Drosophila Melanogaster: The Gift That Keeps On Giving

People may open their kitchen cupboards, only to find that their fruit and snacks have been infested with them. They will find plenty of them buzzing around trash cans and garbage bins. Fruit flies can surely be a nuisance and the services of a pest control agency may be sought out to have them cleared out of homes. In science and research, fruit flies are associated with a different story – a success story. In fact, they have been behind significant discoveries in the field of neuroscience, the most recent one being the complete mapping of their brain (Winding et al., 2013). The present article will introduce the Drosophila melanogaster fly, before tackling how they emerged as an animal model in research. Then, their advantages and disadvantages will be outlined, before touching on several landmark neuroscience findings leading to the present day.

The Fruit Fly

Drosophila melanogaster is a small yellow-brown, typically with bright red eyes. Even though it is known as a fruit fly, the Drosophila melanogaster does not actually eat fruit. It feeds on microorganisms that grow on unripe or rotting fruit. Its name, melanogaster, hints at the black stripes around its abdomen. There are four stages in the life cycle of the Drosophila melanogaster: embryo, larva, pupa and adult. The flies reach adulthood between nine and ten days after egg fertilization (Fernández-Moreno et al., 2007). The adult Drosophila is about 3 mm in length and 2 mm in width (South African National Biodiversity Institute, 2020). The female fly is bigger in size than the male fly, and the males and females also differ in their patterns of melanization around their bellies (Figure 1).

Figure 1: A female and a male fly (Madboy74, 2012).

Historical Background

To this day, Thomas Hunt Morgan (1866-1945), an American biologist, is hailed as the father of Drosophila research, albeit not the first to use them in laboratory settings. It was the Harvard entomologist Charles W. Woodworth who first reared Drosophila flies in mass quantity, at the beginning of the 20th century (Markow, 2015). Woodworth saw the potential that fruit flies held in genetics research and he recommended it as a research model to early geneticists, such as William E. Castle. Subsequently, Frank E. Lutz developed an interest in Drosophila through Castle’s work and, in turn, it was from Lutz that Thomas Hunt Morgan began utilising fruit flies in his research at Columbia University (Markow, 2015). Morgan was the first to revolutionize Drosophila research. The work that he and his students did with the fruit fly paved the way to two Nobel Prizes in Physiology or Medicine. Morgan identified the white-eyed mutation in the fruit fly (Figure 2) and the Nobel Prize in Physiology or Medicine (1933) was awarded to him “for his discoveries concerning the role played by the chromosome in heredity”. Later, his student Hermann Joseph Muller won the Nobel Prize in Physiology or Medicine (1946) “for the discovery of the production of mutations by means of X-ray irradiation”.

Ever since their introduction in research, fruit flies have been an invaluable model and they have led to other Nobel Prizes. They have contributed to our enhanced understanding of genetics, developmental biology, ageing, perception of smell, neurological disorders, circadian rhythms, and connectomics.

Figure 2: Cross between a red-eyed female (top left) and a white-eyed male (top right) fly (Morgan, 1919, Figure 69).

Advantages and Limitations in Research

Drosophila bears several strengths in research. Fruit flies are easy to breed and maintain; they are cultured at room temperature, in cylindrical bottles or vials, capped with cotton, foam or sponge caps (Figure 3). At the bottom of the container lies their feeding medium, which consists of agar, sugar, and yeast. Drosophila reproduces rapidly, as each mating pair can produce hundreds of flies within the course of two weeks (Miller, 2000), facilitating genetic studies. A further advantage is that there are fewer ethical concerns to Drosophila research than there are to rodent or human research (Yamaguchi & Yamamoto, 2022). 60% of the fly’s genome is conserved in humans and about 75% of genes involved in human disease have got homologs in the fly (Mirzoyan et al., 2019), which renders them ideal as a model for the study of health, disease, and therapeutics.

A limitation of Drosophila is that certain pathogenetic components in disease may be vertebrate-specific, which may impact their reliability as a model for disease (Jeibmann & Paulus, 2009). Furthermore, disease-causing mutations in flies may not be precise representations of mutations encountered in human diseases, or aspects such as neuronal death and disease phenotypes may not be adequately recapitulated in the Drosophila (Koon & Chan, 2017). Processes that are important in cancer biology, such as telomere maintenance and angiogenesis, are also lacking in Drosophila (Allocca, Zola, and Bellosta, 2018). In spite of these limitations, how have Drosophila contributed to our understanding of the nervous system?

Figure 3: A bottle containing Drosophila larva and pupa (Jennings, 2011, Figure 4).

Contributions to Developmental Neurobiology

Drosophila's contributions to the field of developmental neurobiology are summarised by Bellen, Tong and Tsuda (2010). In 1915, mutations were discovered in the Notch gene that resulted in Drosophila with malformed wings. This event acted as a catalyst for the elucidation of the Notch signalling pathway in Drosophila. Components of Notch signalling are conserved in vertebrates and they hold similar roles in their neurodevelopment; as the authors state, Notch signalling is widely implicated in neurogenesis and neuronal differentiation. Other than Notch, vertebrate homologues of Hox genes (identified in Drosophila) are involved in hindbrain patterning and motor neuron-muscle specificity. Genetic screens, such as the one carried out by Nüsslein-Volhard and Wieschaus (1980), yielded many other genes with homologues in vertebrates, which are involved in neurogenesis, neuronal migration, and growth cone guidance, among other processes.

