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After defending the bad press snakes get in Western culture and highlighting the potential their venom offers the field of medicine, I was struck by a dagger of guilt. More than 220,000 species- or approximately 15% of all animal diversity on earth – are venomous. What about their potential in medicine? I decided I couldn’t possibly move on from the topic of venom without giving a shoutout to the fascinating array of cone snails, spiders, scorpions, and other species that seldom get the spotlight they deserve. This guilt weighed me down heavily as I wondered with great futility how to resolve this moral conundrum. That’s when I came across Adam Roy’s article for the magazine Outside, Keep Your Bird-Watching- I’m a Spider Man. It was clear after reading it that my next venomous protagonists would be scorpions and spiders, both arachnids, which are members of the arthropod group and Arachnida class. 

Anon, (n.d.). [Online Image] Pixabay. Available at: https://www.pexels.com/photo/animal-arachnid-close-up-creepy-219959/ [Accessed 9 Dec. 2022].

To paint the picture, I think it’s helpful to get to know the stars of the show. If you aren’t too clear on what constitutes the Arachnida class, according to Britannica, they have segmented bodies, tough exoskeletons, and jointed appendages. Most are predatory and almost all of them lack jaws.This is because instead, they inject digestive fluids into their prey before sucking out the liquefied remains into their mouths. 

(Sidenote: That might send a shiver down your spine, but please don’t go out killing spiders. They are important members of the ecosystem in your home, your garden, and the wild. In fact, they even act as a form of biological pest control for not only flies, but also disease-carrying insects, like cockroaches or mosquitos.)

Scorpions, on the other hand, only use their venom defensively, so as long as you don’t provoke them, you should be safe. They are otherwise fascinating creatures for so many reasons, for example because they glow in the dark for reasons scientists still debate, and have extremely low metabolic rates, allowing them to survive with one tenth the oxygen of other insects. 

G., S. (n.d.). [Online Image] Pexels. Available at: https://www.pexels.com/photo/black-and-brown-insect-with-pincers-1981542/ [Accessed 9 Dec. 2022].

But apart from being absolutely mind-boggling little critters, spiders and scorpions have added to their repertoire in recent years. Their venom, as it turns out, could help treat conditions like chronic pain and cancer. The big question is why. Why can venom, which is so painful when you’ve just been stung by a scorpion, snake, or spider, be used to alleviate pain at the same time? This contradiction is what enticed me at first, and perhaps it’s also what entices you. 

The reason venom can accomplish so much biochemically is because it contains such a large variety of peptides, each targeting a unique type of pore on the cell surface. These targets are called ion channels, and they control the flow of ions across cell membranes, shaping the electrical signals which are the stars behind muscle contraction and relaxation, blood pressure, neuronal signaling, neurotransmitter release, hormone secretion, and ensuring electrolyte balance.

Specifically when it comes to chronic pain, Medical News Today suggests that past studies have found that one of the most common pathways involved is Nav1.7, which is a sodium ion channel. By blocking this channel as some venoms do, researchers predict that the pathways controlling pain will basically be turned off. According to Professor Glenn King of the Institute for Molecular Bioscience at The University of Queensland in Australia, a researcher in this study, “Previous research shows indifference to pain among people who lack Nav1.7 channels due to a naturally-occurring genetic mutation – so blocking these channels has the potential to turning off pain in people with normal pain pathways.”

Another application I mentioned was cancer, in which venom can be used as “tumor paint”, first developed by Dr. Jim Olsen. This would involve using the chlorotoxin peptide found in deathstalker scorpion venom to stick to cancer cells in the patient’s bloodstream alongside a dye which is fluorescent under laser light. This chlorotoxin peptide binds to glioma cells, a type of tumor found in the brain and spinal cord, and blocks chloride channels. This would allow a surgeon to clearly identify the type of cancer and which tissue is cancerous versus normal. Amazingly, this isn’t just a nice idea tossed around in the ether. The FDA has already approved this venom-based tumor paint for use in brain tumor clinical trials. 

Mind-boggling, right? And these are only a few examples! Other peptides with therapeutic potential are margatoxin, ω-CVID, α-GID, μ-PIIIA, ShK, χ-MrIB, and GsMTx4, which you can read up more on by using the sources at the bottom of this post. 

That said, one difficulty to synthesizing these medical tools is that such a small proportion of venom has actually been discovered. Dr. Julie Kaae Klint, a member of the Institute for Molecular Bioscience and another author from King’s study on applying venom to chronic pain, estimates that there are roughly 9 million spider-venom peptides and only 0.01% have been explored so far. Let’s just stop to think about this. Imagine you drew a line half the length of the Grand Canyon or about two times as wide as the English Channel. For every inch of this line, there is a unique spider-venom peptide out there. Now imagine a line only the length of two and a half London buses. For every inch of this line, there is one spider-venom peptide that has been discovered. That still leaves almost 9 million spider-venom peptides that have not been explored. What will we find when we do?

