By Sofia Perez
Once bitten by a snake, one is scared all his life at the mere sight of a rope.
Chinese Proverb
There is something deliciously poetic about using an agent of death to heal. I fell in love with the idea recently, a seductive tango between danger and relief. Venom- a killer and a savior…but how? And what are the implications for medicine?
The story begins deep in the shadowy corners of the earth we have yet to fully explore, where cone snails, spiders, snakes, scorpions, and several other creatures live innocently unaware of the immense biochemical potential of the venom they carry. Like so many great tales, this is one about the underdogs, the unassuming protagonists of a soap opera unraveling in the medical industry right now.
“Like so many great tales, this is one about the underdogs, the unassuming protagonists of a soap opera unraveling in the medical industry right now.”
Venom is not at all uncommon. According to Nature’s review The chemistry of snake venom and its medicinal potential, approximately 15% of all animal diversity on earth is venomous. That’s roughly 220,000 species. These bioactive cocktails are even more varied than the number of alcoholic beverages that exist to date. The Institute of Beer estimates roughly 100+ “distinct styles” of beer, with over 73 different ales and more than 25 different lagers. The infographic below shows about 200 types of wine. Now just think what happens when you add whiskey, scotch, vodka, tequila, and rum. You’re now up to more than a thousand different drinks and that still pales in comparison to the rich diversity of venom that exists in the animal kingdom, each which consists of a mixture of 20 to more than 100 components, with venom composition varying between species and even among the same species depending on factors like age, sex, type of prey available, and the environmental conditions. This means that the venom composition of every given snake is actually quite an individual matter. Don’t worry though- of all this variation, peptides and proteins make up more than 90% of its components.
“You’re now up to more than a thousand different drinks and that still pales in comparison to the rich diversity of venom that exists in the animal kingdom…”
As you might’ve guessed, for the 220,000 venomous species out there, venom is primarily used for prey capture and defense. That means it packs quite the biochemical punch. This makes it fascinating if you’re a medical researcher…but terrifying if you’ve just upset a pit viper. That said, please don’t upset a pit viper. It’s not worth the likes.
With that cleared up, we can address the question we’re all thinking: How does venom even work? First things first: peptide toxins are the stars of the show. There are so many of them though, the vast majority have yet to be explored by some intrepid buccaneer of biomedicine. I personally like to think of these highly structured mini-proteins as tiny assassins, perfect for the job due to their small size, how easy it is to make them, structural stability, and how effectively they identify their target.
(Brief aside: There is such a thing as venom toxins which aren’t peptides, but most venoms which are “medically significant” look at the venom toxins which are peptides.)
Once they’re in the body of a mammal, they have been found to be highly selective for a diverse range of ion channels and receptors associated with pain signaling pathways such as sodium channels (μ- and μO-conotoxins), calcium channels (ω-conotoxins), and the neurotensin receptor (contulakins) to name just a few. It’s this that leads peptide toxins to express neurotoxicity (toxic to the nervous system), cytotoxicity(toxic to the cells), and hemotoxicity(toxic to red blood cells). In my opinion, if peptide toxins had a catchphrase it would be Black Adam’s line, “I’m no hero.”
Medical researchers, however, might dispute this. Think of them like Dr. Fate defending Black Adam to Carter (who represents the public). “You stop believing in absolutes,” he says. The same applies to venom, at least for the two families including nearly all “medically important” snakes: elapids and vipers. Among these groups of snakes, there is plenty of potential to be explored.
Firstly, there is potential for using ω-conotoxins, a group of neurotoxic peptides, to identify and determine the physiological role of different neuronal voltage-sensitive calcium channels, which are voltage-gated ion channels found in the membrane of certain cells, in this case neurons. It has also been established that an influx of calcium ions into nerve terminals through these channels triggers neurotransmitter release. As a result, these conotoxins, which block the channels, show potential for being used as powerful analgesics for relieving chronic pain.
That’s not all! Voltage-sensitive sodium channels, which are much like voltage-sensitive calcium channels except for sodium ions, also play a key role in the nervous system. A number of the subtypes of these channels are connected to clinical states like pain, stroke, and epilepsy. Venoms have evolved to target these channels and block the influx of ions which lead to the adverse side effects of these conditions. That said, sodium channel activators are typically toxic, so only some components of some venoms have considerable therapeutic potential.
Another exciting application of venom is in the treatment of cancer. Chloride channels are one of the many proteins that are part of or interact with membranes in different types of cancer. According to the review by Nature magazine, Therapeutic potential of venom peptides, “Chlorotoxin isolated from the scorpion Leiurus quinquestriatus binds to specific Ca2+-activated chloride channels and certain tumors and gliomas, and so might have potential in the treatment of cancer.”
This is thrilling, but I’m sure the pessimists among us might have picked up on the frequent use of the word “potential” and zeroed in on the copious research gaps in the sprouting field of venomics. While this is true, there are also examples of how venom is already being used, such as in the first ever successful venom-based drug Captopril, which inhibits the angiotensin-converting enzyme, which is crucial for the production of the vasoconstrictor angiotensin that is associated with hypertension.
