It began with a simple observation in 1993. Ulrike Heberlein - then an investigator at the Ernest Gallo Clinic and Research Center at the University of California, San Francisco - placed a fruit fly in a little chamber, gave it a puff of alcohol vapor, and monitored its reaction. "What we observed is that a fly behaves just like any other organism when under the influence of alcohol," she says. "First thing it does is become really excited. It runs around really quickly and starts bumping into things." Keep the alcohol coming, and inebriated flies grow increasingly uncoordinated. "Eventually they just sort of fall over and lie there," says Heberlein. Recovery from a binge is no prettier. "They get up, they fall down again. You just observe these tiny little flies and you can relate to them," she says. "You think, this is awfully similar...
In the years that followed, Heberlein, now a professor at UCSF, turned those sympathetic observations into a career of studying the effects of drugs and alcohol on fruit flies. She and her colleagues have discovered a handful of genes that influence how these creatures respond to ethanol and cocaine, and they hope that their findings will lead to a better understanding of intoxication and addiction in more complex organisms, including humans. "I think she's more motivated than a lot of basic scientists by a desire to do something medically significant," says Cori Bargmann, a Howard Hughes Medical Institute (HHMI) investigator at the Rockefeller University. "Her project is based on a real conviction that alcohol and drug abuse is a human tragedy and [that] people should do something about it."
From the Zambezi to Berkeley
Heberlein didn't set out to devote her life to drunken Drosophila, or even to science. Although she studied biochemistry as an undergraduate in Chile - an experience she imagined would teach her "how life works at a molecular level" - Heberlein was leaning toward pursuing a life of outdoor adventure. "I did river rafting and mountain climbing for a couple of years in the early 80s," she says. But just as she was about to pack her bags for Zimbabwe to help her boyfriend run a rafting operation on the Zambezi River, Heberlein says, "I realized that maybe going back to science wasn't a bad idea. At least in science I knew what I was doing."
That realization brought Heberlein to Berkeley in 1983, to the laboratory of HHMI investigator Robert Tijan. For her thesis project, Heberlein was searching for the transcription factors that bind to the promoter of one of the few fly genes that investigators had identified: alcohol dehydrogenase. Along the way, she worked out the first cell-free transcription system using fruit fly embryos at different stages of development. "Believe it or not, the Drosophila field was well covered genetically, but virtually nobody did biochemistry," says Tijan. "Ulrike really cracked open the entire transcription system in Drosophila, which has been paying dividends ever since."
The time in Tijan's lab gave Heberlein "a very solid education in biochemistry," she says. But it also awakened in her a longing to manipulate genes in an animal. Working with isolated bits of DNA and purified proteins in a test tube, she says, "I felt like I had a little too much control over what was happening. And I thought that if I worked with a whole organism, and used genetics rather than pipetting to change conditions, that ultimately I would learn something about what's important to the organism."
In 1988, this desire to learn a genetic approach drove Heberlein across the hall for a postdoc in Gerry Rubin's lab, where she began to study the development of the fly eye. "It's this incredibly precise, beautifully structured compound eye, with 800 units that are aligned almost like a crystal," she says. Heberlein learned the techniques that would allow her to probe the genes that initiate the wave of differentiation that sweeps across the developing eye. She was again breaking new ground experimentally and biologically.
"Ulrike has a history of initiating interesting fields," says Jay Hirsh of the University of Virginia in Charlottesville. "I think she was one of the first to get into the whole question of what causes movement of the morphogenetic furrow during eye development in the fly," he says. "This has become a huge field unto itself."
Like Flies to Alcohol
After her postdoc, Heberlein needed to find a job. She learned of an opening at the Gallo center, which had been established to study the effects of alcohol and drugs of abuse on the brain. Heberlein wrote to then-director Ivan Diamond and described her interest in the position. "I said I had studied alcohol dehydrogenase as a graduate student, which made me sound like I knew something about the field, although I really didn't at all," she recalls. Diamond was receptive, but asked Heberlein to outline something more specific. "So I started reading and thinking about how you can measure behaviors induced by alcohol in flies," says Heberlein. "I wrote a two-page proposal. Next thing, I had a job interview, and then I had a job."
