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Venom hunters: scientists probe toxins, revealing the healing powers of biochemical weapons.

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When the monitor lizard chomped into Bryan Fry, it did more than turn his hand into a bloody mess. Besides ripping skin and severing tendons, the lizard delivered noxious venom into Fry's body, injecting molecules that quickly thinned his blood and dilated his vessels.

As the tiny toxic assassins dispersed throughout his circulatory system, they hit their targets with speed and precision, ultimately causing more blood to gush from Fry's wound. Over millions of years, evolution has meticulously shaped these toxins into powerful weapons, and Fry was feeling the devastating consequences firsthand.

"I've never seen arterial bleeding before, and I really don't want to ever see it again. Especially coming out of my own arm," says Fry, a venom researcher at the University of Melbourne in Australia.

To unlock the molecular secrets of venom, Fry and other researchers have pioneered a burgeoning field called venomics. With cutting-edge methods, the scientists are teasing apart and cataloging venom's ingredients, some of which can paralyze muscles, make blood pressure plummet or induce seizures by scrambling brain signals. Researchers are also learning more about how these toxins work.

Discovering venom's tricks may allow scientists to rehabilitate these damaging molecules and convert them from destroyers to healers. Venom might be teeming with wonder drugs, for instance. After all, a perfect venom toxin works with lightning speed, remains stable for a long time and strikes its mark with surgical exactitude--attributes that drugmakers dream about.

Already, toxins from a Brazilian viper have provided the key molecule for blood pressure--lowering drugs known as ACE inhibitors, and a medication based on cone snail venom alleviates types of chronic pain that even morphine can't touch. George Miljanich, a researcher who helped develop the snail-derived drug, calls venom an "amazing soup" with "great potential as a source of new medicine."

What's more, researchers are stepping back in time to understand how the toxic proteins that make up venom evolved in different animals, revealing details on how beneficial proteins may have been recruited to the dark side and eventually become toxic. Such studies are also finding rapidly mutating toxin genes and describing how unique environmental conditions shape venoms in different animals.

Despite the occupational hazards, "It's a great time to be doing this kind of research," Fry says. "With the techniques we have today, it's astounding what we can learn."

What makes a venom

The "amazing soup" that is venom brims with proteins and smaller pieces of proteins called peptides. "Snake venom is virtually all protein, thick as honey," says Christopher Shaw, a biological chemist at Queen's University Belfast in Northern Ireland. Figuring out the long list of ingredients in these potent mixtures, and understanding the genetics behind the ingredients, are big challenges--ones that new research approaches are helping to address.

A multinational project called CONCO represents one effort to document venomous genes. In collaboration with the J. Craig Venter Institute in Rockville, Md., CONCO scientists are now sequencing the entire genome of the project's namesake, the venomous marine cone snail Conus consors. Its genome is about the size of the human genome.

"The sequencing is moving ahead nicely," but it is no small task, says Reto Stocklin, a venom researcher at Atheris Laboratories in Geneva who leads the CONCO project.

With the decoded genome in hand, researchers will be able to quickly learn details about any toxin in Conus consors venom. "Once you have a genome, it makes it easier to know what you're looking at," says Baldomero Olivera, a cone snail expert at the University of Utah in Salt Lake City. But just because an organism's DNA has the gene for a protein, that doesn't mean the gene is active and the protein is produced. "As for which compounds you actually find in venom, there is much more play than we realized," says Olivera.

To figure out which proteins and peptides are present in venom, scientists turn to several other approaches. One method relies on identifying messenger RNA, molecules created from DNA that carry a gene's instructions to the cell's protein-building factories. Messenger RNA analysis was used to profile the toxins made by the Komodo dragon, a lizard only recently shown to be venomous. "With the techniques we have, we can point out what the dragon is making at the time, and say with absolute certainty," says Fry, who led the analysis, which was published online May 18 in the Proceedings of the National Academy of Sciences (SN Online: 5/18/09). "We can almost obtain more data than we can process."

