Model Organisms in Drug Discovery

FROM DISEASE TO TARGET 55
resistant isoform of the sarcoplasmatic/endoplasmatic reticulum Ca 2+ -
ATPase (SERCA). This SERCA removes Ca 2+ from the sarcoplasmatic or
endoplasmatic reticulum and plays a role in several diseases, such as
congestive heart failure. Chinese hamster SERCA is resistant to thapsigargin
inhibition due to an F256V mutation (Yu et al., 1999). Introduction of the
same mutation at the homolog’s position in the C. elegans SERCA renders
thapsigargin resistance in animals carrying the transgene (Zwaal et al., 2001).
Genetic screens in C. elegans are sufficiently fast and effective to permit their
incorporation into sophisticated assay formats. As an extreme example, the
C. elegans homolog of a human potassium channel has been identified in a
screen in which each mutated nematode underwent surgery followed by an
electrophysiological examination (Davis et al., 1999).
Rapid gene mapping using single-nucleotide polymorphisms
The phenotypic analysis of mutant animals reveals important information
about biological processes, but a full elucidation of the molecular basis of the
biology of interest requires decoding of the involved genes. Gene identification
using positional cloning is a straightforward approach in C. elegans that entails
two steps: mapping and gene confirmation. The researcher of today can rely on
the availability of a detailed genetic and physical map organized in the database
ACeDB. Several mapping strategies exist and positional cloning incorporating
single-nucleotide polymorphism (SNP) technology has emerged over the last
two years (Jakubowski and Kornfeld, 1999; Swan et al., 2002). Single nucleotide
polymorphisms are detectable as single base pair changes in the genes of strains
or individuals, but small deletions, duplications or insertions are also found.
Single-nucleotide polymorphisms occur once every 100–300 bases in the human
genome (NCBI, April 2002, http://www.ncbi.nlm.nih.gov/SNP) and can
correlate with changes in the amino acid composition of the expressed protein,
thereby changing the activity of the protein. The fact, that an SNP can also alter
the interaction between the protein and a given drug has received much
attention in the pharmaceutical industry. Under the term ‘pharmacogenomics’,
SNP profiles of individual patients are evaluated to tailor drugs and drug
regimens to a patient’s genetic profile, enabling individualized medicine. The
true potential of predicting a patient’s response to a drug, based on an SNP
haplotype, will be shown in the future (Jazwinska, 2001).
Nevertheless, SNP profiling has and will continue to contribute to the process
of target identification. Single-nucleotide polymorphism analysis allows for
rapid gene mapping in C. elegans, mice and humans (Wang et al., 1998;
Lindblad-Toh et al., 2000; Wicks et al., 2001) and can be conducted not only
quickly but also cost effectively in C. elegans. The C. elegans laboratory strain
Bristol N2 has little sequence variation from individual to individual but by