Sci. Aging Knowl. Environ., 30 October 2002
Flies Like Us
In the movie The Fly, a scientist mixes his DNA with a fly's and turns into a giant insect with problem body hair. Outside of Hollywood, scientists are mixing human and fly DNA to tease out the secrets of brain-destroying diseases
Abstract: Although our lineage separated from theirs 500 million years ago, fruit flies are proving to be informative models for human neurodegenerative diseases. Scientists have augmented the insects with human disease-causing genes, reproducing the molecular mayhem and some of the symptoms of Parkinson's disease, Huntington's disease, and other killers. The insects are easy to genetically manipulate, get old in a hurry, and are light on the wallet, making them valuable for untangling the molecular causes of neural degeneration and screening potential treatments. Using flies carrying a gene that is defective in some Parkinson's patients, scientists have already identified a protein that suppresses the neural damage from the disease.
Although they demolish different kinds of brain cells and provoke disparate symptoms, neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's share some striking similarities. In all of these relentless illnesses, abnormal protein clots proliferate inside brain cells, which die in droves. Despite tantalizing clues, neuroscientists are mystified by crucial questions, such as what exactly kills brain cells and how to halt or reverse the neural decline and fall.
To help untangle these gnarled questions about the human brain, a small swarm of researchers is turning to a helper with a brain the size of a poppy seed. The scientists have enlisted fruit flies engineered to produce proteins implicated in the brain-wrecking diseases. Flitting around with chunks of human DNA in their heads, the flies develop some of the same symptoms as do human patients and replicate many of the molecular defects. Flies are cheap and easy to rear. They age fast. And after a century of crossbreeding strains, scrutinizing mutants, and fiddling with Drosophila DNA, scientists understand the fly's genetics as well as that of any other creature. Researchers are already beginning to reap insights from work on engineered flies, and they anticipate many more advances. Untangling the metabolic pathways behind the diseases might flush out genetic accomplices that hurry brain deterioration; researchers might also finger protective genes or pinpoint environmental insults that provoke symptoms.
By enabling researchers to swiftly screen potential drugs, the engineered flies might speed the search for elusive treatments. Neurogeneticist Nancy Bonini of the University of Pennsylvania in Philadelphia describes the souped-up insects, which have been in use for only 4 years, as the "premier model for studying human neurodegenerative diseases."
Catching the Buzz
Fruit flies keel over from their own brain-destroying diseases, which some neuroscientists hope to harness as models of human illnesses. The names of the mutants vividly describe what happens to the unfortunate fly (drop-dead) or its brain (swiss cheese, spongecake). However, the bubblegum mutant, named for the blisters that form on the outer surface of the optic lobes, is one of the few flies whose fault has a counterpart in humans. The insect's brain clogs with extra-long chains of fatty acids, just as in the rare childhood disease adrenoleukodystrophy, featured in the movie Lorenzo's Oil.
For most human neurodegenerative diseases, no fly version has surfaced. So in 1998 Bonini and colleagues decided to make one. They outfitted Drosophila with a fragment of the gene that triggers Machado-Joseph disease, also known as spinocerebellar ataxia type 3. In people with the disorder, large numbers of neurons in the cerebellum and brain stem perish, short-circuiting muscle coordination and leading to clumsiness, immobility, and sometimes death. Like the culprit in the more famous Huntington's disease, the defective protein responsible for Machado-Joseph disease totes too many copies of the amino acid glutamine.
The researchers switched on the gene fragment only in the eye. "I figured it would just kill the cells," says Bonini. It did: The flies' eyes turned to mush as the light-gathering cells died. But the researchers noticed something else. The deterioration followed the same pattern as in human neurodegenerative diseases: It was progressive and began late in life. Before they melted, the cells accumulated abnormal gobs of protein, a defining characteristic of Machado-Joseph disease, as it is in Alzheimer's disease, Parkinson's disease, and Huntington's disease (see "Detangling Alzheimer's Disease"; Alzheimer's Disease Case Study; Andersen Review; and Parkinson's Disease Case Study).
