This story starts not with Jenica but with fruit flies, billions of them. Over the years, these common insects, the length of an "f" on this page, have become an ideal experimental animal for studying how genes control an organism's development from single cell to complex, fully formed creaturea journey that fruit flies make in less than 10 days.
At the University of Colorado, where he set up his first lab in the 1980s, Matthew Scott used Drosophila melanogaster to examine two kinds of developmental genes. One kindthe segmentation genesdivide the fly embryo into segments that eventually become the different body parts of the adult fly. The other kindthe homeobox-containing genesgive these segments their different attributes: a head, two wings, six legs, a thorax, and the 10 sections of the fly abdomen.
A segmentation gene called patched, which was discovered by the German researchers Christiane Nüsslein-Volhard and Eric Wieschaus, seemed particularly intriguing. Work on it was prompted by the arrival in Scott's lab of Joan Hooper, who is now at the University of Colorado Health Sciences Center in Denver. If patched was mutated in a fly embryo, it was as if the compass that determined the polarity of each body segment in the fly was broken. "Structures would be partially reversed," says Scott. "You'd get a mirror image duplication of patterns." In 1989, Hooper and Scott cloned the patched gene.
But the researchers still had little idea how the patched gene did what it did. To find out, several groups went looking for similar genes in other organisms. It turned out that a fly gene known as hedgehog, which was functionally related to patched, did have a matching gene, or homolog, in mice. This news made Scott's team even more eager to find mammalian homologs to patched itself.
It had proved very difficult to jump directly from the fly patched gene to an equivalent gene in mice, however, so Scott and his colleagues decided to use an evolutionary "stepping stone" approach. They started with various insectsfirst mosquitoes and then butterflies and flower beetles, where in each case they found a homolog. At each step, they learned more about the gene and which parts of it had stayed the same during hundreds of millions of years of evolution.
Finally they felt ready to tackle mammals. After a year and a half of work, a graduate student and a postdoctoral fellow in Scott's labLisa Goodrich and Ron Johnsonfound a patched homolog in mice. Johnson calls it their "big success" and gives much of the credit to Goodrich, whom he describes as extremely tenacious in her approach.
With the mouse patched gene under their belts, Scott's team went after the human version. Finding it turned out to be relatively easy, especially when they looked at the amino acids (building blocks of proteins) for which genes hold the recipes. Each amino acid is specified by a three-base-pair sequence of DNA. When the researchers compared the amino acids made in mouse and human cells, they found that 94 percent of the amino acid sequence of the mouse patched gene was identical to that of humans. (In contrast, only 40 percent of the amino acid sequence of the fruit fly patched gene was identical to that of humans.)
"We had never worked with any human material before," Scott recalls. But Stanford has a human genome center, so they asked Rick Myers and David Cox, the two geneticists who run it, to map the new gene to a human chromosome for them. "Then it became really interesting," Scott says. "What you get back is this rough map location and a list of other genes in the vicinity, and you look at the other genes and hope something will turn out to be relateda birth defect syndrome, for example."
Only one disease rang bells in the region near patched. That was basal cell nevus syndrome. "The affected tissues matched almost exactly the areas where we knew this gene pathway was working, based on our mouse studies," says Scott. "In
people, defects in the patched gene can cause spina bifida, polydactylywhich is extra fingersrib anomalies, and cancer of the skin and of the brain. These are all places where the patched gene is active in mice."
Nevertheless, "we had a lot of skepticism in my lab," says Scott. "Rick Myers had already warned me that whenever you map a gene, you always find something near the map location that looks really good'and it's almost always wrong."
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Starting with the patched gene in flies, Lisa Goodrich and Matthew Scott found an equivalent gene in mice, which soon led to the equivalent gene in humans.
Photo: Barbara Ries