The mouse model for cystic fibrosis, as with models for many diseases, owes its existence to a technique called gene targeting, which was developed in the 1980s by Mario Capecchi, a professor of human genetics and biology at the University of Utah who won the 2007 Nobel Prize in Physiology or Medicine for his work. Gene targeting makes it possible to study the effects of single genes, including those that don’t occur naturally in mice.

Capecchi recently used this approach to solve a biological mystery about a rare, aggressive childhood cancer called synovial sarcoma. For reasons no one had been able to discover, this cancer’s tumors usually settle near joints, and it was unclear where the cancer originated, or when. But researchers did know the genetic mutation that induced it, so Capecchi inserted that mutation into the embryonic stem cells of mice, then coaxed those cells into becoming embryos. Implanted in a surrogate mother, the cells grew into offspring that carried the mutation in every cell of their bodies.

Capecchi had equipped the target gene with “stop” codes that kept the mutation turned off until he gave the mice an enzyme that snipped out the code and allowed the mutation to become active. He and others had developed that technique, known as conditional expression, to turn a gene or mutation on or off only in a desired tissue or at specific life stages. That’s important, because many mutations cause harm only in specific organs or at particular times, as in early- or late-onset diseases.

In this experiment, Capecchi used different sets of mice to turn on the mutation in three developmental stages—early embryonic, prenatal and postnatal. And in different mice, he activated the genes in different tissues. To his surprise, the mutation arose only in immature muscle cells that occur mainly in early development. Usually, the activated gene immediately kills its host cells, which (self-defeatingly for the mutation) puts a stop to the cancer. But joints secrete a still unidentified protective factor that keeps the cells with the mutation alive, so only mutated cells near joints survive to grow into tumors.

Having started with many sets of mice, Capecchi narrowed the search to a single set that now serves as an animal model of synovial sarcoma. Researchers, able to concentrate on that one model, can learn more about the cancer’s pathology and then design drugs that protect cells from harm. Many other types of cancers also remain biological mysteries, and Capecchi expects that each may require its own animal model, as will other complex diseases and neurodegenerative and neuropsychiatric disorders. So, instead of leveling off, it appears that the number of animal models will proliferate rapidly.