Sam Robinson had his first excruciating brush with the giant stinging tree during a rainforest hike in 2018. He came across Dendrocnide excelsa in Australia’s Main Range National Park, and he reached for the tree’s hairs with his left hand to see if the sting lived up to its fearsome reputation.
“Turns out, it was as bad as everyone said it was,” he says with a laugh. “It was really shocking to experience that level of pain from a plant.”
The “intense, gripping pain” crept up his left arm and pounded the left side of his chest. A few months later, he touched the same kind of tree again, this time with his right hand, and the twinge hit only the right side of his chest—suggesting the pain was side-specific.
Robinson, a research fellow at the Institute for Molecular Bioscience at the University of Queensland, Australia, doesn’t go looking for painful wilderness encounters just for kicks—although he does chronicle how each sting feels on social media. He is part of a growing cadre of scientists who are convinced there is untapped medical potential in nature’s menu of venoms.
Thanks to technological advances in the past decade, there’s now a wealth of data about how different venoms behave and affect the body. While venoms are mostly famous for causing harm, this research shows that the chemistry and mechanisms of venom could lead to exciting new therapies to treat pain, cancer, and more.
A few proven medications derived from venom are already available for prescription today. One of the first blood pressure drugs approved for clinical use, Captoten (captopril), came from studying the venom of Bothrops jararaca, a pit viper whose bite makes its prey’s blood pressure drop. The drug Byetta (exenatide), which lowers blood glucose levels in patients with type 2 diabetes, was developed from the saliva of the Gila monster, a venomous lizard that’s native to North America. And the venom of cone snails inspired the development of Prialt (ziconotide), a painkiller injected into a patient’s spinal fluid.
But Robinson and others argue that there’s far more work that can be done to turn venom chemicals into safe and effective drugs for humans.
Venom is both “the supervillain and the superhero,” says Mandë Holford, an associate professor of chemistry at Hunter College and City University of New York Graduate Center. Focusing on venomous snails, Holford studies the evolution of venoms with the ultimate goal of deciphering its genetics, or what she calls the “Rosetta Stone of venom.”
“Unless we can understand the language of how venom genes evolve and function,” she says, “then we're really just sort of tinkering at the surface.”
Rating the pain—and deconstructing its mechanisms
Scientists who study venomous creatures commonly get stung as an occupational hazard, and a few of them have set out to document the sensations of some of the world’s most painful envenomations. It’s a hobby with a purpose—rating the pain from a variety of stings allows researchers to compare the distinct sensations, which is one way to determine that components of different venoms interact with the nervous system in different ways.
Entomologist Justin O. Schmidt, now based at the Southwest Biological Institute in Arizona, began a project in the late 1970s to catalog his subjective experiences of being stung by all kinds of insects, producing the famous Schmidt sting pain index. The sting that inspired him came from a big red ant called the Florida harvester.
“Say you get stung on your arm,” Schmidt says of the experience. “It causes the hair to stand up erect, kind of like a scared dog.”
The unusual reaction piqued his curiosity. “That was what really got me realizing that we needed to have some way to compare the pain of one insect to another,” Schmidt says. His book, The Sting of the Wild, describes stings from 83 species and rates the pain they cause on a scale from a mild 1 to an excruciating 4.
Robinson, who is a National Geographic Explorer, began studying venom professionally some 40 years after Schmidt. Inspired by the Schmidt pain index, he started rating his stings on social media using the same criteria. He has also been working to decode some of nature's most infamous venoms, recently collaborating on studies of the stinging tree, limacodid caterpillars, and spitting cobras, among other creatures.
In one study, Robinson joined Schmidt in Arizona to collect velvet ants, which are actually brightly colored wingless wasps with hairy bodies. Nicknamed "cow killers,” the wasps cause a sting that Robinson describes on Twitter as “building, pulsating sharpness descending to itch and swelling.” Schmidt is even more descriptive in his book: “Explosive and long lasting, you sound insane as you scream. Hot oil from the deep fryer spilling over your entire hand.” They both give the sting a 3 out of 4 on the pain scale.
