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Vol 19, no. 6
December 2016/ January 2017


The Defeat of Agony 
Story By: Christie Wilcox
Photos By: Kent Nishimura

At 3 a.m., the after-hours clubs on the ‘Ewa end of Waikiki are still crowded with the lovers and the love-seekers, but the Diamond Head end is quiet. The hotel signs and streetlights keep the area well lit, but there are few people in sight. This is just about the only time of day when it’s easy to find a parking spot near the Honolulu Zoo, which is good for Angel Yanagihara’s research team considering the amount of gear they need to drag to the beach. While the humans on the far end of Waikiki are just about finished with their nocturnal mating rituals, the box jellies are just getting started. 

Most of the month they feed on fish, shrimp and the other prey that dwell in the deep water offshore. But a little over a week after peak full moon, at about mid-night, box jellyfish rise from the depths and swim doggedly against the current toward shore to reproduce. After spawning, their spent, gelatinous bodies wash onto the sand. And every month on such nights, researchers from Yanagihara’s lab, myself among them, come to count the dead and collect tentacles. 

As founder and director of the University of Hawai‘i at Manoa’s Pacific Cnidaria Research Laboratory, Yanagihara has been collecting data on box jelly populations off Waikiki for almost two decades, ever since she herself fell victim to the monthly influx in 1997. She was a freshly-minted PhD about to begin a career in biochemistry when she ignored the palm-size blobs on the beach and went for an early morning swim. Once far from shore, she hit a swarm of jellies and was stung so badly that she almost drowned. “The closest I can come to describing the sting is immediately feeling hundreds of burning needles stuck deep into your skin,” she says. “There’s a certain indescribable terror that occurs—I’ve been stung by other jellies while swimming, but they are nothing like the pain of a box jelly sting.” Curious about the chemistry behind such agony, Yanagihara combed the scientific literature, only to discover that no one knew what exactly was in box jelly venom. She applied for a grant from the Hawai‘i Community Foundation to find out, and she’s been studying jellyfish venoms ever since.

Box jellies are the deadliest members of the phylum Cnidaria, which contains corals, anemones and Portuguese man o’war in addition to jellyfish. Box jellies are named for their rectangular bodies, a distinction that sets them apart from other species of jellyfish, which are almost uniformly round. Though their diaphanous bells look fragile, box jellies are formidable predators. They lack bones or brains, but they have highly developed eyes—twenty-four of them—eight of which have a retina and lens. Their vision is so sophisticated that they see their meals in exquisite detail and color, and once they spot prey they can swim toward it with surprising speed. When their long, threadlike tentacles make contact, they can kill almost instantly by puncturing prey with hundreds to thousands of explosively discharging, needle-like tubules that inject a potent venom.

It’s this venom that Yanagihara is after. Every night during the monthly influx, her team of students, staff and volunteers comb the beach between the 2C and 2D lifeguard stands at Kuhio Beach to collect and count every animal they can find. The number of jellies on that short stretch of beach—roughly one-third of a mile—can vary from a couple handfuls to several thousand per night, though usually at the peak of the influx there will be a couple hundred. Ron Bregman, who has worked as a lifeguard in Hawai‘i since the mid-1990s, says that influx days are extremely difficult, as the number of stings can be overwhelming. “Sometimes we have very large influxes,” he said. “There are days in Waikiki when we arrive at the beach at nine o’clock and there are already people waiting at the lifeguard tower who have been stung.”

Once Yanagihara’s team collects the animals, they clip the tentacles and place them in a solution that prevents the stinging cells from firing. Back in the lab, tubes full of the tentacles are gently rocked to separate the stinging organelles, called nematocysts, from the rest of the tentacle. Then a high-pressure cell disruptor extrudes the venom. It’s a process that took Yanagihara years to perfect, and with it she can collect more potently active venom per animal than anyone else in the world.

“What we do here is really unique,” Yanagihara had told me in 2014 when I interviewed for a postdoctoral position in her lab. “We’re one of a kind.” She pointed out that the lab is equipped to study these animals in almost every imaginable way. Yanagihara separates venom components to study their individual physiological effects. She then uses that information to understand the effect of those components—or the complete chemical cocktail—on live tissue. The lab’s sophisticated sequencing tools allow Yanagihara to study these toxins down to the genetic level. “And what other lab can say their animals come to their doorstep?” she added smiling.

With these tools and easy access to otherwise rare and difficult-to-collect animals, Yanagihara has conducted pioneering science on box jelly venom. One of her team’s earliest breakthroughs was isolating the most deadly component, a molecule called CAH1. It’s what scientists refer to as a “porin” because it opens pores on cells with which it comes in contact. Porins literally punch holes in cellular membranes, allowing the contents to leak out. “The way these porins work is more primitive and sinister than anyone thought,” says Yanagihara, “and similar to pathogenic bacteria.” Indeed, CAH1 is structurally similar to the main toxin in anthrax. 

