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Mice genetically modified to be smarter may feel more pain

Monday, January 29, 2001

By Byron Spice, Science Editor, Post-Gazette

Mice that have been genetically modified to boost their memory and learning abilities may not only be smarter than the average mouse, but painfully so.

A new study by neuroscientists at Washington University School of Medicine in St. Louis found that the same brain cell modification that made the so-called "Doogie" mice smarter may also have sensitized them to chronic pain.

The study findings, being published in the February issue of the journal Nature Neuroscience, are not clearcut. The researchers found evidence that persistent pain seemed to be enhanced and that the mice even responded to what should have been non-painful touches. But it's also possible that the mice might have been displaying a learned response, rather than feeling actual pain.

But the study is a cautionary reminder that genetic manipulations meant to enhance a desirable trait can have side effects that may prove detrimental, said Min Zhuo, a neuroscientist and one of the lead scientists of the Washington University study.

Genetic enhancement, such as designer babies, is something that most scientists insist is still far in the future. A national panel of experts last year concluded that inheritable genetic modifications are not yet safe and should be banned until procedures and standards are in place. And no one claims to know precisely which genetic changes are necessary to safely make a person smarter, more charming or a more talented athlete, musician or writer.

Nevertheless, the recent news that Oregon scientists have transferred a foreign gene into a near relative of humans, a rhesus monkey, has renewed speculation about designer babies. The earlier creation of the smart mouse, announced in September 1999, likewise seemed to suggest that increasing intelligence by genetic changes might turn out to be relatively simple.

That was an understandable reaction, admits Joe Tsien, the Princeton University neurobiologist whose team developed the smart mouse. But that wasn't the team's intention, or conclusion. Rather, they created the mouse strain, dubbed Doogie after the precocious TV character Doogie Howser, to test a 50-year-old theory about how memory works.

Scientists had speculated that memories are stored and behaviors are learned by strengthening or weakening various connections between brain cells in the forebrain. Proteins on the surface of brain cells, called NMDA receptors, were known to play a role in changing the strength of these interconnections.

So Tsien created a mouse with extra copies of NR2B, a gene that produces one type of NMDA receptor. Tests, including some by Zhuo, showed that the mice did indeed have better memory and more learning ability, as predicted by the theory.

That did not necessarily make the mice more intelligent, Tsien emphasized last week. "Learning and memory is just one component of intelligence," he said. But it did suggest that memory and learning might be enhanced by drugs that targeted the NR2B gene.

The researchers realized, however, that the same changes in brain interconnections that affected memory also could affect pain perception, or even contribute to drug addictions.

In the latest experiments, Zhuo and his colleagues in St. Louis found that the Doogie mice responded to acute pain, such as hot and cold, in the same way as regular mice. But when their hind paws were injected with substances that cause prolonged discomfort and inflammation, the researchers noticed that the transgenic mice displayed more painful reactions or would withdraw their paws when touched, even thought the amount of inflammation was the same.

Based on that evidence, Tsien isn't sure the transgenic mice necessarily are feeling greater chronic pain. "I'm not sure if that produces a perception of pain or records a memory of pain," he said. They may simply have learned better than other mice what to expect of certain painful experiences.

If the mice are feeling greater chronic pain, however, the experiment may serve not only as a warning about the side effects of genetic modification, but provide a clue to treatment of chronic pain. Rather than using opiates that numb chronic pain sufferers and make them sleepy, it may be possible to design drugs that target NR2B instead, relieving chronic pain while preserving protective reflex responses to acute pain.

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