By Maggie Koerth-Baker
Need a mouse that's resistant to anthrax but will get drunk easily? There's a lab mouse designed for that. Need a mouse that can get Parkinson's disease but will never catch polio? There's a mouse for that, too. The caged rodents in today's labs aren't the guinea pigs of yesteryear. They're specifically bred and highly standardized. And credit for that goes to Clarence Cook Little, a visionary researcher who saw the potential in an overlooked rodent and revolutionized biology in the process.
Little Big Man
The son of a dog-show judge, C.C. Little arrived at Harvard in 1906, set on studying man's best friend. But one day during class, Professor William Castle gave him some career advice. He slid a mouse across his desk to Little and told him to find out everything he could about that organism. "This," he said, "will be the one to watch." Castle, a founding father of genetics in America, was not the kind of person you ignore. Fortunately, Little listened.
Between 1909 and 1914, C.C. Little toiled in the biology labs of Harvard's Bussey Institute, using mice to learn how mammals inherit traits from their parents. But when he ran his experiments, Little found that the creatures lacked the sort of standardization expected of other lab subjects. At the time, experimenting on mice usually meant catching a bunch in the basement of some campus building and carting them over to the lab. While certainly fresh and feisty, Little's test subjects were difficult to obtain and differed greatly from one another. So he began to dream of mice strains that were identical and docile, "like newly minted coins." Little's solution? Inbreeding.
Take two closely related specimens, play some Barry White, and presto! You've got pure white mice. If only it were that easy.
In reality, C.C. Little's process for creating inbred mouse strains was neither quick nor exact. One of the biggest problems with inbreeding is that it can lead to rare genetic diseases. Little got around this problem, but his solution required years of trial and error. He would mate mice, then sit back and wait for something weird to happen ... or not happen. If a mouse was born with a trait that Little didn't like, he'd remove it from the gene pool. If a mouse possessed a trait that Little considered desirable, he'd launch a multi-generational inbreeding process to create a new strain. Once Little had his own lab, he employed assistants whose sole job was to check mouse litters for mutants.
Sometimes, the traits that Little and his team found most useful were the ones that produced the least healthy mice. He discovered, for instance, that you can breed strains of mice with bodies that readily accept transplanted cancer tumors. These mice provided some of the first evidence that susceptibility to cancer can be inherited, just like hair color.
In the early part of 1929, Little became the director of the American Cancer Society, and later that year, he opened a research institute in Bar Harbor, Maine, called the Jackson Memorial Laboratory. Unfortunately, the timing wasn't ideal. Within days, the stock market crashed, and Little lost nearly all of his funding. For the next three years, he struggled to keep the lab afloat. At one point, Little's researchers were actually doing their own construction work on the building and getting food from staff fishing trips.
Finally, Little made a crucial decision that would change medical and genetic research forever: He compiled a catalog of the inbred strains he'd created and used for his own research, and he offered to sell it to other institutions. In the world of research, where scientists traditionally shared their resources, Little's for-profit catalog was considered gauche. But while the move defied convention, it may also have been Little's biggest contribution to science.
Researchers quickly realized the value of using standardized mice strains, and the money began pouring in. The reliability of Little's breeding techniques, along with his lab's commitment to quality control, helped scientists reduce the number of variables in complex experiments.
Today, it's estimated that 95 percent of the world's lab mice are descended from mice born in the Jackson Laboratory.
Yet, it would be almost 40 years before mice got the public kudos they deserved. In 1978, Little received the Coley Award, created in 1975 expressly to honor lab mice and the people responsible for them. But by then, C.C. Little had already been dead for seven years. Critics believe the delayed recognition had something to do with the fact that Little had spent the last 15 years of his life tirelessly campaigning for Big Tobacco. In 1956, he'd resigned from the lab to become the scientific director for the Tobacco Industrial Research Committee, where he argued against the idea that smoking causes lung cancer. Despite this late-life misstep, Little's contributions to the scientific world are impossible to dismiss.
These days, when geneticists want to create a new strain of mice, they often take a more hands-on approach. In the early 1980s, researchers began genetically manipulating mice by inserting genes from other species (including humans) during the earliest stages of embryonic cell division. The result was "transgenic mice." Scientists also began turning off specific genes during early development, creating "knockout mice." Both types of mice are incredibly important in today's research. For instance, unaltered mice can't get polio, because they don't have the right cell receptors for the virus to latch onto. But transgenic mice with human genes can catch polio just like people. Thanks to transgenic poliovirus receptor mice (known to their friends as TgPVR), we have a better way to test polio vaccines, making them safer and more effective.
Knockout mice are every bit as special. In 1996, scientists created knockout mice that stopped being able to produce a protein called Nrf2. This caused the mice to have low dopamine levels, and they developed the telltale physical symptoms of Parkinson's disease. Their condition directly contributed to a February 2009 finding by researchers at the University of Wisconsin-Madison, which stated that mice that produce ultra-high levels of Nrf2 are immune to Parkinson's, even when they are injected with chemicals known to cause the disorder. Currently, there is an international effort to uncover even more breakthroughs by systematically creating a knockout mouse variety for every gene on the mouse genome. Scientists have created knockouts for about 5,000 genes, and there are only 15,000 more to go.
Although the history of lab mice began with inbreeding, their future almost certainly lies in higher technology. And this time, the innovators won't die before being properly lauded. The three scientists responsible for transgenic and knockout mice were rightly honored in 2007, when they were awarded the Nobel Prize.
This article originally appeared in the September-October 2009 issue of mental_floss magazine.