Timing flies By studying heartbeals and courtship songs of common fruit flies, a UMaine biologist and his students advance understanding about humans

loading...

Editor’s Note: The following story is reprinted with permission from “UMaine Today,” the University of Maine magazine.

Harold “Dusty” Dowse looks at fruit flies differently from the rest of us. While we may wonder how the pests magically appear when a ripe banana calls, he wonders what makes their little hearts beat, and what governs their biological clocks and sonorous courtship “songs.”

For 25 years, Dowse, a professor of biological sciences at the University of Maine, has probed and measured and recorded Drosophila melanogaster, or the common fruit fly, using the insect’s remarkable modeling of fundamental mammalian biology to seek clues to human disease and development.

Along the way, he has established a niche as one of the research community’s leading “fly people,” as the tight-knit group of Drosophila investigators is called. Dowse has published more than 50 papers in peer-reviewed journals and shepherded generations of graduate students into professional research careers, many focused on fruit flies.

“You have to pay homage to Drosophila,” Dowse says, referring to the fly’s nearly 100-year history as an intensively studied model organism, and its major contributions to the modern understanding of genetics and developmental biology. “Their genome is moderate in size, they have short life cycles, they’re easy to care for. Why use anything else?”

Those who conduct research with mice or worms could probably come up with some reasons. Fruit flies are just a sixteenth of an inch long and tend to escape to far corners of the laboratory unless soundly anesthetized with carbon dioxide. An entire experiment can be ruined by a sneeze or stumble. Manipulating them calls for the dexterity and the patience of a jeweler.

But Dowse, 60, knows his flies, inside and out, after working with Drosophila for much of his career, and he relishes spreading the gospel about the “exotic” research taking place in his various inner sanctums located throughout Murray Hall, assisted these days by graduate students Nick Brandmeir and Allison Cox.

Widely recognized on campus, not just for his longtime tenure and ubiquitous teaching, but for his dark bushy beard, colorful do-rag, earring and the Harley he rides from his home in rural Cambridge, Dowse is an independent sort, a laid-back father figure to his many students and a tinkerer who invents and builds much of his own laboratory equipment.

“I walked in the front door here in 1979 and said to the secretary, ‘I’m looking for work,'” recalls Dowse, who graduated with a Ph.D. in biology from New York University in 1971. During his eight-year, post-graduate hiatus, the Albany, N.Y., native worked as a short-order cook at a truck stop and as an electrician’s helper, and built custom wood cabinets in his own business.

He was rescued from the UMaine doorstep by Frank Roberts, then-chair of the Zoology Department, and hired as a half-time instructor in comparative anatomy. By 1986, he was solidly established in a tenure-track position in what is now the Department of Biological Sciences and collaborating with colleague John Ringo, a Drosophila geneticist who studies their cardiac rhythms and mating behavior; with fruit fly neurogenetics researcher and National Academy of Sciences member Jeffrey Hall of Brandeis University; and others around the country.

Dowse’s entry into the Drosophila research arena came some 70 years after Thomas Hunt Morgan and three of his students at Columbia University pioneered the study of mutations in fruit flies to formulate the chromosome theory of inheritance. Within a few years, Drosophila had enabled a slew of discoveries, including the first proof that chromosomes contain genes and that ionizing radiation causes genetic damage.

But it was in the late ’70s and early ’80s that the field took off, hand in hand with the revolution in molecular biology.

“The closer we looked, the more it became clear how similar the basic development processes are in all living things,” Dowse says. This conservation of biological function between species means that, if a gene can be identified in Drosophila, researchers have a good idea where to look for a “homologous” gene in humans.

In addition to such basic processes as the systematic implementation of the body’s structural blueprint during embryonic development, the homology extends to higher-order processes like learning, memory, sleep, neurodegeneration and addiction behaviors.

The release of the Drosophila genome sequence has further accelerated discovery, Dowse says. The collaborative sequencing effort – first published in March 2000 and steadily refined since then – confirmed that Drosophila has approximately 13,600 genes, compared to upward of 25,000 in humans, and only eight chromosomes, compared to 46 in humans.