Launching her career in 1993 at the Gallo, her friends and colleagues say, was a curse and a blessing. "It wasn't exactly the easiest place for a young researcher to get going," says Tijan. The Gallo is physically isolated, located across the Bay Bridge in Emeryville, rather than on the UCSF campus, which he says made it more challenging for Heberlein to recruit talented graduate students and postdocs to aid in her pioneering work.
On the other hand, says Bargmann, the Gallo was willing to support studies that weren't ready for prime NIH funding. "Ulrike's work got started at a point where the whole thing just seemed too wacky for words," she says. "But it's those early times when people think you're crazy that somebody has to step up and support you." The Gallos, who'd donated a portion of their winery profits to address some of the problems associated with alcohol abuse, were willing to give Heberlein that support.
Funding in hand, Heberlein needed to develop a screen that would allow her to tease out the genes that control how a fly responds to alcohol. Enter the inebriometer. The device is a tall cylindrical column, lined with slanted platforms, through which alcohol vapors can be circulated. Flies are placed at the top of the apparatus and, as they become inebriated, lose their footing and tumble to the bottom. Flies fall faster the more sensitive they are to the effects of alcohol. Using the inebriometer, which she built from scratch, Heberlein isolated mutants that are either more sensitive or less sensitive to intoxication than are wild type flies.
"I remember how the audience chuckled, half amused, half bemused," when Heberlein discussed her inebriation assay at a fly meeting in 1998, says postdoc Adrian Rothenfluh. That changed the following year, though, when Heberlein and her team isolated cheapdate, a mutation that lowered flies' resistance to the intoxicating effects of alcohol. "After the cheapdate paper, flies and alcohol were no longer a laughing matter," says Rothenfluh.
Cheapdate, cAMP, and Memory
Cheapdate disrupts a peptide called amnesiac, which Chip Quinn's lab at Massachusetts Institute of Technology had previously identified. Amnesiac is involved in learning and memory, reinforcing the theory (proposed by others in the field) that addiction might be a maladaptive form of learning. Heberlein and her colleagues are still trying to identify the receptor to which the neuropeptide binds. They have learned that cheapdate activates cAMP signal transduction in a subset of fly neurons; the same cAMP pathway has been implicated in mediating alcohol's effects in mammals. "So we think we're barking up the right tree," says Heberlein.
The approach was a gamble, says UCSF colleague Cynthia Kenyon. "Going in, it wasn't clear whether she could find single genes that would produce specific effects instead of just a jumble. Or maybe there would have been nothing there to study," she says. Heberlein's experimental rigor allowed her to find specific genes and to follow through and determine their functions, says Tijan. "Cloning a gene might be easy. But you then have to go and actually figure out what the heck it does."
Although the connection with learning was a surprise, the discovery highlights "why flies are great for this kind of study," says Linus Tsai, Heberlein's former MD-PhD student. "With flies you can do an unbiased search for genes and molecules that might be involved in drug response. You're not limited to what's already known."
Heberlein and her colleagues continue to push those limits, expanding their studies to include cocaine, nicotine, and other drugs of abuse. "We throw everything we can get our hands on at these flies," she says, and additional genes have emerged. For example, Heberlein, Tsai, and other lab members have conducted cocaine sensitivity studies, which have turned up lmo, a tiny little protein expressed in a set of circadian pacemaker cells. These neurons help coordinate various rhythmic behaviors, including locomotion, an activity that goes awry when flies are exposed to cocaine.
Alongside the fly studies, Heberlein is working on proving that the corresponding genes play a role in drug response in mice. "It was a bit of an extrapolation to believe that flies would be a good model to study addiction," says Heberlein. "A lot of people questioned whether that was the right way to go." But the approach, which Heberlein likens to jumping off a cliff, "has really paid off," she says. In addition to the cAMP connection, Heberlein has evidence that lmo is also involved in cocaine sensitivity in mice.
Perhaps, given Heberlein's penchant for adventure, the cliff-diving method should come as no surprise. "Bold and daring things appeal to her," says Bargmann. Tijan agrees: "Ulrike ? takes risks. She goes for the throat. She tries things that other people haven't tried. She's a very strong person. You have to be to start something that other people think is bound to fail."
"I really admire where the work has gone," adds Bargmann. "It probably isn't even zany anymore. Which is too bad."
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