Small flies—Big discoveries: Nearly a century of Drosophila genetics and development†
The authors are Guest Editors of this Sepcial Issue on Drosophila as a Model System.
It was almost 100 years ago, in 1909, that a classically trained embryologist, Thomas Hunt Morgan, chose the fruit fly Drosophila melanogaster as a model organism for an experimental study of evolution. Ever since Morgan's auspicious choice of the fruit fly as an experimental organism, scientists have been eyewitnesses to the “awesome power” of Drosophila genetics—from the transmission geneticists best exemplified by Thomas Hunt Morgan and his students to the developmental geneticists who have been led by Ed Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus. There is no doubt that, even now, in the postgenomic age of the 21st century, we find ourselves ever indebted to our genetics forebearers.
Building on the productivity of previous generations, present day Drosophila scientists continue to establish paradigms and achieve technological breakthroughs that help advance not only fly research but many different fields of the life sciences as well. Here, we give a short overview of the history of Drosophila genetics. We hope that an understanding of how we got where we are today and an appreciation of past discoveries will help to place the current excitement about genomes, molecules, and mechanisms within the context of a long-established scientific culture and history of Drosophila experimentation.
TRANSMISSION GENETICS IN DROSOPHILA
In the earliest years of the twentieth century, a founding generation of geneticists focused on problems of transmission. They exploited the fruit fly to answer classic questions such as, how are genes inherited? What is a chromosome and how does it recombine? Arguably the greatest breakthroughs in this arena were those of the first Drosophila geneticists: Thomas Hunt Morgan and his students, Calvin Bridges, Alfred Sturtevant, and Hermann Muller. It is perhaps somewhat surprising to realize that Morgan chose his organism as an anti-Mendelist, hoping to disprove the canons of genetics that we hold so dear today. After two “wasted” years of attempting to induce mutations in Drosophila by altering selective pressures, Morgan spotted a mutant white-eyed Drosophila male in his culture of wild-type red-eyed flies. The rest is history, as Morgan's analysis of white inheritance quickly led him to abandon his evolutionary studies and to embrace the “rediscovered” genetic theories of Mendel.
Morgan demonstrated that genes are on chromosomes. The studies for which he earned the Nobel Prize in Medicine (1933)—“discoveries concerning the role played by the chromosome in heredity”—are elegant in their simplicity. In Drosophila breeding experiments, Morgan showed us that transmission of white eye color is linked to inheritance of the X chromosome, and thus eye color and gender are linked traits. This seminal finding led Morgan to conclude that some genetic traits are not inherited independently (as Mendel had supposed) but rather must be linked (Morgan, 1910).
Morgan's students, Bridges, Muller, and Sturtevant, went on to no less illustrious careers of their own. Bridges used the fruit fly to prove that chromosomes are structures of inheritance; thus, we began to understand the cellular basis of heredity. As an aside, it is notable that Bridge's landmark study of nondisjunction was quite possibly a victim of capricious review. Indeed, Morgan was sufficiently irritated by the rejection of his student's manuscript from the Journal of Heredity—a premier journal of the day—that he and his colleagues founded a new journal, Genetics, that still exists. Bridge's manuscript launched the inaugural issue (Bridges, 1916).
Bridge's contemporary, Hermann Muller, used the fruit fly to identify and physically map chromosomal aberrations and perhaps even more importantly to decipher the chemical nature of mutation (Muller, 1927). As was his mentor before him, Muller too was the recipient of a Nobel Prize (1946)—“for the discovery of the production of mutations by means of X-ray irradiation”. There can be no doubt as to Muller's intelligence and astuteness; well before the onset of the atomic age in which we now live, Muller anticipated and articulated the genetic risks we would face as a consequence of the irresponsible and weaponized use of ionizing radiation (Muller, 1946). Importantly, the implications of his irradiation studies were not overlooked when we did finally enter the atomic age. In response to Muller's experimental discoveries and musings, extensive genetic studies in Drosophila (and the mouse) were undertaken to assess the relative mutation rates in these model organisms as an indicator of the genetic risk posed to humans from the utilization of atomic energy.
