Mice play a critical role in medical research

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.”

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