In a study published online July 1 in BMC Genomics, researchers used a similar approach to identify toxins in the scorpion Scorpiopsjendeki. The scorpion venom had 10 types of compounds that scientists already knew about, but surprisingly, nine unknown classes of molecules also turned up. These mystery molecules are unlike anything else in venom, the researchers write.

Researchers including St6cklin rely on mass spectrometry, in which small pieces of proteins are identified by their motion through an electromagnetic field. This process results in a "chemical fingerprint," which can be used to reconstruct the compounds in venom.

Taking venoms' fingerprints has allowed researchers to make surprising finds about how venom composition can vary, even venom that comes from the same animal. For instance, in a study published in the Journal of Proteomics, St6cklin and his colleagues showed that the composition of venom milked from live C. consors differed greatly from that of venom taken from dissected C. consors venom glands. The team hypothesizes that--similar to a snail ejecting venom in natural settings--the milking allows the cone snail to control venom composition by inserting some toxins into the venom and keeping others out.

Shape-shifting toxins

Venomous creatures are found throughout the animal kingdom. Everyone knows to beware of envenomed snakes, spiders and scorpions. But beware, too, of shrews, sea anemones and platypuses, to name a few. Researchers estimate there to be some 100,000 venomous species, each with its own blend of venom containing, in some cases, hundreds of different toxins. "It's pretty clear that there are convergent features in all venoms," says Olivera. "But each group has its own peculiarities."

Researchers have found venom glands to be a rich source of information, not only for discerning differing molecular makeups of venoms (as in the cone snails), but also for anatomical comparisons. Such analyses could shed light on the evolution of various venomous creatures. In the Komodo dragon study, Fry and colleagues used an MRI scanner to reveal an intricate and unusual array of a dozen venom ducts, more than in other venomous lizards. The results show how the dragon's venom system may have evolved from other, older lizard species, and help solidify the notion that Komodo dragons kill their prey with a combination of a powerful bite and venom injection.

Such a glimpse into the predatory life of a venomous creature has opened a research floodgate. "We've been chucking everything into the machine," says Fry. "Vampire bats, cone snails, spiders, octopuses, you name it, we're chucking it into the machine now and getting incredible images of the glands."

Camilla Whittington of the University of Sydney focuses her studies on the platypus, one of just a handful of venomous mammals. "Venom in mammals is very unusual, and to see how it evolved is interesting because it might lead to insights about mammalian evolution," says Whittington. Publishing last year in Nature, she and others used data from the platypus genome to show that some platypus toxins evolved independently from those in snake venom.

Even though platypus venom and snake venom arose separately, the way it happened might have been similar. Many researchers think that the genes for normal, "good" proteins may have been duplicated by accident, leaving the second copy free to encode what turned into a havoc-wreaking venomous molecule. For instance, immune system proteins called defensins, which normally help fight off invading pathogens, were turned into molecules with the ability to slice up "good" proteins in victims (usually other platypuses or dogs), Whittington and her colleagues suggest in their report.

To be king of the hill in any given environment, though, venomous animals are often forced to invest in more than one weapon. "It's like investing money in a business. No one puts all their money in a single option. It's best to diversify," says Juan Calvete, a venom researcher at the Institute of Biomedicine in Valencia, Spain. "It's the same philosophy in nature. A cocktail of toxins is better suited as an arsenal that can be used in quite different environments."

One way proteins diversify is through mutation. Some genes that code for venom proteins mutate faster than genes that code for most other proteins. A report published online June 30 in BMC Evolutionary Biology shows how a special mutation process in toxin genes causes some snake venom proteins to change rapidly. Called accelerated segment switch, this process can make a venom toxin recognize a different target, leading to greater variety and utility.

In a study published last year in the Journal of Proteome Besearch, Calvete and colleagues found that venom from Bothrops asper pit vipers in Costa Rica differed depending on the population's geographical location. Snakes that lived on one side of a steep mountain range had markedly different venom profiles from those of snakes on the other side.

In the same way a particular Southern twang identifies a Texan, the composition of venom can reveal where a snake hails from, Calvete says.

