WEBVTT

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In the 1950s, a group of ranchers in Idaho

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were baffled when their sheep gave birth
to lambs with a singular deformity.

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Mystified by these cyclops sheep,

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they called in scientists from the US
Department of Agriculture to investigate.

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The researchers hypothesized
that the pregnant ewes

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had snacked on poisonous 
birth defect-causing plants.

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They collected the local flora
and fed samples to lab rats,

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but struggled to replicate the effect.

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So they decided 
to directly observe the sheep

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with one scientist even living
with the herd for three summers.

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After a decade of trial and error,
the scientists finally found the culprit,

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wild corn lilies.

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The lilies contained an active molecule
with six connected rings

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that they named cyclopamine
in reference to the cyclops sheep.

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They didn't know exactly
how cyclopamine caused the defect,

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but told ranchers to steer clear.

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It took about four decades before
a team of biologists,

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led by Professor Philip Beachy,

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stumbled upon the answer.

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His lab was studying a specific gene
found in many species,

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from mice to humans,

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called the hedgehog gene.

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It was named by two scientists, who later
shared the Noble Prize for their work,

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who found that mutating 
this gene in fruit flies

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produced pointy spikes like a hedgehog.

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Beachy and his colleagues performed
genetic modifications

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to turn off the hedgehog genes in mice.

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This resulted in severe defects 
in the development

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of their brains, organs, and eyes

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or rather, eye.

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Then while perusing a textbook, Beachy 
came across photos of the cyclops sheep

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and realized what had alluded scientists
for four decades,

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something must have gone awry 
involving the hedgehog gene.

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Let's take a step back.

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Genes contain instructions that tell
cells what to do and when to do it,

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and they communicate their directives
using proteins.

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The hedgehog gene itself tells cells
to release a so-called hedgehog protein,

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which kicks off a complex 
series of cellular signals.

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Here's how it works in normal
healthy development.

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Hedgehog protein latches on to
a protein called patched.

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That inhibits, or holds, patched back,

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allowing another protein called
smoothened to freely signal the cells,

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telling them where to go
and what kind of tissues to become.

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Cyclopamine, say in the form 
of a delicious corn lily,

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interrupts this pathway
by binding onto smoothened.

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That locks smoothened up so that
it's unable to send the signals

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needed to mold the brain 
into two hemispheres,

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and form fingers or separate eyes.

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So even though the hedgehog
protein is still doing its job

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of keeping the way clear for smoothened,

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cyclopamine blocks smoothened
from passing along its chemcial message.

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That settled the science
behind the one-eyed sheep,

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but Beachy and his team 
caught the glimmer

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of another more beneficial connection.

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They noted that uncontrolled activation
of the smoothened protein

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was associated with a human syndrome.

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It's known as Basal Cell Nevus Syndrome,
and predisposes people to certain cancers.

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The scientists proposed

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putting cyclopamine's smoothened 
binding powers to good use

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as a treatment for these cancers,

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as long as the patient wasn't pregnant.

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Unfortunately, researchers eventually
found that cyclopamine

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causes negative side effects,

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and its chemical properties
make it difficult to work with.

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But they did discover that closely
related molecules are safe and effective,

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and two of these drugs were approved
in 2012 and 2015 as skin cancer medicines.

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When those farmers first saw
the cyclops sheep,

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they could have chalked it up to
a freak genetic mutation and walked away.

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Instead, their decision to investigate
turned a mystery into medicine

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showing that sometimes
there's more than meets the eye.