From bacteria and yeast to fish, frogs and mice - a myriad of 'model organisms' are used by biomedical researchers in their investigations. But arguably the granddaddy of such models is the fruit fly, Drosophila melanogaster.
In its natural habitats, this 3 mm-long fly is widely regarded as a pest by farmers, as it feeds on decaying vegetation and overripe fruit. Yet in the laboratory, it has developed into one of the most powerful tools available to scientists. While it has made its name in studies of genetics and in development, the fruit fly is used for the study of topics as diverse as alcoholism, learning and behaviour, ecology and evolution, human disease and the development of new pharmaceuticals.
What has driven the fruit fly's rise to pre-eminence? Its short lifecycle, ease of culturing and reproduction, and low cost relative to other models are undoubted advantages. The fly's true power lies, however, in the long and distinguished history of research that has been devoted to its study. Today, a remarkable amount is known about its biology, and sophisticated genetic tools are available to analyse its tissues, organs and behaviour.
The Drosophila story begins in the early years of the 20th century. Mendel's work on the basic rules of inheritance has been rediscovered, but the mechanisms of inheritance are only hazily understood. Embryology is still the talk of the day, with German research groups leading the way in describing how an organism develops from a single cell. Into this world steps an American embryologist, Thomas Hunt Morgan, the founding father of Drosophila research - and arguably of the science of genetics in the USA.
"Morgan was interested in the problems of development," says Alfonso Martinez Arias, a Drosophila researcher at the University of Cambridge. "But he drifts from embryology, as he cannot address the questions he wants to answer, and he gets completely sidetracked by the issue of genes."
Speculation that chromosomes might in some way be linked to organisms' characteristics spurred Morgan's interest in heredity. After a frustrating and fruitless two-year search for Drosophila with altered characteristics, white-eyed flies suddenly appeared among his normal red-eyed stocks. Analysis of the 'white' variation showed not only that it was a specific and permanent change, but also, crucially, that its inheritance was linked to the sex of flies - and so could be assigned to a specific chromosome (a sex chromosome). Here, then, was the first unambiguous link between a chromosome and a characteristic, and it heralded a flurry of fundamental discoveries about the nature of fruit-fly inheritance and about heredity in general.
Equally important, however, was Morgan's style of research and leadership. He insisted on an experimental, rather than a descriptive approach to science, and he ran the famous 'fly room' in Columbia University as a democracy (in marked contrast to the autocratic style of German laboratories). The cadre of gifted scientists who worked with Morgan in the fly room spread this philosophy worldwide, and trained the next generations of researchers.
Between the 1940s and 1970s, fly research continued to be productive, without touching the heady heights of the Morgan years. It was, perhaps, an era of consolidation and learning: mutants were accumulated, new techniques were developed, and researchers learned which questions were interesting and which were not. Important foundations were laid, yet the relationship between heredity and development went unresolved. "As the fly is there, people keep trying to work out the issues of genetics and development," says Dr Martinez Arias. "But they fail. There was a long period where it wasn't clear that the fly was going to yield anything. What you do find in the papers of the time, however, is an air of mystery, which spurred the researchers on."
Then in the 1970s and 80s, genetics, embryology and molecular biology came together in a glorious union, and Drosophila research hit top gear. For the new science of molecular biology brought with it the ability to manipulate DNA, and researchers could finally get at the genes behind their favourite mutants.
Particularly influential were mutations studied in exquisite detail by Ed Lewis, which caused bizarre transformations of the body plan. Mutations in genes in the 'bithorax complex' led to flies with two sets of wings or legs on abdominal segments. Even more startling, mutations in genes in the 'antennapedia complex' created flies with legs where antennae should be. The strangeness of the changes was in fact a clue to the crucial role of the bithorax and antennapedia genes, for they turned out to be groups of master control genes that programme the final body plan of the organism. The molecular analysis of these genes uncovered a related set of proteins with a conserved universal role in the generation of diversity along body axes.
Around this time, Christiane Nüsslein-Volhard and Eric Wieschaus began working together on the fruit fly in a small laboratory at the European Molecular Biology Laboratory in Heidelberg, Germany. Instead of haphazardly searching for mutants affecting development, they had the idea of systematically searching for mutant genes that affect the formation of segments in the fly embryo. They blitzed the flies with a mutagen and examined thousands of mutated embryos with disrupted development. Not only did they identify a series of new genes that drive the early development of the organism, but they were also able to classify the genes into functional groups and show the order in which these groups were important during development.
"This is one of the few occasions where you can justifiably use the word 'seminal'," says Dr Martinez Arias. "One never thought that the screen would find so many different genes, influencing so many different systems, or that the implications of the screen would be so profound."
This work also profited from molecular studies, which showed that the genes were conserved in vertebrates. Thus the genetic analysis had far-reaching consequences beyond the fly. It would soon become clear that close relatives of the genes, performing similar roles, exist in many other different organisms, including humans. Indeed, it is thought that more than 75 per cent of genes involved in human disease have counterparts in the fly.
Power of the fly
In the modern-day era of genomics, where the headline news is ever of the human and mouse genomes, does the fly still have a role to play? Dr Martinez Arias argues that it is more important than ever, in particular as we try to unpick the more complex systems of mice and men.
"There are so many questions that remain to be answered," he says. "We now know a great deal about how cell diversity is controlled, through differential gene expression, transcription factors and so on. The fly has contributed enormously to this field, showing us the elements involved and how these elements are integrated into networks and pathways.
"But how is the information from different pathways integrated, and how does the cell cope with all the different inputs it receives? How do cells integrate to produce tissues?"
Having found an answer in the fly, the lessons learned can then be tested in vertebrates. "At the molecular level, mechanisms are conserved," says Dr Martinez Arias. "Whether a cell is from a fly, a mouse or a human, it has a basic set of signalling systems - its 'hardware'. This hardware runs the software, the programmes of development that will produce a leg or a wing in a fly, an eye or an ear in a human. There are incredible genetic tools available for Drosophila that we can use to understand how these hardware mechanisms work in the fly; then we can look at the mechanisms in vertebrates. There must be a dialogue between research in both areas."
New technologies are also being brought to bear on the study of the fly. Since 1999, the genome sequence of Drosophila has been available, and researchers are using functional genomics - high-throughput technologies - to look at global patterns of gene and protein expression. Equally exciting are the latest developments in live imaging, where the actions of cells, proteins and other molecules can be followed in a living embryo. This latest fusion of disciplines - cell biology and genetics - is likely to be as exciting a cocktail as the union between molecular biology and genetics proved to be in the 1970s and 80s.
Nearly a century on from Drosophila's entrance on the world stage of biological research, this tiny fly has become probably the most well understood organism there is - and hundreds of scientists remain committed to unravelling its remaining secrets. "The fly has made a huge contribution to our understanding of biology," concludes Dr Martinez Arias, "and it will continue to do so in years to come - most importantly because it is an experimental system in which we can probe in exquisite detail the function of the proteins and macromolecular aggregates that shape and run human beings. The fly has taught us a great deal about our molecular make-up and now it will teach us how this make-up works."
The Nobel Prize in Physiology or Medicine 1933: Thomas Hunt Morgan
The Nobel Prize in Physiology or Medicine 1995 : Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus
Adams MD et al. The genome sequence of Drosophila melanogaster. Science 2000 Mar 24;287(5461):2185-95. Abstract