Willinger, M. (n.d.). [Online Image] Pexels. Available at: https://www.pexels.com/photo/close-up-photo-of-spider-3482977/ [Accessed 9 Dec. 2022].

On that note, there’s another challenge to synthesizing venom-based drugs- and that is how to actually identify the peptides that we can put to use. In a paper published online on February 11 2014 in Current Biology, a team of researchers led by Michael Nitabach, Yale Medical School, New Haven, US, described a “new approach to identifying novel peptide toxins, a method that could bolster the design of new drugs targeting ion channels”. This method has a name that I love, mostly because you can’t find it in the dictionary. It’s toxineering. 

This is essentially a method of screening all the different molecules in venom to find the ones that do the job you want. You can think of it as LinkedIn for venom, scrolling through the properties of each molecule until you find just the right candidate who will (1) bind and who will (2) bind to the receptor you want it to. In the Nitabach’s Yale study, researchers were specifically looking for a molecule to bind to the TRPA1 receptor and as a result of combing through their t-toxin library using toxineering, found the ProTx-I peptide which is now used for several clinical applications. 

This is very promising, but as always, there remains vast uncharted territory in the field of venomics and toxineering, and arachnid and snake venoms are not the only types to hold promise. There are also fascinating developments in the venoms of animals like komodo dragons, which have applications in treating strokes, heart attacks and pulmonary embolisms, and northern short-tailed shrews, whose venom is being used to explore cancer treatment. All in all, it is a field overflowing with questions, innovation, and potential. What will we find in the daunting ocean of undiscovered peptides? How will the medical industry work with nature to benefit human health? Who will brave the unknown in order to finally answer these questions for the world?

Thought to Action 

1. 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. 
2. Don’t kill the spiders you find in your home. If you must remove them, use a jar to capture and release them outside. Why? In brief, because spiders are natural pest controllers and are important biological control of pests. If you want to read up more, check out the articles below:
   1. Here’s Why You Should Never Kill A Spider
   2. Don’t Kill Spiders
3. Plant native trees, shrubs, flowers, vegetables, and herbs in your garden to promote biodiversity locally. 
4. Did you know that if every single person in France deleted 50 emails, the energy savings would be equivalent to turning the Eiffel tower’s lights off for 42 years or to New York City not consuming any electricity for 4 hours? If you want to contribute to saving energy on this scale:
   1. refuse unnecessary notifications that clog your inbox
   2. unsubscribe to newsletters/subscriptions you no longer find useful
   3. delete emails with large attachments
   4. clear out your junk mail folder regularly
5. Try Tru Earth’s laundry eco-strips to save space, money, and the planet. If not, at least watch their wonderfully amusing ads to put a smile on your face: Things You Should Never Mix with Water or Real Men do Laundry.
6. Replace your arachnophobia with arachnophilia. The Cornell Library’s Arachnophilia online exhibit explains the nuanced way spiders understand the world around them while discussing the diversity of arachnids, amazing properties of spider silk- which has a higher strength to density ratio than steel- and the use of spider venom in medicine. 

Sources

This is your gentle reminder to always fact check…always.

abc2.org. (2021). FDA Approves Scorpion Venom-based Tumor Paint for Brain Cancer Clinical Trial. [online] Available at: https://abc2.org/press-blog/2014/09/fda-approves-scorpion-venom-based-tumor-paint-brain-tumor-clinical-trial/ [Accessed 9 Dec. 2022].

Animals and Cartoonists. Http://Twitter. com/Johnrplatt Http://Johnrplatt.com Https://Www.instagram.com/Johnrplatt (2021). We Need to Talk About Spider Conservation • The Revelator. [online] The Revelator. Available at: https://therevelator.org/spider-conservation/ [Accessed 9 Dec. 2022].

Arachnophilia – Online exhibitions across Cornell University Library. (2020). Spider Senses. [online] Available at: https://exhibits.library.cornell.edu/arachnophilia/feature/spider-senses [Accessed 9 Dec. 2022].

britishspiders.org.uk. (n.d.). Arachnids and arachnology | British Arachnological Society. [online] Available at: https://britishspiders.org.uk/arachnids [Accessed 9 Dec. 2022].

