Mithridates VI of Pontus : Scientists are unlocking the medical potential of venom

Michael decided to go for a swim. He was on vacation with his family in Guerrero, Mexico, and it was hotter than blazes. He grabbed his swimming trunks from where they’d been drying on a chair, slid them on, and jumped into the pool. Instead of cool relief, a burning pain ripped through the back of his thigh. Tearing off his trunks, he leaped naked from the pool, his leg on fire.

Behind him a small, ugly, yellow creature was treading water. He scooped it into a Tupperware container, and the caretaker of the house rushed him to the local Red Cross facility, where doctors immediately identified his attacker: a bark scorpion, Centruroides sculpturatus, one of the most venomous species in North America. The fierce pain from a sting is typically followed by what feels like electric shocks racking the body. Occasionally victims die.

Luckily for Michael (who asked me not to give his full name), the bark scorpion is common in the area, and antivenom was readily available. He had an injection and was released a few hours later. In about 30 hours the pain was gone.

What happened next could not have been predicted. For eight years Michael had endured a condition called ankylosing spondylitis, a chronic autoimmune disease of the skeleton, a sort of spinal arthritis. No one knows what triggers it. In the worst cases the spine may fuse, leaving the patient forever stooped and in anguish. “My back hurt every morning, and during bad flare-ups it was so horrible I couldn’t even walk,” he says.

But days after the scorpion sting, the pain went away, and now, two years later, he remains essentially pain free and off most of his medications. As a doctor himself, Michael is cautious about overstating the role of the scorpion’s venom in his remission. Still, he says, “if my pain came back, I’d let that scorpion sting me again.”

Venom—the stuff that drips from the fangs and stingers of creatures lurking on the hiking trail or hiding in the cellar or under the woodpile—is nature’s most efficient killer. Venom is exquisitely honed to stop a body in its tracks. The complex soup swirls with toxic proteins and peptides—short strings of amino acids similar to proteins. The molecules may have different targets and effects, but they work synergistically for the mightiest punch. Some go for the nervous system, paralyzing by blocking messages between nerves and muscle. Some eat away at molecules so that cells and tissues collapse. Venom can kill by clotting blood and stopping the heart or by preventing clotting and triggering a killer bleed.

All venom is multifaceted and multitasking. (The difference between venom and poison is that venom is injected, or dibbled, into victims by way of specialized body parts, and poison is ingested.) Dozens, even hundreds, of toxins can be delivered in a single bite, some with redundant jobs and others with unique ones. In the evolutionary arms race between predator and prey, weapons and defenses are constantly tweaked. Drastically potent concoctions can result: Imagine administering poison to an adversary, then jabbing him with a knife, then finishing him off with a bullet to the head. That’s venom at work.

Ironically, the properties that make venom deadly are also what make it so valuable for medicine. Many venom toxins target the same molecules that need to be controlled to treat diseases. Venom works fast and is highly specific. Its active components—those peptides and proteins, working as toxins and enzymes—target particular molecules, fitting into them like keys into locks. Most medicines work the same way, fitting into and controlling molecular locks to thwart ill effects. It’s a challenge to find the toxin that hits only a certain target, but already top medicines for heart disease and diabetes have been derived from venom. New treatments for autoimmune diseases, cancer, and pain could be available within a decade.

“We aren’t talking just a few novel drugs but entire classes of drugs,” says National Geographic Society Emerging Explorer Zoltan Takacs, a toxinologist and herpetologist. So far, fewer than a thousand toxins have been scrutinized for medicinal value, and a dozen or so major drugs have made it to market. “There could be upwards of 20 million venom toxins out there waiting to be screened,” Takacs says. “It’s huge. Venom has opened up whole new avenues of pharmacology.”

Toxins from venom and poison sources are also giving us a clearer picture of how proteins that control many of the body’s crucial cellular functions work. Studies of the deadly poison tetrodotoxin (TTX) from puffer fish, for instance, have revealed intricate details about the way nerve cells communicate.