Other researchers have broadened the stable of models by inserting the huntingtin protein that triggers Huntington's disease (see "Procrastination Pays"). Neuropathologist Mel Feany of Harvard Medical School in Boston and colleagues created flies that make the protein tau--tangles of which clutter the neurons of Alzheimer's patients--or carry the gene for -synuclein, which is mutated in inherited types of Parkinson's disease.
The Parkinson's disease flies mimic several features of the human illness. In patients, neurons that exude the neurotransmitter dopamine die off, but only in a small brain region known as the substantia nigra. Flies don't have a substantia nigra, but Feany and colleagues saw a similar selectivity in the insects: Only dopamine-producing neurons perished. Like Parkinson's patients, the flies amassed clumps of -synuclein in their brain cells and grew immobile with age. They normally prefer to rest at the top of their home tube. Knock the flies to the bottom by rapping the tube, and young, hale insects immediately begin scaling the walls. But as flies grow older, fewer and fewer can climb to the top. The insects carrying the -synuclein gene lost their climbing ability faster than normal, the researchers found, suggesting that they were also losing muscular control.
All of these gene-addition experiments tell the same story. The flies display late-onset, progressive neurodegeneration; death of certain types of cells; and protein clumping inside neurons--the hallmarks of human brain diseases. "The striking similarities [between fly and human conditions] have made people take note," says Bonini.
Researchers have also taken note of how easily and cheaply they can nurture vast swarms of engineered flies. Rearing 100+ flies from egg to adulthood costs about 25 cents, says Bonini, a third of the cost of raising a single mouse for a day. The bugs boast other assets, too. Their brief life-span of 1 to 2 months means that investigators don't have to wait a year or more for late-onset ailments to erupt. Despite more than 500 million years of independent evolution, the genetic pathways that orchestrate development are very similar in humans and fruit flies. And a clever trick makes it easy to create a variety of transgenic animals. Scientists yoke the disease gene to an on-off switch. Then they crossbreed flies carrying this combination with standard lines, available from biological supply houses, that produce the molecule that flips the switch only in certain tissues. With a minimum of genetic fiddling, the researchers can dictate where in the offspring the gene will be active--down to the tissue or even to the cell type--and can govern how much protein the cell will crank out.
Flies are cheap, but so are worms and yeast. However, single-celled yeast don't grow neurons or brains. Flies rise above worms for a couple of reasons, says Bonini. The insects have more genes in common with humans than do worms. Furthermore, flies seem to better mimic human diseases. For example, Feany notes that in worms engineered to carry the huntingtin protein, the protein clots do not appear inside the nucleus--unlike in flies and humans.
No one expects flies to replace other model organisms, says Bonini. Yeast, worms, and mice continue to furnish insights about neurodegenerative diseases. For example, researchers have concocted "Alzheimer's mice" that sport mutant forms of tau and the -amyloid precursor protein, which enzymes snip to release amyloid, the main ingredient of Alzheimer's plaques. Mice with both mutated genes have the defining features of human Alzheimer's disease: amyloid plaques and neurofibrillary tangles.
Researchers are mindful of the physiological, genetic, and anatomical differences between humans and flies, says neurogeneticist Huda Zoghbi of Baylor College of Medicine in Houston. Because of their low cost and genetic flexibility, flies are ideal for exploratory work, such as screening drugs or identifying genes that abet disease-causing genes, whereas mice serve as a reality check. "Ideally, you would want to validate any discovery in mice," says Zoghbi, who has used both animals in her studies of inherited brain degeneration.
However, one apparent advantage of mice--their more humanlike brain--isn't important, says Bonini. Although flies are pinheads, brain size doesn't really matter, she says. No fly will ever deconstruct Proust or solve a differential equation, but "the fly has a pretty good brain." Like ours, it is made of units with different functions and controls an assortment of complex behaviors.
Studies of humanized Drosophila are just getting off the ground, but fly mavens can already hail some provocative results. For example, many scientists have assumed that tau clusters kill brain cells. But a paper published last year by Feany and colleagues suggests otherwise. In tau-making flies, they found, neurons died but the telltale tangles never appeared. The difference could reflect a peculiarity of fly metabolism, but it could also signal that tau is a byproduct of an unidentified cell-killing process rather than a cause, says Feany.
