Photo. http://www.americanheritage.com/assets/images/articles/web/20070712-mouse.jpgMOUSE WORK
By Terri Peterson Smith
http://www.americanheritage.com/events/articles/web/20070712-jackson-laboratory-mouse.shtml
A mouse at work at an in vitro fertilization lab; opposite, a rendering of the Black 6 (C57BL/6) mouse, first to have its genome sequenced.
(AP Photo/Joel Page)
How a small animal made it big in research.
They have shared our homes and our food for Millennia. No doubt the relationship first became close when humans took up farming and stored grain. Since then mice have colonized our warehouses and silos, invaded our basements and garages, and raided our kitchens. The house mouse’s scientific name, Mus musculus, says it all: Mus may be derived from a Sanskrit word meaning “thief.” But mice are cute too. So while we’ve been inventing all sorts of ways to exterminate them, they have been burrowing their way into our imagination and culture, from the “wee, sleekit, cow’rin’, tim’rous beastie” of Robert Burns’s poem “To a Mouse” to Stuart Little and, of course, Mickey.
We have another thing in common: Ninety-nine percent of human genes share a comparable version in the mouse, and many of them appear in the same order in our chromosomes. We also have similar reproductive and nervous systems. That’s why the mouse has served as the principal model for biomedical research for more than a century. Now, with the advent of increasingly sophisticated genetic engineering techniques and ever more powerful computer technology, mice have become stand-ins for humans upon which it seems every imaginable disease or condition is being studied, along with compounds to treat them. Hardly a week goes by without some new findings about heart disease, cancer, obesity, anxiety, or the life-prolonging benefits of red wine, all based on mouse models. The Minneapolis Star Tribune columnist James Lileks wrote: “I have come to suspect that mice are Nature’s Play-Doh; you can probably prove any thesis, given enough mice. They are resilient, up to a point, and unlikely to assemble class-action suits, so you can do all sorts of things to them.”
David Largaespada, an associate professor in the University of Minnesota’s Department of Genetics, Cell Biology and Development, broadens the point: “Without mice in biomedical research, we’d lack a lot of fundamental knowledge about human physiology and the basic cause of human disease. For instance, research using mice helped prove that cancer is really caused by mutant genes.”
Largaespada, who studies the genetic mechanisms of cancer, says: “Other organisms or cultured cell lines can be better models for some purposes. It really depends on the question being asked. That dictates the best model to use. Yeasts, worms, fruit flies, and even computer models all offer excellent insight into the workings of cell biology. Mice are better tools to study the immune, endocrine, nervous, cardiovascular, skeletal, and other physiological systems of humans and other mammals.” Mice get many of the same diseases that humans do—cancer, diabetes, osteoporosis, glaucoma—and they even develop anxiety and aggressive behavior. Moreover, manipulating their genetic material can cause them to develop cystic fibrosis, Alzheimer’s, and other diseases that do not naturally afflict them.
By some estimates, 25 million mice are used in medical research each year. Yet they haven’t always commanded the heights of scientific investigation. Their path to prominence has been a circuitous one, leading from mouse lovers in Victorian England and an interlude with Gregor Mendel to a former Massachusetts schoolteacher, a descendant of Paul Revere, and two captains of the auto industry, with a lot of computing and genetic theory thrown in along the way.
There is an irony to the fact that the people who most loved mice set them up for their role in medical research.
The rise of the mouse in science resulted from the developing bond between humans and animals in the mid-nineteenth century, the emergence of a leisure class, and a growing understanding of genetics and the natural world. In her 1987 book The Animal Estate: The English and Other Creatures in the Victorian Age, the MIT professor Harriet Ritvo writes that by the middle of the eighteenth century, with natural history emerging as a “prestigious Enlightenment scientific discipline, it was also quickly becoming a fashionable amateur avocation.” Animals were no longer valued simply for the work they could perform in service to humans: “Sentimental attachment to both individual pets and the lower creation in general—a stock attribute of the Victorians—became widespread in the first half of the nineteenth century.”