Understanding Key Players in Neurological Disorders: The Example of Neurexins

Mutations in neurexins have been regularly identified in people with schizophrenia or autism spectrum disorders (Tromp, Mowry & Giacomotto, 2021). Although there are questions that remain still in relation to their function, great strides were made in understanding their role as cell adhesive proteins, with Drosophila as a reference. It was Li et al. (2007) that revealed the crucial role of neurexin in synaptic transmission. Deletion of the Drosophila neurexin gene (dnrx) resulted in defects in synaptic ultrastructure with areas of detachment between presynaptic and postsynaptic compartments; this was also associated with defects in synaptic transmission. Of note, the ratio of excitation and inhibition in key neural systems has previously been hypothesized to play a causative role in autism spectrum disorders (Kim et al., 2008).

Elucidation of the Olfactory System

Although the Nobel Prize in Physiology or Medicine (2004) was awarded for work done in mice, one of the two recipients, Richard Axel, is a drosophilist. Specifically, Richard Axel and Linda B. Buck discovered odorant receptors and their organization in the olfactory system. During his Nobel lecture, Axel (2004) mentioned the usefulness of Drosophila in the study of the sense of smell. Axel’s research group had previously carried out two-photon imaging of the antennal lobe in Drosophila to draw the functional map of the olfactory system in the model organism (Wang et al., 2003). The researchers expressed a Ca2+ indicator, GCaMP2, in primary olfactory cortex neurons and their projection neurons. This indicator causes cells to fluoresce when neurons are activated. Fibres of sensory olfactory neurons terminate onto units of projection neurons called glomeruli. This allowed the researchers to study neural responses to different kinds of odour stimuli in 23 glomeruli of Drosophila. The researchers essentially discovered that different odours result in different patterns of glomerular activation, and that these patterns are conserved among different species. Thus, the findings in Drosophila led to a greater understanding of the vertebrate and mammalian olfactory system.

An Award for Circadian Rhythms

The Nobel Prize in Physiology or Medicine (2017) was awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young “for their discoveries of molecular mechanisms controlling the circadian rhythms”. According to the National Cancer Institute (n.d.), circadian rhythms are natural cycles “of physical, mental and behavioural changes that the body goes through in a 24-hour cycle.” In the 1980s, it was discovered that circadian rhythms, e.g. locomotor activity and courtship song, were disrupted in Drosophila when an unknown gene (now known as period) was mutated, and that restoring the function of this gene led, in turn, to the restoration of its circadian rhythms (Bargiello, Jackson & Young, 1984; Zehring et al., 1984). The protein encoded by period was found to undergo circadian oscillation, as it was expressed at night and it was degraded during the day (Hardin, Hall & Rosbash, 1990). Further work led to the discovery of other components of the inner biological clock, such as timeless (Sehgal et al., 1994). These discoveries paved the way towards the elucidation of the mechanisms of the inner biological clock (Figure 4) that is conserved from flies to humans (Bellen, Tong & Tsuda, 2010).

Figure 4: Gene expression in Drosophila is regulated by transcription factors, e.g. per, whose activities oscillate in a 24-h rhythmic pattern (Chhandama, 2017).

A Complete Map of the Brain

The complete “connectome” of the entire fly brain has recently been elucidated, as all 3016 neurons and 548,000 synapses have been mapped with the aid of three-dimensional electron microscopy and algorithms (Winding et al., 2023). The only other animals to have had their nervous systems fully mapped are the C. elegans nematode (Brittin et al., 2021), the tadpole larva of the “sea squirt” Ciona intestinalis (Ryan, Lu & Meinertzhagen, 2016), and the larva of the Platynereis dumerilii annelid worm (Verasztó et al., 2020). These animals have a nervous system that is less complex in comparison to that of the fruit fly. To date, the technology to map the human brain does not exist. Using the complete brain map of the fruit fly brain will allow researchers to study how brain wiring changes in certain conditions, such as autism spectrum disorders and schizophrenia (Winding, 2023).

Conclusion

The Drosophila melanogaster is an invaluable animal model in biomedical research, owing to traits such as its rapid reproduction cycle and its genetics. From Morgan’s straightforward genetic assays to today’s complex map of their entire brain, the fruit fly has been at the forefront of significant findings tied, in some cases, to Nobel Prizes. The major asset of this model is that many of its genes and biological mechanisms are conserved in humans, allowing it to be used towards an enhanced understanding of human biology. As Bellen, Tong and Tsuda (2010) say, “the fly toolbox has an unparalleled sophistication and precision that allows scientists to tackle almost any question in biology and answer it in a timely fashion.” It is, thus, in this sophistication that the Drosophila melanogaster will continue to be the gift that keeps on giving.

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