One hundred years ago in a lab at Harvard University, a young zoology student was busily overseeing the breeding of pair after pair of brother and sister mice. The "Mouse Man", as he was known on campus, was trying to create the first inbred lab animal - a strain of mouse whose genes would be stable and identical.
Such a mouse would allow biologists to reliably replicate their experiments for the first time. His professor said it couldn't be done, but the Mouse Man proved him wrong. We are all indebted to those inbred mice and their descendants, which have helped researchers develop treatments for a wide range of human diseases.
IT BEGAN with one small mouse and a simple, if tedious, instruction. Clarence Cook Little was a Harvard undergraduate when his zoology professor thrust a live mouse across the lab bench and told him to learn everything he could about it. Little went one better.
In the third year of his degree, in 1909, he created the first inbred strain of mouse, providing researchers with a homogeneous genetic background on which to experiment. Before that, they could never be certain whether the results of their research were genuinely the result of an experiment or stemmed from genetic inconsistencies in their test animals.
Little, the great-grandson of America's most famous patriot, the Revolutionary Paul Revere, would remain a champion of the laboratory mouse all his life. He was particularly interested in cancer and was convinced that the key to understanding the disease lay in the study of genetics and that the best way to study genetics was by using inbred mice.
In 1929, the student who had once sketched mice in the margins of his zoology notes founded the Jackson Laboratory, a centre for research into mouse genetics, in Bar Harbor, Maine. But even he could not have foreseen the enormous power of inbred strains, says Steve Brown, director of the Mammalian Genetics Unit at MRC Harwell in Oxfordshire, UK.
"The concept of creating inbred strains is fundamental to genetic studies," says Brown.
Today, Little's original lab mouse has been joined by thousands of strains. About 25 million mice are used in labs around the world each year, making it the most common animal research model. Tiny Mus musculus has helped clarify the nature of a raft of human illnesses, from cancer and diabetes to Alzheimer's disease and obesity.
Crucially, the lab mouse has been a stand-in for humans, testing treatments which have led to the development of drugs for rheumatoid arthritis, leukaemia and osteoporosis to name but a few.
While Little is indisputably the man behind modern lab mice, he was not the first to experiment with them. Researchers of yore recognised that mice share many physiological systems with humans. They are also easy to feed and house, have a three-week gestation, produce large litters and reach maturity in just 10 weeks.
They have one other big advantage, says Karen Rader, a historian at Virginia Commonwealth University in Richmond, who has written the definitive book on lab mice, Making Mice. "The mouse is enough like us that results can apply to us, but not so much like us that people get upset about conducting experiments on them."
In fact, the lab mouse might have got off to a much earlier start if Gregor Mendel - the father of genetics - hadn't been thwarted by his bishop. In the 1850s, Mendel began his investigation of inheritance by studying coat-colour traits in mice. But he was a monk and his bishop decreed that a monastery was no place to experiment with copulating mice. Mendel switched to a study of peas.
Nor were biologists the only people to experiment with mice. Breeders of fancy mice had tinkered with mouse genes for centuries. Seventeenth-century illustrations show how people in Japan bred and collected unique strains, creating albinos and mice with spotted coats.
They also bred "waltzing mice" that seemed to dance, a peculiarity later discovered to be the result of an inner-ear defect.
By the 20th century, such breeders had established clubs and exhibited their prize specimens at mouse shows. As a student, Little often judged these shows at the behest of his professor William Castle, who saw it as way to scout for genetic mutants of interest to science. It was this link to mouse fanciers that ultimately led to Little's lab mouse.
More specifically, it led to one mouse fancier, retired schoolteacher Abbie Lathrop. After a failed attempt at raising poultry, Lathrop hoped to make a living from the fancy mouse craze and began to breed popular strains on her farm in Granby, Massachusetts. She soon attracted scientific customers. "I know it sounds bizarre, in terms of genetics, that people would seek out this mouse breeder on a farm in Granby," says Rader. "But she always had the best mice. She was a local celebrity."
Lathrop was also a scientist in her own right. When she noticed some of her mice suffered from skin lesions, she sent samples to her scientific clients, including Leo Loeb, a pathologist at the University of Pennsylvania. He confirmed Lathrop's suspicions that the lesions were cancerous and the pair spent the next five years publishing joint research on tumour transmission in mice.
Little, meanwhile, had recognised the potential in Lathrop's stock. Lathrop had bred many generations of brother and sister mice to create unique strains, and such relative genetic similarity would make an excellent starting point for his work. Little began his project largely because he needed to do some independent research to qualify for Harvard's doctoral programme, but he was also eager to prove one of Castle's hypotheses wrong, says Rader.
Castle believed interbreeding could never create a stable and pure genetic strain. He also doubted that the mice would remain fertile after generations of inbreeding.
Indeed, Little soon found he had taken on something of a challenge. As fancy mouse breeders had already discovered, few progeny of brother-sister matings survive. Litters are small and the young sometimes sterile. But Little eventually found a strain that flourished.
He named it dilute brown non-agouti (DBA) - dilute because it had less pigment than its wild cousins, brown as opposed to the more common black, and non-agouti because it didn't have the grizzled-looking fur of other mice.
By 1947, scientists understood the value of inbred mice. That year, the Jackson Laboratory was destroyed in a fire that consumed the town of Bar Harbor, killing 14 people and 90,000 mice. The following day, research institutes and individual geneticists who had acquired mice from the lab began sending back breeding pairs so that Little could re-establish his colonies, says Rader.
Little claimed to have received just one angry letter from an anti-vivisectionist women's club, which suggested it might have been better if he and his scientists had burned instead of the mice. Anti-vivisectionists of the time were largely concerned with cats and dogs. The public's sympathy rarely extended to rodents, which were regarded as vermin and carriers of disease.
The return of the mice paved the way for two important discoveries. George Snell's studies of tumour transplantation and rejection in mice in the late 1940s laid the foundation for modern immunology. Without it, human organ transplants would be impossible. Another of the rebuilt lab's scientists, Leroy Stevens, also made great strides with his own studies of tumour transplantation, which eventually led to the discovery of embryonic stem cells.
The decoding of the mouse genome in 2002 opened up still greater possibilities. We now know that 99 per cent of human genes have a comparable version in mice and many of them are located in the same place on the chromosome. That means scientists can work out the role of any human gene by creating mice lacking the equivalent gene. When the mice exhibit a defect, scientists can pinpoint the gene's function and test treatments.
"Little wouldn't have dreamed about this, but he would have been thrilled," says Rader. Indeed, on his 80th birthday in 1968, Little drew a cartoon of a lab mouse on a pedestal. The drawing shows him looking up at the mouse which says: "You're not so damn smart. You've had 80 years. Look what my family has done in 39 years."