Three years ago, wading in the sun-warmed waters of the Florida Keys, I felt a sharp pinch and looked down at my feet in surprise. My friend Jen and I had driven down from Miami for a weekend full of strong Cuban coffee and Hemingway’s six-toed cats. Tempted by water so warm and aquamarine it was almost a cliche, we had stopped to swim at a roadside beach on Bahia Honda Key. I had eased in, careful to drag my feet slowly across the seafloor in a dance known to beachgoers as the “stingray shuffle,” hoping to alert any local sealife to my approach. But not careful enough.
My foot throbbing, I stumbled back to the beach toward Jen, who wondered if I might have stepped on some glass. But in the next half hour, as my ankle and foot ballooned and the pain ratcheted up—from stinging to aching, from aching to bone breaking—it became clear I must have been stung by something. Then my foot started to turn blue, and we drove to the hospital.
“Bahia Honda?” the nurse said. “You’re the fourth person to come in with a stingray sting from there today.”
The pain didn’t subside until the next day, when my foot had returned to its normal color. That was the start of a six-week recovery, which also involved crutches, painkillers, heavy-duty antibiotics, and a horrible rash. I wouldn’t wish the experience—which involves a level of discomfort that some have compared to a gunshot wound—on anyone. But in retrospect, it’s an interesting one to consider. Because, it turns out, animal venoms like the one coursing through my veins on Bahia Honda Key are sought after for drug development, with seven FDA-approved drugs derived from venom toxins on the market so far. Harnessing their power to hurt opens up a world of possibilities for healing.
Chemical biologist Mandë Holford, who studies venom science at her lab at Hunter College, compares what was happening in my foot in the moment after the sting to a “cluster bomb.” The toxins in animal venom have been engineered by evolution over many millennia to incapacitate by affecting some component in the blood, brain, or cell membranes, she says. “You’re getting invaded with 200 to 300 different toxins, all trying to figure out how to reach their target, moving through and rupturing cell membranes, doing all sorts of damage.”
The nurse at the emergency room told me stingrays were migrating through the area, their path bringing them close to the cove where I went wading. Stingrays deliver their venom through one or more serrated barbs that lie along their tails. While at rest, a stingray keeps its barb tucked away, immunologist Carla Lima told me in an email. But when it feels threatened—say, by the feet of a clueless human out for a swim—it pushes its tail perpendicular to its body, puncturing that human’s flesh with its venom-laden spine.
Lima studies toxins in venomous fish at the Butantan Institute in São Paolo, Brazil. Her research into stingray venom has shown that what’s in that venom actually changes as a stingray matures. In the freshwater species she studies—whose venom properties are better explored than the marine stingray that got me—the venom of young rays tends to contain toxins that cause pain to the target. Lima hypothesizes this may be to chase predators away. In contrast, the toxins in adult venom have a necrotizing effect, meaning they destroy tissue, which would be helpful for hunting.
Peptides, short chains of amino acids that play key roles in the biological functions of all kinds of organisms, make up a large part of most animal venoms—and some are only found in those venoms. Lima and other researchers have identified the peptides porflan and orpotrin as two of the elements in the freshwater stingray’s toxic cocktail, along with a number of different proteases, which are enzymes that break down peptides.
As I sat cradling my foot on the beach in Bahia Honda, similar proteases and related proteins worked to break down the structure of cells in my heel, helping the venom spread further, and to prompt an inflammatory reaction that led to the swelling I saw. The peptides, on the other hand, likely caused the arteries to constrict and blood to pool, creating more inflammation and blocking circulation—perhaps the cause of my foot turning blue.
That a substance that causes so much pain and wreaks so much biological havoc can be used in medicine is what Holford calls “the yin and yang of nature.” And the fact that damage and healing are, at least in this case, two sides of the same coin forms the basis for the work she does in her lab, identifying new drug applications for various components of animal venom.
Venoms have great potential to contribute to drug development because they are both potent and highly targeted, Holford says, with peptides that fit physically into cell receptors and change how those cells function. Thanks to this dynamic, venom-based drugs can work almost instantaneously. And they’re not what people in the pharmaceutical business call “leaky,” meaning they tend to only act on the intended cell component and don’t stop at other spots along the way causing side effects.
Most stingray venom research, like Lima’s, takes place in areas where stingrays pose a threat to people: tropical spots like Brazil and Australia. On a drug-development level, we still don’t know much about it, Lima says. But we do know a lot about other venoms—in particular those created by cone snails and snakes.
