The business of mice, mighty and otherwise

~ Mouse farms meet experimenters' demand for millions

BAR HARBOR, Maine -- When it comes to the price of mice, you pay extra for defects.

A mouse with arthritis runs close to $200; two pairs of epileptic mice can cost 10 times that. You want three blind mice? That'll run you about $250. And for your own custom mouse, with the genetic modification of your choosing, expect to pay as much as $100,000.

Always a mainstay of scientific research, mice have become a critical tool in the quest for new drugs and medical treatments because their genes are remarkably similar to a person's.

With proper manipulation -- either by man or nature -- a set of mouse genes can produce an animal with just about any human ailment, or a reasonable facsimile of it. Strains of mice that succumb to Alzheimer's disease, obesity, diabetes, cancer and countless other conditions are being used to study both the illnesses themselves and potential treatments. As many as 25 million mice are now used in experiments each year.

Where do they come from?

Where else? Mouse farms.

There are many vendors: The Jackson Laboratory, a not-for-profit supplier in Bar Harbor, Maine, ships more than 2 million a year. Commercial breeder Charles River Laboratories of Wilmington, Mass., makes about $500 million annually selling and caring for lab animals, most of them mice.

Yet the mouse business is a challenging one. What was once a relatively simple business of breeding and shipping animals has become an extremely challenging enterprise that requires cutting-edge technology and a mastery of difficult logistics.

"It's not just putting two animals together any more," said Terry Fisher, general manager for business development and surgical services at Charles River Laboratories, a Wilmington, Mass., which offers laboratory animals and services to pharmaceutical companies and researchers.

All in when, where and how

Mice gained their new significance not long after the completion of the human genome project in 2001. Scientists rushed to finish sequencing the mouse's DNA sequence the following year, and when they put the two genetic codes side by side they found something they'd always suspected -- the genes of mice and humans are virtually identical. The obvious differences between us and them lie not in the genes themselves but in where, when and how those genes are activated.

"It means that the anatomy and physiology of a mouse is pretty darn similar to what you see in a human," said Roy Woychik, director of the Jackson Laboratory.

When scientists began working with mice a century ago they didn't know anything about DNA, and had only the foggiest notion of genes. But mice were the obvious choice for breeding experiments. Small, docile and more than willing to reproduce, they were readily available from the collections of Victorian mouse fanciers who bred the animals to have interesting coat colors and patterns. Many of today's most popular lab mouse strains are direct descendants of those original "fancy mice."

Over decades, researchers created inbred lines of lab mice by repeatedly mating siblings to one another until every member of the strain was virtually the same genetically. That standardization made it possible for a researcher in Japan to replicate the experiment of a colleague in California without having to worry about genetic variation affecting the result.

It also gave each strain a distinct character that made it preferable for certain experiments. The strain BALB/c, for example, is especially useful for immunological studies. Another strain, C3H, is known for its susceptibility to breast tumors.

For much of the 20th century new strains of lab mice were created either by selective breeding or by chance. If a sharp-eyed lab technician or graduate student spotted an unusual animal that turned out to have a novel mutation, a new line would be produced in order to study that particular gene.

Now researchers -- and increasingly biotechnology companies -- can create their own mutations, inserting or deleting genes at will.

Companies such as Deltagen of San Carlos, Calif., will create a "knockout" mouse that lacks a particular gene. Artemis Pharmaceuticals of Cologne, Germany, offers to insert human genes into a mouse's genetic code. PolyGene Transgenetics, a Swiss company, will insert genes whose output can be turned up and down as if they were on a biological dimmer switch.

And the award for sheer weirdness goes to Xenogen, an Alameda, Calif., outfit that can hitch the gene of interest to one that codes for the protein that makes fireflies glow. The result: Whenever and wherever the gene being studied switches on inside the mouse, it glows.

Depending on the specific genetic manipulation, the cost to create a custom mouse is usually in the tens of thousands of dollars. Once the line has been established, individual animals can run into the hundreds.

"Not that much to pay if you want to see how a disease affects a mammal or how a drug is going to work," said Lee Silver, a Princeton University biologist who has worked with mice since 1978.

This year the NIH spent $10 million to purchase 250 strains of knockout mice, along with detailed information about their physiology, from two biotechnology companies, California's Deltagen and Lexicon Genetics of The Woodlands, Texas. The acquisition is just an "hors d'oeuvre" for a much larger international effort to create a knockout strain for every one of the mouse's 20,000 to 25,000 genes, said Chris Austin, director of the National Institute of Health's Chemical Genomics Center.

Some researchers believe studying knockout mice will even lead to the development of new drugs, perhaps dozens of them. One of the first steps in drug development is the identification of what biologists call a target -- a biological molecule that is involved in the disease process and can be blocked or otherwise affected by a small, relatively harmless compound.

Good targets are hard to come by. But knockout mice are virtual target factories, because they are missing a single gene, and thus a single biological molecule. For example, if researchers found a knockout mouse that stayed skinny no matter how much it ate, they would immediately have a promising target for an obesity drug.

"You can manipulate the genes ... and use the mouse as a translator of mammalian physiology," said Brian Zambrowicz, executive vice president of research at Lexicon Genetics.

Lexicon has knocked out 3,000 mouse genes already, and has designs on 2,000 more. With each knockout, the company performs a detailed battery of tests to determine how the function of the deleted gene correlates to human physiology in six areas: opthalmology, cardiology, immunology, cancer, metabolism and neurology.

If Lexicon can find just a few dozen good targets among the 5,000 genes it is knocking out, it could easily revolutionize the pharmaceutical industry. Zambrowicz claims that the company has already identified 70 new targets, which is pretty impressive when you consider that the 100 top-selling prescription drugs on the market exploit no more than a few dozen.

Still, it remains to be seen whether a leap can be made from mice with knocked-out genes to therapies for humans. In the past, discoveries that looked promising in rodents have often failed in human patients.

"These mice are not going to tell us everything, and sometimes they tell us nothing. But as a starting point," Austin said, "mice play a central role."