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Spec Tech: Monsters

September 2, 2010

Well, not real monsters as such. But the genetic mutations that inspire and inform our concept of monsters. But what is a monster anyway? A deviation from the norm. An aberration. The story of a mutant passed from one person to the next until, pushed and pulled beyond the bonds of reason, it bears little resemblance to the character that inspired it. And in so doing serves to confirm and reinforce our fear of the unknown.

Today, I’ll consider the Werewolf and the Cyclops. But there are plenty more where these came from, and I hope to return to this topic in the future.

The Werewolf

Or to be more exact those suffering from excessive hair growth, ‘hypertrichoses’ in the scientific vernacular. Generalized hypertrichoses is a condition in which excessive hair growth occurs over much of the body and has been depicted in art since the Middle Ages. Many of the afflicted, such as Jo-Jo the Dog Faced Boy (aka Theodoro Petrov), have worked as freaks or exhibitionists.

How does this occur? Well, our distant ancestors were covered with thick hair but the genes for hairiness were suppressed during the evolution. However, these silenced genes are still present in our DNA and mutations can result in their becoming expressed again. African tribes with hairy men and women were reported by explorers in the mid-1800’s and, if these tribes actually existed, might be explained by retention of an active gene for hypertrichoses in the population.

One of the most studied examples of hypertrichoses involves a dominant mutation found on the X-chromosome. The fact that the mutation is dominant means that you need only one mutation in the gene to see the effect (remember that humans are diploid and so, in most cases, mutations are recessive and don’t show an effect unless you inherit two copies of the defective gene). The fact the mutation is linked to the X-chromosome means that both men (XY) and women (XX) can exhibit the syndrome. This gene is known as CGH, standing for Congenital Generalized Hypertrichoses and, although the approximate location of the gene is known on the X chromosome, the specific gene itself has not yet been identified. But given the cheapness of sequencing genomes, as discussed in my previous blog, I expect its secret identity to be revealed any time now.

After all there is money to be made from CGH.

No, not because ‘werewolves’ represent a major medical concern. But because a good percentage of the world’s population wear toupees and wigs, apply salves, or get hair transplants, all to combat hair loss and baldness. There’s a ready and waiting market for a means to induce hair growth in humans, as long as it can be controlled.

The Cyclops

Or as we know it, the congenital disorder of cyclopia, in which the brain fails to properly develop and only one eye cavity is formed instead of the usual two. Most embryos with cyclopia spontaneously abort, but there are rare live births that account for the entrance of the Cyclops into our popular mythology.

What gene is involved in cyclopia? A good clue to this comes from the discovery of a natural toxin from corn lily (Veratrum californicum) that induces cyclopia. Pregnant sheep that mistakenly graze on the corn lily give birth to lambs with cyclopia, and an 11-year search for the cause resulted in identification of a chemical compound called cyclopamine (so named for the obvious reason). One thing that makes cyclopamine interesting is that it is a steroid, very similar in structure to our good friend cholesterol.

This immediately suggests that cholesterol is somehow involved in cyclopia.

Your doctor may warn you away from cholesterol because “it will clog your arteries,” but cholesterol performs some very important functions in our bodies. Most common is a structural role in which cholesterol is incorporated into the outer membranes of your cells to make them more watertight. But that function isn’t where cholesterol plays a role in cyclopia. Cholesterol also turns out to be important in the “hedgehog signaling pathway” that controls early development of the embryo.

Sidenote: The hedgehog signaling pathway gets its name because mutations in a fruit fly gene resulted in the embryos being covered with small pointy projections. Scientists often name genes based on the appearance of the mutant, and so they called this gene HEDGEHOG. Since then scientists have had a field day coming up with permutations of the hedgehog name. One of the genes in humans is named SONIC HEDGEHOG after the video game. And genes in zebrafish were named TIGGYWINKLE HEDGEHOG (from the book by Beatrix Potter) and ECHIDNA HEDGEHOG (from a character in the Sonic the Hedgehog video game).

Ah, you say, early development of the embryo…that makes sense. After all, cyclopia results from a defect in embryo development. But what exactly is cholesterol doing in this developmental pathway? To answer that question, you need to know that the protein encoded by the HEDGEHOG gene is the signal that initiates the whole developmental pathway (Translation: HEDGEHOG is important and if you mess with it the whole pathway gets messed up). The second thing you need to know is that the HEDGEHOG protein is initially made in an inactive form. Cholesterol turns out to be required for processing of the HEDGEHOG protein to its mature active form, becoming physically attached to the protein at one point.

The reason that cyclopamine screws up this pathway is that the toxin looks enough like cholesterol that it can interact with HEDGEHOG, but it is different enough that HEDGEHOG can’t be processed to its mature active form. As a result the hedgehog pathway doesn’t get activated. Which results in embryonic development being inhibited. Which results in incomplete separation of the regions that dictate where your eye(s) get placed. Which results in cyclopia.

So there are several ways to get cyclopia. One is to have a mutation in HEDGEHOG or other genes in the hedgehog pathway such that the embryo doesn’t develop normally. Another is to have a chemical toxin like cyclopamine that inhibits the hedgehog pathway.

The moral of the story: don’t eat corn lilies.

Recommended reading:

1. GRENDEL, by John Gardner. Sympathetic retellings of myths and fairytales from the monster/villain’s point of view is practically a subgenre in itself nowadays. This was one of the first and remains one of the best.

2. THE SWORD OF THE LICTOR (Chapters XIV-XVII), by Gene Wolfe. It’s very hard to incorporate a werewolf into a story nowadays without coming across as hokey, but Wolfe nevertheless manages to do this successfully all the time, so much so that it is almost a game to spot the werewolf references in his stories. This section from volume two of Wolfe’s Book of the New Sun is a personal favorite.

3. “The Company of Wolves” by Angela Carter. With her collection THE BLOODY CHAMBER, Carter stakes a solid claim to being one of the chief movers in the re-invention of the fairy tale for our modern sensibilities. This story forms the nucleus of the fabulous movie of the same name directed by Neil Jordan.

4. “The Other Eye of Polyphemus,” by Harlan Ellison. The Cyclops as metaphor, with a dash of fantasy thrown in for good measure.

5. “The Cage,” by Jeff VanderMeer. See if you can spot the Cyclops in its brief but effective cameo appearance.

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