Animals became more prominent in children’s literature (as with the tales of Beatrix Potter), and the era gave rise to the anti-vivisection and animal-welfare movements. While the dog became man’s best friend during this period, mice gained their own following. As early as the eighteenth century, the Japanese were collecting and breeding mice much the way we breed roses—for their color and size (though probably not their scent). A century later these prize specimens, known as “fancy mice,” came on the social scene in England. Victorian mouse enthusiasts bred and traded them and founded the National Mouse Club in 1895, the mouse world’s equivalent of the Westminster Kennel Club.
Fancy in nineteenth-century vernacular meant “hobby,” particularly an animal hobby, rather than the look of the mice. Still, they were indeed fancy. Those years of breeding had turned the common field mouse into a creature with a coat of many colors, including black, blue, silver, champagne, red, lilac, and white. Its hair could be short, long, curly; some were bald. The National Mouse Club is still going strong in Britain, and according to its Web site, “There are now approximately 40 standardised varieties with up to 200 possible variations, giving a mouse colour and pattern, or even coat type, that will appeal to everyone!” The fanciers bred their mice for behavior too. For example, they crossed fancy mice with pink-eyed Japanese waltzing mice, so named because this kind of mouse seemed to dance, behavior that scientists later learned was a result of an inner-ear defect.
The enthusiasm continued well into the twentieth century. In 1937 a Reader’s Digest article reported, “Over 1000 people are breeding mice in the British Isles today and scarcely a week passes without a Mouse Show somewhere.” (For some breeders, the interest in mice took a pragmatic turn. The article continues, “Still another factor in making the raising of mice a ‘coming industry’ is the demand for ladies’ coats of mouse skins. About 400 skins go into a full-length coat, which sells for $350.”) That same year Time magazine reported, “Top mouse-supplier for London drawing rooms is Mrs. E. D. Blowers, the ‘Mouse Queen.’… Mouse Queen Blowers would like to make the U.S. mouse-conscious… . In November the U.S. will be introduced to Mouse Queen Blowers and several hundred of her choicest mice at a Manhattan cat show.”
In fact, America had long had its own contingent of mouse lovers, including members of the short-lived American Mouse Fanciers’ Club. Abbie Lathrop, a former schoolteacher, started raising chickens on her farm in Granby, Massachusetts, but when that didn’t pan out, she set her sights on mice. She began with a single pair, and by 1913 she had a supply of more than 10,000 in her barns and outbuildings. Orders poured in for her mice. Along the way, she started getting orders from a different kind of customer, a Harvard University zoologist named William Castle, which would ultimately change the mouse’s fate from fancy to pharmacology.
There is perhaps an irony in the fact that the people who most loved mice were the ones who set them up for their future in medical research. Breeders had systematically selected mice with the most pleasing behavioral qualities. Their mice, for instance, didn’t mind being handled, a trait that made them easy to keep in the lab. The National Mouse Club describes the animal as “a delightful little creature, which is undemanding, clean and easy to breed.” Mice were cheap, reproduced quickly (a 3-week gestation period and 10 weeks or less to maturity), and didn’t take up much room. And thanks to the fanciers, there were plenty of them available.
Most important, having bred generation after generation of mouse siblings together to achieve a wide variety of coat colors and other traits, fanciers had inadvertently created strains of mice that were genetically identical. Such pure strains were to prove invaluable in biomedical research.
In her book Making Mice: Standardizing Animals for American Biomedical Research, 1900–1955, the historian Karen Rader writes that the fact that researchers could collaborate with fanciers suggests that mice never quite shook their image as pilfering pests and so never attained the beloved and protected status of other pets: “The ethical yardstick by which antivivisectionists determined felines and canines to be the most threatened experimental animals was calibrated primarily on measures of an animal’s social worth. Cats and dogs occupied an unambiguously positive place in American culture.’”
About the time the fanciers were toying with the mouse’s genetics, the Austrian monk Gregor Mendel was also studying mice, which he bred with the goal of deciphering the inherited traits of coat color. However, to Mendel’s conservative bishop, the thought of a monk spending his time with copulating mice seemed inappropriate. He banned the mice, and Mendel set his sights on a less prurient subject for investigation, peas.
The laws of inheritance that Mendel discovered through his pea research languished for more than 30 years. They were rediscovered in 1900, and scientists soon wondered if the same principles that applied to the genetics of peas might apply to animals too. By 1910, though the field of genetics as a distinct academic specialty was very new (the word was first used in this sense in 1905), biologists began to see the validation of Mendel’s laws in many kinds of plant and animal. One of the leading researchers of the field was Abbie Lathrop’s customer William Castle, who along with his student Clarence Cook Little published seminal papers on mouse-coat color genetics.
