THE SMART GENE.

Having Scientists Fount It?

Meet "Doogie," an ordinary-looking, furry brown mouse. He scurries around his cage, eats, sleeps, and burrows in cedar shavings on his floor. But give him a series of "rodent SAT" tests that judge his ability to quickly learn and remember tasks--like repeatedly locating a hidden platform in a tank of murky water--and Doogie proves he's a genius. How did he get so smart?

Doogie inherited what some experts are calling the "smart" gene (hereditary instructions in all cells that determine everything from hair color to personality traits). As a new millennium dawns, scientists are rushing to decode every gene in the human body in order to learn how genes work--and how to manipulate them to fight diseases like cancer (see $W 3/22/99). In the Doogie experiment, researchers led by Joseph Tsien, a Princeton University neurobiologist (scientist who studies brain function), altered a specific gene that affects how the brain forms lasting memories (see diagram below).

Tsien was trying to learn how the gene--called NR2B--helps form memories, but there was a startling result: Tsien "manufactured" a strain of rodent Einsteins, nicknamed "Doogies" aider the know-it-all character on TV's Doogie Howser, M.D. The mice successfully performed mental tests 40 percent faster than normal mice. Since mouse and human brains are similar in some ways, these findings will help researchers better understand the workings of the human brain--and could lead to new treatments for learning disabilities, Alzheimer's disease (characterized by memory loss), or brain damage. "In the future," Tsien says, "pharmaceutical companies may come up with a memory pill."

MAKING DOOGIES

Tsien created his Doogies by injecting a group of mouse embryos, or fertilized eggs, with an extra copy of the NR2B gene. The gene controls the brain's ability to link one event to another and remember the link--like picturing a friend's face and remembering his or her phone number. The embryos absorbed the extra gene into their own DNA, the molecule in each cell that houses all genes. The result: mice were born with a double copy of the "memory" gene, which they passed on to some of their own offspring--the Doogies. This "double whammy" quickened the way Doogies learn and remember by speeding up reactions between neurons, or brain cells.

In animals and humans, memories are created when neurons communicate. The NR2B gene is part of a brain cell receptor that acts like an antenna, receiving chemical signals from other neurons. The receptor and chemical signals have a unique and specific function: they train brain cells to transmit or fire in repeating patterns. These patterns are what you experience as a memory. In Spanish class, say, when you hear vocabulary words over and over again, the repeated firing of specific cells in a certain order makes you remember the words and makes it easier for your brain to repeat this fling pattern later--so you ace the Spanish vocab quiz.

BRAIN POWER

Tsien's discovery is one more step in scientists' understanding of the human brain. But there's still much that they simply don't know. "The brain is the most complicated known system in the universe," says James McGaugh, a neurobiologist at the University of California in Irvine. Researchers hope to reap answers about how genes work in the brain through the Human Genome Project, a monumental effort to map every gene in the human body. (Scientists recently upped their estimate of the number of human genes from 80,000 to 140,000.)

FILE SYSTEM

Researchers do know that the brain organizes knowledge into categories--like a filing cabinet with infinite file folders--and stores that information in different parts of the brain. A single thought or memory is actually a complex series of events. When you ride a bike, for example, you know how to operate the pedals, and get to your destination without consciously thinking about it. While riding, you may remember the bike trip your family took on vacation last summer and hum the song you learned on the trip. Although you learned and experienced these things at different times, they trigger associations.

So how does the brain store, file, and integrate all of them? Scientists think that memory systems are fried in different brain regions, but work together as a team. Each system handles specific things you learn, McGaugh explains: Physical motion like riding a bicycle is filed in one system; mental tasks involving facts or reasoning, like remembering the words to a song, are filed in another system.

Once scientists better understand where memory centers are located, they might use genetic techniques similar to those that created Doogie to heighten healthy memory regions in the brain to make up for damaged ones. For now, Doogie is a giant mouse-step towards understanding how genes affect both memory and the human brain.

RELATED ARTICLE: How Building a Better Mouse Could Potentially Benefit PEOPLE

Adding more of a single gene ...

The gene NR2B is part of a brain cell receptor called the NMDA receptor. It receives specific chemical signals that train brain cells to fire in repeating patterns. The patterns are what we experience as memories.

In mouse and human brains, the hippocampus is crucial to learning; permanent memories are created there.

... opens lots of tiny gates ...

The NR2B part of the NMDA receptors works well in young mice, but its efficiency drops drastically after puberty. Scientists believe that by boosting NR2B in adults, they can give mature animals the learning skills of youngsters.

1. Without two independent signals, the NMDA receptor remains closed.

2. One signal is a chemical signal from a neighboring cell.

3. The other is an electrical signal triggered within the cell.

4. Opened by the signals, calcium flows in, helping to form a memory.

... that make mice "smarter" ...

Genetically-altered mice consistently outperformed normal mice in six tests of learning and memory; their brain cells showed increased sensitivity to new stimuli.

In one test, mice had to find a hidden platform underwater; the altered "Doogie" mice remembered where it was from one test to the next.

... and may help humans someday.

No one is yet proposing to alter the human NR2B gene. But in the future, scientists may create drugs to boost its activity. That could mean new therapies for learning disabilities, memory problems, and perhaps even Alzheimer's patients.

HOT Job

Name: Joseph Tsien

Hot Job: Neurobiologist

Where: Princeton University, Princeton, NJ

Q Why did you become a neurobiologist?

A When I was in middle school, I became fascinated with how the brain works.

Q What exactly do you do?

A I spend 80 percent of my time in a lab. We come up with ideas--like does a single gene affect human memory?--and then test them by doing experiments. A lot of ideas don't work out, so you have to be patient, and very persistent.

Q What's your message to kids?

A This is the century of brain research--exploring the inner universe.

Neurobiologists earn a starting salary of $60,000. A Ph.D. is necessary.

Think About it

Tsien's research also raises ethical questions about tampering with nature's genes: If better memory and learning can be perfected in humans, should healthy people turn to genetic engineering (altering genes) to boost intelligence? Should the creation of "designer mice" pave the way to creating designer humans in the next millennium? What do you think?