Model Organisms in Drug Discovery

DROSOPHILA AS A MODEL ORGANISM FOR BIOMEDICAL SCIENCE 85
Conservation is more limited at the cellular, tissue, organ and system levels.
Many mammalian cell types are not found in flies, e.g. chondrocytes and
erythocytes. It is also not clear whether fly fat body cells are more closely
related to hepatocytes or adipocytes in mammals. In some cases differences in
signaling outputs from pathways must be recognized and taken into account.
For example, although the SREBP pathway is conserved between flies and
humans, the pathway controls cholesterol homeostasis in humans and
controls saturated fatty acid and phospholipid biosynthesis (such as palmitate
to maintain membrane integrity) in the fly (Dobrosotskaya et al., 2002;
Seegmiller et al., 2002). Thus, whether a disease pathway can be modeled in
flies and to what extent it can be modeled must be decided carefully on a caseby-case
basis.
Using Drosophila for drug target identification and validation
Drug targets can be broadly defined as molecules in a human body whose
functions can be modulated by pharmacological agents to treat diseases. In
practice, the majority of the 500 drugs in market are targeting proteins, which
are encoded by their cognate genes. The most prevalent use of Drosophila in
drug discovery is for drug target identification. This is a logical extension of
the long history of academic research using Drosophila as a genetic system to
identify genes controlling biological processes. Target identification implies
that the newly discovered genes were not known previously to have roles in a
particular disease pathway. Target validation implies that there is some
experimental evidence for an association between a gene and a disease
pathway, but, additional evidence is needed to substantiate the linkage.
Drosophila provides a model system for the identification and validation of
candidate genes for drug discovery through the use of relatively low-cost,
high-efficiency forward and reverse genetic screens. Ultimately, these
candidate genes must be used to identify the corresponding mammalian
genes and follow-up assays must be performed in mammalian cellular assays
or transgenic models. Thus, one could argue that Drosophila is used in this
regard as an efficient genetic system for indirect functional annotation and
prioritization of human genes as potential drug targets.
Forward genetics
Forward genetics (from mutant phenotypes to genes) involves identification of
mutations that cause or modify specific phenotypes, followed by identification
of the genes in which the mutations have occurred. This has been the major
approach used in flies to dissect disease-related pathways and identify