On the morning of July 29, 1997, Angel Yanagihara, a biochemistry professor at the University of Hawaii, was swimming off the coast of Waikiki when she felt a sudden, excruciating pain. “I’ve been hit by a car, broken multiple bones, and had three children, all by natural childbirth, but this was far worse than anything I’ve experienced before,” she said recently. “My lungs were filling with fluid, and it felt like burning hot needles were stuck in my neck. The weirdest part of it was this overwhelming sense of impending doom.” Yanagihara managed to swim to shore by counting her breaths, then passed out. She came to in an ambulance at the scene, covered in meat tenderizer, vinegar, and Saran wrap, and later spent four days at home in bed. So began a career spent studying—and being stung again, several times—by the culprit: the box jellyfish.
There are fifty or so species of box jellyfish, which belong to the class Cubozoa, so named for the boxy shape of its translucent bell, or body. Sponges are more ancient, but the box jellyfish is the oldest animal with a complex body plan; its evolutionary history goes back six hundred million years, predating the emergence of creatures with shells, claws, teeth, or bones. It has survived for so long thanks in part to a potent security system. Its tentacles are covered in tiny stinger capsules; these can fire into a swimmer’s flesh in milliseconds and release venom that can trigger a massive inflammatory response, and sometimes rupture red blood cells. Unlike other jellyfish—gelatinous and typically passive bags of tissue—box jellies express intent. Their bells contain twenty-four eyes, including the most sophisticated eyes of any jellyfish, with retinas, corneas, and lenses, enabling the organism to see specific points of light. They lack conventional brains, but their nervous systems are capable of learning, memory, and complex behaviors, such as avoiding obstacles and swimming in unusual patterns to capture prey. Malo kingi and Carukia barnesi, two box jellyfish named for people whom they’ve stung, and each the size of a thumbnail, are known to induce Irukandji syndrome, which can cause a rapid heart rate, difficulty breathing, back pain, brain hemorrhaging, and the sensation, as Yanagihara experienced, that you are about to die. “This anxiety is very hard to manage,” she told me.
There isn’t yet a “Jaws” for jellyfish (or a week of television programing devoted to them), but if there were Chironex fleckeri, or sea wasp, would be a leading villain. Its sixty ribbon-like tentacles can grow longer than nine feet, and each is equipped with what scientists in the Medical Journal of Australia called “the most explosive envenomation process presently known to humans.” If you are touched by several feet of tentacle, you will almost certainly go into cardiac arrest within minutes. “At any time, a four-pound Chironex has enough venom to kill ninety to one hundred and twenty humans,” Bryan Fry, a University of Queensland biologist who collects “neglected” venoms, said.
This and other species of box jellyfish are considered to be the most lethal species on Earth, killing more people every year than sharks do. In Australia, the box jellyfish kills about one person every year; in the Philippines, the annual figure is as high as forty. Last week, a German woman died after being stung by a box jelly on a Thai beach, the third reported fatality in Thailand in fourteen months. The National Science Foundation has noted that, owing to poor record-keeping, “fatalities from box jellyfish may be seriously underestimated,” a common issue with venom- and poison-related statistics. As reporting improves and ocean currents and biomes change, scientists are discovering jellyfish in greater numbers in nearly every ocean, and various species of box jellyfish have shown up in places where they have not recently been abundant, including Japan, India, Israel, and Florida. Last fall, a dangerous Tamoya box jellyfish washed up on the Jersey Shore. “As the numbers go up along the Eastern Seaboard, all coastal communities could face more clinically significant stings,” Yanagihara said.
In the weeks after her own encounter, Yanagihara, who had no previous experience with jellyfish, was surprised to discover how little research had been published on the box jelly; she quickly began applying for funding to study it. “They brought the battle to the wrong person,” she said. While writing her grant proposal, “I broke all the rules, insulted all the papers that had been done up to that point, missing this and missing that, and not having used proper techniques,” she said. “I was sort of outraged.”
She was soon surprised at what she learned. “At the beginning, I thought this was a six-hundred-million-year-old animal that probably has a very primitive, aqueous cocktail of compounds,” she said. “It’s completely opposite of that.” As it turns out, the box jellyfish contains an array of toxins that are representative of those found in organisms throughout nature, from pathogenic bacteria to cobras.
