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THE ZIGZAG OF PROGRESS:
A scientist performs an animal experiment // Which yields data for computer analysis // Which generates leads for yet more experiments // Which begs the question...

Will Animals Ever Leave the Lab?

By Cathryn Delude // Photographs by Jana Leon // Winter 2008
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For those who dream of a future without animal testing, Jackson Laboratory, in Bar Harbor, Maine, may seem an unlikely place for this story to begin. Jackson is home to legions of mice, many of them genetically altered to exhibit particular traits that make them ideal research subjects. And Gary Churchill, a statistician-turned-biologist who serves as one of the laboratory’s principal investigators, spends much of his time devising experiments for the sometimes odd-looking creatures.

For example, there was a 2005 Jackson study involving a long, lean, muscular mouse—affectionately named Adonis—and a short, round mouse that looked rather like an ottoman. Wondering why only some people on a particular diet become obese, Churchill crossbred several hundred pairs of Adonises and ottomans to produce offspring with a mixed bag of body types and cholesterol profiles. He fed the offspring a buttery diet; tracked each mouse’s weight, muscle mass and bone density; and noted where on its body pockets of fat accumulated. Then he used computers to scan the mice’s genomes and scour their genetic variations in search of combinations that might act as an adiposity, or fat factor, that predisposed some animals to become obese.

The computer model then looked for causal connections and interactions among these genetic patterns and the mice’s physiological traits. Did a single genetically programmed characteristic, such as the length of a leg bone, determine muscle mass or another trait related to body weight, or were other factors involved? Was the influence of one trait on another a one-way street, or did it work in the other direction as well? The computer displayed the answers graphically, with arrows indicating all links and bolder arrows representing the strong connections. The analytical model further untangled those correlations and identified a few genes that seemed to determine which mice would become fat, independent of body type.

Could this still hypothetical adiposity factor predict obesity in mice—and perhaps someday in humans? Investigating that question is on Churchill’s agenda, and it will require more animal experiments—and a lot more mice. “You have to keep testing your model in mice,” Churchill says. “When you find a gene, you have to know its context in the body. What does a gene that helps clear cholesterol from the liver do in other organs? And what are the effects of environment and diet? You need animals to learn that.”

It’s Churchill’s approach to testing, which employs sophisticated computer models as well as animals, that could well become the norm for biomedical research in decades to come. And for those who dislike animal testing, that’s not the worst-case scenario.

Rhesus macaque: lab animal
Rhesus macaques—in which the red blood cell protein rhesus, or Rh, factor was discovered—and other nonhuman primates are invaluable test subjects.

The killing of millions of mice and other laboratory animals—cats, dogs, frogs, birds and monkeys—is controversial, to say the least. Many who find the practice abhorrent contend that it’s unnecessary. They point to advances in testing drugs and other products without the use of animals as indications of what could be. A determined quest for alternative ways to gauge toxicity, allergies and drug interactions has eliminated virtually all animal testing for cosmetics. Now, instead of dropping a dollop of shampoo in a rabbit’s eye to check for an allergic reaction, the shampoo goes into a dish containing cultured human cells or artificial skin tissue. And during preliminary drug development, researchers may feed a compound’s chemical makeup into a computer that crunches data about how the body metabolizes compounds and predicts whether a drug would be toxic to the liver or would interact with other drugs. 

Those methods have fueled expectations that in vitro testing and computer models could also reduce the need for animals in studying diseases. With ever greater power and speed, computers should be able to sort through bewildering mazes of data about genetic and environmental factors to help determine how their effects in one organ influence other physiological systems.

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Virtual Dissection

See-through animals are reducing the number of lab animals needed for each experiment.

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hed-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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