Fruit Flies as Models in Biomedical Research – A Drosophila Asthma Model

Abstract

Inflammatory diseases of the lung such as asthma and COPD show an increasing prevalence in western countries. Although these diseases are typically complex ones, they have an important genetic component. Genome-wide association studies have provided us with a comprehensive list of asthma susceptibility genes that will be extended substantially in the near future. To identify the role of these genes in the physiology and pathophysiology of the lung genetically tractable model organisms are indispensable. The inherent limitations of present models such as the mouse represent a constant urge for novel, complementary models. The fruit fly Drosophila has the potential to close this gap, as it might prove to be extremely helpful in the translation process from genetics to biological function. Except for those asthma susceptibility genes associated with adaptive immunity, we found unequivocal homologues for all of them in the fly genome. In addition, most of these candidates are indeed expressed in the airway epithelium and/or in other organs relevant for asthma, namely the blood cells and the brain. A majority of them are regulated upon airway infection in the Drosophila airway epithelium pointing to an important role in airway immunity and development of asthma-like phenotypes in the fly. These surprising similarities at the molecular level, in combination with the unmatched technical possibilities available to researchers using Drosophila should complement murine models in various aspects of asthma research. Biomedical research critically depends on animal models to understand the molecular basis underlying the pathogenesis of human diseases and to provide systems for developing and testing new therapies. Despite the supremacy of murine models, other model organisms are able to provide new and relevant information. All these organisms, including mice, are characterized by a set of features allowing us to categorize them as real model organisms. In addition to the sequenced genomes, the short life cycles, and the similarities with human genes/proteins, the ease of genetic manipulation is of prime importance. Among the limited number of well established and generally accepted model organisms (yeast, C. elegans, Drosophila, zebra fish, and mice), the fruit fly Drosophila is the only insect. It is the oldest model organism and was introduced almost a century ago by Thomas Hunt Morgan. Sequencing and analysis of its genome revealed a completely unforeseen degree of similarities with our own genome. More than 60% of all human disease genes have homologous counterparts in the fly (Fortini et al., 2000), which led to the development of a special database listing all these candidate genes (Chien et al., 2002). Among the first studies that utilized Drosophila with the goal to learn more about the molecular events underlying these diseases are those that established corresponding models for neurodegenerative diseases (Feany and Bender, 2000). In addition to this Parkinson model, very informative models of Huntington’s and Alzheimer’s disease have been established (Chan and Bonini, 2000), which triggered a great number of follow-up studies. In the last years, various different Drosophila disease models have been introduced (Bier, 2005). Only two out of a plethora of corresponding studies should be mentioned, i.e. models for the analysis of cardiac diseases (Wolf et al., 2006) and diabetes (Baker and Thummel, 2007). For the unprejudiced reader it may be hard to understand why Drosophila should be that well suited. The fruit fly is central to all model organisms; its organization is much simpler than in mice. Drosophila is simple enough to function as an easy to use model, but major organs, physiological processes, and behaviors are very similar to those found in men. This is of special importance, because it makes comparisons between men and flies much easier than comparisons between men and worms or even between men and yeast. The major question is what makes Drosophila so special? It is a combination of a vast amount of knowledge that has been accumulated during the last century and the availability of countless technical opportunities to manipulate the fly that are beyond comparison.