Title: What's Your Poison
Author: Michael Tennesen
Source: NEW SCIENTIST, 30 September 2006 p51.
Data Base: D Base

What's Your Poison
(Buy a snake in a pet shop and you'll probably be told it's harmless. Don't be so sure.)

by Michael Tennesen

Snake venom researcher Bryan Grieg Fry made his first discovery the hard way. During his PhD, he handled a snake whose venom was largely unknown."As far as anyone knew, Stephen's banded snakes were not considered dangerous," he says. "I clearly discounted this as my body hit the ground seconds after the bite.

Several thousand snakes and more than twenty bites later, Fry, now deputy director of the Australian Venom Research Unit, at the University of Melbourne, has gone one better. Now, he says, pretty much nearly every snake on the planet is venomous, even some previously thought to be harmless - and even some commonly kept as pets.

Fry has spent the last five years exploring caves, climbing trees and scuba diving, on a mission to catch and milk venom from as many snake species as possible. Along the way he has not only gained something of a reputation as a fearless snake wrangler, he has also single-handedly re-written the story of snake venom evolution.

Before Fry came along, the story went something like this. Early snakes were small burrowing creatures, less than a meter long, which evolved from burrowing lizards. Around 60-80 million years ago they split into constrictor style snakes and the 'advanced snakes,' which are divided into four families: Viperidae (vipers), Elapidae (cobras and coral snakes), Atractaspididae (stiletto snakes) and Colubridae (everything else).

With the exception of the colubrids, which lack front fangs and were thought to have nothing more dangerous that slightly toxic saliva, true venom was assumed to have evolved three times, arising independently in each family, after they split off from their non-venomous ancestors. In these three families there was thought to be a grand total of 250 venomous species, all of which gained their venom by developing increasingly nasty saliva.

Fry began his venom collecting mission in 2001. It's dangerous work. Fry lost a friend and colleague to a snakebite in 2001 and has himself been bitten numerous times. "It happens, but it doesn't make me nervous, it's all part of the job." he says, pointing out that he never goes anywhere without a doctor and a supply of anti-venom.

Between trips around Africa, Australia, and the South Pacific Fry set to work analyzing the venoms he'd collected and the glands that produced them. By sequencing samples of messenger RNA from inside the venom glands he determined which toxic proteins were being produced in each species, and in what amounts. Once he had a run-down of the toxins, he was able to create a phylogeny - an evolutionary tree based on physical similarities - from the venom of different species of snakes and closely related lizards.

He then compared his results to an existing snake phylogeny created by Nicholas Vidal at the National Museum in Paris. Vidal had traced snake evolution through DNA extracted from liver tissue so provided a check that similarities between venoms really did reflect evolutionary relationships. Finally he compared his new evidence to the fossil record.

Fry's phylogeny was to overturn everything scientists thought they knew about snake venom. Similarities between the venom glands of advanced snakes and venomous lizards revealed that the venom-secreting glands evolved not, as was previously thought, a common snake ancestor that lived 60 -100 million years ago, but in a common lizard ancestor that lived 200 million years ago. Venom evolved only once, a hundred million years before the advanced snakes even appeared on the evolutionary tree, in the common ancestor not only to all snakes but some other reptiles including the Komodo dragon, the green iguana, and the Gila monster.

What's more modern snake venom didn't arise out of the development of ever more toxic saliva but from what Fry calls "recruitment events." Rather than tweaking proteins already expressed in their saliva, snakes recruited and altered cells from other parts of the body, including the brain, eye, lung, heart, liver, muscle, ovary and testis. By duplicating these 'borrowed' proteins over and over genetic mutations arose which altered their normal functions, and concentrated them into catastrophic overdoses. Their arsenal has been growing ever since. The common ancestor had nine toxin types in its venom, modern advanced snakes have recruited 17 between them, for a total of 26.

The upshot of all this is that while 'non-venomous' colubrids were previously thought to have only mild toxic saliva, Fry's work shows that they actually possess true venoms. In fact, Fry says he has found snakes in pet stores which "have enough poison in them to kill a human." The rat snake, a common choice of pet, has a cobra-style neurotoxin, which is as potent as the cobra equivalentÑthough its crude delivery system makes it far less dangerous.

On the flip side, snakes like king snakes, pythons, and boas that use constriction to catch prey were previously thought never to have evolved venom. Now it seems they may have evolved out of producing venom, in favour of killing by constriction. Fry has found evidence that some snakes are currently of evolving "out" certain venom components, perhaps because of the huge amounts of energy it takes to create them. The marbled sea snake, for example may have developed venom 50- to 100-times less toxic than that of similar species after it began to feed exclusively on fish eggs, rather than fish.

According to Martin Kreitman, professor of evolutionary ecology at the University of Chicago, the findings through a whole new light on the snake evolutionary tree. "It means that venom may have evolved first, and that what separates other advanced snakes from the colubrids are simply more advanced delivery systems for injecting the venom," he says.

The good news is that while 'colubrids' like garter snakes, American racers, and radiated rat snakes may have as much venom as their more deadly cousins, they drip venom from their back teeth, so unless you plan on sticking your hand down a snake's throat, you would be unlucky to get a deadly bite. And in many cases what is toxic to a two gram frog may not be toxic to a 50 kilogram human.

"The vast majority of the colubrids are perfectly safe," says Fry, but be careful of any new snake from Asia, Madagascar, and Latin America. Previously sold as pets, the olive sand snake has huge venom glands and big teeth and the Egyptian catsnake is as toxic as a cobra, and there's no anti-venom.

But caution at the pet store is not the only spin-off from Fry's work. Snakebites account for tens of thousands of deaths each year in South America, Africa, the Middle East, and Southeast Asia. The more venoms that are catalogued and understood, the greater the chance of the right anti-venom being available at the right time.

It also opens up a vast new area of venom research. There are only about 450 elapids, vipers, and atrascaspidids total, but there are over 2000 colubrids, accounting for over half the snake species on the planet. Fry estimates that at least 2700 species are venomous if he's right that's a lot of potential new molecules which could work as drugs.

Some snake toxins are incredibly specific, binding to a single site of just one subtype of a certain nerve receptor. You would be hard pressed to design a drug that specific, but that 200 million years of a very intense predator prey chemical arms race has done the job nicely.

There are a number of drugs on the market derived from snake or lizard venoms. Captropril, developed from the venom of a lance head viper, which causes catastrophic drops in blood pressure for snake bite victims, in modified form is one of the most widely used medications for high blood pressure. Byetta (Exenatide), a promising new drug from the venom of a Gila monster, may soon start stabilizing the blood sugar of diabetics. And researchers at the University of South Australia and elsewhere are currently researching the venom of a number of deadly Australian snakes which may stunt tumor growth by disrupting its blood supply.

The snake that bit Fry early in his PhD, a Stephen's banded snake, turned out to immobilize its prey using a blood pressure regulating hormone that is almost identical to one that is used in the human body. Fry recently patented the venom component that does this in Stephen's banded snake and the inland taipan and hopes it will one day be used to treat patients with congestive heart failure. There may be many more waiting in the wings.

But don't expect a mad rush of scientists to join Fry in the field. "It's a dangerous job," says Kreitman, "Fry is truly a modern adventurer, one of a bunch guys who think it's great to travel to the most remote places in the world and risk death."

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