U of G grad suffering from Friedreich's ataxia helps put human face on research
BY ANDREW VOWLES
Helping scientists battle a rare genetic disorder that normally kills by early adulthood is the research goal of Guelph fruit fly geneticists whose new model may eventually lead to the development of therapies for treating the disease.
Prof. John Phillips, Molecular and Cellular Biology, and PhD candidate Peter Anderson have published a journal article on the first-ever fruit fly model for studying the neurodegenerative disease. Their paper, listing Anderson as the lead author, was published this fall in Human Molecular Genetics.
The scientists hope their work will ultimately yield treatments for Friedreich's ataxia, an inherited disease that affects one in about 50,000 people in the United States — and that afflicts one particular Guelph graduate who, wheelchair and all, has visited their lab to see their research first-hand.
People normally develop the disorder between the ages of five and 15 and are usually wheelchair-bound within 20 years of showing the first symptoms. It causes progressive muscle weakness and loss of co-ordination in the limbs, vision and hearing impairments, spine curvature and serious heart disease. Most people die in early adulthood of heart complications.
No cure or treatment exists. The disease is named for Hans Friedreich, the doctor who first diagnosed the disorder separately from other forms of ataxia — neurodegenerative diseases that affect movement.
The Guelph scientists have developed the first-ever “knockdown” model in fruit flies for this particular disease. Scientists already use “knockout” mouse models in which rodents bred with the disease-causing mutation are unable to make a protein involved in cells' energy-making machinery.
In the U of G model, fruit flies make reduced amounts of this frataxin protein as in human patients. That may give other researchers and clinicians a new tool to study treatments such as nutrition or other environmental factors, says Phillips.
“If anyone has a potential therapeutic molecule or we have an idea about how to correct this failure of frataxin synthesis and make flies better, that might be something that could be used for people,” he says.
He became interested in Friedreich's ataxia after noting similarities between the disease and his own research field, especially the effects of free oxygen radicals on normal aging and in Lou Gehrig's disease.
People with Friedreich's have severely reduced amounts of frataxin, a protein that normally helps to control iron distribution in tissues. They also have excess iron in their blood.
“Excess iron is a co-conspirator with reactive oxygen in doing bad things to cells,” says Phillips.
In his Axelrod Building lab, he and Anderson created mutant fly embryos, raised the larvae on a corn meal “porridge” in growth chambers and tested the adults on a kind of fruit fly jungle gym. (They stuck together a series of plastic pipette tips — normally used to deliver precise amounts of liquids — to assemble an upright tower about as long as a forearm, then compared the climbing abilities of normal and mutated flies inside it.)
Altering the frataxin gene had a dramatic and unexpected effect on the flies' life cycle. Normally, fruit flies spend about 10 days as larvae, doing nothing but bulking up for metamorphosis. Adults live for about 90 days.
But the genetically altered flies didn't metamorphose until after 45 days — almost half the normal lifespan of a fruit fly. Many plumped out to more than twice normal size, then died before pupating.
“Ours want to stay larvae,” says Anderson.
In fact, fewer than one per cent become adults, and they survive for only about five days. They appear normal for the first two or three days, then rapidly lose co-ordination and motor skills and are soon unable to move at all.
Anderson says he hadn't known what behaviour to expect, let alone the delayed larval stage. “It's like a medical student walking into a hospital and the instructor says: ‘Tell me what's wrong with this patient.'”
To make sure, he repeated his experiments and did other genetic and biochemical tests to verify the results.
Phillips stresses that they're not actually witnessing human ataxia symptoms in the flies. What's important, he says, is that the flies offer an experimental model in which changes may be traced to the mutated gene.
Noting that U.S. researchers have asked about the model and a candidate treatment compound, he adds that more work needs to be done using various animal models and approaches.
“It would be naive to say we're going to find a cure for Friedreich's ataxia. We'd be happy to identify other genes that would improve lives and that would give ideas of therapeutic interventions.”
That idea gained poignancy when Phillips got a phone call last year from Brent Moore, a Guelph zoology graduate. Moore was initially diagnosed with the disease during the first year of his undergraduate degree at U of G. He was still walking unaided when he graduated in 1995 but was falling more often. By age 29, he was using a wheelchair all the time.
Two years ago, Moore spotted a description of Phillips's work on animal models at an ataxia conference in Georgia. After reading again about the U of G research in a magazine published by the National Ataxia Foundation based in Minnesota, he called Phillips.
“I thought it'd be good for both of us,” says Moore, who lives in Ayr. “He and Peter could put a person to the fruit fly.”
Recalling his Guelph studies — and especially how he'd been able to put his own face on things he'd learned in genetics and molecular biology classes — Moore adds: “I'm interested in the biological aspect of it.”
He was also keen to learn what their research might ultimately hold for ataxia patients like himself, his girlfriend and a younger brother (another brother doesn't have ataxia but is a carrier of the genetic disorder). Acknowledging the distance between a fruit fly model and a treatment — let alone a cure — for the disease, he insists that the researchers' work is important.
“The fruit flies may seem trivial to some, but John and Peter could help a lot of people.”
Moore plans to return to college next year to study geographic information systems. Noting that some people with less severe forms of Friedreich's have lived into their eighties, the 34-year-old says: “I'm optimistic about the future and not sitting around waiting for a cure. I'm going ahead and living my life. But if a treatment comes along — great.”
Having the rare chance to put a human face on his research has made a difference for Phillips as well (he was also contacted this fall by a man whose 12-year-old son has the disorder). He confesses he had mixed feelings about meeting Moore, who is about his own son's age.
“I wasn't flooded with any sense of: ‘Gee, aren't we wonderful, we're saving humankind here.' It was an overwhelming sense that here's a person who had such a positive and healthful attitude about himself, including being realistic about his prospects.”
Their research is supported by the National Ataxia Foundation, the Canadian Institutes of Health Research, and the Natural Sciences and Engineering Research Council.
