There are two opposite paths to achievement in science. The first is straightforward: Identify a problem and set about solving it. The second is rather unscientific-sounding and perhaps more faith-based: Study in obscurity and hope serendipity strikes.
In 1980, a young gastroenterologist named Jean-Pierre Raufman wound up taking the latter road through the digestive-diseases branch of the National Institutes of Health. His goal there was to gain research experience. While doing so, he chanced to meet the lead chemist of another laboratory, John Pisano, who had a passion for seeking out new and interesting examples of a specific kind of hormone, called a peptide, in animal venoms. Pisano regularly appealed to local insect and reptile enthusiasts in the classified pages of The Washington Post; in response, they would show up at his office door carrying plastic bags wriggling with possibility.
Pisano offered some venom samples to Raufman for his meandering analyses. Over the following month, Raufman experimented with them to see if they stimulated pancreatic cells harvested from guinea pigs. The venom with the biggest effect by far came from a desert reptile that Raufman had never heard of: the Gila monster.
Gila monsters — sluggish, thick-tailed ground dwellers — are native to southern Arizona and northern Mexico. They have blunt noses and bumpy black skin with tan, pink or orange squiggles. They spend 95 percent of their lives underground. Like their cousins to the south, Mexican beaded lizards, they are one of the very few lizard species that produces venom, which they excrete from mouth glands into grooves in their serrated teeth. The strength of their jaws is typically enough to subdue their prey (chicks, frogs, worms and the like). But if threatened and unable to escape or hide, they may bite a predator. Whenever they clamp down, piercing the skin, venom enters the victim’s bloodstream. This causes intense pain and can initiate a cascade of other symptoms that, in people, includes vomiting, dizziness, rapid heart rate, low blood pressure and, in rare circumstances, death.
Raufman experimented with the Gila-monster venom for a while, then moved on to other projects. Years passed. He took a faculty position at what was then the State University of New York Health Science Center in Brooklyn and set up his own lab. Soon he found himself collaborating with a group at the Veterans Affairs Medical Center in the Bronx. One of the scientists there, an endocrinologist named John Eng, was impressed by Raufman’s work with the Gila monster. He was especially intrigued by its glacial metabolism — the lizard can survive on fewer than a handful of meals per year. Eng and Raufman paired up, screened the venom again and found molecules Raufman had not observed before. They called these molecules exendin-3 and -4.
Eng recognized the exendins as a potential diabetes therapy. He had patients with the condition who needed to calibrate their insulin injections carefully to avoid both hyper- and hypoglycemia. Exendin-4, on the other hand, resembled a human hormone called GLP-1, which works as a natural insulin manager in people without diabetes. When we eat, the small intestine releases GLP-1, prompting the pancreas to produce more insulin only when blood-sugar levels get too high. The molecule also slows digestion and makes us feel full. Scientists suspected that injections of GLP-1 would be a much easier and safer diabetes treatment than insulin, except for one crucial problem: The hormone lasts only a few minutes in the bloodstream before it breaks down. But the Gila monster analogue, Eng and Raufman were surprised to note, lasts for hours.
Eng was eager to patent the exendin molecules. The V.A. declined to do so; it didn’t see any obvious benefits for veterans. Raufman opted out, too. Diabetes wasn’t his area, and patenting molecules wasn’t common practice then. “You did science, people read your papers,” he told me. What they went on to do with what they learned was their business.
Yet Eng persisted. He patented the molecule at his own expense in 1995 and spent vacation time calling pharmaceutical companies, trying to get them to develop it into a drug. Ultimately, he licensed the patent to a start-up called Amylin Pharmaceuticals for less than a million dollars. In 2002, Eli Lilly and Company agreed to pay up to $325 million to Amylin for its drug exenatide. Under the brand name Byetta, exenatide was approved by the Food and Drug Administration for the treatment of Type 2 diabetes in 2005.