“We’re motivated to look for new compounds to lessen human suffering,” Angel Yanagihara of the University of Hawaii told me. “But while doing that, you may uncover things you don’t expect.” Driven in part out of revenge for a box jellyfish sting she endured 15 years ago, Yanagihara discovered a potential wound-healing agent within the tubules that contain jellyfish venom. “It had nothing to do with the venom itself,” she said. “By getting intimate with a noxious animal, I’ve been informed way beyond my expectations.”

More than 100,000 animals have evolved to produce venom, along with the glands to house it and the apparatuses to expel it: snakes, scorpions, spiders, a few lizards, bees, sea creatures such as octopuses, numerous species of fish, and cone snails. The male duck-billed platypus, which carries venom inside ankle spurs, is one of the few venomous mammals. Venom and its components emerged independently, again and again, in different animal groups. The composition of the venom of a single snake species varies from place to place and between adults and their young. An individual snake’s venom may even change with its diet.

Although evolution has been fine-tuning these compounds for more than a hundred million years, venom’s molecular architecture has been in place much longer. Nature repurposes key molecules from around the body—the blood, brain, digestive tract, and elsewhere—to serve animals for predation or protection. “It makes sense for nature to steal the scaffolds already in place,” Takacs says. “To make a toxin to wreck the nervous system, it’s most efficient to take a template from the brain that already works in that system, make some tiny changes, and there you have it: Now it’s a toxin.”

Not all venom kills, of course—bees have it as a nonlethal defense, and the male platypus uses it to show rival males who’s boss during mating season. But mostly it’s for killing, or at least immobilizing, an animal’s next meal. Humans are often accidental victims. The World Health Organization estimates that every year some five million bites kill 100,000 people, although the actual number is presumed to be much higher. In rural areas of developing countries, where most bites occur, victims may not be able to get treatment or may instead choose traditional therapies and are therefore not counted.

The 44-year-old Takacs, Hungarian born and with a voice like tires crunching gravel, recently left the University of Chicago to launch World Toxin Bank. When not at the lab bench, he can be found wrangling puff adders in South Sudan, sampling kraits in Vietnam, and milking Gaboon vipers in Congo. His goal is to collect blueprints for “toxin libraries” that could eventually hold the venom toxins of every animal on Earth.

His quest also takes him out to sea. From afar, the tiny tree-lined coral island of Mabualau, about eight miles east of Fiji’s main island, Viti Levu, seems a tropical paradise. Up close, thousands of squawking red-footed boobies, frigates, and gulls clog the trees and sky. Their waste turns the shallow water into a fetid white soup whose stench somehow infiltrates the back of my throat. Before we’ve even anchored our tiny boat, Takacs hops over the side and wades ashore.

Yellow-lipped sea kraits, smooth-scaled silver-blue snakes with zebra stripes, thrive here, essing along the sandy bottom. The land-and-sea-going snakes, which need air to breathe, ascend the island’s rough coral and limestone banks. They coil up under shells and foliage to digest their food and, every few months, shed their skins.

The kraits feed almost exclusively on eels, and their neurotoxic venom has evolved accordingly. The eels are big and strong and have sharp teeth, and it’s hard to pry them out of their burrows. “The snake needs a potent and fast venom aimed at vital body parts,” Takacs says, “so it can get the meal with low risk of injury to itself.” Snake venom and the eel’s defenses have been in an evolutionary one-upmanship for ages, he says.

The reefs also harbor venomous anemones, blue-ring octopuses, and a host of toxin-spewing fish about which little is known. And cone snails. Lovely as jewels, each of the more than 600 Conus species concocts a unique and wicked brew, some strong enough to kill a person with a single shot. (No matter how pretty it looks, never put a cone snail in your pocket.)

After a shallow dive, Takacs strolls along the water’s edge holding treasure: a sea krait wriggling in one glove and a fist-size cone snail in the other. “The best the sea has to offer,” he grins. “I have hundreds of toxins in my hands.” The cone snail’s shell is a gorgeous mosaic of brown paint-daubs on white. After I admire his finds, Takacs drops the snail into a seawater-filled container for later examination. Snakes are his first priority.

