Drosophila have something to say about climate, diet and survival
Lining a wall in the Daniela Drummond-Barbosa Lab sits a row of unassuming, windowless incubators — the homes of vials and vials of fruit flies, all kept at a specific temperature and humidity. Some are genetically modified, some are on special diets, some are destined for dissection under a microscope.
Within these flies as well as every animal, small populations of stem cells help maintain the numerous tissues that all connect to make up a complete organism. For these stem cells to function correctly, they need to respond to the changes in diet, metabolism and physiology that affect the whole body.
To understand this complex process, Drummond-Barbosa — Morgridge investigator and professor at the UW– Madison Department of Genetics — finds that fruit flies are a great place to start. Drosophila melanogaster is a powerful model system that Drummond-Barbosa uses to answer big questions about the how environmental factors affect the production of reproductive cells, processes known as oogenesis in females and spermatogenesis in males.
With a focus on fundamental research, the Drummond-Barbosa Lab adopts a curiosity-driven approach to its work. By asking interesting questions about fundamental biology, Drummond-Barbosa can advance understanding of these systems. Down the road, other scientists could rely on that past discovery or approach to solve an important problem.
“People ask, ‘How’s that going to cure this or that? But they forget that everything comes down to some basic knowledge that somebody got just by being curious about how things work.”
Daniela Drummond-Barbosa
Drummond-Barbosa believes that all researchers benefit from understanding the history of science, where basic research regularly served as the foundation for a transformative application. The CRISPR/Cas9 genome editing method that has revolutionized genetic research, for example, stemmed from fundamental discoveries about repetitive sequences in E. coli DNA made in the late 1980s.
Graduate student Emily Wessel says the curiosity driven approach drew her to the Drummond-Barbosa Lab. Her project investigates the steps of stem cell lineage differentiation in Drosophila and the role of sugars and fats in that process.
“If we get a cool result that maybe doesn’t match our hypothesis, we get excited and follow it,” Wessel says. “We listen to what the flies tell us. If it wasn’t what we were thinking, we’re not bummed. It’s interesting.”
Making an impact requires both basic and applied science. Drummond-Barbosa sees a movement toward universities and funding agencies placing more emphasis on applied science. If that trend continues, she fears paradigm-shifting findings may dwindle.
“People ask, ‘How’s that going to cure this or that?’” Drummond-Barbosa says. “But they forget that everything comes down to some basic knowledge that somebody got just by being curious about how things work.
When Drummond-Barbosa moved her lab from Johns Hopkins University to UW–Madison in 2022, they discovered a haven in the Morgridge Institute. Ana Caroline Gandara, an assistant scientist in the lab, finds that here she shares a common language with other researchers, making collaborations easier.
“I think the Morgridge Institute is a really rare example where the leadership really believes in fundamental science,” Drummond-Barbosa says.
Sugar, Obesity and Fertility
Drummond-Barbosa fell in love with Drosophila in graduate school. Her doctoral work was in a virology lab, but she was exposed to cutting edge developmental biology research using Drosophila as a model system. Coming from Brazil, she struggled to understand the professors during lectures and spent a lot of time puzzling over new papers.
“That was really great because I had to read so much that it started really clicking,” Drummond-Barbosa says. “I was amazed at the power of a mutagenesis screen . . . and figuring out how the mutants fell into a certain pattern.
Using Drosophila as a model system allows researchers to tease apart different variables that would be difficult with other organisms. Researchers know that a high-sugar diet leads to obesity in humans and mice, for example, which can then lead to fertility issues. But Rodrigo Dutra Nunes, a scientist in the lab, uses Drosophila to better understand the precise relationship between obesity, diet and infertility. “[With Drosophila], there are so many tools and there’s so much you can do with the short generation time,” Drummond-Barbosa said. “You’re not restricted by how many flies you can analyze so the power of your analysis and your confidence in your results is really huge.”
Previous work in the lab established a connection between the fat cells and oogenesis. So initially, Dutra Nunes thought they were embarking on a relatively simple paper regarding the effects of obesity on fertility in female flies. They started by feeding the flies either a normal diet or a high-sugar diet, which caused obesity and reduced fertility. But then they introduced another group of flies and knocked down two different anti-obesity genes in their fat cells. These flies became just as fat as those with the high-sugar diet — but their fertility remained normal. Surprisingly, obesity alone wasn’t causing the fertility issues in the flies.
