“My entire body submerged in hot, burning oil.” This is how long-distance swimmer Diana Nyad described the pain of being stung by box jellyfish during a big swim several years ago.
For Nyad and other swimmers, there may soon be better treatment options. Researchers in Australia have used CRISPR to learn how human cells interact with this potent venom, and from this, are testing a compound as a possible antidote for this most vicious of stings. The team believes that box jellyfish venom, which has some 250 compounds in it, is a goldmine for understanding pain and tissue damage (Nat. Comm. 2019, DOI: 10.1038/s41467-019-09681-1).
Finding a universal treatment for the sting of these Jello-like blobs has been difficult because their venom is complex, says Greg Neely, a neuroscientist at the University of Sydney who led the research. The venom, only parts of which have been described, blows apart blood cells, drills through membranes, and can stop a beating heart in as little as five minutes. The box jellyfish’s body is small enough to fit in a human hand, but its tentacles can reach 3 meters in length. It’s one of the most venomous animals in the world, and antidotes including vinegar, heat and cold, and another antidote made in sheep are not always effective, Neely says.
Neely’s team discovered a host of proteins and cellular processes affected by box jellyfish venom. To do the experiments, Neely used a genome-wide CRISPR screen, a method of treating cells with the popular gene editing system so that a single gene is mutated in each of several individual cells. After the CRISPR treatment, the research team tested the cells with a preparation of the venom, and pulled out all the survivors. They then analysed the cells to find out what gene had the mutation that allowed it to survive. The research led them to several interacting pathways, including one that is responsible for putting cholesterol into cell membranes. Neely’s group decided to test the therapeutic potential of 2-hydroxypropyl-β-cyclodextrin, which depletes cholesterol from cell membranes. When tested on mice given a preparation of jellyfish venom, it seemed to quickly quell pain and tissue damage.
The team found that surviving cells also had mutations in genes associated with inflammation, membrane protein destruction, and endosome formation. One protein, ATP2B1, might be a good candidate to study pain relief, says Neely.
“Now we are trying to figure out more detailed mechanisms of action for individual toxins within the jellyfish venom, to see if we can use any of these toxins or knowledge gained from how they work or what they target to make new medicine, with a primary focus on new drugs to treat pain,” Neely says.
The work is a tour de force, says Angel Yanagihara, a box jellyfish expert at the University of Hawaii. But she says Neely needs to test the compound in a live tentacle sting scenario. Preparations of venom are typically not complete, she says. For example, she says, venom proteins that drill holes in membranes degrade rapidly, she says, and the concoction Neely is using may not be fully representative of the box jellyfish’s destructive capabilities.
“These inhibitors may or may not have utility in the treatment of acute symptoms of authentic stings. They are likely effective in reducing some venom effects” but not necessarily sufficient to save lives, she says.
Andrew Walker, a venom researcher at the University of Queensland, agrees. Neely’s work is promising, Walker says, but more needs to be done in humans to really understand how best to treat this burning, painful sting.
This article was updated on May 2, 2019, to correct the spelling of Angel Yanagihara’s name and clarify information about the jellyfish venom and current antidotes.