“What we’re trying to do is change the way that people think about diseases,” says Gary Churchill, a statistical geneticist at Jackson Laboratory. “They’re out there looking for broken genes, but the idea of broken genes just doesn’t make sense. We’re saying, ‘Hey, reality isn’t like that.’”
The search for single disease-related genes has certainly had some major successes. One of the greatest came in 1989, with the discovery of a gene linked to cystic fibrosis. Cystic fibrosis causes inflammation in the lungs, almost like a bad case of flu, and is usually fatal by age 35. Unlike the flu or meningitis, however, cystic fibrosis is not caused by a virus or other pathogen. It runs in families.?
Studies on families with cystic fibrosis showed that the disease gene is passed along in a fairly simple way, much as in Mendel’s smooth and wrinkly peas. Only if a child inherits a defective gene from both parents does he or she get sick. Even so, it took years to find the actual gene. First scientists scanned distinctive stretches of DNA that are spread out across the genome like mile markers on a highway. They then found one particular marker more often in family members with cystic fibrosis than in healthy ones. When they began to search the DNA around the genetic marker for candidate genes, they uncovered a link between cystic fibrosis and a gene for a channel that pumps chloride (electrically charged chlorine atoms) through cell membranes. Mutations to that gene prevent cells from making the channel, disrupting the balance of fluid in the lungs. If scientists can find a way to insert working versions of the gene into lung cells, it may be possible to reverse the disease.
Even in the instance of cystic fibrosis, though, the story is not so simple. The single chloride mutation does not always doom a person to the illness. Many people possess this mutation, “but the clinical outcome is vastly different,” says Rick Woychik, director of the Jackson Laboratory. “Some people have a poor outlook, and others actually live till a ripe old age. So why? One reason is genetic networks.”
Genes do not work in isolation. Many of them make proteins that switch other genes on or shut them off, or that come together to create a giant molecular machine. Other proteins relay signals through the body, like a line of people playing the telephone game. Gene networks tend to be remarkably robust. Even if one gene is hobbled by a mutation, the network still generally manages to do its job. “There are other genes that participate in the network, and they can compensate for the absence of this gene,” Woychik says.?
Because of this, single-gene diseases are rare and affect relatively few people; common diseases tend to be network driven. “If you think about all the major killers—cancer, heart disease, diabetes, stroke—they’re not single-gene diseases,” says Paigen. For instance, if researchers find one particular gene associated with stroke—the kind of discovery that used to make headlines—it will typically have only a small effect on a person’s chances of getting the disease.
In a sense, today’s disease hunters are finally making sense of clues that emerged a century ago in the work of Jackson Laboratory’s founder, Clarence Cook Little (pdf). Before there was a high-rise community of inbred mice in Bar Harbor, there was the bathtub full of pet-store rodents that started it all.
As an undergraduate at Harvard in the early 1900s, Little joined in the effort to push genetics beyond Mendel’s peas. One of his professors urged him to study mammals, specifically mice, since they shared many traits with humans but were fast breeding and easy to rear in a lab. So in 1907 Little paid a visit to a local pet store and started raising mice in his tub. He bred the mice incestuously, pairing brothers and sisters in each generation. Over time, each lineage shared more and more gene variants, or alleles. After about 20 generations, they were as similar to one another as are identical twins.
Once Little had created several inbred strains, he could cross yellow mice with black mice, for example, and observe how many pups grew coats of various colors. These studies helped show how Mendel’s simple rules could account for complicated patterns of heredity. Little realized that it takes several genes to determine coat color and learned how to estimate how many genes were involved in a trait based simply on comparing the descendants of his hybrids. In one of his most important experiments, he bred two strains of mice to see how their offspring accepted or rejected tissue grafts. In 1916 he calculated that at least 14 genes were involved. This was a radical idea at a time when nobody even knew what a gene was. “It was the ultimate case of chutzpah,” says Paigen. “Amazingly enough, he turned out to be right.”
After getting his Ph.D., Little served as president of the University of Maine and then the University of Michigan. But his controversial tenure at Michigan (he wanted to ban drinking at fraternities, for one thing) got him fired in 1929. Little promptly persuaded several automobile tycoons to bankroll an independent lab in Bar Harbor where he could go on studying his inbred mice. Jackson Laboratory—named after Roscoe Jackson, a cofounder of the Hudson Motor Car Company—was born.
Little had the misfortune of launching his grand project on the eve of the Great Depression. The funds from his patrons soon dried up. When his scientists went from one room to another, they had to unscrew the lightbulb and take it with them. But Little came up with a way to stave off bankruptcy: He would sell his mice. Inbred mice were rapidly becoming the favorite lab animal for medical studies, and the Jackson Laboratory mice were recognized as the world’s best. Soon Little was doing a booming business in the mouse trade. The tradition continues today. Jackson Laboratory ships 2.5 million mice to labs each year, making it one of the world’s leading suppliers.
Over the years, Little and later scientists expanded the collection of inbred mouse lines. The lab now houses three-fourths of the world’s known mouse varieties. In 1999 Ken Paigen, then the director of Jackson Laboratory, had his team examine a thousand mice from 40 inbred strains. They measured 500 different traits in the mice, from their white blood cell count to the shape of their brains to how salty they liked their water. The mice had a huge range of variations for many of the traits, and the variations stemmed from their genes.
