In the 1950s, a group of ranchers in Idaho were baffled when their sheep gave birth
to lambs with a singular deformity. Mystified by these cyclops sheep, they called in scientists from the U.S.
Department of Agriculture to investigate. The researchers hypothesized
that the pregnant ewes had snacked on poisonous
birth defect-causing plants. They collected the local flora
and fed samples to lab rats, but struggled to replicate the effect. So they decided
to directly observe the sheep with one scientist even living
with the herd for three summers. After a decade of trial and error,
the scientists finally found the culprit, wild corn lilies. The lilies contained an active molecule
with six connected rings that they named cyclopamine
in reference to the cyclops sheep. They didn't know exactly
how cyclopamine caused the defect but told ranchers to steer clear. It took about four decades before
a team of biologists, led by Professor Philip Beachy, stumbled upon the answer. His lab was studying a specific gene
found in many species, from mice to humans, called the hedgehog gene. It was named by two scientists, who later
shared the Noble Prize for their work, who found that mutating
this gene in fruit flies produced pointy spikes like a hedgehog. Beachy and his colleagues performed
genetic modifications to turn off the hedgehog genes in mice. This resulted in severe defects
in the development of their brains, organs, and eyes or, rather, eye. Then while perusing a textbook, Beachy
came across photos of the cyclops sheep and realized what had eluded scientists
for four decades. Something must have gone awry
involving the hedgehog gene. Let's take a step back. Genes contain instructions that tell
cells what to do and when to do it, and they communicate their directives
using proteins. The hedgehog gene itself tells cells
to release a so-called hedgehog protein, which kicks off a complex
series of cellular signals. Here's how it works in normal
healthy development. Hedgehog protein latches on to
a protein called patched. That inhibits, or holds, patched back, allowing another protein called
smoothened to freely signal the cells, telling them where to go
and what kind of tissues to become. Cyclopamine, say in the form
of a delicious corn lily, interrupts this pathway
by binding onto smoothened. That locks smoothened up so that
it's unable to send the signals needed to mold the brain
into two hemispheres, and form fingers or separate eyes. So even though the hedgehog
protein is still doing its job of keeping the way clear for smoothened, cyclopamine blocks smoothened
from passing along its chemical message. That settled the science
behind the one-eyed sheep, but Beachy and his team
caught the glimmer of another more beneficial connection. They noted that uncontrolled activation
of the smoothened protein was associated with a human syndrome. It's known as Basal Cell Nevus Syndrome,
and it predisposes people to certain cancers. The scientists proposed putting cyclopamine's smoothened
binding powers to good use as a treatment for these cancers, as long as the patient wasn't pregnant. Unfortunately, researchers eventually
found that cyclopamine causes negative side effects, and its chemical properties
make it difficult to work with. But they did discover that closely
related molecules are safe and effective, and two of these drugs were approved
in 2012 and 2015 as skin cancer medicines. When those farmers first saw
the cyclops sheep, they could have chalked it up to
a freak genetic mutation and walked away. Instead, their decision to investigate
turned a mystery into medicine showing that sometimes
there's more than meets the eye.
