Marshall A. Lichtman
Rochester, New York, United States
|A fruit fly displaying its large red eye. Among Thomas Hunt Morgan’s many contribution to the burgeoning science of genetics, he observed some male fruit flies had a mutant white eye. By cross-breeding males with mutant white eyes with females with the dominant trait and, subsequently, their offspring, he demonstrated for the first time that the white eye mutation was linked to the X-chromosome (carried by the female with sex chromosomes XX but expressed in the male with sex chromosome XY). Photo by Sanjay Acharya. 2017. Via Wikimedia. CC BY-SA 4.0.|
Animal models have been essential to medical research for millennia. Ethical concerns about their use has led to a decrease in use of large animals (e.g., dogs, cats). Perhaps the smallest of research animals is Drosophila melanogaster, a fruit fly, one tenth inch in length, which has contributed profoundly to our understanding of genetics, gene mutations, and gene regulation for over 100 years.
In the wild, the twelve species of fruit flies are found in homes, food stores, and eateries—anywhere in which food ripens or spoils. What makes Drosophila melanogaster, the species used principally in biomedical research, useful for genetic studies? Fruit fly populations are inexhaustible, simple to breed, and inexpensive to maintain. Males and females can be distinguished easily and virgin males and females can be identified by their physical characteristics. The female lays eggs every day, which results in laying hundreds over its lifetime. Their reproductive cycle is approximately ten days at room temperature; thus, multiple generations can be studied over a few weeks. Since the flies are tiny, thousands can be maintained in a laboratory. Sterile containers of various sizes and shapes may be used to house or study flies, depending on the population size desired.
The fruit fly genome has been unraveled. Not unexpectedly, it is different from that of humans in several respects. For example, it has four chromosome pairs compared to twenty-three pairs in humans. One pair is the sex chromosomes and the other three pairs are autosomes. The fruit fly genome is only four percent the size of the human genome. Nevertheless, among its approximately 14,000 protein-encoding genes, about 8,000 have human analogues. The human genome has around 19,000 protein-encoding genes. Remarkably and importantly, a majority of the genes identified as causing human disease, perhaps two-thirds, is represented in the fruit fly genome.
In an astounding insight regarding the relationship of lower species to humans, William Blake in the stanza of a poem penned in 1794 entitled “The Fly,” wrote:
Am not I
A fly like thee?
Or art not thou
A man like me?
Could he have known, deep in the recesses of his unconscious mind, how his profound quatrain would be confirmed over 150 years later, and that the fly’s similarities to humans would contribute to the well-being of humankind as a result of their genetic likeness?
Thomas Hunt Morgan, a scientist of unusual insight, started using fruit flies at Columbia University around 1909 because they were cheap and took up little space, were conducive to his very limited resources, and in an era in which specially designed and sized containers were unavailable, he could maintain stock populations of flies in milk bottles. He moved to Columbia from his faculty position at Bryn Mawr College. Using the fruit fly, he was the first to describe how genes are arrayed linearly on a chromosome and confirmed that the gene is responsible for determining inherited characteristics. He was recruited to the newly established California Institute of Technology in 1928 (formerly Trinity College) to chair the biology department; there he explained and described gene linkage. The distance between genes was measured in a unit designated the centimorgan, so named in recognition of Morgan’s findings. The centimorgan represents a one percent chance (one in one hundred times) that a gene will be separated (unlinked) from its neighboring gene during crossing-over in a single generation. In the human genome, a centimorgan is approximately one million base pairs of DNA sequence in length. He elucidated recombination, the process that results in the exchange of information among chromosomes and critical to ensuring genetic diversity in a population. Morgan also described genes linked to a sex chromosome. Morgan’s work on gene linkage, sex chromosome-linked traits (a human example of which is hemophilia), and gene mapping using Drosophila melanogaster resulted in his being awarded the Nobel Prize in Physiology and Medicine in 1933, the first American Nobel laureate in this field. Although previously nominated, he was passed over for several years because the Nobel Foundation was unclear about the importance of his studies and what, if any, relationship they had to physiology or medicine. Perhaps his being awarded the Darwin Medal several years before opened their eyes. I suspect that they also wondered what the genes of a fruit fly had to do with men and women. Thus far, ten scientists using fruit flies as their experimental model have been recognized through the award of six Nobel Prizes in Physiology or Medicine: in 1933 (gene regulation), 1946 (mutagenesis), 1995 (embryonic development), 2004 (olfaction), 2011 (activation of innate immunity), and 2017 (determinants of circadian rhythms). The use of Drosophila has resulted in major advances in the understanding of evolutionary and population genetics; molecular, developmental, and neurological biology; and cellular biology.