C. C. Little, Paul Revere’s great-great-grandson, may be the person most responsible for the mouse’s leap from the drawing room to the research laboratory. Known as the “mouse man” among his Harvard colleagues, Little further inbred Lathrop’s already inbred mice, resulting in creatures that were virtually clones of one another. His most famous strain, C57BL/6 (also known as Black 6), was developed in 1921, and in 2002 it became the first strain to have its genome sequenced.
Professor Favell compares the magnitude of his investigation of mouse immune systems to that of the Manhattan Project.
Pure strains allowed experiments that were consistent, repeatable, predictable, and easily analyzed. According to Rader, “Genetically standardized mice were the standard-bearers for a genetic approach to biomedicine; their production represented, to paraphrase Karl Marx on technology, the power of genetic knowledge objectified.” Yet Little’s contribution didn’t end with inbred mice. He left Harvard in 1922 to become the president of the University of Maine. In the summers he took groups of zoology students for field study around Mount Desert Island and spent time mingling with the residents of the island’s tony summer resort community, Bar Harbor. There he met the Detroit auto barons Edsel Ford (Henry’s son) and Roscoe Jackson, president of the Hudson Motor Car Company. Jackson, an engineer by training, took a liking to Little and supported his work.
Little’s Bar Harbor connections eventually led to his selection as president of the University of Michigan in 1925. Soon he left Michigan and his life as an academic administrator and, with funding from Ford and Jackson, set up a center for research on cancer and genetics using inbred mice. Founded in 1929, the Jackson Laboratory, in Bar Harbor, Maine, now sells around two million mice a year. It is the country’s largest resource for genetically defined and genetically modified mice, as well as a renowned research center for the study of cancer and other medical conditions.
C. C. Little’s work began at a time that is hard to imagine now. There was scant understanding of genetics. High-speed computers and scanning electron microscopes didn’t exist. Cancer research was on the fringe of science, and the concept of mice as stand-ins for humans in medical research had yet to take hold. Yet over the following decades, scientists at the Jackson Laboratory and around the world created and studied mice with cancer, mice with drinking problems, and mice that were fat. They studied the effects of radiation on mice and gained a greater understanding of cancer and countless other afflictions. By serving as a proxy, the mouse has helped solve one of the major dilemmas of biomedical research—that it’s unethical to test drugs or therapies on humans before they are shown to be safe and effective.
The mouse’s role in research has increased in conjunction with advances in biochemistry, understanding of DNA, and the power of computers to process mountains of complex data at lightning speed. By the 1960s scientists had developed bio-chemical markers that allowed them to look at protein variations in different strains of mice. In 1977 the first mouse gene was isolated and, with increasingly sophisticated techniques, scientists learned to isolate, examine, and modify DNA. In the early 1980s “transgenic” mice were created when scientists injected DNA into fertilized mouse eggs. This allowed researchers to observe what happens to an entire organism during the progression of a disease.
When the mouse genome was decoded in 2001, the rodent gained even greater value in the lab by providing scientists with a powerful research tool to extract meaning from the human genome sequence, decoded the year before. Today, to understand the role of any human gene, researchers can identify the counterpart gene in mice, engineer a strain of mouse that lacks the gene (known as knockout mice), and figure out from that mouse’s defects what the gene does. Scientists have already “engineered” thousands of mouse strains with the same genetic diseases seen in humans.
Mapping the human and mouse genomes led to new standards in biomedical research. Now, says Largaespada, “everyone is trying to understand disease processes at the molecular and genetic levels. To understand the human system, one needs to understand the function of human genes. The questions revolve around what genes, when present in specific forms, can cause disease or make a disease more likely. The proteins or RNA molecules encoded by these genes can then be considered as potential targets for new therapies.” Such research has yielded an explosion of information about what genes do in the body.
In September 2006, for example, scientists at the Allen Institute for Brain Science in Seattle unveiled the Allen Brain Atlas, basically a map of the mouse brain that pinpoints the working of individual genes. It allows researchers studying human diseases such as Parkinson’s, multiple sclerosis, and brain cancer to learn about the genetics of the brain cells that are affected by the diseases. It will also provide greater understanding of how the human brain’s circuits and chemistry work in relation to conditions such as schizophrenia, autism, and various addictions.
