The strange case of the cyclops sheep - Tien Nguyen

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.