Clockwise from top left: Nancy Bonini, Arthur Horwich, Hugo Bellen, and Kevin Eggan. These HHMI investigators are contributing new models for studying ALS and testing new treatments.

Fruit flies have been a favorite of developmental biologists since the 1970s, with their rapid reproduction and easily manipulated genome. In 1998, however, Bonini authored an idea that radically extended the scientific reach of the humble insect. She mused that inserting genes related to human brain diseases might yield critical insights into poorly understood neurodegenerative conditions, including Huntington's disease, Parkinson's disease, and ALS. "I saw it as, 'Hey, there are all these terrible diseases and nobody is really studying them in model organisms,'" Bonini says. "I knew it was a high-risk thing."

That risk is paying off. In August, Bonini and colleagues announced in Nature a genetic factor that contributes to ALS in some patients. Bonini collaborated with Aaron Gitler, a Penn colleague who studies ALS genetics in yeast. Both are keen to define additional genes involved in ALS. Says Gitler: "My hope is that in the next three to five years we find all of the genetic contributors to ALS."

		Studying Neurodegeneration in Fruit Flies Fruit flies on the left carry a human gene that’s linked to ALS, while those on the right are normal.

Bonini and Gitler's powerful fly and yeast tools are proving themselves just as other advanced animal models to study the disease are coming online. At Yale Medical School, HHMI investigator Arthur Horwich has developed Caenorhabditis elegans roundworms as a model organism for studying nerve degeneration, while both Horwich and HHMI investigator Hugo Bellen at Baylor College of Medicine have bred colonies of mutant mice that reliably develop ALS. Meanwhile, at the Harvard Stem Cell Institute, HHMI early career scientist Kevin Eggan is incubating dishes of human motor neurons grown from the skin cells of patients with the disease. Never before have researchers had access to human motor neurons in the laboratory, let alone nerve cells harboring the disease.

During the past 5 to 10 years, there has "almost been a renaissance in model organism genetics, applying them to human brain diseases," says Bonini. "It's been really exciting."

Sorely Needed Methods

Collectively, these new weapons in the fight against ALS provide a huge leap in scientists' ability to divine the genetic and molecular origins of the disease, says Amelie Gubitz, program director for neurodegeneration at the National Institute of Neurological Disorders and Stroke (NINDS). The menagerie of ALS animal models should also speed the development of drugs, she says.

In the past 15 years or so, patients and their families have experienced disappointment after disappointment as two dozen initially promising ALS drugs ultimately failed to help patients. Most recently, in 2009, a NINDS safety board halted a large trial of the brain drug lithium after determining it provided no benefit to patients. Though there could be many reasons why the trials failed, says Gubitz, one possibility is that the drugs were tested in animal models that did not faithfully reproduce the disease. That's why there is now "a big push to integrate the new animal models into the drug discovery pipeline."

Photos: Bonini: Nick Antony, Horwich: Chris Jones, Bellen: Misty Keasler, Eggan: New York Stem Cell Foundation

	PAGE 1 2 3 4 5	Go Back | Continue