Patients who took Byetta and other exendin- and GLP-1-inspired drugs also experienced substantial weight loss, trials revealed, but pharmaceutical companies were slow to realize how useful that side effect could be. Once they did, and had improved their formulations, the consequences transformed society: Ozempic and Wegovy, followed by Mounjaro and Zepbound, became blockbuster drugs for treating diabetes and spurring weight loss. What’s more, many of them appear to have additional beneficial impacts that researchers are only beginning to understand. Some seem to be protective against kidney and heart disease and may reduce inflammation in the brain that is linked to the development of Parkinson’s and Alzheimer’s. You might say that the Gila monster — this shy, subterranean reptile — harbored a blueprint all along for medicines that may be among the most consequential health advances of our time.
Medical interest in venom has long centered, reasonably enough, on snakebites. As many as five and a half million people per year — usually agricultural workers and children in Africa, Asia and Latin America — are bitten by venomous snakes. Those bites are responsible for more than 100,000 deaths, along with many more amputations, leading the World Health Organization to declare them “a neglected public health issue.”
But most venomous interactions take place outside our awareness, among invertebrates that we are liable to squish without a second thought. Now that researchers can, with the tiniest venom sample, identify every constituent molecule down to the last amino acid, they are discovering substances of extraordinary complexity. Tarantula venoms, for example, contain more than a hundred molecules. In the venoms of some spiders and snails, that number runs into the thousands.
Venom is generally considered distinct from poison. Whereas poison is passive — a substance, like a laundry-detergent pod or berries from a black nightshade plant, that can be lethal if ingested — venom must be actively administered by an animal, often via fangs, teeth or barbs, usually to capture prey or defend against predators. Nature has engineered this capacity surprisingly often. There are at least 1,250 species of venomous catfish alone, each with its own venom formula. Venomous creatures include insects, spiders, corals, mollusks, snakes, lizards and a few mammals (platypuses, shrews). Many of them, such as marine species, are difficult to observe in their natural habitats, and so we know next to nothing about how and why they use their toxins.
But in the venoms of creatures that researchers have been able to examine more closely, two features stand out that hint at their significant medical potential. They are incredibly potent and fast-acting — necessary qualities if they are to aid the survival prospects of the creatures deploying them. They can be produced in advance and stored for long periods at ambient temperatures (in the animals’ glands). They are composed of hundreds — or sometimes thousands — of molecules that often serve multiple purposes, making venoms “essentially ecological Swiss Army Knives,” as a 2019 review in the journal Toxins put it. And a majority of those molecules are peptides and proteins honed over millions of years to target other animals in the host’s ecosystem, including plenty of creatures whose biology overlaps that of humans.
Peptides have long been especially tantalizing for drug discovery. These molecules are composed of short chains of between two and 50 amino acids, the building blocks of proteins. They are smaller and simpler than proteins are. Yet they are larger and more complex than the molecules — consisting of a single atom, or atoms bonded together — that are used in most drugs; such drug formulations can slip unnoticed through the membranes of cells and influence how they function. Peptides, by contrast, must engage with particular receptors on cells’ surfaces. Because these surface receptors differ considerably, depending on what role the cells play, any peptide that manages to interact with them tends to have a highly specific impact.
The first peptide used for therapeutic purposes was the hormone insulin, which Canadian researchers extracted from the dog pancreas in 1921. It soon began to be harvested and purified from the pancreases of pigs and cows; human insulin wasn’t synthesized in a lab until 1978. In general, peptides have limitations that make them less than ideal for commercial development: For example, they typically need to be injected into the bloodstream, because they are quickly digested if swallowed, and even then they have a relatively short biological half-life.
