Deadly box jellyfish antidote discovered using CRISPR genome editing

Researchers at the University of Sydney have discovered an antidote to the deadly sting delivered by the most venomous creature on earth - the Australian box jellyfish.

The Australian box jellyfish (Chironex fleckeri) has about 60 tentacles that can grow up to three metres long. Each tentacle has millions of microscopic hooks filled with venom. Each box jellyfish carries enough venom to kill more than 60 humans.

A single sting to a human will cause necrosis of the skin, excruciating pain and, if the dose of venom is large enough, cardiac arrest and death within minutes.

The researchers uncovered a medicine that blocks the symptoms of a box jellyfish sting if administered to the skin within 15 minutes after contact. The antidote was shown to work on human cells outside the body and then tested effectively on live mice.  Researchers now hope to develop a topical application for humans.

"We were looking at how the venom works, to try to better understand how it causes pain. Using new CRISPR genome editing techniques we could quickly identify how this venom kills human cells. Luckily, there was already a drug that could act on the pathway the venom uses to kill cells, and when we tried this drug as a venom antidote on mice, we found it could block the tissue scarring and pain related to jellyfish stings," said the senior author. "It is super exciting."

Published in the journal Nature Communications, the study used CRISPR whole genome editing to identify how the venom works. Genome editing is a technology that allows scientists to add, remove or alter genetic material in an organism's DNA.

In the study, the researchers took a vat of millions of human cells and knocked out a different human gene in each one. Then they added the box jellyfish venom - which kills cells at high doses - and looked for cells that survived. From the whole genome screening, the researchers identified human factors that are required for the venom to work. 

Peripheral membrane protein ATP2B1, a calcium transporting ATPase, as one host factor required for venom cytotoxicity. Targeting ATP2B1 prevents venom action and confers long lasting protection. Informatics analysis of host genes required for venom cytotoxicity reveal pathways not previously implicated in cell death.

"The jellyfish venom pathway we identified in this study requires cholesterol, and since there are lots of drugs available that target cholesterol, we could try to block this pathway to see how this impacted venom activity. We took one of those drugs, which we know is safe for human use, and we used it against the venom, and it worked," said the lead author on the paper. "It's a molecular antidote."

"We know the drug will stop the necrosis, skin scarring and the pain completely when applied to the skin," said the senior author on the paper. "We don't know yet if it will stop a heart attack. That will need more research and we are applying for funding to continue this work."

"You need to get it onto the site within 15 minutes. In our study, we injected it. But the plan would be a spray or a topical cream. The argument against a cream is when you are stung it leaves lots of little stingers in you so if you rub the cream on it might be squeezing more venom into you. But if you spray, it could neutralise what's left outside of your body."

https://sydney.edu.au/news-opinion/news/2019/05/01/pain-researchers-find-antidote-to-deadly-box-jellyfish-sting.html

https://www.nature.com/articles/s41467-019-09681-1

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fmolecular-dissection-of_2&filter=22