The third of the Morgan student triumvirate was Alfred Sturtevant who used the fruit fly to demonstrate that chromosomes constitute a linear array of genes (Sturtevant, 1913). In addition to bolstering the chromosome theory of inheritance, Sturtevant's work is notable for its application of mathematics to biology. In fact, his study highlighted an emerging trend in biological method—this was a replacement (or at least supplementation) of descriptive science with an approach that was both more analytical and mathematical. Taken altogether, Morgan and his students' use of breeding experimentation in the fruit fly Drosophila led them to an enviable record of achievement. Their contributions, which are certainly far too extensive to enumerate here, have been fully discussed and especially nicely annotated with respect to the historical record by Sturtevant (1965).
Before leaving the contributions of the classical geneticists, two additional issues (one scientific, the other societal) warrant mention here. First the scientific: T.S. Painter, a student of Theodore Boveri who in 1903 along with Walter Sutton proposed that chromosomes contain genes, discovered the Drosophila giant salivary gland chromosomes. Importantly, Painter understood that this biological material offered an excellent opportunity to visualize chromosome structure (Painter, 1934). Second the societal: Morgan in addition to establishing the fruit fly as a model genetic organism endowed us with a new scientific culture: “The open, critical, yet fully democratic and egalitarian atmosphere that was evident in the Fly Room soon came to characterize the distinctively American atmosphere of university research—an especially significant development as American graduate education increasingly became the model for graduate education throughout the world” (Kandel, 1999). Given the rich intellectual atmosphere and the relatively free exchange of ideas in Morgan's fly room, it is perhaps not too surprising that, in addition to Muller, another of Morgan's trainees as well as two of his “academic grandchildren,” also went on to win Nobel prizes: George Beadle (1958), Joshua Lederberg (1958), and Ed Lewis (1995).
FROM FLIES TO CELLS
In subsequent years (at the end of the 1930s and for most of the 40s), the rules of mitosis and meiosis as well as the nature of the gene were elucidated, but not in the fly. For this relatively short period in our modern scientific history, the modest fruit fly fell from experimental favor. It did, however, re-emerge as an experimental organism with the birth of molecular genetic analysis: Boris Ephrussi and George Beadle used the fruit fly to give biochemistry and molecular genetics an initial experimental push. Ephrussi and Beadle transplanted larval eye discs from genetically marked larvae into the abdomens of genetically dissimilar larvae. Here, a third eye could develop ectopically and experimenters distinguished between tissue autonomous and nonautonomous requirements for gene products (Beadle and Ephrussi, 1936). Drosophila mosaic studies, like these, set the stage for mosaic studies in a wide variety of experimental organisms. The ability to deliberately replace wild-type genes with gain- and loss-of-function alleles in almost any setting and time frame using the UAS-Gal4 (Brand and Perrimon, 1993) and FLP-FRT (Golic, 1994) binary gene regulatory systems (or any of their various imaginative permutations) has proven invaluable in deciphering the rules by which cells interact with one another to control cell growth and differentiation.
MUTATION ANALYSIS AND DEVELOPMENTAL GENETICS IN DROSOPHILA
When most of us think about genetics, we think of mutants. Although surely not synonymous terms, one most certainly often invokes the other. But how we used mutants as tools of learning differed dramatically in the early and late parts of the twentieth century. Until the 1970s, investigators had collected mutants, by and large as chromosomal markers that facilitated the study of chromosome mechanics. Although the first fly “monster”—one with two sets of wings—was discovered in 1916, it was not until the 1970s that the idea that single genes could lead to morphological “transformations” was considered experimentally. This intellectual leap was recognized by the 1995 Nobel committee in their tribute to three “modern” Drosophila geneticists: Ed Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus, “for their discoveries concerning the genetic control of early embryonic development.”