Bonini and Feany say they're confident that more insights are on the way. Feany asserts that flies might allow scientists to attack some of the refractory problems in neurodegenerative diseases, such as what drives mass cell death once protein clumps start to materialize. To nab genes that aid or hinder the disease of interest, researchers can systematically knock out fly genes, determining how the loss of the protein affects the progress of neural destruction. Two years ago, for instance, Zoghbi and colleagues disabled scores of genes in flies programmed to produce ataxin-1, the protein responsible for spinocerebellar ataxia type 1, another crippling neurodegenerative disease. They found 17 genes that slowed neural deterioration and 43 that sped it up. Some of the targets helped regulate other genes or detoxified nasties, which suggests that ataxin could kill by fouling up these cellular tasks. To perform the same studies in mice would have taken years and shattered most researchers' budgets.
Drosophila buzzing around with human genes won't solve every question about neurodegenerative diseases. "Flies are an excellent model for what goes wrong inside a neuron," says Feany. "They aren't so good for what goes wrong with a neural circuit," such as the network of cells that allows us to perform precise movements: hitting a backhand or plucking a guitar. As a result, she says, flies will probably tell us little about how brain damage produces symptoms such as tremor, muscle rigidity, and clumsiness.
The speed and low cost of fly experiments might help scientists parlay molecular discoveries into treatments, which would be the biggest payoff of the models. Work by Bonini and colleagues, published in the 1 February issue of Science, identifies a possible approach for treating neurodegenerative diseases. The researchers halted neurodegeneration in Parkinson's disease flies by also engineering them to make a human protein called HSP70. The protein, normally spilled out during times of stress, helps other proteins fold into the correct shape. The findings suggest that errors in this molecular origami might underlie cell death and that cranking up HSP70 production could curtail or even reverse neural damage. Bonini's group showed 3 years ago that the same molecule can suppress Machado-Joseph disease in flies. "As a physician, I think that [drug screening] will have tremendous implications for therapy," says Feany.
I've Fallen and I Can't Get Up
A nagging question about neurodegenerative diseases is why they most often pick on the elderly. The lack of reliable markers of aging in humans and other creatures hampers work on this question. For example, rumple-faced guitarist Keith Richards of the Rolling Stones is the butt of late-night comics' jokes, whereas sleek Mick Jagger wins raves for keeping his physique and looks. Yet no test can tell us whether Richards, who was born 5 months after Jagger in 1943 but looks years older, is older physiologically.
A newly discovered fly behavior might help track the progress of aging in the insects, although it probably won't tell us much about rock musicians. Older Mediterranean fruit flies, cousins of Drosophila despised by California fruit growers, fall onto their backs with no apparent stimulus. If prodded with a pencil, they usually right themselves; often they flip over on their own after lying motionless for minutes or hours with their legs sticking up in the air.
Entomologist Nikos Papadopoulos of the University of Thessalon�ki in Greece, demographer Jim Carey of the University of California, Davis, and their colleagues described the "supine behavior" in the September Proceedings of the Royal Society. Flies begin flopping in late middle age, and as they grow older they spend more and more time inverted. From the first time a fly flops, it has only about 16 days to live, which makes the behavior an accurate clock for death: the first precise marker of aging in these organisms. The behavior might allow scientists to pinpoint the onset and causes of neural deterioration. Drosophila researchers haven't noticed the behavior, but Carey says that they might have mistaken the fallen flies for dead ones and pitched them into the trash.
Like many of the Drosophila results so far, the flopping flies raise a cloud of questions that await further study. As research on flies as models of neurodegeneration advances, scientists expect to start answering those questions. If you want to spot new developments in these fields, they say, keep your eyes on the flies.
October 30, 2002
Mitch Leslie writes about science and squashes flies in Albuquerque, New Mexico.
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Citation: M. Leslie, Flies Like Us. Science's SAGE KE (30 October 2002), http://sageke.sciencemag.org/cgi/content/full/sageke;2002/43/ns7
Science of Aging Knowledge Environment. ISSN 1539-6150