Considering that more than 50,000 conopeptides exist, with less than 0.1% having been characterized pharmacologically, I think it’s safe to say that the field of venomics is ripe for discovery and filled with promise. That said, let’s play devil’s advocate for just a minute. After all, I said it would be a soap opera, and if we take a step back, we must recognize that venom is still dangerous enough to kill you.
Anon, (n.d.). [Online Image] Pexels. Available at: https://www.pexels.com/photo/pit-viper-612964/ [Accessed 18 Nov. 2022].
This suggests a plethora of safety concerns. There are also questions related to cost of production, delivery, and pharmacokinetics, a branch of pharmacology dedicated to studying what will happen to the substances administered to a living organism. Another issue is that peptides are too big to cross the blood-brain barrier and are by nature hydrophilic, or attracted to water, meaning they would have to be administered to the site of action directly. There is also the matter of functional selectivity, or ensuring that the peptides bind to the right place on the membrane. All in all, this means we can’t really be sure how many of the peptides present in venom can find clinical utility.
Nonetheless, there is still so much we simply don’t know about the venoms that are out there. Yet research gaps, in all their mysterious allure, are something to be excited about. Much like all the best soap operas, this one leaves you hanging on the edge of your seat, gushing with questions about what our unassuming protagonist will reveal to us next, whether the tiny peptides are assassins or the unexpected saviors of the plot, whether society will ever accept a different narrative for the “villains” of nature such as snakes, scorpions, or (gasp) cone snails. Until then, let’s stay tuned. The journey has only just begun. For now, perhaps we could take the ambiguity as an invitation to follow Dr. Fate’s advice to “stop believing in absolutes”, but this time about venom.
“…perhaps we could take the ambiguity as an invitation to follow Dr. Fate’s advice to “stop believing in absolutes”, but this time about venom.”
Thought to Action
- For free, switch your search browser to Ecosia, the search engine which uses the profits produced from your searches to plant trees where they are needed most. Ecosia is currently using its profits to plant trees all around the world, a mission which supports biodiversity, helps to fight climate change, and gives you the chance to make a real difference.
- Plant native trees, shrubs, flowers, vegetables, and herbs in your garden to promote biodiversity locally.
- Using this link, donate to Save the Snakes, whose mission is to “protect snake populations around the world through education and community outreach to create a harmonious relationship between humans and snakes”. This is vital, because snakes are important creatures toward maintaining balance within food webs worldwide. Meanwhile, according to the IUCN Red List of Threatened Species, 12% of assessed snake species are listed as threatened.
- According to Advocated for Snake Preservation (ASP),“negative attitudes about snakes may be the biggest barrier to their conservation”. Help ASP to change the narrative by following some of the tips suggested in this factsheet from their website:
- Respect and appreciate wildlife from a distance.
- Don’t buy wild-caught animals or collect wildlife.
- Drive carefully, watching for small animals.
- Share positive stories about snakes.
- Coexist, modify your yard.
- Don’t relocate wildlife.
- Say “defensive” or “scared”, not “scary” or “aggressive” when describing snake behavior.
- Don’t use bird nesting.
- Volunteer for Macmillan Cancer Support or a similar charity related to epilepsy, chronic pain, etc. or make a one-off donation using this link.
Sources
This is your gentle reminder to always fact check.
Lewis, R.J. and Garcia, M.L. (2003). Therapeutic potential of venom peptides. Nature Reviews Drug Discovery, 2(10), pp.790–802. doi:10.1038/nrd1197.
Oliveira, A.L., Viegas, M.F., da Silva, S.L., Soares, A.M., Ramos, M.J. and Fernandes, P.A. (2022). The chemistry of snake venom and its medicinal potential. Nature Reviews Chemistry, [online] pp.1–19. doi:10.1038/s41570-022-00393-7.
The Institute of Beer. (2021). Often asked: How Many Types Of Beer Are There? [online] Available at: https://theinstituteofbeer.com/beer/often-asked-how-many-types-of-beer-are-there.html [Accessed 18 Nov. 2022].
Hannon, H. and Atchison, W. (2013). Omega-Conotoxins as Experimental Tools and Therapeutics in Pain Management. Marine Drugs, 11(12), pp.680–699. doi:10.3390/md11030680.
Sato, C., Ueno, Y., Asai, K., Takahashi, K., Sato, M., Engel, A. and Fujiyoshi, Y. (2001). The voltage-sensitive sodium channel is a bell-shaped molecule with several cavities. Nature, [online] 409(6823), pp.1047–1051. doi:10.1038/35059098.
Wilson, D. and Daly, N. (2018). Venomics: A Mini-Review. High-Throughput, 7(3), p.19. doi:10.3390/ht7030019.
Shaw, A. (n.d.). How venoms are shaping medical advances | BBC Earth. [online] www.bbcearth.com. Available at: https://www.bbcearth.com/news/how-venoms-are-shaping-medical-advances [Accessed 18 Nov. 2022].
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