MADISON - With a slight tweak of temperature, geneticist Barry Ganetzky's flies drop like, well, flies. For 25 years, Ganetzky has been identifying, breeding and studying a raft of fly mutants that, when exposed to minor temperature change, become completely paralyzed. The flies, which quickly recover when returned to room temperature, are now finding many uses in studies of human neurological disorders, drug discovery and insecticide development.
Ganetzky, a University of Wisconsin-Madison professor of genetics, and his colleagues have become the undisputed champions of finding such mutants, raising the tally to upward of 100 such strains over the years.
"At room temperature, they are almost indistinguishable from normal flies," says Ganetzky of the genetic variants of the fly species Drosophila melanogaster, a workhorse of modern genetics and molecular biology. But if you expose them to slightly elevated temperatures in the range of human body temperature, "in less than 10 seconds, some mutants are completely paralyzed. Others become totally incapacitated by convulsive seizures. It's like flipping a switch. All we change is one variable - temperature."
The effect is a rapid loss of normal motor activity.
Such a handy model, Ganetzky explains, has tremendous potential for studies of disorders such as epilepsy, muscular dystrophies and a range of other neuromuscular disorders. What's more, the flies promise a window to identifying genes - many of which have human counterparts - involved in neural function and disease.
"Because the molecular mechanisms of neural function are highly conserved, whatever we learn from studying flies is likely to have important implications for humans as well," says Ganetzky.
The flies' sensitivity to temperature provides a unique ability to control the onset of their physiological defects, and is useful in helping researchers identify specific genes that may be involved in regulating how brain cells function.
For instance, molecular analysis of one of their mutants enabled Ganetzky's group to identify and clone a gene that encodes sodium-channel proteins in brain cells. The influx of sodium ions into brain cells through sodium channels is the essential step in generating nerve impulses.
The isolation of the fly sodium-channel gene has spurred research on insecticide development because sodium channels are key targets of commonly used insecticides, and resistance to these insecticides is often associated with mutations of this gene. Using the Drosophila gene as a probe, other labs have now cloned the corresponding genes in many other insects, including such major pests as cockroaches and mosquitoes.
Moreover, the type of ion channel deficiencies found in some of Ganetzky's fly mutants manifest themselves in humans suffering from such afflictions as epilepsy and cardiac arrhythmias.
"Each fly (mutant) is a door or a window into some biological activity I want to understand," Ganetzky notes. "When those activities are perturbed because of a mutation, the mutant flies become paralyzed at elevated temperatures. Disruption of the same or similar functions in humans could also produce some type of disease manifestation. As a result, these mutants potentially give us some insight into these disorders."
As one example, Ganetzky's group discovered and cloned a human gene known as Herg. That gene was the counterpart to one of the fly genes identified among their many mutants. In humans, mutations of Herg cause a cardiac arrhythmia that can result in ventricular fibrillation and sudden death. Dozens of labs worldwide are now investigating Herg and the potassium channel protein it encodes.
Such discoveries have engendered significant interest on the part of the pharmaceutical industry. For instance, in the United States all drugs now headed to market must be screened to ensure that they do not perturb the function of Herg channels and possibly cause heart problems in patients. The tendency to affect such channels was the reason that Seldane, a popular asthma medication, was pulled from the market.
Adding to the mutant flies' cachet, recent work by Ganetzky and post-doctoral fellow Michael Palladino showed that some of the mutants in their collection undergo progressive, age-dependent neurodegeneration resulting in the widespread death of brain cells.
"The neuropathology observed in these mutants is very reminiscent of that in human disorders such as Alzheimer's disease and Parkinson's disease," says Ganetzky. "Such disorders are a growing human health concern, but the underlying cellular mechanisms are still poorly understood. These mutants should provide us with valuable new insights into the molecular basis of neurodegeneration in both flies and humans."
Ganetzky believes his collection of fly models, which has been licensed by the Wisconsin Alumni Research Foundation, could become a rich resource to help pharmaceutical companies identify new biological targets and develop new high-volume screens for drug development.
"I think the mutants have real value to give us novel information about neural disorders and human disease," Ganetzky asserts. "We can't even begin to guess what new insight might be lurking in these flies."
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