Phil Beachy, associate professor of molecular biology and genetics and associate Howard Hughes Medical Institute investigator, likes to say that he "found the molecule that keeps on giving," and his molecule just "gave" him a top prize, the National Academy of Sciences' Molecular Biology award.
Beachy won for his work to isolate and study hedgehog protein, a growth-controlling compound whose quirky name only hints at its ingenious and seemingly unpredictable behavior.
Hedgehog helps supervise animal and human development from fertilized egg to newborn, and has been linked to some cancers.
Beachy, who came to Hopkins in 1988, will receive the award and $20,000 April 27 in a ceremony at NAS headquarters.
When his group first isolated hedgehog in 1991 in the fruit fly, they knew it was a signaling molecule because of the way it was put together. What they didn't know was how important that signal would turn out to be in other organisms.
Manufactured only in certain cells in an embryo, hedgehog acts like a local construction supervisor, turning on genes in nearby cells that allow them to develop as parts of hands, eyes, the brain and other specialized tissues and structures.
Hedgehog gets its name from an early experiment in which scientists knocked the gene out in fruit fly larvae. Normally, such larvae have several rows of bristles for locomotion. Without the gene, the larvae were uniformly covered in bristles, like tiny hedgehogs.
Scientists subsequently found hedgehog in species ranging from mice to humans, and Beachy's lab showed that altering hedgehog produced embryos with such developmental abnormalities as a single eye and nostril. These animals also had malformed limbs, missing rib cages and defects in the spine and the brain.
Some of these symptoms match up to a relatively rare human birth defect syndrome called holoprosen-cephaly, notes Beachy, confirming that hedgehog is a key to normal development.
When they isolated it, Beachy's lab also found that hedgehog activates by splitting itself in two. They later learned that cholesterol is involved in the split, and binds one of the divided segments to the surface of the cell where it is made.
"This also may have a connection to a birth defect syndrome: Smith-Lemli-Opitz syndrome, which disables the body's ability to make cholesterol and produces multiple serious birth defects," notes Beachy.
Other investigators have linked the hedgehog signaling pathway to two human cancers.
"A protein on the surface of cells called PATCHED is damaged in these cancers," Beachy explains. "It's not conclusively proven yet, but we think hedgehog may bind to PATCHED, and that this binding causes cells to start reproducing. With PATCHED damaged, this pathway is inappropriately activated, triggering out-of-control cell proliferation."
More recently, Beachy has worked with biophysicist Dan Leahy to study the structure of hedgehog protein, and found more surprises.
"One of the ends, or terminals, of the hedgehog protein pieces has a structure similar to rare, self-splicing proteins called inteins and exteins," says Beachy. "Another hedgehog terminal closely resembles a protein found in the cell walls of certain bacteria. It's clear that we've still got a lot to learn from hedgehog."