Researchers at the School of Medicine have created a high-tech puppet show, only their marionettes are alive and have no strings attached. With the help of some genetic tweaking, the team got fruit flies to walk, jump and fly on command—simply by flashing a light at them.

Over centuries, to better understand the brain’s normal functions and the roots of disease, scientists have devised many methods of manipulating animal behavior, but they have had to rely on invasive techniques like stimulating nerves and muscles with implanted electrodes. The new Yale study marks the first time an animal’s behavior has been shaped by remote control without such invasive tactics. “We do not have to poke them with electrodes,” says Gero A. Miesenböck, M.D., an associate professor of cell biology at the medical school, who led the study.

The research, which appeared in the April 8 issue of the journal Cell, prompted a flurry of international headlines that made comparisons to video games and mind control. It even became fodder for Jay Leno’s monologues on The Tonight Show—twice.

But jokes aside, Miesenböck says that the research is a new way to learn how nerve cells govern behavior, and that it will open new avenues to understanding neurological illnesses. “Initially, scientists are often passive observers,” Miesenböck says. “But at some point, active control becomes essential in order to establish causes and mechanisms.”

Using meticulous genetic techniques, Miesenböck and graduate student Susana Q. Lima, now a postdoctoral fellow at Cold Spring Harbor Laboratory on Long Island, inserted rat ion channels, microscopic pores that admit calcium into cells, in nerve cells that control fruit flies’ escape movements. In rats, these channels activate cells by opening in the presence of adenosine triphosphate (ATP), but Miesenböck and Lima injected the flies with a “caged” form of ATP that only functions when exposed to light.

The tiny flies were placed into an arena the size of a dime, where they dawdled until Lima and Miesenböck flashed laser pulses at them, which “liberated” the caged ATP and caused the flies to perform characteristic escape responses. The flies behaved on cue up to 82 percent of the time. “There was all this hope that it would work,” Miesenböck says, “but I think the extent to which it did was a very pleasant surprise.”

Because escape behavior also occurs when a fruit fly detects a shift from light to darkness that might signal danger—from a descending fly swatter, say—the researchers did the same experiment on a strain of flies in which the visual system was engineered to be insensitive to light, and they got the same response. In another experiment that hints at the technique’s potential for restoring neural function, Miesenböck and Lima even got headless flies to perform the trick. Because of the architecture of their nervous system, fruit flies can live for a day or more without their heads, but they remain motionless. However, when equipped with Miesenböck and Lima’s “phototriggers,” the headless flies took flight whenever the laser was turned on.

In addition to studying the escape circuit, Miesenböck and Lima placed their phototriggers in fruit fly neurons that produce dopamine, a neurotransmitter involved in movement that has been implicated in Parkinson’s disease and addiction. When they activated the cells with light, the flies displayed “quite surprising” behaviors reminiscent of dopamine pathologies in humans, Miesenböck says, adding that before these experiments, “very little was known about what these neurons do.”

“It’s a really cool technique,” says Ronald L. Davis, Ph.D., a professor of molecular and cellular biology at Baylor College of Medicine, citing the study’s unique strengths as “the untethering of the animal, and using light as the stimulus.”

The method is also extraordinarily precise: in one experiment, Miesenböck and Lima were able to place rat ion channels in just two of the 100,000 cells that make up the fly nervous system. And the procedure allows scientists to selectively turn on parts of an intact nervous system. These parts need not be next to each other, and their locations need not be known in advance. This creates enormous potential for discovering which groups of neurons control which aspects of behavior.

Both Miesenböck and Davis say that applying the technique to human illness is still far off, and for now, Miesenböck is sticking to fruit flies. Next he plans to probe the neural activity around their courtship behavior—essentially, he’ll be playing Cupid. “It’s not just the sex act that interests us,” he says, but “it’ll get us on The Tonight Show again, I’m sure.”