Always equipped with a sampling kit, Takacs sets up a basic field lab on the boat: lidded containers, tubes filled with preservatives, syringes and needles, a pair of snippers for tissue sampling, a camera for documenting each animal’s patterns, and a big black glove. Sea kraits are quite passive, so the chances of getting bitten are almost nil. But Takacs wears the glove anyway. He’s allergic to venom, which would cause him anaphylactic shock in addition to its usual paralyzing effects. He’s also allergic to antivenom, made with serum from horses, so it’s extraordinary that he’s survived a total of six snakebites.

I help by holding the snake’s tail, belly scales up. Takacs grips the biting end, stretches the snake to its length, and runs a finger down the body, feeling for the heart. When he locates it, pulsing against the skin about a third of the way down, he carefully inserts a needle and draws blood. He also clips off a fragment of tail tissue and shoots a few photos before setting the snake back in the water and watching it swim away.

Takacs processes numerous snakes this way during our days on the water. And anytime we encounter local fishermen, he motors up to ask about their sea snake sightings, hoping to hear of other species in the area. “If you see the one with the yellow and black bands,” he says, “would you let me know?” Indeed, one day he was summoned to the dock, where a slender-necked sea snake awaited in a bucket. Takacs is known to have engaged entire villages to look for snakes.

In Fiji, and wherever else he collects venomous animals, Takacs is adding to his venom library. Meanwhile, in the lab he teases out variations in the makeup of toxins between species, within species, and even within populations. He also investigates what makes animals resistant to their own venom—information that could help yield better venom-derived therapeutic drugs.

I was surprised that Takacs wasn’t milking the venom of the sea kraits, but he explained that DNA underpins his work. Venom itself can offer important information, but when you have tissue, Takacs says, “you can take it home and extract the blueprint for the entire animal—including most of its toxins.” Each toxin is expressed by a gene, and genes can be copied and manipulated. “We can make bucketloads at a time, and then we have the luxury of being able to modify the toxins any way we want, and screen quickly to see which version has the most promising effects.”

At the University of Chicago, Takacs co-invented Designer Toxins, a system that allows researchers to make variations of nature’s originals by recombining toxins and comparing therapeutic values. Designer Toxins encompasses the millions of years of evolutionary wisdom preserved in venoms. This makes it possible to create vast numbers of variants (more than a million so far), potentially streamlining efforts to develop drugs. “We’re mining the molecular biodiversity in nature,” Takacs says.

Venom-based cures aren’t a new idea. They show up, for example, in Sanskrit texts from the second century A.D., and around 67 B.C. Mithradates VI of Pontus, an enemy of Rome who dabbled in toxicology, was supposedly saved twice on the battlefield by shamans who administered steppe viper venom to his wounds. (Crystallized venom from the snakes is now a medical export from Azerbaijan.) Cobra venom, applied for centuries in traditional Chinese and Indian medicine, was introduced to the West in the 1830s as a homeopathic pain remedy. John Henry Clarke’s Materia Medica, published around 1900, describes the venom as alleviating many ills, even those caused by venom. “We should always endeavour to use the same drug to cure as produced the symptoms,” the author wrote. Clinical applications of carefully diluted cobra venom included “Angina pectoris. Asthma. Dysmenia. Hay-fever. Headache. Heart, affections of. Oesophagus, spasmodic stricture of. Ovaries, affections of. Plague … Throat, sore.” But be careful, it was noted: “The curative dose [is] just within the limit of the pathogenetic dose.” Walking such a fine line, physicians of old likely hastened patients’ deaths as often as—or more often than—they prolonged their lives.

The science of transforming venoms into cures took off in the 1960s, when an English clinician named Hugh Alistair Reid suggested that the venom of the Malayan pit viper might be used against deep-vein thrombosis. He’d discovered that one of the snake’s toxins, a protein called ancrod, saps a fibrous protein from the blood, preventing clotting. Arvin, a clot-busting drug derived from pit viper venom, reached clinics in Europe in 1968. Today Arvin has been replaced by other viper venom anticoagulants.