For one thing, not all venom toxins cause pain. Some peptides present in snake venom focus on manipulating proteins in the wound so blood flows freely, acting as natural anticoagulants. Other peptides in Gila monster venom promote insulin production, helpful for a hungry lizard that hasn’t eaten for awhile. And yet other peptides in cone-snail venom do the opposite of what stingray venom does: paralyze and suppress pain, keeping the snail’s prey from going into fight-or-flight mode and slowing it down until the (also slow) snail can come nab it for a snack.
This last type of venom is one of the focuses at Holford’s lab. Many cone-snail venom peptides are rich in cysteine amino acids, whose structure she compares to Velcro. That makes it relatively easy for them to stick in the hourglass-shaped pores on the surface of cells that let important minerals like sodium, calcium, and potassium flow in and out. The free movement of those minerals is part of how cells talk to each other.
With those channels shut down, neurons can’t communicate with one another to indicate pain. That’s what makes Prialt, the commercial version of the cone snail’s ziconotide peptide, an effective pain medication. Holford and her colleagues are also exploring the potential of other related cone-snail peptides to help dampen signals firing too fast in someone having a heart attack or an epileptic seizure.
She even sees possible applications here for cancer treatment. Current chemotherapy regimens “don’t discriminate between normal cells and tumor,” she says. But because venom peptides work on specific receptors—receptors that some tumors grow too many of as part of their development—they could help create a cancer drug that specifically starves cancer cells of essential minerals, stopping their growth.
The venom that nearly ruined my Florida Keys vacation (though I still got to enjoy some beautiful sunsets, and the seafood was fantastic) was incredibly sophisticated, honed by evolution to inflict pain and physiological damage with laser precision. It was almost comforting to learn this in the weeks after, as I hobbled around on my crutches and watched with fascinated disgust as the wound developed a stingray-shaped blister. (My boyfriend said it was a sign I was developing superpowers, but sad to say none appeared.)
“We know from nature that these peptides work,” Holford says. “What we don’t know is massive: where they work, how they work, how effective they are. And that’s a huge game of ‘Where’s Waldo.’” Holford and her colleagues have come up with a protocol for finding new venom components that have potential in drug applications, then figuring out how to get them there. The first step is a practical look at the natural world: identifying which animal species are creating venom, especially venom that can be extracted manually. Next, the team uses new technologies that Holford refers to as the “omics”— genomics, transcriptomics, proteomics—to identify the toxins within those venoms, by examining the instructions the animals' DNA and RNA contain and the proteins built by following those instructions.
From there, the team is able to use that genetic code to manufacture more of a chosen peptide in the lab, which is especially useful when it comes to studying venoms that are produced in small quantities in nature. They then test the synthetic toxin on the animal’s natural prey to make sure it’s effective and further tweak it to ensure it’s as specifically targeted as it can be for humans. And finally, they start to think about drug delivery. Does this drug need to cross the blood-brain barrier? Would it work if administered orally? These are essential questions, since potential drugs that can’t be delivered effectively can’t really be drugs at all.
Much like the experience of the sting itself, the possibilities for new drugs here are dizzying. Most venom-based drugs on the market are derived from a single peptide. But my stingray’s venom (just like other naturally occurring venoms) featured hundreds of peptides. And with the advent of the “omics,” drug development with venom has become more efficient. Time- and resource-intensive experiments can now be run much more quickly using computer modeling, making the whole process more viable and opening up a whole world of drug prospects.
Lima and her colleagues in Brazil, for example, are continuing to explore the realm of fish venom. One synthetic peptide derived from the venom of a species of toadfish shows particular promise. A 2017 study suggested that peptide, known as TnP, has powerful anti-inflammatory and therapeutic effects in mice. Effects that could potentially help stem the autoimmune reactions that lead to spinal cord damage in patients with multiple sclerosis.
As Holford and her team navigate the new technological landscape, they’re also looking for ways to simplify their process. One innovation Holford is excited about is organoids, in this case, venom glands grown independently in a laboratory. Growing organoids would make acquiring venom samples much easier, she says, and would not require sacrificing an animal for the initial sample.
That’s especially important with climate change and habitat loss fueling a looming biodiversity collapse that could take with it undiscovered venoms with the capacity to heal. “In 10 years we’re heading toward this major shift that’s coming if we don’t change our attitudes and lifestyle,” she says. “We could lose a lot of things on the planet that are potentially lifesaving.”