"Thousands of years ago, the ancient Greeks observed that asthma ran in families," says Symula, a post-doctoral fellow who joined Rubin's research group nearly four years ago to begin an intensive hunt to identify the genetic factors. "What we knew, at the outset of our studies, was that one region of the human Genome, on Chromosome 5, tended to be inherited in individuals with asthma."

Rubin’s group has previously developed mouse models for a variety of human conditions, including Down syndrome, sickle cell disease, and atherosclerosis. For the asthma study, they decided to forego the conventional approach for identifying genetic links to a specific disease. "Rather than looking at one gene at a time," Rubin says, "we chose to simultaneously examine several genes in parallel, by introducing eight to ten human genes at a time into the genome of mice."

EDDY RUBIN Dr. Edward Rubin earned his bachelor’s degree from the University of California at San Diego, then moved to the East Coast where he earned both a medical degree and a Ph.D. in biophysics from the University of Rochester. After a pediatrics residency at UC San Francisco, followed by a research position with the Howard Hughes Medical Institute, he came to Berkeley Lab. A recognized leader in genomic research with transgenic mice, he most recently was awarded a grant from NIH to initiate a major new program called "Comparative Genomic Analysis of Cardiovascular Gene Regulation."

Adds Symula, "We had this several- million-base-pair region from human chromosome 5 that we knew was somehow involved. The strategy was to subdivide the region into a few large pieces of DNA and then introduce these pieces, each composed of several hundred thousand letters of the genetic alphabet coding for several genes, into mice. We expected to then see changes in processes that are controlled by these genes."

By genetically engineering a library of transgenic mice, each containing a different segment of the human genome, Rubin and Symula and the other members of the team were able to rapidly sift through 25 genes located in the genetic interval where the "asthma suspicious" genes had been localized. They then matched physical features, or phenotypes, of these mice with characteristics seen in human asthmatics, to eventually identify IL 4 and IL13 as the genes responsible for asthma susceptibility in these animals.

Says Rubin, "Although these studies were conducted in mice, not humans, there are several different lines of evidence supporting the role of these interleukins in human asthma susceptibility."

Interleukins have long been known to play a role in regulating the immune system and, in particular, modulating the inflammatory response. Evolutionarily, IL4 and IL13 are thought to prevent parasitic infection by generating localized inflammation.

Because asthma is a complex genetic condition in which several genes, working in concert, ultimately determine an individual’s susceptibility, it posed a major challenge to the traditional approach to genetic research which was used to identify single genes responsible for disorders such as cystic fibrosis and sickle cell disease.

Says Rubin, "The approach we used to pursue asthma genes may now be applied to other common complex genetic conditions, for instance hypertension and obesity, where large genomic regions have been implicated as containing genes contributing to a particular disease."

"This research is a prime example of biology made possible by the Human Genome Project," Rubin adds. "Our proximity to Jan-Fang Cheng’s lab, the actual group engaged in the Joint Genome Institute’s mapping effort, led us to investigate this area of research.."

In addition to Rubin and Symula, other contributors to the paper in Nature Genetics were Kelly Frazer, Yukihiko Ueda, and Mary Stevens of Berkeley Lab, and Richard Locksley and Zhi-En Wang of UC’s  San Francisco campus. — David E. Gilbert