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 mice” 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 a simplified explanation:

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

To these cells, add the gene construct containing the mutated, inactive OhNo gene (red), and an antibiotic resistance gene (pink).

Inactive OhNo Gene

Antibiotic Resistence Gene

By mechanisms that are not completely understood yet, similar genes will swap places. The mutant OhNo gene is now incorporated into the genome and the normal version is no longer active.

Inactive OhNo Gene

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

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

By transplanting your brown mouse cells into a white mouse embryo, you’ll create what is called a chimera. Chimeras have patches of cells throughout their bodies that grew from one of the two types of cells. These patches will show up as either brown or white.

Brown Mouse Cells with Inactive OhNo Gene

Inspect your chimera’s egg and sperm cells (reproductive cells). Some of the chimeras have reproductive cells that originate from your brown mouse cells. This means that they will pass on the inactive OhNo gene to their offspring if a male and female are mated. Mate a male and female of this type.

Sperm with Inactive OhNo Gene

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