Repurposing venom

The customized toxins in venom also make up a vast collection of potential weapons against diseases. "Venomous animals have an extraordinarily rich history in this regard," says Fry. "If you know anybody that takes high blood pressure medication, odds are they're taking a class of compounds called ACE inhibitors." The founding member of this class, says Fry, is a modified toxin from a pit viper- "one of the biggest, meanest, most horrible snakes in South America."

Another example comes from the cone snail Conus magus. In 2004, ziconotide, a drug based on the snail toxin omega-conopeptide MVIIa, was approved by the U.S. Food and DrugAdministration to treat chronic pain. Years earlier, Olivera had given Miljanich cone snail toxins to help with experiments on nerve cell signaling. In the experiments, conducted at the University of Southern California in Los Angeles and later at Neurex Corp. in Menlo Park, Calif., Miljanich and his colleagues recognized that the omega-conopeptide MVIIa toxin blocked a specific protein crucial for moving pain signals through the spinal cord to the brain. Interfering with this protein, called the N-type calcium channel, offered a way to stop some kinds of pain better than even morphine.

"We've taken advantage of 50 million years of evolution of those N-channel toxins," says Miljanich, now the CEO of the pharmaceutical company Airmid Inc. in Redwood City, Calif. Miljanich and his team at Airmid are currently working with a sea anemone toxin that has potential as a therapy for autoimmune diseases such as multiple sclerosis, psoriasis and type 1 diabetes. This toxin, he says, appears to halt rogue immune cells that are attacking the body's own tissue. The team is tweaking the toxin by adding or removing chemical groups to make the molecule more stable and effective.

A growing number of researchers are exploring the wealth of molecular resources venoms offer. "We don't want to leave any potential source [of medicines] off our radar," Miljanich says.

Beyond treating medical conditions, venom toxins may offer clues to deeper mysteries about the body and brain. "Venom has turned out to be very useful in telling us what's important about how the nervous system works," says Andres Villu Maricq, a neurobiologist and geneticist at the University of Utah.

While screening dozens of toxins from the fish-hunting cone snail Conus striatus, Stori densen, a student in Maricq's laboratory, hit upon one that inhibited a brain process called desensitization, which alters brain cell activity by dampening nerve cell cross talk. The toxin, the researchers found, clamps open a pore that is usually shut in the desensitized brain, making the cell respond to certain signals from other ceils it normally would ignore.

Understanding how brain cells communicate and having a precise way to interrupt some of those messages may offer new ways to look at neurological conditions like Alzheimer's disease in the laboratory, says Maricq. "There were really no fresh approaches."

In the wild, C. striatus venom causes fish to spin around, as if chasing their tails, although Maricq says he doesn't yet know exactly why. The team, which included Olivera, named this new toxin con-ikot-ikot, which means "spinning" in Filipino, and published the results June 9 in Current Biology.

Olivera and other toxin hunters aim to identify more such molecules and figure out how they work. This is the next great challenge for his research, he says. "What we would like to do is be able to explore the whole biodiversity of venomous snails," says Olivera. "This opens up the possibility of a huge group of compounds that could be interesting. In my case, we've suddenly realized that looking at cone snails, what we've been looking at is only scratching the surface."

The snake's 'meat tenderizer'

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Venom from the western diamondback rattlesnake (Crotalus atrox, far left) contains a toxic protein (left) that targets blood vessel walls and kills tissue, earning it and similar toxins the nickname of "meat tenderizer." By analyzing the sequences of amino acids that make up such toxins in related species of snakes, Stephen Mackessy of the University of Northern Colorado in Greeley and his colleagues found that the amino acid sequence changes more rapidly in certain regions (red) and less frequently in other regions (yellow) compared with the rest of the protein (white). Highly changeable regions enable toxins to diversify more quickly, the team proposes.

When venomous animals strike

Toxins in venom interact with a range of targets in the human circulatory and nervous systems, leading to a variety of effects.

Toxin producers

A handful of groups from the roughly 100,000 known venomous animals are shown.