Caba, J. (2013). ‘Tumor Paint’ Made From Scorpion Venom Could Be Viable Brain Cancer Treatment Option [VIDEO]. [online] Medical Daily. Available at: https://www.medicaldaily.com/tumor-paint-made-scorpion-venom-could-be-viable-brain-cancer-treatment-option-video-264133 [Accessed 9 Dec. 2022].

Culin, J. (2020). arachnid | Definition, Facts, & Examples | Britannica. In: Encyclopædia Britannica. [online] Available at: https://www.britannica.com/animal/arachnid.

EcoWatch. (2021). We Need to Talk About Spider Conservation. [online] Available at: https://www.ecowatch.com/spider-conservation-2652937580.html [Accessed 9 Dec. 2022].

Gui, J., Liu, B., Cao, G., Lipchik, Andrew M., Perez, M., Dekan, Z., Mobli, M., Daly, Norelle L., Alewood, Paul F., Parker, Laurie L., King, Glenn F., Zhou, Y., Jordt, S.-E. and Nitabach, Michael N. (2014). A Tarantula-Venom Peptide Antagonizes the TRPA1 Nociceptor Ion Channel by Binding to the S1–S4 Gating Domain. Current Biology, [online] 24(5), pp.473–483. doi:10.1016/j.cub.2014.01.013.

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.

https://www.facebook.com/thoughtcodotcom (2019). There Are at Least 10 Things You Probably Don’t Know About Scorpions. [online] ThoughtCo. Available at: https://www.thoughtco.com/scorpion-facts-4135393 [Accessed 9 Dec. 2022].

jversteegh (2022). Keep Your Bird-Watching—I’m a Spider Man. [online] Outside Online. Available at: https://www.outsideonline.com/culture/essays-culture/spiders-fears-misconceptions/?utm_source [Accessed 9 Dec. 2022].

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.

March 12, C.N., 2017 and Am, 9:22 (2017). On The Horizon: Scorpion venom as cancer treatment. [online] www.cbsnews.com. Available at: https://www.cbsnews.com/news/on-the-horizon-scorpion-venom-as-cancer-treatment-tumor-paint/.

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.

Peterson, J. (2012). Don’t Kill Spiders. [online] HowStuffWorks. Available at: https://home.howstuffworks.com/green-living/dont-kill-spiders.htm [Accessed 9 Dec. 2022].

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 9 Dec. 2022].

Silva, W. da (2022). Venom: The New Miracle of Medicine. [online] ILLUMINATION-Curated. Available at: https://medium.com/illumination-curated/venom-a-revolution-in-medicine-d163eb065e28 [Accessed 9 Dec. 2022].

src=”https://secure.gravatar.com/avatar/6a9e2dae2b328b5cdfa3221e8fa8f071?s=96, img class=”avatar” alt=”Kiersten H., #038;d=mm, Sep. 05, 038;r=g” width=”50″ height=”50″>Kiersten H. and 2022 (2019). Here’s Why You Should Never Kill A Spider. [online] Family Handyman. Available at: https://www.familyhandyman.com/article/heres-why-you-should-never-kill-a-spider/.

Weller, C. (2014). Tarantula Venom Promises Painkiller Development. [online] Medical Daily. Available at: https://www.medicaldaily.com/tarantula-venom-offers-hope-painkiller-development-thanks-novel-screening-method-269479 [Accessed 9 Dec. 2022].

Whiteman, H. (2015). Newly identified compounds in spider venom could help treat chronic pain. [online] www.medicalnewstoday.com. Available at: https://www.medicalnewstoday.com/articles/290338 [Accessed 9 Dec. 2022].

Yong, E. (2011). Why do scorpions glow in the dark (and could their whole bodies be one big eye)? [online] Science. Available at: https://www.nationalgeographic.com/science/article/why-do-scorpions-glow-in-the-dark-and-could-their-whole-bodies-be-one-big-eye [Accessed 9 Dec. 2022].

The post A Tale of Toxineering & Tarantulas appeared first on Green Also Green.

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.

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. 

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. 

Thought to Action

1. 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. 
2. Plant native trees, shrubs, flowers, vegetables, and herbs in your garden to promote biodiversity locally. 
3. 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. 
4. 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:
   1. Respect and appreciate wildlife from a distance. 
   2. Don’t buy wild-caught animals or collect wildlife. 
   3. Drive carefully, watching for small animals. 
   4. Share positive stories about snakes.
   5. Coexist, modify your yard. 
   6. Don’t relocate wildlife. 
   7. Say “defensive” or “scared”, not “scary” or “aggressive” when describing snake behavior. 
   8. Don’t use bird nesting. 
5. 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].

The post Life, Death & Drugs: Why We Need Venom In Medicine appeared first on Green Also Green.