The sting of a box jellyfish can kill a person in minutes. But scientists have long been at pains to figure out the secret of its fast-acting venom, which can also cause severe agony, inflammation, and heart attacks. A new study may have the answer—and a potential antidote.
The finding is “tour de force,” says Angel Yanagihara, a biochemist who studies jellyfish venom at the University of Hawaii in Honolulu, but who wasn’t involved with the work.
Up to 40 people die each year from box jellies, according to available figures. But that number is vastly underreported, Yanagihara says. “People die and there is no trace in the public records.” In the Philippines alone, she estimates some 500 people die from box jelly stings each year. And as the ocean warms—and as the range and number of box jellyfish rises—problematic encounters will likely increase.
But to date, no one knows how the box jelly’s venom targets and enters human cells. Previous work on their venom has shown that pore-forming proteins, called porins, destroy red blood cells and damage cell membranes, potentially resulting in pain and death. Yet, more components could be responsible.
In the new study, geneticist Greg Neely of the University of Sydney in Australia and colleagues collected live Chironex fleckeri, the species of box jellyfish responsible for most human deaths, from coastal waters off of the Northern Territory of Australia. They soaked the tentacles in seawater, recovered the capsules that contain the stinging cells, and then broke them with tiny glass beads to release the venom, which they freeze-dried.
Next, the scientists generated a pool of millions of myeloid cells, each of which was missing one of 19,050 genes. (Because the cells, derived from a leukemia patient, have just one set of chromosomes, they are often used for genetic screening tests.) Then, the scientists added the freeze-dried venom and looked for cells that didn’t die. If a cell survived, they sequenced its DNA to identify which gene was missing—and thus, which made proteins that were likely targeted by the venom.
The screen suggested four genes involved in cholesterol production were the venom’s targets, they report today in Nature Communications. So, Neely’s team tested the ability of existing cholesterol-targeting drugs to see whether they could also block the venom. Two drugs, MbCD and HPbCD, prevented the venom from killing the human myeloid cells and rupturing mouse red blood cells in a well-plate for up to 15 minutes after exposure, Neely says. The team then gave HPbCD, considered safe for humans, to mice that had been injected with C. fleckeri venom. For 15 minutes, the drug blocked pain, tissue death, and scarring.
Neely says he was surprised that he and his colleagues could block the venom’s action with a single drug, given that the venom itself is composed of more than 250 proteins. “It’s kind of lucky that it worked out.” The researchers hypothesize that because HPbCD works by pulling cholesterol out of the cell membrane, jellyfish venom may rely on cholesterol to gain an entryway into the cell. However, Neely says, MbCD may also act directly on the venom to neutralize it.
Yanagihara, who has developed a topical cream to help treat box jellyfish stings, says she’s skeptical that the cholesterol drug treatment will be sufficient by itself, because it has so far only been used against processed venom—not stings from live animals, thought to be more potent. “The next step would be to ground truth these findings by live tentacle sting tests on live animals.”
Neely says that because their venom caused all the symptoms of a typical sting in the mice, he believes the results will translate to the real world. And he’s already looking forward to the next step: testing whether the cholesterol drugs protect the heart in live animals. Eventually, he hopes to bring the potential antidote to human clinical trials.
If those should work, the antidote has much promise, says Cheryl Ames, a marine biologist from the Smithsonian Institution’s National Museum of Natural History in Washington, D.C., who was not involved in the study. “It’s very cool stuff, [and] I’m pumped.”