Since the late 19th century, researchers have known that snake venoms contain amino acids and therefore probably proteins as well. And their profound, and varied, effect on human cells was easy to see. Cobras, mambas and other members of the elapid family, snakes whose fangs are always erect, deploy powerful neurotoxins that paralyze the muscles — eyelids first, then skeletal muscles and diaphragm — until a victim asphyxiates. This prevents their prey from struggling while they eat it. Vipers, on the other hand, including rattlesnakes and adders, have fangs that fold back when not in use. Their venom breaks down blood vessels, causing profuse bleeding, which leads to clots, strokes and other related damage. “When a rattlesnake bites, it’s like a shotgun blast,” Stephen Mackessy, a biology professor at the University of Northern Colorado, told me. “It knocks out of kilter a lot of different control systems.”
Whether or not something is damaging or beneficial, however, depends on the dose and the context. In the 1960s, John R. Vane, a British pharmacologist who would go on to unravel the anti-inflammatory effects of aspirin, was studying hypertension when a postdoctoral student from Brazil joined his lab. The student, Sergio Ferreira, brought with him peptides from the venom of the Brazilian viper, Bothrops jararaca, which he had shown could dilate blood vessels, allowing more blood to flow through them. Too much of the peptide helped cause the unchecked bleeding characteristic of viper bites, but the lab discovered that the peptide could also block an enzyme, known as ACE, that causes hypertension. The peptide became the model for the first ACE inhibitor, captopril, which the F.D.A. approved in 1981 to treat high blood pressure. It went on to become a billion-dollar drug.
The use of exendin-4 to develop exenatide, the diabetes drug, was very likely the first occasion when venom was co-opted to serve a metabolic function in people. Even so, it has remained unclear why the lizard would have a metabolic hormone in its venom. In fact, the central mystery of nearly all venoms is their extravagant complexity. The Blue Mountains funnel-web spider of southeastern Australia, for example, has 3,000 molecules in its toxic cocktail, one of which happens to be deadly to humans. Are those thousands of other molecules vestiges of the evolutionary process — the spider version of our appendix, say? Or might each one serve a contemporary purpose?
Steven Trim was a molecular biologist at the pharmaceutical giant Pfizer when he realized that his hobby — keeping pet snakes and spiders — could be critical to his career. Trim’s team had been tasked with developing new pain treatments by identifying molecules that could turn off specific nerve cells. Making their project trickier, those molecules would also have to ignore other, similar-seeming cells that take care of processes like breathing and heart pumping. Most drugs in use today aren’t so discriminating. Instead, they enter all kinds of cells and cause all sorts of outcomes, some of them beneficial but others unpleasant or even dangerous as side effects.
Trim began his search as he usually did, looking through research publications for any mention of the cells he was trying to turn off. He was in luck. An academic group had indeed found a substance that could engage them: a tarantula’s venom. Naturally, Trim wanted to test that venom on his cell cultures. And, because tarantula venom contains hundreds of molecules, he hoped to purchase it already sequenced, or separated into its component parts.
Unfortunately, such a product didn’t exist. The problem, as far as he could tell, was that the people who study tarantula venom are biologists, and they generally lack the experience and technology to sequence it efficiently. On the flip side, his pharma colleagues had the tools and know-how to dismantle and reassemble infinitesimal droplets, but they tended to think of venom (if they thought about it at all) as a blunt instrument of pain and death, not a treasure trove of compelling molecular designs. And, of course, they had no idea where to get it.
Trim did, though. Because he and his wife, Carol, a cancer biologist, happened to have several tarantulas in their menagerie at home. The question confronting him was: How? In February 2010, Pfizer downsized its facility in Sandwich, England, where Trim worked. Laid off, severance in hand, he formed a new company less than a month later: Venomtech.
In one of his first acts to set up his business, Trim bought carbon dioxide from an aquarium-supply store and, on his dining-room table, began to experiment with anesthetizing spiders. He needed to be sure he could harvest their venom without hurting them. (He later found that a tarantula’s heart can stop for as long as 10 minutes before it starts beating on its own again. “We didn’t have that defined knowledge of what is ‘dead,’” he told me. “We often step off the edge of science.”)
