Ralph Waldo Emerson is reputed to have said that if a man makes a better mousetrap "though he build his house in the woods, the world will make a beaten path to his door."
Gary A. Churchill hopes this is also true if a man builds a better mouse.
Actually, it is already true.
Biologists have been beating a path to the town of Bar Harbour on Mount Desert Island, in Maine, since 1933, when the Jackson Laboratory began selling inbred mice for genetic research.
Today, the laboratory offers about 3,000 strains. Individual animals in each strain are essentially all the same at the genetic level — an endless stream of identical twins, except for the genes determining sex.
Many have traits that mimic human ailments — diabetes, hypertension, osteoporosis and Alzheimer's disease. Others have the tendency to develop problems such as obesity, cancer or infection when subjected to the "right" environmental conditions.
Genetic soup
In most cases, these traits (and hundreds more) arose through chance mutations in single animals. They caught the eye of a scientist, who in turn "captured" the trait by mating the animal with its siblings, and then those offspring with one another. After 25 generations, such animals are all identical and — if things go as planned — all carry the gene or genes responsible for the trait of interest.
In recent decades, genetic technology has also allowed scientists to knock out or, in some cases, add genes to animals. Of the laboratory's 3,000 strains, about one third are genetically engineered.
The usefulness of these animals is hard to overstate. They help biologists understand basic physiology. They help identify genetic defects that lead to disease. The benefits or risks of experimental drugs are often easier to detect when tried on animals that are the same. Mice became workhorses of medical research in the decades after the First World War. They were cheap and easy to raise, prolific, reached maturity quickly and were all around more practical than larger animals such as dogs.
At the time, the mouse's genetic malleability was well known and the source of popular entertainment.
Clubs of "mouse fanciers" in the early years of the 20th century bred animals to have exotic coat colours and strange behaviours. (A type of "waltzing mice" from that period turned out to have an inner-ear defect.)
A big source of early mice for research was a farm in the western Massachusetts town of Granby run by a retired school teacher named Abbie E.C. Lathrop. She began breeding them in 1903.
A pair of mice from the Granby farm produced a lineage that became known as "Black 6" or "B6". It is the most popular research mammal in the world. It was a B6 mouse whose genome was sequenced in 2002 as part of the effort to get full DNA transcripts of many life-forms, from yeast and mustard plants to microscopic worms, cats and human beings.
Through much of the 20th century, scientists collected mice from around the world (including places as remote as the Faroe Islands in the North Atlantic) for breeding stock. The idea was to ensure genetic diversity in the mix of animals used to create inbred strains.
Potential for diversity
How successful this effort was — or was not — became clear only this summer.
A paper published in July in the journal Nature Genetics analysed the DNA sequences of 15 strains of mice. Eleven were "classical" inbred strains used in laboratories for years. Four were strains derived from animals caught in the wild more recently, including one from the sewers of Prague. To the researchers' surprise, the older strains had much less genetic diversity than anyone assumed. About 92 per cent of all those strains' genomes derive from the Mus musculus domesticus subspecies native to Western Europe. There was relatively little contribution from subspecies of Central Asia or South East Asia, or from a hybrid of the two found in Japan.
This told mouse geneticists there were many more variations of DNA in the mouse universe that could potentially go into making new strains of the animals.
This diversity takes the form of single-letter variations that individuals or inbred strains have by chance in their DNA chains. The chains, comprising an ordered sequence of four chemical letters (called nucleotides and designated A, T, C and G), otherwise differ very little from one strain to the next. Regardless of where they occur, these variations, called single nucleotide polymorphisms, or SNPs, are extremely important in genetic research.
Diversity in the form of more SNPs will provide more mile markers in the genome and possibly allow the production of mice with new, unrecognised traits.
To that end, the Jackson Laboratory and the US government's Oak Ridge National Laboratory in Tennessee are creating about 1,000 new strains of inbred mice.
The scientists are starting with a more diverse group of "founders" than went into existing laboratory strains. They are creating the inbred lines through the classic technique of brother-sister mating.
The work will take about seven years. The result may not be better mice but it will be more varied ones.