Robinson, Schmidt, and their collaborators published the first detailed account of the composition and function of velvet ant venom in February. They found that the venom disrupts cell membranes by allowing charged particles called ions to pass to and fro through a gate-like structure called an ion channel. Molecules in the venom attack the ion channel by binding to it, keeping it open when it should be closed and sending a pain signal to the brain.
By understanding how venoms like this one work, scientists may be able to create new drugs that target the same receptors, but alleviate pain instead of causing it.
Venomous trees and cancer treatments
The giant stinging tree offers another example of how venom in the wild may hold clues to the cellular mechanisms of pain. Unlike the sting of the velvet ant, the creeping pain of Dendrocnide excelsa can be reignited by cold temperatures, even hours after it naturally subsides. “If you put cold water on that area, the pain comes straight back to its original intensity,” Robinson says from firsthand experience.
Some chemotherapy drugs also cause this effect, called cold allodynia, which creates discomfort for cancer patients taking the drugs if they make skin contact with cold objects.
“So we thought, you know, if we can figure out what the toxin is in this tree and how it's working, maybe that'll tell us something about the mechanism behind cold allodynia,” Robinson says, “and maybe we can come up with a rational way for preventing it.”
To study these strange trees, one of Robinson’s colleagues brought Dendrocnide excelsa seeds back from the rainforests of Northern Queensland and grew them in the lab. The scientists shaved off some of the stinging hairs—which can reach seven or eight millimeters long—and extracted the venom. (Some scientists then adopted the trees for their backyards).
Preliminary research suggests that, in a chemical sense, the toxin from this stinging tree species acts similarly to that of a scorpion or tarantula. The team also found the stinging tree toxin targets an ion channel called a voltage-gated sodium channel, which is found in all nerve cells in the animal kingdom. Robinson’s colleagues at the University of Queensland, Irina Vetter and Thomas Durek, are currently conducting more studies on how the tree’s sting produces cold allodynia.
“All I can say is that it's surprisingly complex, but we're making progress,” Robinson says via email.
The chemistry of different venoms may also provide a tool to combat cancer directly. Venom peptides, which are short chains of amino acids, manipulate cellular signals by targeting specific receptors. That means some venom components may be able to turn off tumor cell production while leaving healthy cells alone.
In the United Kingdom, Carol Trim, a senior lecturer at Christchurch University, and her Ph.D. student Danielle McCullough have been investigating a protein found in certain cancer cells called the epidermal growth factor receptor, and how venoms from snakes, scorpions, and tarantulas can block this receptor’s activity. In New York, Holford is working on characterizing snail venom peptides with the goal of developing new therapies for cancer and pain management.
Holford is also attempting to decipher the genetics of venom by growing mini-glands, or organoids, from stem cells. Other researchers have had recent success in growing snake venom glands, but Holford is focusing on modeling the venom-producing organs of snails. Eventually she hopes to create an entire library of model venom glands to study the genetics of these lab-grown organoids.
“What the organoids will allow us to do is to not only learn that language, but be able to manipulate that language,” says Holford, who also founded an educational technology company called Killer Snails. “And then we will have much more powerful control of what venom peptides can do for us.”
One of the core challenges is that many existing drugs based on venom peptides have to be injected because most peptides break down in the digestive system. To develop a venom-based pill, the drug needs to resist being broken down in the gut or liver, but still dissolve in the bloodstream, says Steve Trim, a pharmaceutical scientist, founder of the company Venomtech Ltd. in the U.K., and husband of Carol Trim.
That means re-engineering the peptides themselves—a line of research that “is the exciting new science for me,” Trim says.
But despite all the technological advances of venom science, Holford never loses sight of the fact that all this work hinges on mimicking and manipulating what nature has already invented.
“The animals are showing us the way, and they're showing us the way with tools that we know work,” she says. “The question for us is figuring out how they work.”
