In 1908, when the word genetics was just three years old, a biologist began studying trait inheritance in a fruit fly called Drosophila melanogaster. His students grew the flies in milk bottles stolen from the cafeteria and inspected the insects using hand lenses.
Today, labs still have rooms full of bottles of fruit flies. Interest in Drosophila hasn’t waned since the early twentieth century; if anything, it’s gotten stronger. Why?
When scientists want to understand the genetics behind human biology — from how our cells get energy to what causes autism — they can’t learn it all by studying humans. They can turn genes in our DNA on and off in a Petri dish, but they can’t see what effect those changes would have in a fully grown person. Scientists need an animal they can study from birth to death. It should have a simpler genome than ours, one that’s easier to manipulate, but with genes that build the same proteins as ours and perform similar functions. And its generation time should be measured in days, not years, so that scientists won’t have to wait long to see the product of an experimental genome.
Enter Drosophila. Inside its two-to-four-millimeter body is a surprisingly familiar anatomy, from a bilobed brain organized like ours to cells that grow, move, and divide the same way human ones do. A hundred years after scientists began studying this little insect, it’s still giving us clues about how our own bodies work.
Ask any Carolina researcher who works with fruit flies what makes Drosophila special, and the first part of the answer is always the same. “It’s this amazing history,” says biologist Corbin Jones.
Fruit fly research began in Thomas Hunt Morgan’s lab (the one with the stolen milk bottles). “He picked Drosophila because it was easy to take care of and he could breed it rapidly,” Jones says.
Morgan’s lab screened thousands of fruit flies for mutations. Eventually they found one that had white eyes. When they bred the fly, only male offspring inherited the strange eye color. That led Morgan and his students to prove that chromosomes determine sex and that genes are on chromosomes.
Some fly researchers today still do pretty much what Morgan did a century ago. It’s now called discovery biology, says Jay Brenman, who started out looking for neuro-degeneration in flies. His lab fed thousands of flies a chemical known to create mutations, then screened them for evidence of neuron dysfunction. “It’s like opening up the hood of your car and hitting something with a hammer, and then trying to figure out what the piece you broke was for,” he says.
Brenman enjoys working backwards from a mutant fly to its genetics because he never knows where the genes he finds will take him. The neurodegenerative flies in his lab had a mutation in an enzyme, AMP-activated protein kinase (AMPK). Other researchers had discovered that AMPK regulates how cells use glucose. Some think that it could be a target for type 2 diabetes treatment.
Brenman isn’t working directly on diabetes. He’s still doing what he likes best — breaking stuff under the hood of the car. But now his lab is wielding the hammer a little more selectively, studying parts of AMPK and the other proteins it interacts with, trying to discover how they work together.
AMPK is in just about every living thing you see, animal and vegetable alike. It’s one of the countless structures we all inherited from a common ancestor hundreds of millions of years ago. On the level where Brenman operates — studying the basic machinery of cells — many of the differences between humans and fruit flies disappear.
Steve Rogers works on that same level. In fact, his lab rarely works on whole organisms — only on cells. The group studies how cells divide and how they crawl. Flexible cytoskeletons that make our cells move in an uneven crawling gait are another thing humans and flies inherited from our common ancestor.
“Most people actually die of cell motility disorders,” Rogers says. “For example, cancer metastasis: the bad prognosis usually comes when cells break off and form secondary tumors. And there’s heart disease, atherosclerosis. It occurs when macrophages that normally guard the body crawl to a site of blood vessel damage and metabolize cholesterol improperly. So the idea is, if we can understand how cells crawl, we can come up with therapeutic strategies to prevent harmful movement.”
Rogers can, and has, studied human cell movement. But even though he can alter the genome of a human cell culture however he likes, he still needs his fruit fly cells.
For Rogers and other scientists, the problem with human genomes — all mammalian genomes — isn’t just that they’re big. It’s that they’re redundant. By current estimates, humans have twenty to twenty-five thousand protein-coding genes, compared to thirteen thousand found in Drosophila. Yet about 70 percent of human genes that cause genetic diseases have orthologs in fruit flies, many fly researchers say.
