New genetic research reveals antidote to deadly venom and holds implications for greater understanding of pain causality

Jason Wang 22′

A box jellyfish (Chironex flekeri) photographed off the coast of Indonesia

New genetic research has created an antidote to effectively counteract life-threatening box jellyfish venom, the first of its kind. Through CRISPR molecular dissection of the deadly venom, Australian scientists at the University of Sydney have revealed the cell death pathway mechanism of the box jellyfish venom. This team, led by Professor Greg Neely and Dr. Raymond Lau, also developed an effective venom antidote to suppress both pain and local tissue necrosis.

The Australian box jellyfish, Chironex fleckeri, is among the most venomous animals in the world. Each of its roughly 60 tentacles is specked with venomous barbs, and direct skin contact can result in excruciating pain, cardiac arrest, and even death within minutes of exposure. Despite the lethal consequences of such stings, prior to this study, a complete and effective treatment option had not yet been developed. Historically, stings have been treated with an antivenom of dubious efficacy generated in sheep. More modern alternatives such as the use of intravenous zinc or applying heat to the site of the sting have aided in suppressing some effects of the venom. None of these treatment options provide direct relief for the two most common symptoms of envenoming: pain and local tissue necrosis. This lack of effective treatment was in large part due to limited understanding of the molecular pathway governing pain and necrosis effects of the venom.

The use of CRISPR genome editing has enabled the identification of the mechanism through which the jellyfish venom kills cells. By using CRISPR to target and differentiate test cells by specific genomic loci, Neely and Raymond were able to run genome-scale functional screens and identify the pathways by which the venom operates. They found that by blocking apoptotic and/or necroptosis pathways, cell death was significantly reduced. They also found that the cytotoxicity of C. fleckeri venom was highly dependent on cholesterol biosynthesis. The research team administered an existing cholesterol-inhibiting drug upon venom-impacted cells, the verifying it as a molecular antidote.

This research has implications not only for acute box jellyfish stings but also for developing greater scientific understanding of the neurological pathways causing pain. Neely and Lau intend to first develop a topical application of the jellyfish venom antidote and make it available to the public. In the longer term, Neely and Lau expect that their future study of a variety of deadly organisms, including the box jellyfish, will help understand what causes pain and enable the development of more general-purpose pain painkillers.

References:

1. Andrepiazza. (2011). English: Box Jellyfish. Retrieved from https://commons.wikimedia.org/wiki/File:19-Indonesia-Bali_Nusa-Penida_Manta-Point_17_(Box_Jellyfish)-APiazza.JPG
2. Deadly box jellyfish antidote discovered using CRISPR genome editing: Pain researchers uncover secrets to box jellyfish venom. (n.d.). Retrieved May 7, 2019, from ScienceDaily website: https://www.sciencedaily.com/releases/2019/04/190430173205.htm
3. Lau, M.-T., Manion, J., Littleboy, J. B., Oyston, L., Khuong, T. M., Wang, Q.-P., … Neely, G. G. (2019). Molecular dissection of box jellyfish venom cytotoxicity highlights an effective venom antidote. Nature Communications, 10(1), 1655. https://doi.org/10.1038/s41467-019-09681-1