October 8, 2007 - Mario R. Capecchi, Ph.D., a founding member of The Brain Institute at The University of Utah, received the 2007 Nobel Prize in Physiology or Medicine - the world’s highest recognition for contributions to basic and clinical medical research.

Capecchi was honored for his work in mouse gene targeting, a method for precisely manipulating genes to create animal models of human development and disease. First developed in 1989, this groundbreaking technique changed the landscape of biomedical research. (See how mouse gene targeting works.) He shares the prize with Martin Evans of Cardiff University and Oliver Smithies of the University of North Carolina at Chapel Hill.

Lessons from a mouse: How does gene targeting work, and what we can learn from this unlikely teacher? Find out more

The Nobel prize – a first for The University of Utah – is awarded by the Nobel Assembly at the Karolinska Institute in Stockholm, Sweden.

Pushing the Boundaries of Science

Capecchi always had a talent for thinking outside the box. “I like working on the edge,” he says. “If there are a lot of people doing what I’m doing, then my time is better spent on other projects.” His desire to pursue new ideas has been fortunate for the research world, as it ultimately produced mouse gene targeting, the work that earned him the Nobel Prize.

Despite his momentous achievements, Capecchi didn’t set out to be a leader in biology. Originally, he was inspired to study physics by his uncle, a research physicist. He switched to the then-new field of molecular biology because of its seemingly endless research possibilities. “In a sense, molecular biologists were naïve. We had no idea how complicated biology was,” Capecchi says. “We felt that we could solve any biological problem using this new approach.”

To a degree, Capecchi believes this naïvete enabled him to tackle complex problems such as mouse gene targeting – a project many of his peers thought would fail.

Mario's Newest Question: Genetics and the Brain

Even now, Capecchi periodically shifts his research focus to refresh his perspective. And after 40 years working as a molecular biologist, he still is not constrained by what people believe is possible, and what is not.

His research team currently is pursuing one of biology's most complex questions: What is the genetic basis for neurological disorders? In 2002, they found the first known link between a gene and a specific behavior, after noticing that one of their experimental mouse strains acted strangely. These mice groomed themselves excessively, even to the extent of pulling out their fur and causing skin wounds.

H. Steve White and the University of Utah Anticonvulsant Drug Development Program: In search of better treatments for epilepsy. Find out more.

What caused the odd behavior? The mouse strain was created through gene targeting to have a mutation in Hoxb8, one of a family of genes shared by mice and humans. What’s more, the behavior closely resembled those seen in humans with Obsessive-Compulsive Disorder (OCD), which is typified by repetitive behaviors. Some people with OCD continually wash their hands, often to the point of injury. “They’re never getting the input saying, I’ve washed my hands, they’re clean now, and I can quit,” says Capecchi.

In mice, the Hoxb8 protein functions in a part of the brain that is abnormally active in patients with OCD. Might human OCD behaviors be caused by mutations in Hoxb8? Capecchi and colleague Mark Leppert, Ph.D., a professor of human genetics at The University of Utah, are on the case.

Wired for Movement

Capecchi also is asking how the neural circuits that control movement are wired. Billions of neurons connect the brain to tissues in our body, enabling us to sense pain, feel hunger, and move our arms and legs. When a neuron must choose one out of thousands of different tissues to connect to, how does it know where to go?

His team found that another Hox family gene, Hoxb1, helps neurons locate their target tissue. Hoxb1 protein is found in the part of the brain where neurons that go to the face begin their journey, and also in facial tissues where they end up. Removing Hoxb1 from either site causes facial paralysis, suggesting that the protein acts as a road sign, guiding neurons to their connections. Scientists are now investigating whether people born with certain types of facial muscle paralysis carry non-functioning Hox genes.

Scott Rogers is using mouse models to explore connections between aging and addiction. Find out more.

What's Next? A View to the Future

Capecchi’s mouse research has advanced neuroscience by leaps and bounds. But primate brains, like our own, are obviously more complex than a mouse’s. Therefore, scientists cannot hope to fully understand intricate neurological processes like vision using today's techniques. Capecchi has a plan for overcoming this hurdle: make the mouse brain more like a primate’s.

How difficult might this be? Will it involve changing thousands of genes, or just a few? He reasons that during evolutionary history, it took relatively short periods of time to make radical transformations in brain structure and function. Thus, it is likely that modifying only a modest number of genes will produce big changes in the mouse brain.

Capecchi believes that new technologies, like those he is inventing for brain research, spark scientific progress. “If you look at how science evolves, it is not in a straight line but rather in jumps and spurts,” he says. “New technologies allow you to do new things that were not possible before, thereby stimulating rapid advancements.”

Author: Julie Kiefer

Quick Reference

• Mario R. Capecchi, Ph.D.
• Distinguished Professor and Co-Chairman of Human Genetics
• University of Utah School of Medicine
• Investigator, Howard Hughes Medical Institute

For more information

More about Mario Capecchi

• University of Utah News Release (October 8, 2007)
• Mario's Transgenic Technology "Knocks Out" Nobel Prize (from Learn.Genetics.utah.edu)
• From Rags to Research (Nature magazine, July 2004)
• Mario Capecchi: Pushing the Boundaries of Science
• The Nobel Foundation
• The Howard Hughes Medical Institute
• Capecchi Laboratory Web page
• Mario Capecchi Scores Technical"Knockout" with Gene Targeting (1993, from ScienceWatch)

Hox genes

• Genes Determine Body Pattern, from the University of Utah Genetic Science Learning Center

Obsessive-Compulsive Disorder

• Obsessive-Compulsive Disorder, from the National Institute for Mental Health
• The Obsessive-Compulsive Foundation