When I visited the lab in April, Venomtech had four employees and rented laboratory space on the mostly vacant Pfizer campus where Trim previously worked. It exported the product Trim wanted to buy years earlier: venoms separated into their constituent molecules.
At that point, Trim said, the success of recent diabetes drugs had yet to kick-start a race to exploit “venomics” to find more human therapies. Indeed, persuading would-be customers to invest in the venomic future he knew was coming was his main challenge as an entrepreneur. It proved insurmountable: Four months later he ran out of money and was forced to liquidate the company.
Our view of venom as a weapon turns out to underestimate the fecundity of natural selection. Tawny crazy ants use their venom as an antidote to the venom of fire ants. Moles and shrews paralyze earthworms and insects so that they stay put in their larder and are fresh when it’s time to eat them. Jewel wasps sting cockroaches with a serum that turns them into “zombies” that willingly accompany the wasps back to their lair, to be devoured by their larvae. The venom of bees and many other invertebrates is painful but deliberately not fatal, presumably so that victims will survive to teach their offspring and other members of their species to avoid the stinger. Assassin bugs make at least two kinds of venom and can choose which to use in a given situation.
Occasionally, the redeployment of the molecules found in venom for human needs are nearly as clever. Glenn King, a molecular-biology professor in the division of chemistry and drug discovery at the University of Queensland in Australia, first became interested in toxins in the mid-1990s, a period of mounting concern about the environmental impact of chemical pesticides. “Where could we find some natural insecticides that were more eco-friendly?” King asked me. “In retrospect, the answer was obvious — spiders. They’ve been working on it for millions of years.” (Vestaron Crop Protection, which King founded before later selling his stake, manufactures his bioinsecticides.)
King switched his focus to medical applications when he realized that many venom peptides, especially those of smaller invertebrates, target ion channels. An ion is an atom or molecule with a positive or negative charge. Ion channels function as gates that determine which ions can enter or leave a cell, thereby activating or deactivating that cell by changing its voltage. Ion channels are critical to countless basic functions; they have been implicated in conditions from diabetes to cancer to epilepsy to autoimmune disorders to chronic pain. There are a lot of them in the brain and nervous system, where cells signal one another electrically.
A peptide of considerable interest to King is found in spider venom. In rodent trials, injecting it as many as eight hours after a stroke resulted in 60 percent less neural damage from oxygen deprivation compared with those rodents that didn’t get the treatment.
Other applications being investigated in other labs include a scorpion peptide that binds precisely to malignant tumors, including those in the brain. This peptide is engineered to be fluorescent so that during surgery to remove a tumor, doctors can see whether they have cut it all out. Eventually, similar molecules may be programmed to kill cancer cells outright, without chemotherapy or radiation, says Jim Olson, a professor at the Seattle Children’s Research Institute and the University of Washington, who initiated the project. A peptide from sea-anemone venom is in clinical trials as a treatment for some autoimmune diseases, according to Christine Beeton, the immunologist leading the investigations at the Baylor College of Medicine. In Brazil, a biochemist and neuroscientist, Maria Elena de Lima, is developing a peptide derived from the venom of a banana spider to treat erectile dysfunction.
Ion channels can be tough to manipulate with lab-designed molecules. Finding those molecules in nature, though, at least when it comes to venom, means bridging a crucial gap between what biologists know about how a certain creature uses its venom and what clinicians know would help their patients.
This is the gap that Steven Trim set out to close. Before Venomtech folded (he has since started another company, Ventera Bio Ltd., to develop biopesticides) he would collect all the venomous creatures he could get his hands on and milk them every few weeks — snakes less often than spiders because snakes yield so much venom. That was “a bit like juicing an orange,” he told me. “It just pours out.” Then he used liquid chromatography to separate out the different chemical components and mass spectrometry to identify them, based on the weight and charge of their atoms.
