Veteran ‘Lord of the Flies’ Takes a Crack at Addiction

By Deborah Borfitz 

June 12, 2025 | The brain of fruit flies and humans may be vastly different in size and complexity, but at the circuit level they are not all that different, according to a veteran fly geneticist who has spent much of his career trying to understand why humans abuse drugs. An interest in alcohol dependence segued to another major health problem, cocaine abuse disorder, which has some of the same genetic underpinnings, says Adrian Rothenfluh, Ph.D., associate professor of psychiatry at the University of Utah. 

Most recently, Rothenfluh and his colleagues published a study where bitter-sensing neurons stopped Drosophila melanogaster from voluntarily self-administering cocaine (The Journal of Neuroscience, DOI: 10.1523/JNEUROSCI.1040-24.2025). Fruit flies didn’t initially like the substance but quickly acquired a preference for it, which is the essence of addiction.   

Many genome-wide association studies have been done with humans over the past 20 years to discover gene variants correlated with addiction, says Rothenfluh, but it is unknown whether these genes cause addiction. The list of genes could be long, so the fruit fly is an ideal choice for finding the relevant ones since it breeds quickly and the testing can be done fast.  

The bigger problem is that many of these genes are not dedicated to addiction, making the mission to discover the impacted pathway and design therapeutic interventions that specifically target the problem, he says. “You could just get rid of the reward pathway that makes people abuse drugs, but that might generate people who are chronically depressed because they can’t experience any reward at all. So, the key may be a combination of a therapeutic pill together with a local release [mechanism] that only affects brain changes induced by drugs of abuse.” 

Mashing Bananas 

The basic laws of inheritance are credited to an Austrian monk named Gregor Mendel who 150 years ago famously crossed different varieties of pea plants, says Rothenfluh. It was another 30 years before another researcher at Columbia University, geneticist Thomas Hunt Morgan, picked up on this work using fruit flies because they supplied terrific conditions for scientific experiments. They’re cheap—“all you need is a bunch of mashed-up bananas and they are plentiful; a single female can give rise to a 100 or more offspring”—and a full generation takes two weeks or less.  

At the time, “people knew what DNA was, but nobody knew that genes were associated with DNA, and nobody knew how exactly this works,” he continues. Morgan received the Nobel Prize in Physiology or Medicine in 1933 for his work on hereditary transmission mechanisms in Drosophila and his graduate students also went on to make many seminal discoveries. 

The new knowledge included the fact that genes were indeed in DNA, and those genes are arranged in a linear fashion, says Rothenfluh. Investigators also subsequently learned from flies that X-rays can harm genes by causing DNA damage. 

The 1980s, when people started cloning genes, was another heyday for Drosophila-based research, he notes. This is the period when basic science revealed how genes play a crucial role in determining body segmentation and overall body plan during embryonic development, establishing where the head and tail are supposed to be. 

“Amazingly, it turned out that we use the same genes to do this, so people started realizing that we are much more like flies on the molecular level even though we obviously look quite different,” says Rothenfluh. In research conducted around 2000, primarily driven by the completion of the Drosophila genome sequence, it then became known that about 75% of genes associated with human disease are conserved in flies.  

Apparently, eight years later, no one had yet told Sarah Palin, who denounced fruit fly research when she was a vice-presidential candidate. The sentiment today is more indifference, Rothenfluh says, which given plans in the White House to end animal testing is perhaps a good thing. 

Except for fly geneticists, “nobody cares about flies,” says Rothenfluh. Even People for the Ethical Treatment of Animals (PETA) is focused more on larger animal models used in research. Thankfully, he adds, “I have never had PETA demonstrate in front of my office.” 

From Flies to Humans

Significant work also emerged from the lab of physicist and neurogeneticist Seymour Benzer in the 1970s, with the discovery of a gene in fruit flies that plays a crucial role in their circadian rhythm. He and a graduate student did a genetic screen and found flies who “slept with no rhyme or reason,” unlike normal flies who slept for 12 hours each night and stayed awake for 12 hours each day even in complete darkness, shares Rothenfluh. 

They also found some flies that thought the day was only 19 hours long rather than 24, and others that thought it extended to 29 hours. Remarkably, all three phenotypes—random, short-day, and long-day sleepers—represented different variants from the same gene, Rothenfluh says.  A trio of 2017 Nobel laureates subsequently investigated how the 24-hour biological clock regulates behaviors like sleep and wakefulness. 

For the longest time, he continues, people thought this internal clock was a genetic quirk that happened only in flies and, of all things, bread mold. The way it worked was essentially the same for both species.  

“Then the 90s came around and, what do you know, it turns out that the genes that govern the circadian clock in flies actually are conserved in mammals and even in people,” says Rothenfluh. Humans can have mutations giving them a short-running clock, a rare condition known as familial advanced sleep phase syndrome that causes an “uneasy equilibrium” whereby individuals fall asleep and wake up four to six hours earlier than the average person. 