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Cone snails

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Cephalopods

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Irukandji jellyfish

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Lampreys

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Sea anemones

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Leeches

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Hookworms

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Assassin bugs

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Dipteran insects

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Hymenopteran insects

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Fleas

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Ticks

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Spiders

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Frogs

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Caterpillars

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Scorpions

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Snakes

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Toxicoferan reptiles (lizards and snakes)

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Short-tailed shrews

Bad blood

Many venoms contain toxins that can wreak havoc on the circulatory system, leading to excessive blood loss, weakness and a loss of consciousness in the victim. Some toxins expand blood vessels--a process called vasodilation--leading to a dip in overall blood pressure. Others prevent the formation of clots or aggregation of platelet cells that would stanch blood loss, making uncontrollable bleeding more likely.

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Scrambled signals

Toxins target several sites at the junctions, or synapses, where nerves signal muscles. On the nerve cell, molecular pores called channels that allow ions (calcium, sodium and potassium shown) to pass can be blocked or improperly activated, impairing or rewing up the messages sent from nerve to muscle. On the muscle side, messages from nerves may be muddled when ion channels are improperly opened or closed or signal-receiving molecules called receptors are improperly stimulated or inhibited. Scrambling nerve cel signals can cause paralysis or seizures.

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Toxin targets:

Animal icons show venomous organisms that make each of the following known toxins.

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Blood and blood vessels

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eledoisin; tachykinin-like peptides

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sialokinins

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tachykinin-like peptides

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blarinatoxin; kallikrein

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peptidase S1 toxins

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Anticlotting toxins

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aegyptin; anopheline antiplatelet protein; apyrase; thrombostasins; anophelins

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pallidipin and related lipocalins; infestin and related kazal-type proteins; rhodnius prolixus aggregation inhibitor-1

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leech antiplatelet protein; saratin; hirudins; ornatins

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snake venom metalloproteinases; C-type lectin toxins; factor Xa-like proteases; bothrojaracin

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moubatin and related lipocalins; apyrase; savignin and related kunitz-type proteins; variegin; variabilin

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apyrase

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lopap, lonomin Ill

Nerves and muscles

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Calcium-channel blockers

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assassin bug toxins

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[omega]-conotoxins

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lamprey salivary CRISP

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calcicludine

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[omega]-neurotoxins

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CRISP toxins

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Potassium-channel blockers

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K-conotoxin

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apamin

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short scorpion toxins

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cnidaria kunitz4ype proteinase inhibitors; sea anemone type 3 potassium channel toxins

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dendrotoxins

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K-atracotoxins

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CRISP toxins

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Sodium-channel blockers

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[mu]-O-conotoxins (pre- and post-synaptic): [mu]-conotoxins (pre- and post-synaptic)

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hainantoxins; protoxin-II; huwentoxin-lV

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Sodium-channel activators

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[beta]-toxins

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[mu]-neurotoxins

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Sodium-channel prolongers

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[delta]-conotoxins

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irukandji-toxins

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[alpha]-toxins

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sea anemone sodium channel inhibitory toxins

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[delta]-atracotoxins

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Nicotinic receptor antagonists

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[alpha]-conotoxins

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[alpha]-neurotoxins

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Muscarinic receptor antagonists

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uncharacterized toxin or toxins

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three-finger toxins; phospholipase [A.sub.2] toxins

ILLUSTRATION BY NICOLLE RAGER FULLER; SOURCE: S, FRY ETAL./ANN. REV. OF GENOMICS ANO HUMAN GENETICS 2009

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From defense to attack molecules

Some proteins in venomous creatures evolved into toxins when certain genes were duplicated. A family of molecules called beta-defensins--immune system heroes that help fight off disease-causing invaders by chopping up proteins--were repurposed as toxins in lizards and snakes and, independently, in platypuses. Nontoxic beta-defensins are common in chickens and mammals, including the platypus. This tree traces the various lineages of defensin molecules that led to the platypus toxin (dark red) as well as the lizard and snake defensin-derived toxins (blue) that probably share a common ancestor.

Explore more

* Read about the cone snail venomics CONCO project at www.conco.eu/
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Title Annotation:animal toxin defense
Author:Sanders, Laura
Publication:Science News
Geographic Code:1USA
Date:Aug 15, 2009
Words:2966
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