In a 2012 paper, Yanagihara and her co-author identified a key group of toxins, present in the venom of every box-jellyfish species, called porins. They are named for their ability to create small pores in blood cells, causing them to leak potassium into the bloodstream. “It acts like buckshot,” Yanagihara said. Recently, some of her funding has come from the U.S. Special Operations Command. The Army Special Forces Underwater Operations School is located in Key West, Florida, which also hosts a formidable population of box jellyfish. More than a dozen divers have presented with Irukandji syndrome, and one had to be dropped from the program as a result; it was a “career-ender,” Yanagihara said.
Unlike snake or scorpion venoms, Cubozoan venoms act too quickly for typical antivenoms to be useful. Army divers and other members of the special forces now apply a topical cream, developed by Yanagihara and sold under the name Sting No More, that uses certain metal salts to neutralize the porins; Diana Nyad employed it in 2013 during her record-breaking swim from Havana to Key West. (Her encounter with box jellyfish, during a previous swim attempt, in 2011, was captured on video.)
A better understanding of box-jelly biochemistry may also point to better defenses against fatal infections from anthrax and the antibiotic-resistant “superbug” MRSA, and to other therapies, too. In the nineteen-seventies, the venom of the Brazilian arrowhead viper spawned a new class of drugs known as ACE inhibitors; one of those drugs, captopril, used for treating hypertension, has made billions in sales. A drug for people with Type 2 diabetes, exenatide, which is sold under the brand name Byetta, is based on a hormone found in the venom of the Gila monster. Venom from the Caribbean sea anemone, a relative of jellyfish, has been explored as a treatment for autoimmune diseases like multiple sclerosis. All told, the Food and Drug Administration has approved six drugs derived from venom peptides or proteins, and nine other agents are being investigated in clinical trials.
But research into the complex biochemical compounds found in box jellyfish “has remained in the dark ages,” Fry said. “More papers are published in a typical year on snake venoms than have ever been published on jellyfish venom.” Funding for basic research is one hurdle. “The folks who have not been stung by these animals really tend not to prioritize it,” Yanagihara said. And obtaining enough clean venom is difficult: box jellyfish don’t last in captivity, so researchers often must wade into Indo-Pacific coastal waters—cyclone-prone and populated by crocodiles—to find a specimen. They’re also “nearly impossible to see,” she said, being almost perfectly transparent.
Fry and a global team of researchers have sought to make the collection of venom easier and cheaper, with a new technique that uses pure ethanol to prompt the jellyfish to fire its stingers. Their approach, Fry said, “will crack open this entire research field.” In a paper published in the journal Toxins, Fry and his colleagues also identified previously known toxins in the jellyfish venom that they collected using the new method, as well as some unknown proteins and peptides. Yanagihara, who is a co-author on the paper, called the new approach a “good tool to have,” but said that she still relies on her own method for obtaining venom. It involves a machine known as a French press, which, unlike a coffeemaker, uses high pressure to recover proteins by rupturing a jellyfish’s venomous capsules. The technique is more laborious than Fry’s approach, but is designed to yield the entire toxin content of jellyfish venom. “It requires old-school biochemical techniques, and a lot of these young guys”—Yanagihara is fifty-six, a decade older than Fry—“want to go on the quickest route from A to B.”
Fry’s choice of ethanol to milk the venom draws upon surfer lore: never pour beer on a box-jellyfish sting, as it can worsen the effects. (Human urine is also a poor antidote, despite a persistent myth spread by an episode of “Friends_._”) C.S.L., an Australian pharmaceutical company, sells “antivenom” for box jellyfish, made by harvesting antibodies from the blood of partially envenomed sheep. But Yanagihara’s research has shown that the antivenom actually hastened death in some mice. “It doesn’t make sense to talk about an antivenom, given that these venoms work in seconds,” she said.
Yanagihara predicts that box jellies will become harder to avoid. The range of jellyfish species seems to be expanding as the seas are warmed by climate change, while overfishing, pollution, and acidification endanger the vertebrate marine animals that prey on jellies and keep their numbers in check. (The sea turtle, which eats box jellyfish and is basically unaffected by its stings, is now considered “vulnerable.”) “It’s like a return to a more primordial era, in which basically they were kings of the sea, not the vertebrates,” Yanagihara said. “It feels a bit like a sci-fi movie. It’s alarming, but it does get the public’s attention.”
