The common house mouse has been tagging alongside humankind, mostly as an uninvited guest, since the dawn of civilization some 10,000 years ago. That's about when humans developed the ability to farm, build abodes, store grain and foodstuffs—and spill just enough tidbits and crumbs to support furtive populations of domestic rodents.

"With food reserves in granaries and cupboards, the house mouse began its long interwoven history with humankind," writes Lee M. Silver in his book Mouse Genetics. Indeed, he notes that the scientific name of this particular mouse, Mus musculus, can be traced back to the ancient Sanskrit word mush, meaning "to steal."

Despite that legacy of thievery and stealth, the mouse is about to bestow one of the greatest possible gifts upon human beings: a tool that will help us make biological sense of ourselves. That is because, among all the model organisms used by scientists to explore genetics, the mouse is, biologically speaking, a uniquely kindred spirit. Mice are so genetically close to humans that Ira Herskowitz, a yeast geneticist at the University of California, San Francisco, once remarked, "I don't consider the mouse a model organism. The mouse is just a cuter version of a human, a pocket-sized human."

Over the past 5 or 10 years, biology has seen a dialogue emerge between genetic research on mice and attempts at a fuller understanding of human beings (at both the genetic and medical levels). It is a dialogue that grew into a din of conversation as the Human Genome Project, the massive federally financed initiative to map and sequence every human gene, entered its final stages.

Unlike every other model organism whose genes can be mutated at will, the mouse promises to tell us things about the role of genes in how we think and feel, how we remember, how we reproduce, even how we grow fat. Mice are already telling us how certain human diseases occur, and they will someday tell us how effective new medicines are likely to be. "The mouse sequence will be the Rosetta stone that will help us interpret the human genome," predicts Shirley Tilghman, a former Hughes investigator and now President of Princeton University.

"Just look at this," says Tilghman. Spread out upon her lap is a journal containing a foldout of human chromosome 22, the first of the 23 human chromosomes to have all its DNA sequenced. "Look at the spaces here and here," she says. A schematic map of the sequence, showing an overlapping series of long, multicolored lanes extending across the page like a psychedelic musical score, indeed possesses numerous unexplained gaps, little patches of terra incognita in the midst of a magnificent new genetic vista just coming into view. "There's so much in this sequence we still don't understand."

That may be the best explanation for why researchers believe it is essential to keep the mouse as a traveling companion as we embark on our journey into 21st-century biology, even after the human sequence has become available.

"The short answer is because humans are not an experimental organism," Tilghman says. She says it with a laugh, but it's a deceptively simple observation. Just outside her office are rows upon rows of lab benches, outfitted with all the high-powered tools of modern biological inquiry. Here, as in countless other labs throughout the world, researchers are busy erasing, enhancing, turbocharging, and otherwise tinkering with the genes of a mammal biologically close to us, in hopes of creating mutants that display startling effects. Deliberately creating mutants, of course, is not something you can do with humans.

— Stephen S. Hall

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The first mammalian gene ever cloned—the mouse gene for beta-globin—is projected behind Shirley Tilghman, a prime mover in the drive to sequence both the mouse and human genomes.

Photo: Kay Chernush

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