That means those human genes and fly genes can be traced to a common ancestor. It also means that fly genes do a lot of the same things ours do; the flies just have fewer genes involved in each function. This is one of the reasons why a lot of genetics research begins with flies instead of mice, a common animal model that’s more closely related to humans. “With mice, there would be less of a chance we’d get a gene that has an observable effect,” Rogers says.
Scientists can explain the redundancy. In the distant past, some time after our ancestors diverged from insects’ ancestors, one or more whole-genome duplications occurred, so that a mutant ancestor had a genome twice as large as its parents’. “We think of a genome as this stable thing that gets passed from generation to generation,” says geneticist Jeff Sekelsky. “But all sorts of things happen to it — gene duplications, chromosomal rearrangements.”
Sekelsky studies genes involved in DNA repair pathways in Drosophila. These are the mechanisms that maintain genome stability. Without them, our bodies wouldn’t be able to repair cell damage. “The theory is that in an early step in cancer, cells lose the mechanisms for preserving stability,” Sekelsky says. The genes his lab studies have orthologs in humans. People with mutations on those genes can’t repair cell damage well and tend to get cancer when they’re young.
The lab focused on two of the many DNA-repair mechanisms in fruit flies. If one mechanism gets knocked out by a mutation, the other one compensates. But when both fail, the flies die. “If tumor cells lack one repair pathway, as we think they do, we might be able to knock out a second pathway,” Sekelsky says. Radiation and other treatments could then target the weakened tumor cells without doing as much damage to healthy cells. “If we have a direct impact on treatment, I think it’s going to be there,” Sekelsky says.
When we’re looking at AMPK, cytoskeletons, or the behavior of DNA, it’s pretty clear how studying fruit flies helps us understand other animals. But researchers also use Drosophila to study the genetics of things that don’t translate quite so simply between species.
Take our sense of smell. You might not think it’s at all like how Drosophila detects its food — after all, fruit flies don’t have noses.
“Their antennae are their noses,” Corbin Jones explains. “The human nose has olfactory sensilla, tissue that has all these chemical receptors. Flies have them too, but on little hairs coming off the antennae.”
Flies and vertebrates also share a system for processing odor information. “If you had one receptor for every odorant, you’d need hundreds of thousands,” Jones says. Using the receptors in combination gives us a more subtle ability to perceive scents.
Jones is studying the genetics of scent perception in a species of Drosophila that’s particularly finicky in its food preferences. His lab is pinpointing the genes connected to Drosophila sechellia’s food choice behavior. Once he’s found the right genes, Jones will try to find out whether they’re also involved in behavioral responses to odors in other fruit fly species. And since the scent machinery is fundamentally similar to ours, he may be on the way to identifying genes that are involved in food choice in vertebrates.
Other researchers use Drosophila to make an even bolder connection, studying the flies to learn about conditions that are unique to humans. Manzoor Bhat’s lab genetically altered flies to not produce neurexin, a protein that’s thought to be abnormal in the neurons of people with autism. Neurexin is controlled by several genes in mice and other vertebrates, and no one else had been able to produce an animal model lacking the protein. Bhat found that his neurexin-knockout flies had defective synapses — the channels through which neurons signal to each other. Bhat thinks that similar synaptic changes in humans probably contribute to autism.
Working in an area of fruit fly research explicitly linked to human health, Bhat is used to explaining how his work on a tiny insect can relate to the much more complicated human brain. “It’s not that our flies have autism,” he says. “It’s that the same protein mutations that are thought to cause autism can be seen in the fly.” By explaining the protein’s function in a simpler system, he hopes to give researchers clues about how neurexin works in other animals.
“Obviously, the fly is not a human,” Bhat says. “But there are many things that are the same between the systems. This protein just happens to be one of them.”
Corbin Jones and Steve Rogers are assistant professors of biology and Jeff Sekelsky is an associate professor of biology, all in the College of Arts and Sciences. Jones receives funding from the National Science Foundation, Rogers from the National Institutes of Health (NIH) and the American Heart Association, and Sekelsky from the American Cancer Society. Jay Brenman is an associate professor of cell and developmental biology and Manzoor Bhat is a professor of cell and molecular physiology, both in the School of Medicine. Brenman’s research and Bhat’s neurexin study were funded in part by the NIH. Steve Crews and Mark Peifer also provided information for this article.