The Brazilian pit viper’s venom led to the development in the 1970s of a class of drugs called ACE inhibitors, now widely used against hypertension. Researchers began by asking why Brazilian banana plantation workers bitten by these snakes collapsed with crashing blood pressure. The researchers then teased out the key pressure-lowering component in the venom. But drug-company managers needed convincing that what comes from snake fangs would save human lives. And you can’t just put venom in a pill and hand it to patients, so the useful component of the venom had to be modified at the molecular level—resized and tinkered with to survive the harsh effects of the human digestive system. Eventually a synthetic version made it to human trials, and in 1975 the first oral drug for hypertension, captopril, was approved for use. The ACE inhibitor class of drugs pioneered by captopril now treats tens of millions worldwide, with multibillion-dollar sales.

The molecular gifts of toxic animals offer hope in the fight against a host of debilitating diseases. Heart patients owe gratitude to the Eastern green mamba, a deadly African tree snake whose venom impairs its victim’s nerves and blood circulation. Researchers at the Mayo Clinic fused a key peptide from the venom with a peptide from cells in the lining of human blood vessels to make cenderitide, the subject of clinical trials. It is intended not only to lower blood pressure and reduce fibrosis (the growth of excess connective tissue) in a failing heart but also to shield the kidneys from an overload of salt and water. “That’s the beauty of this drug,” says Mayo cardiovascular researcher John Burnett. “It’s designed to cover both things.” The closely related black mamba, a snake whose open mouth resembles a coffin and whose venom can quickly put you in one, holds a toxin with huge potential to be a powerful new painkiller.

Gila monsters, pebbly-skinned lizards found in the deserts of the U.S. Southwest, eat as few as three big meals a year (storing fat in their tails for the long wait), but their blood sugar remains stable. In 1992 an endocrinologist named John Eng at the Bronx/James J. Peters VA Medical Center in New York identified a component in Gila venom that controls blood sugar and even reduces appetite. Exenatide, a drug derived from the venom in their saliva, works like a natural hormone, stimulating cells to deal with sugar overload but remaining inactive when sugar levels are normal. It even helps diabetics produce their own insulin and lose weight. With almost 25 million people suffering from type 2 diabetes in the U.S. alone, the Gila monster is nothing short of a medical superhero.

Venomous mammals, though rare, are in the game. The current drug for ischemic stroke victims works only if administered within three hours. A drug based on an anticoagulant toxin in the saliva of the vampire bat is now in clinical trials and would extend the time to nine hours. Even some arthropods are skittering down the venom-to-medicine track. Recall Michael’s run-in with the scorpion in Mexico. Takacs, in what may be his first Designer Toxins breakthrough, is investigating a novel toxin fused from the venoms of three different scorpion species that selectively blocks immune T cells, implicated in numerous autoimmune diseases. Several drug companies are also pursuing this lead.

Meanwhile, a neurotoxin from the venom of the giant deathstalker scorpion has been found to attach to the surface of brain cancer cells. The overwhelming reason tumors come back is that surgeons can’t reliably distinguish good cells from bad at the growths’ edges. Magnetic resonance imaging—the best available diagnostic tool—doesn’t detect masses smaller than about a billion cells. This means surgeons have to find the boundaries between tumors and healthy tissue “purely by visual and textural cues,” says James Olson of the Fred Hutchinson Cancer Research Center in Seattle, Washington. “It’s a very imperfect science. Glioma cells weave into normal tissue, and pieces sometimes get left behind.”

Doctors who treat glioma, the most common form of brain cancer, created a “molecular flashlight” by marking chlorotoxin with a near-infrared dye. On the very first trial, Olson says, the “tumor paint,” as he calls the scorpion-derived marker, “lit up the cancer beautifully. We were literally jumping up and down because we knew what incredible potential this had.” The paint reveals masses with as few as 200 tumor cells. “You can truly see the tumor almost cell by cell,” Olson says. “This will let surgeons get more cancer out, maybe even 100 percent.” Human trials on the dyed toxin will start later this year, and if tests go well, the paint could be used for prostate, colorectal, lung, breast, pancreatic, and skin cancers, as well as glioma, potentially saving or prolonging millions of lives every year.

