Fruit Fly's Beating Heart Helps Identify Human Heart Disease Genes
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."