Mario R. Capecchi, Ph.D., of the University of Utah, has won the 2007 Nobel Prize in Physiology or Medicine. Capecchi shares the prize with Oliver Smithies of University of North Carolina, Chapel Hill and Sir Martin Evans of Cardiff University in the UK.

The prize recognizes Capecchi’s pioneering work on “knockout mouse” technology, a gene-targeting technique that has revolutionized genetic and biomedical research, allowing the creation of animal models for hundreds of human diseases.

During the 1980s, Capecchi devised a way to change or remove any single gene in the mouse genome, creating strains of mice that pass the altered gene from parent to offspring. In the years since, these “transgenic” and “knockout” mice have become commonplace in the laboratory.

Capecchi’s pioneering work in gene targeting has taught us much about how the body builds - and rebuilds - itself. He has given scientists worldwide the tools to make important discoveries about human diseases from cancer to obesity.

And he has raised a key question for the future of human medicine: if we can replace a perfectly good gene with a mutated one, can we also go the other way, replacing problem genes with those that work?

As a child, he wandered homeless in Italy. As a researcher, his first attempts at gene targeting were deemed “not worthy of pursuit” by the National Institutes of Health. Capecchi is an individual whose personal life proves that, while some events are not probable, anything is possible. Read Mario’s story.

What makes an arm an arm? Capecchi’s research team is working on answering that question using gene targeting. They have systematically “knocked out” a set of genes in mice, called homeotic genes, which govern body patterning during development. For example, one of the lab’s most recent genetic discoveries may explain why we lack spare ribs. Find out more about how homeotic genes work in Genes Determine Body Patterns.

YOUR GOAL: You are studying how a particular gene, named OhNo, might play a role in panic attacks. You want to study mice with this gene turned off. To “knockout” the OhNo gene you will replace it with a mutated copy that doesn’t work. Here’s how:

Isolate embryonic stem cells that originated from male brown mice with a normal OhNo gene (blue).

To these cells, add a copy containing a mutated, inactive OhNo gene (red), and a drug resistance marker gene (pink).

By mechanisms that are not completely understood yet, similar genes will swap places. The mutant OhNo gene plus drug resistance marker gene is now incorporated into the genome and the normal version is kicked out. This is called homologous recombination.

Cells that haven’t incorporated the inactive OhNo gene don’t have the drug resistance marker gene (pink).

Adding the drug kills cells without the marker, leaving you with a clean batch of cells that all have an inactive version of the OhNo gene.

By transplanting stem cells that carry the inactive ohNo gene into a white mouse embyro, you’ll create what is called a chimera. Chimeras have patches of cells throughout their bodies that grew from white mouse cells and patches that grew from brown stem cells. Some of the cells that have the inactive OhNo gene may develop into reproductive cells.

Chimeras are easy to identify because they have both brown and white patches of fur.

If a male chimera has some reproductive cells (sperm) that originated from the brown stem cells, he will produce some brown offspring when mated with a white female.

Half of the brown offspring will have a copy of the inactive OhNo gene in all of their cells - including their reproductive cells. These mice have one normal copy of the OhNo gene (not shown) and one inactive copy. So half of their reproductive cells will contain a normal copy and half will contain an inactive copy.

These mice can be identified by PCR and then bred with each other.

One fourth of your resulting offsping will have two copies of the “knocked-out” or inactive OhNo genes. You can now study these mice to determine how lacking the OhNo gene may affect panic attacks.