No drugs based on scorpion toxins have yet been approved, but these toxins represent a versatile chemical arsenal. One may be a cancer foe, others the basis of cardiac, painkilling, anti-seizure, and antimalarial drugs. There’s even a possible pesticide among them.

The cone snail lacks the menacing air of a scorpion, but as I’d learned with Takacs in Fiji, there’s a beast in this beauty. Cone snails have no jaws and no claws. “They have only a very precarious tether for grabbing their prey,” says Baldomero Olivera, a Conus expert at the University of Utah. “So they compensate by having 50 or more venom components working on different levels.” The fish-eating species Conus purpurascens, one of Olivera’s favorites, uses its extendable, venom-loaded proboscis to essentially Taser a fish, immobilizing it in an instant. That gives time for multiple toxins in the venom to disperse and destroy muscle activity.

Being stung by a cone snail, Olivera says, “is like being bitten by a cobra and eating fugu at the same time.” (The fugu’s TTX is more than a thousand times deadlier to humans than cyanide.) Cone snails, Olivera says, “are like little drug companies that have engineered their own compounds to suit their needs.” Conotoxins in snail venom shut down nerve cell processes—which, it turns out, is an effective way to mask pain in people with late-stage cancer. Snail venom peptides called conantokins, which have exceptionally precise molecular targets, are being tested with some success against epileptic seizures. Both conotoxins and conantokins may be protective against Alzheimer’s and Parkinson’s diseases, depression, and even nicotine addiction. So far, five compounds from the snails have made it to human trials, and one morphine-like pain drug, ziconotide, has resulted. Ziconotide is chemically identical to the component the snail makes.

Another sea creature, the sun anemone, has toxic tentacles that stun its prey before wrapping the victim—often a small fish or a shrimp—into its maw for dinner. But the anemone’s stinging cells, called nematocysts, fire off venom that contains peptides useful in treating human autoimmune diseases. In the 1990s a team led by physiologist George Chandy of the University of California, Irvine revealed that one of the peptides blocks the activity of a protein that promotes inflammation. The researchers reconfigured the peptide into one they called ShK-186. Now Kineta, a biotechnology company based in Seattle, is developing this against autoimmune diseases. What makes it so promising, says Shawn Iadonato, Kineta’s chief scientific officer, is how specifically it binds to diseased cells. “Our drug is very specialized to target the cells at work in these diseases. Other meds are problematic because they have many side effects and leave patients vulnerable to infection and cancer.”

The sun anemone holds promise for treating diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, and lupus. “It will let patients experience a more normal life,” Iadonato says. “It just takes a long time, even when you have a breakthrough discovery. There are so many side avenues to take to make sure there are no unintended effects. There’s a lot of unraveling and putting back together to get it just right.”

Advances in fields such as molecular biology continue to give scientists better ways to understand venoms and their targets. While drug companies once relied on luck, screening thousands of compounds for a particular effect, today’s higher tech options, such as Designer Toxins, give sharper detail, making it easier to shape medicinal keys to fit specific molecular locks. This means that a spray to stop bleeding derived from the venom of the brown snake will likely soon be saving lives at accident scenes, and a peptide from mambas will someday be treating heart failure.

The medical potential of venom, Zoltan Takacs never tires of saying, is “mind-blowing.” But we’re at risk of losing the sources of that potential faster than we can identify their toxin gifts. Snakes, in adapting to fill varied niches all over the globe, have evolved a stunning range of venomous compounds. But snakes are in decline, as are so many other animals. The oceans too are under pressure; their changing chemistry could wipe out promising sources of venom, from cone snails to octopuses.

“In conserving biodiversity worldwide,” Takacs says, “we should better appreciate molecular biodiversity.” That would put the molecules in nature’s deadliest potions high on the agenda when conservation decisions are made. And that would be a lifesaver.

Agencies