Fruit Fly Love
UMaine biologist Harold Dowse attracted to Drosophila heartbeats and
courtship songs
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 coauthored 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." Allison 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.
by Luther Young
January-February, 2006
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