The work of untangling the molecular mechanisms controlling circadian rhythms is credited primarily to Jeffrey C. Hall, Michael Rosbash, and Michael W. Young, who were collectively awarded the 2017 Nobel Prize in Physiology or Medicine for their work. These researchers identified a protein called PER in fruit flies that plays a role in regulating daily biological rhythms. 

Since three-quarters of human genes are conserved in flies, they’ve proven indispensable to the study of disorders in people, Rothenfluh notes. This has been particularly true for rare diseases where few patients exist to incentivize the pharmaceutical industry to invest their development dollars. 

Clement Chow, Ph.D., associate professor of human genetics at the University of Utah, has for example used flies with a mutation-caused phenotype giving them funny-looking eyes to test 1,200 different drugs already approved by the U.S. Food and Drug Administration to see if any of them might help. He had some hits, and those medicines are now being administered to children affected by the same sort of genetic alteration with some resulting improvement. 

Discoveries, in this case, went directly from flies to humans in a matter of a few years, points out Rothenfluh. “In drug development, we’re normally talking 10 to 20 years.” 

Choosing Cocaine

Rothenfluh has been working with flies for over 30 years, making him part of a group playfully referred to as “Lords of the Fly.” As a graduate student, he studied their circadian rhythm before becoming intrigued with what many people at the time viewed as a bit absurd—throwing drugs of abuse at flies. “Soon enough, everybody realized this was actually interesting,” he says. 

Scientists like him often prefer fruit flies as their model organism for genetic screening because of their short life cycle (about 10 days) and well-mapped genome. “We have found genes that have an effect on their response to alcohol, and we have collaborated with human geneticists and shown that the conserved gene in humans also has an effect,” says Rothenfluh. The goal here, in case anyone missed it, is to “figure out the mechanisms that cause humans to abuse drugs.”  

That is not to say that the environment doesn’t matter when it comes to addiction, he adds, in addressing the value of 12-step recovery programs. But addiction is believed to be affected predominantly (50% to 70%) by an individual’s genetic makeup.  

His lab’s focus on understanding responses to alcohol and the underlying genetic mechanisms involved naturally swerved into other drugs of abuse, including cocaine and other psychostimulants like amphetamine or methamphetamine. In the U.S. alone, about 1.5 million people have been diagnosed with cocaine use disorder and roughly 10 million abuse psychostimulants, Rothenfluh reports. “Their mechanism of action is quite similar, so if you learn something about cocaine you may also learn something about amphetamine responses.” 

Other fly geneticists are likewise studying these drugs, but their focus has been on “the immediate response of flies and how they get incapacitated... at high doses, quite similar to what happens when a human takes cocaine,” he says. “But nobody has really dug in to see whether they can make flies voluntarily take cocaine.” 

Rothenfluh’s interest was in establishing that “face validity”—meaning, how much a fruit fly visibly or behaviorally resembles the human condition it’s meant to mimic. “Voluntary self-administration is one way to model addiction,” particularly the escalating intake of a once-distasteful substance. 

Hijacked Pathway

Now that it has been established that flies, like humans, can become addicted to cocaine, the next step for Rothenfluh and his team is to learn which of the genes associated with human addiction causes a change in behavior. It is “somewhat unlikely” that they will find a single relevant gene, as many psychiatric disorders involve a constellation of genes, so gene therapy would be an impractical treatment, he says.   

The other problem is that addiction is not a normal human trait with a normal pathway in the brain dedicated to it. “In fact, what drugs of abuse do is hijack the pathway in the brain that is normally involved for any reward, be that procreation or good food or social interaction,” Rothenfluh says. 

It is therefore going to be crucial to understand what drugs of abuse, versus normal behavior, do to this reward pathway, continues Rothenfluh. Those problematic changes might then be attacked, possibly by a pill or even some kind of non-invasive stimulation with ultrasound to the part of the brain getting overactivated with drugs of abuse to help people “unlearn their liking of the drugs.” 

This could easily take a decade, Rothenfluh says, adding that he’ll be passing the baton to colleagues working with rodent models once the risk genes are identified. 

It is vital that everyone outside the science field recognizes the need for basic research—if only to understand the brain of the fruit fly or Caenorhabditis elegans, another prominent model organism in genetics, says Rothenfluh. “Basic science informs things down the road... for example, gene therapy,” which gets delivered via a virus. “People developed this by studying the basic mechanisms of how the delivery virus infects cells.” 

Basic science also needs funding support from the National Institutes of Health, or the pace of therapeutic drug development will slow significantly, he adds. Profit-driven pharma companies aren’t going to investigate the fly or worm brain, but it remains the starting point for the development of therapies for multiple high-impact diseases like Alzheimer’s and Parkinson’s as well as addiction disorders.