A few months later the journal Cell revealed new information on human biological rhythms based on mouse models. The “Early-to-Bed Mouse,” in which a gene was altered to match a human mutation, demonstrates not only how altering a specific gene can change the circadian rhythms of mice but how the process works in humans. Using mouse models of human biological rhythms helps scientists understand not just how genes work to regulate sleep patterns but also how “biological clocks” regulate everything from body temperature to endocrine gland secretions.
And earlier this year researchers from MIT and Cold Spring Harbor Laboratory reported that they had developed two strategies to reactivate the p53 gene in mice, causing blood, bone, and liver tumors to shrink. The p53 protein is called the “guardian of the genome,” because it triggers the suicide of cells with damaged DNA.
Despite all this, the mouse is still not a true substitute for a human. Treatments that work one way in mice can’t always predict the same outcome in people. Scientists constantly strive to create mice that more closely resemble human physiology. Nowhere is this a greater problem than in immunology research. Though we have many afflictions in common, mice have not evolved with a susceptibility to many of the diseases that affect humans—HIV, for example. To further complicate such research, the immune system involves many organs and systems throughout the body. Consequently, understanding the genetics of the immune system isn’t a matter of simply inserting a gene into a mouse and waiting to see what happens. We must instead learn how genes behave as part of a complex network.
To that end, Richard Flavell, Sterling Professor of immunobiology at Yale University and a Howard Hughes Medical Institute investigator, has undertaken perhaps one of the most ambitious investigations ever to rely on mice. Funded with a $17 million Grand Challenges in Global Health initiative grant supported by the Bill and Melinda Gates Foundation, the project illustrates the tremendous complexity of research using mice today. Flavell says: “The purpose of our Gates Foundation project is to develop a humanized mouse model—that is, a mouse that has a new human system… . Unfortunately, it is not trivial to simply transplant human cells into a mouse. The mouse immune system is very good at rejecting such transplants. As a result, investigators have developed a method to introduce human stem cells into immunodeficient mice. These stem cells grow up into immune cells that are functional. This model has been quite useful, but it has several deficiencies. In order to be able to develop the constellation of all the immune cell types, we are genetically modifying the mouse to provide the factors that human immune cells need in order to develop.”
Flavell compares the magnitude of this investigation to that of the Manhattan Project. He says, “This is technically a highly demanding enterprise, requiring people of numerous different types of expertise. If we are successful, which I believe we will be, it will be possible to realistically test whether human vaccines are likely to be effective in people, long before people will be immunized with them. It will be possible to model human autoimmune diseases, such as Type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and so on. We will be able to study responses to human infections such as HIV. And we hope that it will be possible, using such models, to understand why these infections are so catastrophic.” In all this work, “the laboratory mouse is a critical component” because it is “an unparalleled model system for humans.”
Will the fate of mice and men always be so intertwined? Surely mice and humans will remain forever linked as what Burns called “earth-born companions” as long as we humans have food in our houses. But will we be forever tied in the research lab too? As in the days of the Victorians, the debate over the use of animals in research rages on. Even in the scientific community there are almost as many opinions on the topic as there are researchers. Colin Blakemore, a neuroscientist who heads the UK Medical Research Council in London, was recently quoted in the journal Nature: “I don’t know of a single scientist who would not prefer to use alternatives if they were available.”
Perhaps powerful technology will eventually limit our reliance on mice and other animals for research. David Jacobson-Kram, associate director for pharmacology and toxicology in the Office of New Drugs of the Food and Drug Administration’s Center for Drug Evaluation and Research, says, “I absolutely think that we won’t need animals to test for safety and efficacy of drugs in the future. I’m not sure how long it will take. We can use automated techniques such as high-throughput screening [a process that screens thousands or even hundreds of thousands of genes, proteins, or chemicals for an ability to cause some specific effect in a biological system], in vitro assays and robotics to assess the activity of hundreds of compounds. That will save time, money, and a lot of animals.”
But until that day comes, mice, while they continue to eat in our kitchens and cozy up in our closets, will also be earning their keep.
Terri Peterson Smith is a science writer in Minneapolis.
