Fly Trials of 1950s Evolve

Back in the 1950s, a biologist named Jerry Hirsch embarked on an odd but trailblazing endeavor: He coaxed flies to crawl and fly through elaborate mazes so as to separate ones that prefer to move up from ones that prefer to move down.

In those days, psychologists pooh-poohed the notion that genes could help shape behavior, believing instead that all behaviors were learned. Hirsch’s lovingly selected lines of high- and low-seeking fruit flies forced them to think again.

Hirsch is long retired; descendants of his original flies languished in a few bottles filled with yeasty food. Now, at last, they are back in the limelight--and blazing trails again.

Today, scientists are probing Hirsch’s strange flies with modern molecular tools to try to answer what could never be answered before: Why do some of Hirsch’s flies fly up? And why do the others fly down? What kinds of genetic changes was Hirsch selecting for all those years?

Writing today in the journal Nature Genetics, a team of researchers say they’ve pinpointed several of the genes involved in this trait--and have strong clues about some others.

And that is important for more than just fans of fruit fly behavior. While some genes studied by scientists have large, in-your-face influences, many more have small and subtle contributions. Hirsch’s flies are a prime example of the kind of trait that involves the action of many genes.

Studying the flies, therefore, stands to teach scientists lessons about the genetic nuts and bolts of evolution as well as the ancient art of plant and animal breeding.

For eons--long before recorded history--people have domesticated animals, deliberately selecting for traits such as docility, disease-resistance, milk production and more.

Studies such as the one of Hirsch’s flies “finally give us a way to see what the genes are that are contributing to the selection,” said Tim Tully, professor of genetics at Cold Spring Harbor Laboratory in Long Island, N.Y., and a former graduate student of Hirsch’s.

The studies demonstrate how scientists can more easily get their hands on agriculturally important genes--ones that often are hard to find because dozens, even hundreds, are involved in a trait, each one contributing just a little.

Central to these new lines of investigation is the development of high-tech DNA computer chips, which are loaded with samples of thousands of genes, allowing scientists to quickly probe huge chunks of a genome.

The chips could potentially allow agricultural researchers to ferret out specific genes more readily, easing the quest to breed beefier cattle or fungus-resistant lettuce.

Such studies already are underway for a variety of crops and livestock, said Max Rothschild, the Curtiss distinguished professor of agriculture, animal breeding and genetics at Iowa State University in Ames. The experiments with Hirsch’s flies are an important demonstration that the approach works.

“It’s inventive, revealing, really innovative stuff,” Rothschild said.

Hirsch started his project while in graduate school in the 1950s, working with a scientist who was breeding smart and dumb lines of rats. Hirsch also wanted to study behavior--but decided that fruit flies were handier to use. The flies were small, well-studied and fast breeding: Flat out, they could manage a generation every 10 days.

What’s more, flies do exhibit behaviors--including “geotaxis,” or the preference to move in relation to the pull of gravity.

When the flies are in their larval stage, for instance, they like to move downward. That way they’ll burrow ever deeper into the pungent, moldy fruit they adore.

When the time comes to pupate, they change their tune--heading up out of their food to a nice, dry place where the fly can emerge safely when it’s time to hatch.

And, as anyone who’s opened a smelly garbage can or tried to swat a fly knows, flies like to fly up to safety when startled.

“Other than that, who knows?” said Ralph Greenspan, Cullman Fellow in Experimental Neurobiology at the Neurosciences Institute in San Diego, and senior author of the paper published today. “You’d have to put yourself into their heads and think like them.”

Hirsch, in any case, didn’t need to probe the fly’s psyche: He just needed a way to gauge its preferences. And so he constructed a cunning maze shaped like a candelabrum turned on its side. Into one end, he loaded a fine mix of flies. Then he waited as they slowly moved through it.

At numerous points in the maze, each fly had a choice: Go up or go down. Valve-like cones discouraged any backtracking. At the far end of the maze, each fly ended up in one of a series of tubes, each at a different height.

Generally, flies chose pretty randomly: Most ended up in the middle set of tubes.

But after every run through the maze, Hirsch enriched his population of outliers: flies that ended up highest and flies that ended up lowest. He’d use these outliers as the parents for the next generation.

For decades, Hirsch (now emeritus professor of the University of Illinois at Urbana-Champaign) would re-select those lines, cataloging his findings in a succession of scholarly papers with titles such as “Genetic changes occurring over 500 generations in lines of Drosophila melanogaster selected divergently for geotaxis.” Generations of students helped out with the task.

Yet there was only so much Hirsch could do with the flies. He knew that through his breeding he’d selected for many different genes that all played small parts in this particular fly behavior. But he could never get his hands on them.

And so the lines sat. But Hirsch did not: Over the years, he turned his eye toward other fly behaviors: courtship, speed of running, ability to learn, and more. His lab became a mecca for those enthralled by the quirky side of fruit fly life.

Then came the molecular genetic revolution. In 2000, scientists reported they’d cataloged the structure of the fruit fly’s genome with its roughly 14,000 genes. That, in turn, allowed the creation of Drosophila DNA chips, containing thousands of points, each representing one of those genes.

Today, a scientist can bathe those chips with extracts of fly tissues to figure out which genes are turned on or off in different samples.

In the study reported today, Daniel Toma of the Neurosciences Institute and Kevin White of Yale University, as well as Greenspan and Hirsch, describe just such a DNA chip analysis. The chip, created by White, contains DNA spots representing more than a third of all the fly’s genes.

The team bathed the chip in brain extracts from high-seeking flies and low-seeking flies, and looked for differences in the patterns of brightly colored spots. These would represent differences in the amount of activity in each of the genes. They found differences in 250 genes.

Of those, they studied four in much more detail: testing fruit flies known to have defects in those genes for their preferences while wandering through one of Hirsch’s mazes.

Three of the mutants, they found, walked through the maze in ways detectably different from “normal” flies--two of them emerging at the other end slightly high, one emerging slightly too low. These genes, the scientists argue, could well be among the ones that Hirsch selected for, way back when.

It’s no mean feat to identify three genes involved in a trait you’re studying in one fell swoop, Rothschild said.

But the study is interesting for other reasons too. These three genes, Greenspan notes, have other jobs that have nothing to do with geotaxis--traits such as moving and resting in crisp, daily rhythms. It’s a fine illustration of the way that nature multi-tasks.

“There is not one of them that you could consider a ‘geotaxis gene’--they’re all doing other things as well,” Greenspan said.

Evolution, he said, probably works by making small, subtle changes in this gene and that gene, so as to alter one behavior without messing up other essential functions.

In the future, the scientists plan to explore Hirsch’s “high” and “low” lines further to better identify the genes involved.

Hirsch, meanwhile, is happy to see his classic experiment resurrected more than four decades later.

“It’s gratifying,” he said. “Maybe I didn’t waste my time.”