When I toured Venomtech’s lab, I was impressed by the equipment: The liquid-chromatography machine retailed for more than Trim’s first house. But more spectacular was the entire wall filled with translucent plastic boxes containing tarantulas, scorpions and centipedes. From a bin on the floor came a faint earthy aroma of locusts that served as their food source. The day I arrived, two clinical-pharmacology students, Elfreda Boateng and Rahaf Mohamed, were starting a six-week internship in the lab as part of their program at City St. George’s, an institute at the University of London. Trim’s senior lab technician, Stuart Baker, was showing them how to work with the invertebrates.
For the students’ first try, Baker selected a Chilean rose tarantula from the shelf as a sommelier might a fine wine. “They’re one of the most chilled-out spiders you can get,” he announced. He handed Boateng the top third of a plastic Coke bottle to scoop the spider up with. Mohamed took video with her phone as Boateng gingerly lifted the spider out of its habitat and slid it into a container with a hole for adding carbon dioxide.
“How was it?” Mohamed asked.
“Scary!” Boateng replied.
One of Venomtech’s customers was Helena Safavi, an associate professor of biochemistry at the University of Utah who studies the chemical composition of venom made by cone snails, marine mollusks with beautiful patterned shells. Safavi was born in Iran and grew up in Germany, where she learned to scuba dive in a murky lake. When she finally got to see a coral reef, she was captivated — not by the spectrum of colors or the diversity of species so much as by the sheer density of their interactions with one another. “You have bubbles all over your face,” she told me. “You don’t understand what’s going on around you. You’re basically in this soup, both chemically and biologically.”
There are about 1,000 species of cone snail, and some of them prey on fish and worms and other snails by injecting them with potent neurotoxins. One such toxin is so powerful that it has been known to kill divers who pick the snails up to admire them. (The federal government regulates the possession of a few dozen substances, and this type of cone-snail venom, like botulinum, is one of them.) Utah already had a robust cone-snail research program when Safavi arrived a decade ago. In the early 1990s, a professor there, Baldomero Olivera, had been studying the venoms of two cone-snail species to understand how they paralyzed fish when he figured out that their venoms contain peptides that could block a reaction in the human spinal cord that registers pain. One of the peptides eventually became an analgesic, ziconotide, that was approved by the F.D.A. in 2004.
Safavi is a “rising star” in the field of venom therapeutics, Glenn King says. In 2015, she published, along with Olivera and 14 other colleagues, a paper describing the unexpected discovery that, although cone snails are notorious for their neurotoxins, two species target fish by hijacking their metabolism instead. The snails release a venom containing insulin into the water, disabling nearby fish by rendering them essentially hypoglycemic. The fish become uncoordinated and can experience seizures or pass out, just as a person with low blood sugar might. This allows the snail to “swallow” the fish whole through its rostrum, an appendage that looks like a mouth.
In a windowless room, Safavi and a postdoctoral fellow, Aymeric Rogalski, showed me two aquarium tanks with snails in them. Dragging their shells, they had left ruts on the sandy bottom before disappearing beneath its surface. Only their brightly colored snorkel-like siphons poked out, to draw water in over their gills. Rogalski is a biologist who studies the snails’ behavior. He is also the lab member charged with extracting their venom, which he does by tricking them into reacting to a vial concealed beneath the fin of a fish. The snails shoot the vial with a hollow chitinous harpoon — which at other times they keep retracted within their shell — and plunge their toxin through it as if it were a hypodermic needle. Rogalski’s task demanded patience. He had to dangle a dead zebra fish in the water and wait for one of them to show interest. “They’re snails,” he said, “so they take their time.”
Technology has advanced so far that chemists need barely any venom at all to be able to determine its amino-acid sequence and replicate it synthetically. There are even large online databases containing the sequences of hundreds of venom peptides, and researchers can use this information to make discoveries without ever seeing a cone snail. “Some of us are a little bit sad that the technology is getting so good,” Safavi told me. “It makes fieldwork less important.”
