Buzz from the lab
The dance of intimacy
By Daniel Golden, Globe Staff
Bruce Baker's laboratory is a fertile breeding ground for flies - and for advances in genetics research.
The Stanford University biologist estimates that, at any given time, a million fruit flies representing a thousand different genetic strains are feasting on yeast and cornmeal in test tubes, incubators, and old milk bottles. Not to mention the occasional escapees landing in his coffee cups and trash bins, and the genetically engineered fly DNA refrigerated at minus 80 degrees centrigrade. And me, a fly on the wall in a chilly closeted space where tweezer-wielding graduate student Joy Hatzidakis meticulously aligns embryos on slides.
Beside her, steering a needle with the aid of a microscope, postdoctoral fellow Enrique Reynaud races to inject a cocktail of cloned DNA into the one-celled embryos before they divide. Later, the
researchers will use fluorescent jellyfish protein to track the
DNA's expression in the brain cells of the mature fruit fly.
Hatzidakis's brown eyes glow as she explains the goal of the experiment: pinpointing how a master gene known as ''fruitless'' functions in the male fly's brain to regulate sexual orientation and courtship. Fruit-fly research, she says, ''is a really beautiful thing.''
Drosophila, or the fruit fly, the old standby of genetics research in the 20th century, is enjoying renewed popularity - and controversy - as the 21st is about to begin. A quarter-century after the advent of recombinant DNA technology at Stanford and the University of California, more and more geneticists find it fruitful to tinker with fruit flies. The landmark discovery in 1996 in Baker's lab of the pivotal role of fruitless as a master gene governing sexual behavior contributed to this revival, but it was not alone. Last year, for example, researchers at the California Institute of Technology identified a ''Methuselah'' gene that extends the fly's life span.
This summer, a team of scientists is expected to finish sequencing the fruit fly's genome, which comprises 20,000 genes, as a trial run for tackling the human genome. Baker's own lab is a magnet for aspiring young geneticists, many of them casually dressed in jeans and T-shirts as they splice the fruitless gene to identify which segments affect specific aspects of mating.
Previously valued in academic labs mainly for its hardiness, availability, and rapid reproductive cycle, the fruit fly turns out to offer another bonus: genetically, it has more in common with you and me than scientists ever suspected. In a recent magazine article, a scientist described drosophilae as ''little people with wings.''
For example, even though human hearts look nothing like the fruit fly's simple, tubelike one, the same ''tin man'' gene is fundamental to building both. If a human copy of the gene is substituted in drosophila for a mutant fly gene involved in sex determination, the human DNA will supply the missing function. ''Drosophila research today is bigger than it's ever been and growing very rapidly,'' says the 52-year-old Baker. ''Back in the mid-1980s, few people would have said that humans and flies are built the same way. Yet, what the last 10 to 15 years have shown us is that the same genes working in largely the same way underlie a vast array of biological processes.''
These similarities raise worrisome questions that could affect social policy and psychological theory for generationsThe research of Baker and others shows that genes in fruit flies control not only body construction but also complex sexual behaviors. Male flies with one mutant form of fruitless, for example, no longer court the opposite sex. In a test tube, half a dozen such males march in step in what Hatzidakis calls a ''conga dance.'' They're telling females, ''Shoo, fly, don't bother me.''
It is not known yet whether a similar master gene influences human courtship. Scientists have identified a gene on the Y chromosome that determines gender, but they're just starting to dissect the genetic underpinnings of sexual behavior. A recent article in the journal Science disputed earlier findings linking male homosexuality to a small region of genes on the X chromosome. If the parallels between flies and humans are stretched far enough, ethicists warn, they could justify genetic screening of job and insurance applicants not only for medical conditions but also for aggressive or antisocial propensities. Or they could lead to eugenics - breeding to reduce or eliminate behaviors that are considered undesirable.
As they do in drosophila, Baker believes, genes regulate behaviors required for evolutionary survival in other species, from ducks nurturing their young to spiders preying on flies. ''If evolution has paid attention to making body parts, it must pay attention to making sure that those body parts function correctly,'' he says. ''It seems to me likely that there is a gene-brain-behavior circuit in higher organisms.''
But he stops short of drawing conclusions about human behavior from fruit flies. People may be genetically predisposed to certain behaviors just as they are to diseases such as breast cancer, he says, but environment has an impact as well. Using a computer metaphor, he suggests that humans and flies share the same basic hardware, but flies are running a primitive software program, while humans enjoy an upgraded version, with more options. And he warns against stigmatizing alternative lifestyles. ''There's a touchy ground with any behavior,'' he says. ''What's normal? How does society define that? It's a very dangerous ground. One would hope society would define a lot of behaviors as normal.''
Studying drosophila appears to be the norm in the Baker family; his father, now retired, also devoted his career to it.Because its reproductive cycle takes only 10 days, because one female can have 400 or more offspring, and because it easily adapts to the indoors, drosophila has appealed to geneticists ever since Harvard's William Castle became the first lord of the flies in 1901.
Over three decades, Bruce Baker has sought to identify the cascade of genes governing the fruit fly's sexual behavior, of which 24 are now known. In the early 1990s, research at Oregon State University into an abdominal muscle found only in male fruit flies indicated a gap in the genetic hierarchy. Lisa Ryner, a researcher in Baker's lab, designed a DNA probe to unmask the mystery gene.
''This was totally a side project,'' Ryner says. ''I showed it to Bruce. He was like, 'Yeah, yeah.' He was a little more skeptical than I was. I was fairly new to flies.'' Then an obscure gene - fruitless - matched the probe. Subsequent research at Baker's lab, Oregon State, Brandeis University, and the University of Texas Southwestern Medical Center showed that fruitless is expressed in 500 drosophila brain cells - 0.5 percent of the insect's central nervous system - which command other neurons to carry out courtship rituals such as tapping, singing, and copulation itself. Stanford and the University of Texas Southwestern have patented the fruitless gene, which could have commercial applications in pest control.
Today, fruitless is more than a sideline in Baker's lab, which contains all the technology of modern genetics, such as a $250,000 confocal microscope. Hatzidakis uses this laser scanning device to examine and store cross-sectional images of fly brains. The lab shelves are lined with bottles, each one containing a different genetic strain of flies and a pudding of cornmeal, yeast, sugar, and water. In a hallway, fly genes cloned in bacteria cultures multiply in shaking incubators.
No longer new to flies, Ryner is now mapping the 140,000 rungs in the DNA ladder of fruitless, while Hatzidakis and Reynaud untangle the gene-brain-behavior circuit. ''We know that fruitless controls sexual behavior,'' Reynaud says. ''But we don't know exactly how.''
For her dissertation, Hatzidakis is searching for segments of fruitless that govern the gene's synthesis in as few as eight brain cells. Once she locates these segments, she can introduce another gene called ''reaper'' into the fly embryos. When the fly matures, reaper will induce those eight neurons to commit suicide, and Hatzidakis can identify the missing courtship behavior controlled by the fruitless fragment. One fragment, for instance, might control the fly's extension or vibration of its wings during a courtship song.
From a beaker in her ''dungeon,'' Hatzidakis extracts drosophila embryos, visible as white dots. Then she dips them in a bleach solution to remove their outer shells, strains out the bleach through a mesh, and lays the embryos on double-stick tape on slides - ready to be injected with the DNA cocktail. ''We've got fruitless in 500 brain cells,'' Hatzidakis says. ''We want to track eight cells and selectively kill them. We want to learn what was it in those eight cells that affected reproduction.'' Her eyes shine again with the spirit of discovery. ''Eight is a beautiful number.''
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