Dowse’s early work at UMaine involved probing the genetic control of Drosophila’s biological clock, specifically circadian rhythms. The research benefited from his natural bent for mathematics, signal analysis and computer programming. “I’m the gray eminence in spectral analysis,” he jokes. “I still get calls and e-mails from people around the world asking for help with Fortran programs I wrote 20 years ago.”

But it’s another rhythm that has been the main focus of his laboratory since the early 1990s: heartbeat, which he studies in the pupal stage when Drosophila is still transparent and largely dormant. Heart movements – 120 beats per minute in normal flies – are monitored optically. The signal displays on a computer screen, through an apparatus he designed. “It’s noninvasive, I don’t have to anesthetize them,” Dowse says simply. “It seems the less you do to your organism, the better.”

His goal is to understand the cardiac pacemaker, the electrochemical oscillator that generates heartbeat. In 1995, Dowse co-authored research that proved insect hearts are myogenic – the heartbeat is generated in muscle – as opposed to neurogenic, or nerve-driven, as had been previously thought. Since mammalian heartbeat is also myogenic, and taking into account many other parallels, Drosophila can serve as a useful model for studying basic molecular mechanisms of human cardiac function.

To elucidate those inner workings, Dowse targets mutations in the fly that affect so-called ion channels, directional electrochemical gatekeepers in the cell that are critical to an organism’s nervous and muscular systems. His laboratory has studied a number of ion channel gene mutations that exhibit severe cardiac arrhythmias, including slowpoke, no-action-potential temperature sensitive, amnesiac, and ether-a-go-go, a bizarre defect that causes flies awaking from ether anesthesia “to bounce around like popcorn popping.”

In combination with the use of selective toxins and neurotransmitters, such as serotonin, norepinephrine and dopamine to systematically alter cardiac function, Dowse and his colleagues have identified two ion channels that constitute the core of the Drosophila pacemaker, and most likely play a similar role in mammalian systems.

“No pacemaker in any species has ever been completely worked out, but I’m confident I can get the major pieces in place within the next couple of years,” he says. “We already have most of the key players.”

The implications for human health are promising. Mutations in two genes originally discovered in Drosophila have been proven to underlie cardiac disorders in humans. The first is tinman, a developmental gene, which when defective causes heartbeat irregularities and has led to a screening in humans. Then there is the famous ether-a-go-go: its human counterpart has been implicated in Long QT2 syndrome, a defect suspected in the sudden collapse and death of young athletes.

“We’re not saying the Drosophila heart is identical to the human heart,” Dowse says. “But at the level of these basic mechanisms, Drosophila is making advances possible that can’t be made in humans.”

One such advance that definitely rules out human subjects is his study of Drosophila courtship songs, a frivolous-sounding enterprise that involves depositing male and female fruit flies in a small, clear plastic chamber – a honeymoon suite – and recording the male’s mating entreaties. Dowse places the vocalizations into two categories: a humming “sine song,” and “tone pulse song,” a buzz produced through rapid vibrations of the wings.

Drosophila courtship songs are astounding in their ethereal complexity. Songs of one species other than melanogaster (there are an estimated 900 species worldwide) even include a “female rejection sound.”

So? Through collaborations with Jeffrey Hall, who is in the process of retiring from Brandeis and has joined Dowse at UMaine, the courtship research has focused on the cacophony mutation, which – you guessed it – causes cacophonous mating songs in male fruit flies. And cacophony just happens to involve an ion channel defect that also affects heartbeat frequency and regularity.

“We’re apparently looking at the same thing in heart as in song,” says Dowse, stopping well short of any Valentine’s Day sentiment. “It’s an intriguing connection that we’re continuing to study.” Cox has made cacophony and courtship songs her master’s degree research project.

Down in the basement of Murray Hall, Dowse proudly shows off his collection of dozens of fruit fly-filled test tubes, each containing the food mixture that Drosophila like to eat best: molasses, agar, malt, brewer’s yeast, cornmeal. Each tube houses a different mutation, ordered directly from the nation’s premier fruit fly nursery, the Bloomington Stock Center in Indiana, or generously donated by colleagues.

It’s a deceptively simple, understated operation that belies the importance of what he’s done to help unravel the genetic mysteries of Drosophila melanogaster, and its related species, Homo sapiens.

“You can do so many things with flies,” Dowse says, still marveling after all these years.