Ulrike Heberlein: High Flies Have Heberlein Hopeful
First published May 2003
Humans tend to assume a genetic superiority over other species, even when their loutish or troubled behavior might suggest otherwise. So it is a bit of a comeuppance when a scientific model for one of humanity's most intractable and complicated problems -- drug abuse -- can be created and tested in a fruit fly. But that is precisely what neuroscientist Ulrike Heberlein and her laboratory colleagues have achieved and, in the process, helped to reveal some potential links between genes and drug-induced behaviors. "It's been a long road and one I may not have attempted had I known how difficult it would be," says Heberlein, who will be one of the first occupants of UCSF Mission Bay's Genetics, Development and Behavioral Sciences building. Still, for someone who built her own fruit fly inebriometer (a vertical, glass-enclosed "cocktail lounge") the journey has been worth the trouble. "We're now ready to really dig down into the mechanisms of the 30 or 40 genes that seem to play a role in drug responsiveness."
First let it be said that fruit flies are more complex than they first appear. With 13,000 genes, nearly two-thirds of which have obvious human counterparts (humans have an estimated 35,000 genes), this creature has a long evolutionary history, if a short life. Fruit flies also are cheap, prolific, simple to breed, and perhaps most significant, their genes are easy to examine and manipulate. It was this manipulation that made them particularly suitable for Heberlein's genetic experiments on their nervous systems -- experiments that were guided by the flies' performance in the inebriometer.
Now the concept of getting fruit flies drunk may seem humorous at first, but there is a simple and elegant logic behind the experiment. A cylinder, crisscrossed with platforms, and full of fruit flies, is infused with ethanol. The flies breathe the ethanol and, well, soon have trouble flying. But the rate at which the flies stumble, fall, and pass out on the way to bottom of the cylinder is not uniform. Some flies resist the influence of ethanol; others are overtaken quickly (their genetic moniker is "cheap date"). Still others display withdrawal-like symptoms. Another tracking device -- known as the booze-o-mat -- allows Heberlein and her fellow researchers to measure how fast and how straight flies walk. "Low ethanol doses make flies hyperactive. Higher doses make them walk in wavy lines. Even higher doses make them pass out." A computer then records and quantifies the data.
Taken together, results from the two tracking systems allow the researchers to select and compare nervous system genes in fruit flies that -- either through natural genetic variation or because of induced mutations -- respond differently to ethanol. Heberlein and her colleagues have used this information to gradually narrow the target genetic field.
"We're at the dawn of an era," says Heberlein, a long-time member of the Wheeler Center for the Neurobiology of Addiction. "And we have a long list of questions, beginning with why some of the identified genes are even on the list. Based on what we know about them already, some of them just don't make sense." Understanding the mystery requires tracking where the gene is expressed, the extent of the expression -- in a few cells or many -- and whether the induced mutations increase the sensitivity to one drug or several, including ethanol, cocaine and nicotine. The process is painstaking and labor intensive in large part because, even after narrowing the genetic field, several thousand mutants remain. Moreover, there is no clear path to follow.
As though sifting through resumes looking for the best job candidates, Heberlein and her colleagues are now winnowing the mutant list based upon the relevant behavioral criteria, which include degrees of tolerance (the fruit fly equivalent of needing more drugs to reach the same high) and resistance and the molecular properties they find associated with each. Says Heberlein, "We have to keep asking ourselves, what is the relationship between the behavior and the molecular data. Is it trivial? Is it profound? Is it direct or indirect? Right now, we don't have enough information to know."
Some insight may come from the laboratory's parallel pursuit: analyzing brain regions that participate in what is known as the "reward pathway." As Heberlein explains, "Every organism that thrives needs a system of rewards, particularly for food and sex." Drugs of abuse hijack this reward system and induce changes that bias the pathway toward the addictive substances. Regions of the mammalian brain, namely the mesolimbic dopamine system, have been identified as key players in this pathway. Because similar brain regions are expected to exist in the fruit fly, a major effort is under way to devise methods for measuring rewards in flies and then mapping the functional brain circuitry involved in this behavior. "We're shrinking the black box," says Heberlein.
The move to Mission Bay should help further, Heberlein believes, if for no other reason than researchers with similar affinities will be grouped into neighborhoods. "The extrapolations from fruit flies to higher organisms is very important, and now my colleagues who are working on some of the same questions in zebrafish or mice will be close to each other. Lots of smart people working together is bound to create synergy."
As to whether or not her work with fruit flies will someday contribute to a "cure" for drug abuse, Heberlein demurs. "I don't believe in genetic determinism, so even if we find a genetic component to this behavior, it will not change the importance of environmental factors, which are beyond the control of pharmacological intervention." Still, there is some hope. "The newer antidepressants work pretty well across the board. There's no reason we can't draw on this success and develop a therapy that counteracts some of the abusive effects of drugs." If so, the term "straighten up and fly right" could become as much a tribute as an admonition.