Among Ed Lewis' most significant contributions was his demonstration that single genes, members of the homeotic gene family, could lead to developmental transformations (Lewis, 1978). Homeotic genes, now mostly referred to by their molecular name Hox genes, have been recognized since as principal regulators of pattern in flies, mice, and humans. The notion that Hox genes are endowed with transforming capacity revolutionized our understanding of development. This issue of Developmental Dynamics is dedicated to the memory of Ed Lewis, who passed away last year, and his life and scientific contributions are described in fuller detail in two commentaries (Lipshitz, 2005; Sakonju, 2005).
The contributions of Christiane Nüsslein-Volhard and Eric Wieschaus to developmental biology nicely complemented those of Lewis. This team's saturation mutation screening efforts led to our understanding that genes can be grouped together bases upon their shared loss-of-function phenotypes. Nüsslein-Volhard and Wieschaus suggested that (1) shared loss-of-function phenotypes define genes functioning in single biochemical pathways, and (2) related (but not identical) phenotypes define genetic hierarchies (Nüsslein-Volhard and Wieschaus, 1980).
At approximately the same time that Nüsslein-Volhard and Wieschaus initiated their screens, molecular biology methods were being harnessed in labs world-wide. Coupling this technological boon with a concurrent emerging understanding of how transposons function in fruit flies (Spradling and Rubin, 1982) allowed a second generation of developmental geneticists to identify the gene products associated with the mutants. Thus, tremendous advances in our understanding of embryonic development in flies were the prizes associated with the Heidelberg screens. Happily, the conservation of regulatory mechanisms defined in the fruit fly over the organismal spectrum of evolution has made it possible to use the Drosophila to facilitate our understanding of development and disease in higher eukaryote—most importantly in humans.
FLIES 'R US
Within the context of a century of progress, we have finally entered the genomic and postgenomic ages of Drosophila-facilitated discovery. With Gerry Rubin at the helm of a collaborative undertaking by the Berkeley Drosophila Genome Project and Celera Genomics, Inc., the fruit fly genome sequence was completed in 2000 (Adams et al., 2000). Comprising approximately 14,000 genes, the Drosophila genome has provided us with a new wealth of information as well as the final validation of Drosophila as a first-class model organism. Developmental biologists have long accepted as dogma that what we learn in the fruit fly can be extended to higher eukaryotes. But now there is the code itself—the fly blueprint, which is remarkable in its likeness to our own. Indeed, when compared with mammalian proteins and expressed sequence tags, more than half of the fly proteins have similar mammalian counterparts at a statistical cutoff of E < 10−10, compared with 36% and 38% for worm and yeast, respectively (Rubin et al., 2000).
For approximately 100 years, experimentalists have taken advantage of Drosophila's small size, the low cost and ease with which it can be cultured, its high fecundity and short life cycle, its small chromosome complement, and its ability to withstand mutation and crossbreeding experiments. These past years of successful experimentation and productivity bode well for the next century. Indeed, Drosophila is not about to be retired as a model system for cutting edge research to address pressing questions in biology. In addition to the features that have made Drosophila so amenable to study for the past century, new and powerful resources and experimental possibilities make the research as exciting and attractive as ever in the past century for young and established scientists. We await the genome sequence of 10 or more Drosophila species in the near future, and these will provide a tremendous playing field for bioinformatics approaches to development and organism function. Targeted genome manipulations are possible and will become routine, sophisticated methods of imaging will permit a direct view into the connections between cell topology and function in intact tissues. The powerful and public resources—FlyBase, stock centers, genome projects—built up by the fly community, and by Bill Gelbart and Thom Kaufman in particular, will continue to provide valuable tools for the challenges that we will face and enjoy in the next century. Of course, of immense importance to our continued success will be the excitement and ingenuity of a new generation of open-minded and relentless scientists.