Scientists Create Smarter Mice

September 1, 1999

Scientists Create Smarter Mice

By The Associated Press

Scientists have genetically engineered brainy mice nicknamed ``Doogie,'' pointing the way for research that could lead to human babies with higher IQs as well as drugs to treat Alzheimer's disease and stroke.

Inserting an extra gene, researchers produced a strain of mice that excelled in a range of tasks, like recognizing a Lego piece they'd encountered before, learning the location of a hidden underwater platform and recognizing cues that they were about to receive a mild shock.

The improved learning and memory came from increased production of a brain protein called NR2B. The mice carried the enhanced abilities into adulthood, when learning ability and memory naturally taper off, and passed their heightened learning abilities on to their offspring.

``This points to the possibility that enhancement of learning and memory or even IQ is feasible through genetic means, through genetic engineering,'' said Joe Z. Tsien, the assistant professor of molecular biology at Princeton University who led the research team.

The findings, published in Thursday's issue of Nature, indicate a common mechanism lies at the root of all learning, identify the protein NR2B as a key to brain function, and could lead to a drug to treat memory disorders, such as Alzheimer's, by increasing NR2B levels, Tsien added.

Production of NR2B protein normally decreases with age, correlating with the loss of memory and learning ability commonly experienced by older people, Tsien said.

The new mouse work represents a breakthrough in understanding how the brain functions at the molecular level, said Dr. Robert Malenka, a psychiatrist and behavioral sciences specialist at Stanford University School of Medicine.

``To jump from this very elegant molecular work in a mouse model to humans is a very, very big jump,'' said Malenka, who was not involved in the research. ``Nevertheless, it is a jump we can make and will make eventually. When we jump to humans, it will probably be a lot more complicated.''

One complication is the risk that any drug that would increase NR2B levels could also increase the risk of stroke, because both stroke and learning are related to the same neurological switches in the brain, Malenka added.

Dr. Ron McKay of the National Institute of Neurological Disorders and Stroke said drug companies are already investigating manipulation of NR2B levels to treat strokes. Any research that illuminates how NR2B works in the brain would be valuable in that work, he said.

The prospect of genetically engineering smarter babies raises big ethical questions.

``What we are looking at is the baby steps toward a world in which we can design our descendants,'' said Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania Health System. ``I don't think that is necessarily bad. Finding ways to repair autism or mental retardation associated with Down syndrome or Alzheimer's or other disabling neurological diseases is a very good thing.''

Because of the inherent risks, it makes more sense ethically to begin applying this discovery to treating diseases and disorders, rather than trying to create smarter babies, Caplan added.

``I wouldn't say I would be worried quite yet about seeing hordes of tiny Einsteins in my neighborhood,'' he said.

But just as parents strive to improve their children by sending them to better schools or giving them piano lessons, there will be those who want to genetically enhance their offspring, said Caplan. As in other areas of life, the rich would have an advantage.

``We already have a brain gap in this society when some children go to kindergartens that cost $15,000 a year and other children go to kindergartens that don't have adequate plumbing,'' he said.

Tsien nicknamed the smart mice ``Doogie'' after the teen-age genius in the television show ``Doogie Howser, M.D.''

Using a tiny glass needle, the scientists injected a gene carrying a blueprint for the protein NR2B into the nucleus of a fertilized mouse egg, then implanted the resulting embryo into the uterus of a mother mouse.

Mice born with the extra gene made more NR2B than usual in their brains.

That extra production boosted mental abilities by enhancing the function of brain-cell switches called NMDA receptors. The results confirm the idea, proposed in 1949, that these switches play a key role in learning.

The NMDA switches require two signals to open, which fits in with the idea that learning involves associating pairs of events or facts, like a tone and an electrical shock. Boosting levels of the NR2B protein kept the mouse NMDA switches open longer than usual.

The same protein and NMDA receptors exist in the human brain.

``If you associated food with a bell, a voice with a face, a face with a name, these are all associative learning, the major forms of learning in humans,'' Tsien said. ``To associate those things you require some kind of cellular machinery.

``It is so nice to convince ourselves that we are working in the right machinery.''