What started as a quick paper became a much more intensive, but also more interesting project.
“My creativity can drive me, and I think that’s great,” Dutra Nunes says. “We are not shy of the hard pathways. We went down that path, and it took much longer than we expected to show the whole story and use multiple methods to show obesity is not affecting fertility.”
In the flies fed a high-sugar diet, Dutra Nunes identified two stages of oogenesis where there were higher rates of death in the developing germ cells as well as low hatching rates. Interestingly, when given extra water, those flies remain obese, but their glucose levels decreased and their fertility issues were largely resolved. Taken together, the results indicate that in obese flies insulin signaling is above the required threshold for oogenesis to occur properly.
“Instead of just showing that obesity is not a factor in infertility and moving to another project, which would be easier, we continue to investigate because the biology is interesting,” Dutra Nunes says.
Temperature and Fertility
Drummond-Barbosa had long studied the effects of diet on Drosophila by the time Gandara arrived in her lab. But diet is far from the only environmental factor insects face, and understanding insects’ responses to temperature has become more important with climate change. “All animals are having to adjust to loss of habitat, and with the loss of habitat or micro-habitats, it becomes harder to deal with the higher temperatures,” Drummond-Barbosa says. “So, it’s a double whammy because insects are cold-blooded and they really rely on being able to find micro-habitats to control their temperature.”
Continuing the focus on Drosophila oogenesis, Gandara published her first paper with the lab on the effects of colder or warmer, suboptimal temperatures on female fertility. She raised the flies under normal temperatures, but after they reached adulthood, they were split into warm, normal and cold groups. The temperature changes the flies underwent were minimal by our standards, but they had drastic negative effects on Drosophila oogenesis, especially at higher temperatures.
Gandara’s next paper investigated the effects of cold and warm temperatures on Drosophila male fertility. Many studies have investigated the effects of warm temperatures on male insect fertility, but none have explored their effects on the different steps in spermatogenesis in detail. The warmer temperatures led to a considerable reduction in the quality and amount of sperm. Gandara’s results also indicate that while spermatogenesis proceeds relatively normally at the beginning of the process, the damage seems to occur at the later stages of differentiation.
As the lab’s first publications on temperature research, these papers set out to simply describe the effects of suboptimal temperatures — temperatures whose lethality over time is felt through their impact on fertility. The lab will build on the initial discoveries.
Looking Ahead
Gandara is now comparing Drosophila ovaries at different temperatures using an “omics” approach, which involves analyzing many subsets of biological molecules to better understand cell function. She’s analyzing datasets of RNA, proteins, phosphorylated proteins and lipids. Within this massive amount of data, she’s searching for pathways that control the fly ovary’s response to temperature increases or decreases. This data will help her find a place to begin investigating the mechanisms whose effects she observed in her past research.
Both Gandara and Dutra Nunes are collaborating with research computing experts at Morgridge who can help them better organize and analyze parts of their respective data. Dutra Nunes is working with Anthony Gitter, a Morgridge investigator and UW–Madison associate professor of biostatistics, on his own omics data. And Gandara is collaborating with Ben Anderson, a postdoc in the Joshua Coon Lab. For Gandara, the shared interests, resources and culture at Morgridge are a welcome change from the lab’s previous university department, as it was shifting its focus to more applied science.
“We have more chances to collaborate, more chances to find useful information for us,” Gandara says. “We can offer collaborations and even bring the right expertise to help people. It’s much easier to help and be helped.
Dutra Nunes believes that a high-sugar diet has a systemic effect on the flies — that is, his findings are likely not the result of one gene that he can manipulate. To further investigate the effects of diet on Drosophila fertility, Dutra Nunes is turning to omics to better understand changes in proteins, phosphorylated proteins, and metabolites from different tissues under normal and high sugar conditions.
“With that we will have a process that will be really curiosity-driven,” Dutra Nunes says. “After the results come out, we’ll have too many directions to possibly follow. And that’s a good problem.”
Fearless Science Magazine
This story was featured in Fearless Science Magazine. The inaugural issue focuses on regenerative biology. How do some of the world’s most clever and fascinating organisms redevelop critical body parts after injury? And what might it mean for future advances in human health, from heart repair to infectious disease?