By Cindy Landrum
Photography by Josh Wilson
Study lays groundwork for developing drugs to treat or prevent addiction in humans
To most people, fruit flies are aggravating little pests that show up in their kitchen when they leave ripening bananas or other fruit on the counter too long.
But geneticist Trudy Mackay, who has directed the Clemson University Center for Human Genetics since it opened in 2018, has a much more endearing moniker for the flying insects.
“They are wonderful little beasties,” she says.
And she gets them drunk, plies them with cocaine, exposes them to heavy metals and manipulates their DNA. It’s all a part of her quest to discover the genetic roots of complex traits — traits that are influenced by multiple genes — that are important to human health.
The Center for Human Genetics is a state-of-the-art research and education facility in Self Regional Hall on the campus of the Greenwood Genetic Center in Greenwood, South Carolina. Mackay, widely recognized as a leading authority on the genetics of complex traits, is showing a visitor around the facility when she stops in the hallway at the door to what appears to be a closet.
It’s not.
Inside, there is what looks, at first glance, to be a cooler. But the air is a balmy 77 degrees. “Here’s where we keep the flies,” Mackay says. Trays of test tubes fill the shelves. The vials hold hundreds of thousands of the common fruit fly, Drosophila melanogaster.
You may wonder how flying insects smaller than a grain of rice could answer questions that have puzzled geneticists for decades — how they may reveal why some people who use drugs or drink alcohol become addicted while others do not. Or unlock the secret to longevity. Or explain why a genetic disorder severely affects some members of a family but only causes minor symptoms in others.
Despite the stark differences in physical appearances, Drosophila melanogaster has much more in common with humans than one would think at first glance.
“The remarkable thing is that 75 percent of human disease genes actually have a counterpart in the little fruit fly,” says Mackay, a U.S. National Academy of Sciences member who started working with the fruit fly in graduate school. “Our findings can be translated into humans.”
“They are wonderful little beasties.”
Nearly Impossible
It’s difficult to study some traits in humans.
Take substance abuse. The National Survey on Drug Use and Health estimates that approximately 20 million people in the U.S. age 12 and over have a substance abuse problem. About 5.5 million adults reporting in that same survey used cocaine in 2019, and about 1 million people abused methamphetamine. But researchers know many more people use drugs or drink alcohol and don’t become addicted. What they don’t know is why.
“We can’t give people cocaine or not. We can’t give people alcohol or not,” Mackay explains. “Scientists can do association analysis of people who abuse drugs and those who have taken them but don’t become abusers. But those studies are difficult to do, and there’s always going to be the complication of not being able to control the environment. People self-medicate. They typically don’t do it with just one drug. Often, there’s smoking and nicotine involved, and there may be more than one drug of abuse. It’s a thorny problem that is almost impossible to solve in humans.”
Full Control
But controlling both genetics and environment in fruit flies is easy, thanks partly to Mackay’s decision nearly 20 years ago when she was on the faculty of North Carolina State University.
Her lab needed some fruit flies to use in its research, so Mackay asked Richard Lyman, one of the lab’s research scientists, to go to the State Farmers Market in Raleigh during the peach season to collect some. Lyman captured over 1,000 pregnant female fruit flies. After he returned to the lab, he inbred the flies for 20 generations. The inbreeding virtually eliminated genetic variation in each of the lines.
Those flies were the start of the Drosophila Genetic Reference Panel, a valuable resource Mackay’s lab developed for researchers from all over the world to use. The original panel of 200 lines now comprises 1,200 fly lines with fully sequenced genomes. Lyman also moved to the Clemson Center for Human Genetics to direct the Drosophila Research Core.
Mackay’s latest collaborative research involved giving male and female flies a fixed amount of sucrose or cocaine-laced sucrose over two hours.
“We just dissolve the drugs in a sugar-water solution and give it to them,” says Brandon Baker, who recently earned his Ph.D. in genetics at Clemson and worked in Mackay’s lab both at the Center for Human Genetics and at North Carolina State University. “When we do that, we actually can see some effects that we see in humans in the flies.”
The flies exposed to cocaine in this experiment showed impaired locomotor activity and increased seizures.
It’s what Mackay and her collaborators, including her husband and fellow scientist Robert Anholt, did next — and how they did it — that broke new ground.
They identified specific cell clusters in the fruit fly brain affected by acute cocaine exposure, a discovery that potentially lays the groundwork for the development of drugs to treat or prevent addiction in humans.
To assess the effects of cocaine consumption on brain gene expression, the researchers dissected the fly brains and dissociated them into single cells. Using next-generation sequencing technology, they made libraries of the expressed genes for individual cells. The study looked at nearly 89,000 cells, each of which has thousands of transcripts. Through sophisticated statistical analysis, the researchers could group them into 36 distinct cell clusters.
“We identified the regions of the brain which are important. Now, we can see what genes are expressed when exposed to cocaine and whether there are Federal Drug Administration-approved drugs that could be tested, perhaps first in the fly model. We’ve already spotted several of these genes,” Mackay says.
Researchers can now leverage this work to understand potential therapies, explains Mackay, the Self Family Endowed Chair in Human Genetics.
What a fascinating article about genetics with a tiny slice of biography about the head researcher. It’s just what I needed to finish reading to the end. Very well written. Thank you again Clemson!
Victoria ’06