Featured Poison

Cyclopamine: The Curious Case of Cycloptic Sheep

Cyclops, creatures with a single eye in the middle of their forehead, played an important role in Greek mythologies.  They were often cast as dullards and monsters; the henchman of the Gods, and most likely just misunderstood.  My favorite cyclops is Polyphemus, from Homer’s Odyssey.  In it, the hero Odysseus and his men were returning from pillaging and looting when their ship was blown off course.  They came upon the island of the “Lotus Eaters.”  Partaking in the Lotus made his men not care so much and pretty mellow.  No not marijuana, but something more akin to opium, I think.  But while sedated they were captured by the giant cyclops Polyphemus, son of Poseidon.  Polyphemus, being a tad slow witted, was easily tricked by the wily Odysseus.  It’s a great epic, and one of my favorite college courses.  Yes, I was the chemistry geek that took literature courses for the easy A.  And they were fun, too.

So, can cycloptic beings exist.  Sure.  They most often occur in livestock – lots of things can happen when you have millions upon millions of births a year – but they rarely survive.  Preserved specimens are highly sought after and quite the collectible.  But ranchers take these things seriously.  An epidemic of cycloptic births can have drastic economic consequences.  And that’s where some Idaho sheep ranchers in the 1950’s found themselves.

Cycloptic lamb (public domain)

Cycloptic lamb (public domain)

In southern Idaho, during the summer birthing season, ranchers were shocked to see a high incidence of craniofacial deformities, including cyclopia.  The prevalence was as high as 25% in some flocks, but they withheld discussing the phenomenon because they feared it might be a genetic disease (1).  Unable to suffer continued economic losses, they contacted the Poisonous Plant Research Laboratory in Logan, Utah.  A scientist from the lab spent three summers documenting and studying the flocks, and finally determined that the culprit was Veratrum californicum – also called corn lily or California false hellebore – when grazed upon by pregnant sheep (2).  The corn lily,  growing in mountainous meadows in elevations of several thousand feet, has substantial, beefy leaves that look appetizing to hungry sheep.

Cyclopamine

Cyclopamine

It wasn’t until 1968 that the chemical responsible for the cycloptic births was isolated (3).  The steroid-looking chemical was called cyclopamine, naturally.  And following this discovery all sorts of Dr. Moreau inspired experiments took place.  And not just in sheep, but rabbits, too (4).  If you’re a fan of cute little bunnies, I wouldn’t check out the photo in that last reference.  It’s creepy.

Cyclopamine exerts these effects by inhibiting the hedgehog signaling pathway (5).  Specifically, the sonic hedgehog pathway.

* I swear to you, I’m not making this up.  Ask a biologist, hell, even a chemist if you’re in a pinch.  The hedgehog gene was so named because mutation of this gene produced hedgehog-like spikes in fruit fly larvae.  Makes sense.  What about the sonic part.  The “sonic” part was named after Sega’s video game character Sonic the Hedgehog.  Seriously? Really. It all makes perfect logical sense . . . . if you’re a molecular biologist.

Back to the point.  The sonic hedgehog signalling pathway plays critical roles in development, including limbs, brain, even teeth.  So when pregnant sheep munch down on some delicious corn lilies, they are poisoning their fetuses and damaging their development in monstrous ways through inhibition of the sonic hedgehog pathway. (I can’t type sonic hedgehog without smirking)

But not all is bad.  The hedgehog signalling pathway, shown to be important in development and growth, has been found in certain carcinomas and cancers, including breast cancer.  Turning off, or inhibiting this pathway, may lead to cancer treatments that stop cancer growth and be relatively safer than existing chemotherapies.  That’s the plan, at least, and it may not be an altogether bad one. [Full disclosure, but you probably don’t care, a friend of mine is on the Board of Directors of a biotech company, Curis, that is targeting the hedgehog pathway.]

So enjoy the corn lilies, just don’t make a salad out of them, especially if you’re pregnant.  And kids, don’t feed it to your rabbits.  Cycloptic bunnies are just wrong.  Wrong, I say.

OK, here’s the image . . . I couldn’t resist.

Cycloptic bunnies from ref. 4 (public domain)

Cycloptic bunnies from ref. 4 (public domain)

*** [Homepage featured image of Veratrum californicum by Dcrjsr (CC BY-SA 3.0)] ***

References:

1.  Stephen T. Lee, Kevin D. Welch, Kip E. Panter, Dale R. Gardner, Massoud Garrossian, and Cheng-Wei Tom Chang “Cyclopamine: From Clyclop Lambs to Cancer Treatment.” Journal of Agricultural and Food Chemistry (2014) Article ASAP.
2. Binns, Wayne, Lynn F. James, and James L. Shupe. “Toxicosis Of Veratrum Californicum In Ewes And Its Relationship To A Congenital Deformity In Lambs.” Annals of the New York Academy of Sciences 111.2 (1964): 571-76.
3. Keeler, Richard F., and Wayne Binns. “Teratogenic Compounds OfVeratrum Californicum (Durand). V. Comparison of Cyclopian Effects of Steroidal Alkaloids from the Plant and Structurally Related Compounds from Other Sources.” Teratology 1.1 (1968): 5-10.
4. Keeler, Richard F. “Teratogenic Compounds OfVeratrum Californicum (Durand). X. Cyclopia in Rabbits Produced by Cyclopamine.” Teratology 3.2 (1970): 175-80.
5. Chen, J. K. “Inhibition of Hedgehog Signaling by Direct Binding of Cyclopamine to Smoothened.” Genes & Development 16.21 (2002): 2743-748.

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One thought on “Cyclopamine: The Curious Case of Cycloptic Sheep

  1. Pingback: From one-eyed lambs to ‘targeted’ skin cancer drugs – Cancer Research UK (blog) – NewsBlog

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