How a freakish birth defect among Idaho lambs 50 years ago has led to a powerful new cancer treatment.

Idaho sheep ranchers couldn't figure out why, in the decade after World War II, a random batch of their lambs were being born with strange birth defects. The creatures had underdeveloped brains and a single eye planted, cyclopslike, in the middle of their foreheads. In 1957 they called in scientists from the U.S. Department of Agriculture to investigate.

The scientists worked for 11 years to solve the mystery. One of them, Lynn James, lived with the sheep for three summers before discovering the culprit: corn lilies. When the animals moved to higher ground during droughts, they snacked on the flowers. The lilies, it turned out, contained a poison, later dubbed cyclopamine, that stunted developing lamb embryos. The mothers remained unharmed. The case of the cyclopamine and the one-eyed Idaho lambs remained a freakish chemistry footnote for the next 25 years; researchers never could uncover why cyclopamine caused birth defects.

But now cancer researchers have improbably seized on the obscure plant chemical as the blueprint for a half-dozen promising tumor-fighters. Cyclopamine, it turns out, blocks the function of a gene called Sonic hedgehog that is essential for embryonic development but also plays a lead role in causing deadly cancers of the pancreas, skin, prostate and esophagus. "It's a beautiful accident of evolution," says Philip A. Beachy, a Howard Hughes Medical Institute investigator at Johns Hopkins University and one of the key players in this genetic detective story. In early tests researchers have stopped the growth of the most virulent human tumors, varieties accounting for 25% of cancer deaths.

Genentech and partner Curis, a fledgling biotech in Cambridge, Mass., are first out of the gate with an experimental hedgehog-blocking skin cream for basal cell skin cancer. More drugs in the pipeline are aimed at other cancers. Julian Adams, the superstar chemist who invented the AIDS drug Viramune and cancer drug Velcade, has made a hedgehog inhibitor one of his lead medicines at Infinity Pharmaceuticals. Little is known about his drug, which has not yet entered human trials, but on its Web site Infinity points to the role of hedgehog in pancreatic cancer. Novartis, Abbott Laboratories and Boehringer Ingelheim are all thought to be pursuing hedgehog programs. "It would be a major triumph for basic science if a drug were to come from this,"says Matthew Scott, an HHMI cancer genetics expert at Stanford University.

The discovery of the hedgehog genetic pathway originated in the quest to understand how an embryo knows what body parts to grow and where. A developing embryo starts out as a ball of identical cells with no top or bottom, no front or back. No one knew how this ball of cells figures out where to put an arm, a wing, a head or a foot.

In the late 1970s researchers Christiane Nüsslein-Volhard and Eric Wieschaus completed their massive study of thousands of fruit-fly mutations, a landmark in large-scale biological analysis. They found 50 genes that turned out to be very important to the development of fly embryos. One that they mutated caused the flies to grow a coat of spines all over their undersides, so they dubbed it the hedgehog gene. (The two won the Nobel Prize in 1995 for this work.)

That set off a search by Philip Beachy and a dozen others to explore the hedgehog pathway in higher-order animals such as fish and mammals. They found several in each species, whereas flies have only one. In mammals, the most important may be the Sonic hedgehog gene, named after the Sega videogame character by scientists in the Harvard laboratory of Clifford Tabin in 1993. Mutations of Sonic hedgehog in people may result in babies with a single eye or a hole in the center of their head. The infants' brains can be so underdeveloped that they often don't survive. Usually patients have less serious mutations: a single front tooth or a slightly deformed face.

If Sonic hedgehog is mutated when a mouse is growing its paws, the animal won't grow digits. Interfere with it when the developing brain is casting out the two bulges of nerve tissue that become the eyes, and you get cyclopean sheep. "It's spectacular," says Frederic de Sauvage, a hedgehog researcher at Genentech.