, approaches involving the direct manipulation of specific genes,
either by transgenesis or targeted mutagenesis, are summarized as reverse
genetic strategies. This ‘gene first’ strategy is driven by the manipulation of
DNA, rather than the observation of phenotypes, and investigates the
functional consequences of a specific mutation in the context of the whole
organism (Figure 9.1B).
Both strategies are complementary and have been used widely in all model
organisms. The strength of reverse genetic technologies is the fine dissection of
defined pathways and the testing of specific hypotheses about gene function,
frequently applied in the analysis of complex gene families (Harris and Foord,
2000; Harris, 2001). In contrast, the realm of forward genetics is the discovery
of the molecular basis of physiological pathways where no previous
information exists (Hrabe and Balling, 1998; Justice et al., 1999; Justice
2000; Balling, 2001; Nelms and Goodnow, 2001). Thus, reverse genetics is well
suited for target validation, because it can test the therapeutic hypothesis for a
given drug target. In contrast, forward genetics is the primary tool to put new
molecular signposts into the ‘white spots’ of the functional map of pathways,
and to discover innovative targets de novo.
Mouse genetics in target discovery and validation
INTRODUCTION 225
When discussing the use of murine models in drug discovery, it is very
important to distinguish three typical classes of experimental concepts,
designed to answer fundamentally very different questions: efficacy testing,
target validation and target discovery de novo. Although this text focuses on
the latter two, it is essential to discuss the differences between the approaches
to avoid misconceptions.
For efficacy testing of novel compounds, disease models are needed that
reflect the course of the human disease as closely as possible. These models are
frequently generated by non-genetic experiments using exogenous challenges
to induce disease phenotypes. Typical examples are xenograft models for
antitumor activity, or the induction of autoimmune diseases in collageninduced
arthritis or experimental autoimmune encephalitis. Some models rely
on genetically altered animals, such as Apo-E knock-out mouse displaying
increased susceptibility to atherosclerosis.
Although generally useful and widely accepted as standard tools, these
applications are limited by factors other than the evolutionary conservation of
the primary physiological pathway the target is acting in, i.e. drug
administration, metabolism, excretion, etc. In addition, many of the