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Fruit Fly’s Beating Heart Helps Identify Human Heart Disease Genes

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Duke Health News 919-660-1306

DURHAM, N.C. -- In a discovery that could greatly accelerate
the search for genetic causes of heart disease, a
multi-disciplinary Duke University research team has found that
the common fruit fly can serve as a powerful new model for
testing human genes implicated in heart disease.

The finding is important, the Duke team said, because the
entire genome of the fruit fly is well understood and
catalogued, enabling researchers to systemically screen genes
to identify potential gene mutations or variants implicated in
human heart disease. The achievement also raises the possible
of rapid screening in fruit flies of drugs to treat heart
disease, said the researchers.

The team's bioengineers adapted an existing imaging
technology to visualize in detail for the first time the
beating of the heart of a fruit fly, an insect the size of a
grain of rice. The fly's heart is about the size of the period
at the end of this sentence.

After perfecting the new visualization technique, the
researchers inserted into the fly genome a mutated gene that
causes dilated cardiomyopathy in humans. This condition is
often the cause of heart failure in humans and is characterized
by heart muscle that has greatly enlarged and therefore is
unable to pump blood efficiently. The moving images revealed
that fly heart looked and acted just like a human heart with
the same condition.

"The difficulty in performing studies to find specific genes
that cause disease in humans is that you need large families
with members afflicted with the disease," said Matthew J. Wolf,
M.D., Ph.D., Duke Medical Center cardiology fellow and first
author of paper appearing Jan. 23, 2006, in the Early Edition
of the Proceedings of the National Academy of Sciences. "This
can be a quite a complex and laborious undertaking. Even in
mouse models of human disease, the process of screening for
genes can take a long time.

"However, fruit flies, with their well-documented genome and
rapid life-cycle, have the potential to greatly speed the
process of finding and verifying candidate human genes for
heart disease," Wolf continued. "In our experiments, we were
able to demonstrate for the first time that a mutated gene that
causes a specific heart disease in a human causes the same
disease in the fruit fly."

Senior author on the paper was cardiologist Howard Rockman,
M.D. Other co-authors were fruit fly geneticist Hubert Amrein,
Ph.D. in Duke Medical Center, and bioengineers Joseph Izatt,
Ph.D. and Michael Choma, Ph.D. of Duke's Pratt School of
Engineering. The research was supported by the National
Institutes of Health.

In recognition of his research, the American Heart
Association bestowed upon Wolf its prestigious Louis N. and
Arnold M. Katz Basic Research Prize in November during its
annual scientific sessions. This is the second year in a row
that a trainee in Rockman's lab has won the Katz prize. Last
year, Naga Prasad, Ph.D. received the award.

In the past, researchers could not accurately study heart
disease in fruit flies because of an inability to accurately
image heart function of a living adult fly. Past investigators
have measured the size of the heart and then made assumptions
about what was happening inside, or dissected flies after
death.

For their experiments, the Duke team adapted a technology
known as optical coherence tomography (OCT), which is commonly
used to measure the thickness of the retina in the eye, to
obtain detailed images of the beating heart of an adult,
unanesthetized fly.

"After inserting into the fly the gene that we know is
implicated in dilated cardiomyopathy in humans, we imaged the
adult fly with this novel system and what we saw looked exactly
like the same condition in humans," Wolf said. "We obtained
clear images that looked similar to an echocardiography study
of a human patient with heart failure."

According to Rockman, about 80 percent of the gene mutations
known to cause disease in humans have an equivalent in the
fruit fly.

"If there is a mutation in a gene that causes a disease in
the fruit fly, then there is a very good chance that there is a
corresponding gene in humans," Rockman said. "It is an enormous
breakthrough to demonstrate that a human gene can induce
disease in a fly. With this novel fruit fly model, we can now
screen genes we believe are involved in human heart disease and
test them in the fly model."

If a candidate human gene leads to the same physiological
effects in the fly as it does in humans, researchers can then
not only test different compounds or drugs, but do so much
quicker than in other mammal models of disease.

"These findings have the potential to change the way we do
genetic screening to identify candidate disease-causing genes,"
Rockman continued. "Never before have we been able to actually
visualize in the fruit fly the actual physiologic changes
caused by dilated cardiomyopathy."

The Duke team is currently screening the entire genome of
the fruit fly for additional candidate genes involved with
dilated cardiomyopathy, a process which should take another six
to nine months.

"We are now screening the entire fruit fly genome gene by
gene, and determining whether the removal of the gene or a
mutated version results in heart failure in the fly," Wolf
explained. "With this new model, we can rapidly correlate
abnormal heart functioning with a specific gene mutation."

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