May 6, 2005

Development genes hit center stage at lecture

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Philip Beachy, Ph.D., of Johns Hopkins, delivered the Earl W. Sutherland Jr. Lecture.
photo by Dana Johnson

Development genes hit center stage at lecture

A large crowd filed into Light Hall on Monday afternoon for the 2005 Earl W. Sutherland, Jr., lecture presented by Philip Beachy, Ph.D. In his talk, entitled “Hedgehog Signaling in Development and Disease,” Beachy guided the audience through his pioneering research on the genetics of early development and recent revelations about these genes in cancer.

In 2002, Beachy, professor of Molecular Biology and Genetics and Oncology at Johns Hopkins University School of Medicine and Howard Hughes Medical Institute investigator, was elected to the National Academy of Sciences for his work on the genes involved in embryonic development.

About 20 years ago, scientists searching for genes involved in embryonic development discovered mutant fruit flies, covered in a continuous lawn of bristles along their bodies. The gene responsible for the flies' prickly, porcupine-like appearance was dubbed 'Hedgehog.'

Beachy's lab first cloned the Hedgehog gene and characterized its protein product in 1994. His lab, which has included current Vanderbilt faculty Michael Cooper, M.D., and Chin Chiang, M.D., Ph.D, subsequently detailed how the Hedgehog protein was processed into its active state, revealed its unique mode of regulation by cholesterol, and described a striking pattern of defects in mice that lacked the mammalian Hedgehog gene, Sonic Hedgehog.

Beachy noted that these mice, born dead with a proboscis-like nose above a single eye, bore an uncanny resemblance to lambs born to sheep that grazed on plants containing the chemical cyclopamine. Beachy determined that cyclopamine blocked the Hedgehog signaling pathway, leading to defects that mimicked those of his Hedgehog mutant mice.

This work has revealed the critical importance of the Hedgehog pathway in embryonic development. More recently, a link between this developmental pathway and cancer has come to the forefront.

“This pathway also has a role in tissue homeostasis, is activated in tissue regeneration, and appears to have an important role in stimulating stem cell self renewal,” he said. These functions suggest that Hedgehog activity may contribute to cancer, often regarded as a 'stem cell disease.'

The work of Beachy and others, detailed in his lecture, supports this idea; the Hedgehog pathway is activated in a variety of cancers, including prostate, bladder, gastric, esophageal and small cell lung cancers.

From his finding that cyclopamine inhibits the Hedgehog pathway, Beachy postulated that it may have therapeutic benefit in treating cancer. When treated with cyclopamine, prostate tumors implanted into mice showed significant regression, said Beachy.

Beachy noted that in a screen of several thousand chemical compounds, there were at least 12 structurally distinct families of Hedgehog pathway antagonists, making cyclopamine-related compounds “a pharmaceutical company's dream” for novel cancer therapeutics.

The Earl W. Sutherland lecture was established by the Department of Molecular Physiology and Biophysics in 1997 to honor Sutherland, professor of Physiology at Vanderbilt from 1963 to 1973. Sutherland received the 1971 Nobel Prize in Physiology or Medicine for his research on cyclic AMP.