The Bloomington Drosophila Stock Center at Indiana University is the only center of its kind in the United States and the largest in the world. It houses 77,000 different strains of fruit flies and in 2019 shipped over 200,000 vials to laboratories in forty-nine states and fifty-four countries. The center has a fly-food chef. His task is to feed millions of fruit flies and to keep them healthy and happy. Although their diet is but a mash of cornmeal, the fly-food chef in Bloomington has remarked that they can be particular about the preparation. The flies of each of the 77,000 strains must be “flipped,” i.e. transferred from an old vial to a new sterile one, frequently. The flies mate, lay eggs which hatch, pupate, mature, and reproduce, continuing the cycle. It usually requires a staff of over sixty fly-keepers to manage the vials, a task from which there is no respite.
Another unusual, small, and important animal model for biomedical research is Danio rerio, the zebrafish, a minnow 1.5 inches in length that is popular for stocking home aquariums. They are useful in biomedical research because 1) they lay many eggs resulting in hundreds of offspring, 2) they share the same organs as humans and features of those organs, e.g., eyes, blood, muscles, kidney, and heart, and 3) the zebrafish and its embryos are transparent and develop outside a uterus so it is possible to visually trace the details of development from fertilization through formation of organs.
Other scientists using sea slugs (Aplysia), yeast (Saccharomyces), and pond-inhabiting protozoa (Tetrahymena), among other lower life forms, have received the Nobel Prize in Physiology or Medicine because of their work on processes relevant to human biological functions. Misguided politicians, when scrutinizing and criticizing federal support for research that seems in their limited vision as irrelevant to humankind, have failed to understand the relationship of one species to another, as so eloquently stated by Blake 225 years ago. This relationship was highlighted in Darwin’s explorations, insights, and conclusions described in On the Origin of Species by Means of Natural Selection, his fundamental treatise on evolutionary biology. Darwin’s conclusions have been confirmed over the last 100 years by the most advanced genetic techniques. Thus, I am a fly like thee and thou art a man like me.
- Robert E. Kohler. Lords of the Fly: Drosophila Genetics and the Experimental Life. Chicago University Press, 1994.
- Hales KG, Korey CA, Larracuente AM, Roberts DM. Genetics on the fly: A primer on the Drosophila model system. Genetics 2015;201:815-42.
- Stephanie E. Mohr. First in Fly: Drosophila Research and Biological Discovery. Harvard University Press, 2018.
- Little AG, Pamenter ME, Sitaraman D, Templeman NM, Willmore WG, Hedrick MS, Moyes CD. Utilizing comparative models in biomedical research. Comp Biochem Physiol B Biochem Mol Biol 2021;255:110593.
MARSHALL A. LICHTMAN, M.D. is Professor Emeritus of Medicine and of Biochemistry and Biophysics and Dean Emeritus of the School of Medicine and Dentistry at the University of Rochester. He has been a co-editor of Williams Hematology, editions 3 through 10. He has served on the Board of the American Red Cross and as a Trustee of the State University of New York. In 2017, he received the Wallace H. Coulter Award for Lifetime Achievement from the American Society of Hematology.