An antidote to box jellyfish venom
The Australian box jellyfish (Chironex fleckeri) is among the most venomous animals on Earth. The typical result of even a single sting is extreme pain and skin necrosis; with a large enough exposure, cardiac arrest and death follow in minutes. The classic treatment is to administer an antivenom made from immunized sheep. But the efficacy of that treatment is unclear, and no therapy directly targets the pain and local necrosis.
As part of an effort to understand how the jellyfish venom causes pain at the molecular level, the University of Sydney’s Man-Tat Lau, Gregory Neely , and their colleagues have now found an antidote. To pull off the achievement, the researchers took a tissue culture containing millions of human cells and used CRISPR gene-editing technology to turn off, one by one, every gene in the human genome (see the article by Giulia Palermo, Clarisse G. Ricci, and J. Andrew McCammon, Physics Today, April 2019, page 30 ). They then exposed that culture—with every cell missing a different gene—to a lethal concentration of box jellyfish venom and looked for any surviving cells. That screening allowed them to isolate those genes whose presence was required for the venom’s toxicity.
Of the hundreds of genes the researchers identified, some were associated with cholesterol biosynthesis. That particular identification was key. Cholesterol is a major component of plasma membrane lipids and is a target of other jellyfish toxins. Lau, Neely, and company reasoned that by interfering with the action of a cell’s cholesterol-making genes, they could increase its resistance to the venom. To test the idea, they injected into mice an already existing drug (2-hydroxypropyl-β-cyclodextrin) that reduces cholesterol from cell membranes in humans. The drug—effectively an antidote, they realized—reduced pain and suppressed tissue necrosis in the mice. It was effective even when given up to 15 minutes after venom exposure. (M.-T. Lau et al., Nat. Commun. 10, 1655, 2019 .)
