Though no national registry tracks the numbers of rats and mice employed in research, a few years ago the National Association for Biomedical Research estimated that more than 30 million rodents were bred for this purpose, and that number has undoubtedly risen. But according to the U.S. Department of Agriculture, the number of experimental cats, dogs, rabbits, guinea pigs, hamsters, sheep, swine and primates has been dropping, from 1.5 million (not including many farm animals that are now counted) in 1973 to 1 million in 2006. The numbers of cats and dogs, each accounting for well under 1% of research animals, has been cut by two-thirds in three decades; the proverbial guinea pig, by half. Just two-thirds of 1% of research animals are primates.

One reason for these declining numbers is the increasingly sophisticated use of zebrafish, fruit flies, snails, worms and other simple invertebrates. Work with these creatures, as well as with mice, has decreased the need to do basic research in larger vertebrates and primates, explains Steve Niemi, who directs the Center for Comparative Medicine as the chief veterinarian at the Massachusetts General Hospital.

Among those lower creatures, the first fruit fly (Drosophila melanogaster) model elevated to the lofty region of human neurodegenerative diseases debuted in 1998 in the lab of Nancy Bonini, professor of biology at the University of Pennsylvania. “Drosophila approximates many of the fundamental mechanisms of early development in vertebrates,” Bonini says. “So we thought, why can’t we use it to study late-onset neurodegenerative diseases?”

She chose to look at spinocerebellar ataxia type 3 (SCA3), a “genetic stutter” disease, similar to Huntington’s and fragile X syndrome, in which a triplet of DNA bases gets repeated too often. Those repeats lead to sticky, misfolded proteins that clump in neurons and kill them. As neurons degenerate, a person’s movements become erratic or ataxic. The longer the stutter, the worse the symptoms and the earlier in life they appear.

Researchers had recently identified the SCA3 gene in humans, and when Bonini inserted that gene into a fly, she saw the results of neurons collapsing as the fly entered adulthood. “If you could imagine what a fly with ataxia might look like, that’s what we saw,” she says. “The effects were spectacular.” The fruit flies developed normally but later began staggering as if mimicking humans with the disease, and died early. Plus the stutter often lengthened in successive generations, as it does in humans.

Because the fly modeled the key features of the human disease, researchers can now screen proteins and molecules quickly to see which might have therapeutic effects. “The fly is an extremely powerful way to establish a ‘proof of principle’ for possible therapeutics,” Bonini explains. “We can try many things and narrow down a few promising ones to test in vertebrates. That’s a necessary next step, because vertebrates’ brains are more complicated, and it’s more challenging to get therapeutic compounds through their blood-brain barrier.”

Bonini is collaborating with mouse researchers, and while she doesn’t discount the idea of someday also using her findings to develop analytical computer models, she thinks it’s too early to move in that direction. “We still know so little about brain diseases that it will take a while before we can confidently develop analytic models of such complex biology,” she says.

I wish analytical models could replace animals,” Capecchi says. “It’s a legitimate goal to reduce the animals used in research, for ethical and animal-welfare reasons and for costs. We don’t want to do trivial things with animals, or waste them in ill-conceived experiments. Analytical computer models can help with that, but the success of those models depends on knowledge that is not yet available.”

For now, expanding what we know about disease means continuing to design experiments involving mice, fruit flies and even primates. Churchill and Jain, though both firm believers in analytical models, don’t expect computers to replace animals, at least not for the next 100 years. Indeed, success with analytical models—and with animals genetically engineered to serve very particular experimental purposes—may be as likely to spur animal experiments as to reduce their numbers, though both can help researchers design more targeted experiments that waste fewer subjects. “Computers help extract the maximum amount of data from the minimum amount of animals,” Churchill says. “They also find patterns that researchers would miss in animal experiments.” Future models, it seems, will come in many varieties, ranging from several kinds of animals to in vitro systems to computers, with each approach building on the others. It should be a productive formula.

Dossier

1. "Structural Model Analysis of Multiple Quantitative Traits," by Renhua Li et al., PLoS Genetics, 2006. Exemplifying the useful symbiosis of animal experiments and computer modeling, the paper describes the quest to understand the interplay between genetic patterns and physiological traits that contribute to weight in mice.

2. "Gene Targeting in Mice: Functional Analysis of the Mammalian Genome for the Twenty-First Century," by Mario R. Capecchi, Nature Reviews Genetics, June 2005. The recent Nobel Prize winner explains how the technology of studying the effects of single genes has revolutionized the study of mammalian biology of human medicine.

3. "Drosophila as a Model for Human Neurodegenerative Disease," by Julide Bilen and Nancy M. Bonini, Annual Review of Genetics, December 2005. This overview describes how newly identified genes implicated in human neurodegenerative diseases are making their way into the easy-to-manipulate fruit fly and providing new insights into disease pathology and therapeutic avenues.

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