Yanagihara’s team has shown that these pore-forming proteins in box jelly venom can kill in different ways depending on the dose. High doses can cause cardiac arrest through a sudden surge in potassium in the bloodstream—potassium being the first thing that leaks out of red blood cells when porins puncture them. Potassium is essential to muscle function, but when its levels are too high, muscle cells such as those in the heart can’t work properly. Yanagihara’s work has demonstrated that because of porins, the venom of the world’s largest box jelly, Chironex fleckeri, can stop a human heart in less than five minutes. Fortunately this species isn’t found in Hawai‘i.

If a victim survives the first few minutes or is injected with a smaller dose of venom, they might still be in danger. Molecules released from immune cells hit by the porins can cause massive inflammatory effects, which can fill the lungs with fluid and make breathing exasperatingly difficult, as Yanagihara herself experienced back in 1997; this can lead to death from cardio-pulmonary collapse even in people who are healthy and fit. The case of one snorkeler at Hanauma bay in particular haunts Yanagihara. The woman’s death was officially ruled a drowning, but she was found unresponsive in only two feet of water while other snorkelers around her reported being stung. Yanagihara keeps her picture tacked to the whiteboard in her office to remind her why she does this work—better diagnostic tools and emergency care protocols could save lives.

Such fatalities, while rare in Hawai‘i, are common in other parts of the world. Annually box jellies and their relatives take more lives than sharks. Some twenty to forty deaths occur each year in the Philippines alone, according to the National Science Foundation. Yanagihara has made it her mission to reduce those fatalities. Most recently, with funding from the Department of Defense, Yanagihara conducted extensive testing to develop and bring to market a topical formula that inhibits porins, which she’s named Sting No More. It penetrates the skin quickly, delivering the life-saving components where they are needed. The formula was crucial for athlete Diana Nyad during her open-ocean swim from Cuba to Florida. Military divers training in Florida frequently experienced career-ending and sometimes even fatal stings; since they began using the cream, there have been no more such incidents. “It’s working even better than I anticipated,” says Yanagihara. She’s also developed an intravenous protocol for more rapid delivery in extreme sting cases.

But inventing the treatment is only the beginning for Yanagihara: Effective interventions aren’t accessible where they are needed most. In high-risk areas like Thailand, the public and even first responders are told to treat stings by scraping the sting site and applying ice or by rinsing with seawater, neither of which are proven to work. And no matter what your friends tell you, never apply urine to a sting—that can make things worse by causing the stinging cells to fire and injecting you with more venom.

More research is needed, says Yanagihara, to understand how the venoms work. In some cases victims walk away from what appears to be a mild sting only to suddenly feel ill up to forty-eight hours later. They are overcome with a sense of impending doom and begin to experience spikes in blood pressure, which can cause brain hemorrhage. This constellation of symptoms, known as Irukandji Syndrome, is poorly understood and lacks effective therapies. Yanagihara recently received a National Institutes of Health grant to test what treatments might be most effective against it.

As a postdoctoral scientist in Yanagihara’s lab, my focus is on evidence-based first aid. I stare in awe at the strand full of beached jellies in front of me; I can easily count more than a hundred. As the tide drops, the exhausted animals wash ashore, where my lab mates collect them in small trays for processing. Protected by my three-millimeter wetsuit, gloves and booties, I slip into the gentle waves alongside Yanagihara to catch the animals while they’re swimming to get the freshest, most potent tentacles. My experiments will test whether first aid interventions like rinsing with vinegar can reduce the dose of venom delivered into a victim. If we can empirically determine the best way to respond to a sting, we might save lives, especially in rural areas where there’s no rapid access to medical care. 

I switch on my dive light, and it’s instantly clear just how many there are. We are surrounded—it’s the biggest box jelly influx I’ve ever seen. Their bells pulse as they swim, their thin, pink tentacles streaming behind. I grab each jelly by the bell, lift it gently up and place it into a bucket mounted on a bodyboard in tow. The tentacles retract as the bell leaves the water, continuing to beat. We fill one bucket, then another. And another.

By dawn my lab mates and I have collected more than 2,100 jellies. As tourists begin arriving with their beach bags, I pack the buckets of swimming animals into my hatchback. I wonder how many of these people are aware of the danger, even with the signs posted along the beach. With this many jellies in the water, there’s simply no way we got them all. There will be dozens of stings today, I think. Just before I leave, I see a couple walking with their young daughter toward the water’s edge, and I run to stop them.

“Did you see the signs?” I say, pointing to the one nearby showing the silhouette of a swimmer surrounded by jellies and the word “JELLYFISH” in big, bold letters. They shake their heads. “There are lots of box jellies in the water today. It’s not a good day to swim, especially for her.” Their eyes widen as I explain how dangerous box jellies are, particularly for young children, whose size and delicate skin puts them at greater risk. They thank me for the warning, and I return to my car.

One less sting, I think. One less. Of course a month from now, the jellies will be back. So, too, will the members of Hawai‘i’s cnidarian venom lab, walking the beaches in the wee hours, keeping an eye on the jellies and collecting venom for further research.