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Discovering the Homeobox

While Drosophila research was at the forefront of biology and genetics for the first half of the 20th century, it wasn't until the late 1970s, after the advent of molecular biology, that fly people realized the full extent of what they were learning. "It was then that biologists began to come to grips with the incredible homology across species," says Corey Goodman, former HHMI investigator at the University of California, Berkeley. First came an understanding of how nature lays out the architectural plan of the developing fly embryo. Clusters of genes turn on in sequence, determining the overall body pattern—front and back, for instance, and up and down—and then successive gene cascades lay out increasingly localized structures.

Central to this architectural plan are genes containing the so-called homeobox, a DNA-binding element that was discovered independently in 1983 by Walter Gehring and his colleagues at the University of Basel, Switzerland, and Matthew Scott and Amy Weiner, who were then working with Thomas Kaufman at Indiana University in Bloomington. Homeobox genes encode proteins that tell the cells in the various segments of the developing embryo "what kind of structures to make—antennae for the head, for example, and legs for the three thoracic segments," says Scott. Almost identical homeobox genes were quickly found in the genomes of mice and humans as well.

"Until then," says Scott, "there had been strong sentiment that animals as different as vertebrates and invertebrates would have such different mechanisms of control and growth and patterning that, at most, we could use analogies to compare them, but little else would be directly transferable."

With the knowledge that the same mechanisms were at work, "the whole problem of development was simplified," says Scott. "Instead of having to study genes and proteins and molecular events that are very specific to one tissue, or one developmental stage, or one organism, you can take advantage of the special attributes of whatever your experimental system is, and whatever you learn is likely to be very useful in understanding a great many other events in other tissues, stages, and creatures."

This is what Rubin calls "the take-home message" of Drosophilaresearch and the last five years of molecular biology.

Rubin's own work on the development of the Drosophila eye has borne this out. "In the fly retina, for example, we studied a signaling pathway that starts with a receptor called sevenless. We worked out this whole, long pathway, with about 20 components identified. Some of those components were already known, but some were new. And in at least two cases, we've identified a new component and then been able to show that it was conserved in humans.

"So in fact we discovered genes that are important for these same signaling events in humans but weren't known before in humans. We were able to do it because the experimental techniques are better in Drosophila. We isolate the gene inDrosophilaclone it, and then isolate the corresponding gene in humans. That's a very well proven method of gene discovery, and there are now literally hundreds of examples."

In 1986, Scott and his colleagues began studying a Drosophilagene known as patched, which plays a crucial role in the development of the fly embryo. By 1994, they had discoveredpatched homologs in species ranging from the flower beetle to mice and humans. What's more, they had identified the human homolog of patched as the gene that goes awry both in basal cell carcinoma, the most common human cancer, and in a disfiguring genetic disorder known as basal cell nevus syndrome.

In the few years since then, Drosophila research has led to the creation of the first animal models of these disorders—mice that develop basal cell nevus syndrome or basal cell carcinoma because of defects in their patched genes. Studying these mice should make it easier for scientists to find treatments for the human diseases.

— Gary A. Taubes

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