Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery

Abstract

The common fruit fly, Drosophila melanogaster, is a well studied and highly tractable genetic model organism for understanding molecular mechanisms of human diseases. Many basic biological, physiological, and neurological properties are conserved between mammals and D. melanogaster, and nearly 75% of human disease-causing genes are believed to have a functional homolog in the fly. In the discovery process for therapeutics, traditional approaches employ high-throughput screening for small molecules that is based primarily on in vitro cell culture, enzymatic assays, or receptor binding assays. The majority of positive hits identified through these types of in vitro screens, unfortunately, are found to be ineffective and/or toxic in subsequent validation experiments in whole-animal models. New tools and platforms are needed in the discovery arena to overcome these limitations. The incorporation of D. melanogaster into the therapeutic discovery process holds tremendous promise for an enhanced rate of discovery of higher quality leads. D. melanogaster models of human diseases provide several unique features such as powerful genetics, highly conserved disease pathways, and very low comparative costs. The fly can effectively be used for low- to high-throughput drug screens as well as in target discovery. Here, we review the basic biology of the fly and discuss models of human diseases and opportunities for therapeutic discovery for central nervous system disorders, inflammatory disorders, cardiovascular disease, cancer, and diabetes. We also provide information and resources for those interested in pursuing fly models of human disease, as well as those interested in using D. melanogaster in the drug discovery process.

Fig. 1.

D. melanogaster in the drug screening process. Models of human diseases are created in the fly by generation of mutants, either by mutation of the fly homolog of a human disease-related gene or by expression of the human form of the gene itself, that produce a scorable phenotype. This model can be directly screened for small molecules that rescue the phenotype or subject to genetic screens to identify modifiers of the phenotype, which represent new potential targets or models for the given disease. After initial screening, positive hits can be validated by testing in additional fly models of the disease. Significantly, these whole-animal validation studies can also be performed with the positive hits from traditional in vitro mammalian cell culture HTS to rapidly identify effective lead compounds. Drugs with efficacy in D. melanogaster models, however, will still need to be validated in mammalian whole-animal disease models.

Fig. 2.

Routes of drug administration. For larva (top), drug can be directly injected or drug can be mixed with media. Media can be either solid or liquid with 2% yeast paste to encourage feeding behavior. Adults can have drug delivered as an aerosol or gas, as a mixture with food substrate, as a direct application to exposed nerve cord, or as an injection. Drug administration through feeding generally has the highest throughput.