Organizing collection trips and arranging the necessary permits can take years, and some locations are too dangerous to visit. Such excursions, though, are still the only way to find snails whose venom is new to science. “We have a whole long list of species we would love to sequence and cannot get our hands on,” she told me. All the while, climate change is decimating coral reefs around the world. Many snails that Safavi might be able to find today will be extinct before she can reach them. “In an ideal world, we would just sequence everything right now,” she said. “But I don’t see that happening.”
One morning in Utah, Safavi and I walked into a coffee shop and heard a bang. A sparrow that got indoors had flown into the front window. In a flash, Safavi pulled off her canvas jacket to use as an impromptu net. She and a member of the kitchen staff eventually shooed the bird out through the backdoor. I came to think that what venom researchers grasp better than everyone else — but what they have yet to make the rest of us understand — is more fundamental and less lucrative than the possibly unlimited utility of other organisms to humans. They appreciate that we are all — sparrows, snakes, spiders, snails — at the most foundational, molecular level, the same.
Venom researchers are thus burdened, in a sense, with a close-up view not just of our annihilation of the natural world but of the intricacy and interconnectedness of all the organisms we are snuffing out. Christine Beeton told me that she has stopped squashing spiders. “We are probably scratching the surface of venoms that are beneficial,” she says. “Each time we destroy a little piece of the environment, how many little spiders are in there or centipedes that might be a little pharma company on their own?” Glenn King notes that 99 percent of the venomous creatures in the world are invertebrates. They produce such tiny quantities of venom that, 20 years ago, we had no way to determine its composition. “I think in the next decade, people are going to be pulling out these really interesting drugs from bugs we’ve never heard of,” he told me.
David Julius, a molecular biologist at the University of California, San Francisco, has used spider venom to activate the cellular receptors for temperature and touch to see what those molecules look like and how they work — research for which he won the 2021 Nobel Prize in Physiology or Medicine. Julius notes that venom, in addition to being valuable as a reservoir of potential pharmaceuticals, can provide powerful tools for basic research. “It’s still a great resource, largely untapped, for molecules that if they don’t become drugs can tell us about how to design drugs,” he says.
But first, to tap that source, somebody somewhere has to capture a Gila monster or a viper or a cone snail or a spider, and milk it. While I was at Venomtech, Baker showed Boateng and Mohamed how to complete that process. The students had used carbon dioxide to put a tarantula to sleep. Boateng tipped its container upside down, and the spider flopped onto its back. She took off the lid and probed it with forceps. When it didn’t flinch, she slid tweezers under its fangs. They moved easily, which meant the spider was inert. Baker demonstrated how to grip its abdomen between its four sets of legs and lift it out of the box. “You pick it up with your hands?” Mohamed asked.
I got a turn, too. We all wore gloves. The spider’s heft between my thumb and forefinger was startling at first, like a supple set of car keys. Until that moment, I had not thought much about a spider’s insides. Do tarantulas have stomachs? Brains? Lungs? (Yes. Yes. Yes.)
Under Baker’s direction, I set the spider on a pedestal that held a little test tube. We unfolded its fangs — at rest they’re tucked in, aimed at the abdomen — and pointed them down into the tube. Then we positioned tiny electrodes just above them on either side of the spider’s chelicerae, its mouthparts. Baker told me to rest my finger on the spider’s cephalothorax — what I would have called its “head” — so that its fangs didn’t pop out, and then he zapped it with a jolt of electricity. The spider’s legs twitched, and venom trickled out of its fangs and into the tube. After a few more zaps, I lifted it back into its terrarium to recover, more gently than I would have before.
Kim Tingley is a contributing writer for the magazine. Her recent features have included articles about what living in space might do to the human body and the potential health impacts of exposure to “forever chemicals.” Her work has been recognized with a fellowship at the Nieman Foundation for Journalism at Harvard University and inclusion in “The Best American Science and Nature Writing 2017.” Armando Veve is an artist and illustrator in Philadelphia known for his intricate drawings in whimsical compositions.
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