Cyclopamine, it’s just what it sounds like

Allow me to paint you a picture:

You’re walking through a meadow in Idaho on a lovely warm day.  The grass waves softly in the breeze, and your picnic basket swings loosely from your hand.  The rolling hills are dotted with sheep and flowers.  You turn a corner, and walk into this:

Nooooooo!!! Get away from my picnic basket!. (Public domain image from the USDA).

GAAAAHHHH!!!! You fling your picnic basket at it, spattering wine all over yourself in the process.  What was that??

It’s a one-eyed sheep of course, and it got that way because its mother ate this plant:

Lovely, no? But deadleah. (Photo by Jerry Friedman 2008, used under the Creative commons attribution-Share alike v3.0 uported license)

Which is the corn lily Veratrum californicum (it grows in the Sierra Nevada and Rocky mountains, but the one-eyed lambs that understandably freaked everyone out were in Idaho).  Also known as false hellbore or cow cabbage, it’s a tall plant, about 4-6 feet high, and the leaves, stems, and especially roots produce a robust amount of this compound,  cyclopamine:

It looks harmless enough.

…so named because…well, yeah.  It was causing the farm animals that ate it to give birth to cyclopic babies.

How does it do that?

A better question is: how do you normally end up with two well-positioned eyes, anyway?  There has to be a signal in early embryonic development to tell your facial organs where and how many to form.  An easy way to do this is to tell cells how close they are to the middle of the face.  It turns out that a major “middleness” signal is a protein called Sonic hedgehog that comes from a structure in the developing brain. (Or depending on context, just Hedgehog.  I swear.  Maybe later I’ll write a post on how genes and proteins get such crazy names).  All the cells nearby have another protein, Smoothened, that relays how strong the Hedgehog signal is to the inside of the cell.  If the signal seems strong to the cell, it knows it’s in the middle of the face (nose territory, for example), and if it seems weaker, it knows it’s off to one side.  But when cyclopamine is around, it interferes with Smoothened, so the cells can’t “hear” the Hedgehog signal. Which means not enough middle-of-the-face forms, and structures that should to be further apart think they ought to form right next to each other in the middle.

Losing Smoothened's activity because of Cyclopamine is a bit like taking a picture of a face, cutting down the dotted lines, and gluing the two halves back together. Without enough middle, the eyes end up too close together, or even fused.

So, voila: the cyclopamine in the lily is eaten by the mother sheep during pregnancy.  It gets in the way of Hedgehog doing its job in the embryo, and the eyes creep too close together, in some cases fusing into just one eye.

Can this happen in people?

Yes.  While humans aren’t likely to be exposed to cyclopamine during pregnancy, there are mutations in the gene that encodes Shh or its partners that can cause exactly the same effect (in humans, the resulting condition is termed holoprosencephaly).

Is that what happened to Leela?

Bus driver: "nice eyeball, eyeball." Leela: "nice ass, ass."

Probably not, because Hedgehog signaling is also used for lots of other things, including making fingers and functional kidneys, which seem just fine on Leela.

So that seems pretty awful.  Does it do anything useful?

As it happens, Hedgehog signaling is crucial for the progression of some cancers, including basal cell carcinoma and medullublastoma.  Blocking Hh signaling through the use of Cyclopamine (either as a direct extract from V. californicum or through its derivative IPI-926), is being tested in treatment of these and other cancers.

Want more details?  Here’s a useful review of Hh, cyclopamine, and cancer:

Targeting the hedgehog pathway: the development of cyclopamine and the development of anti-cancer drugs targeting the hedgehog pathway.  Gould A, Missailidis S.  Mini Rev Med Chem. 2011 Mar;11(3):200-13.


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