By Shreyas Kuchibhotla
For most living beings, risk is inevitable. Far antedating our arrival on the planet, efforts to alleviate this risk engendered in various animals a lethal cocktail of chemicals known as venom. In our perennial bid to widen the chasm between ourselves and risk, we have harnessed the power of this potent brew for our own purposes. Venom has simultaneously been feared and revered, establishing itself among myriad biological molecules in our arsenal against disease. A flavour of this powerful concoction derived from one particular class of creatures appears to have been deemed essentially priceless – today, deathstalker scorpion venom sells for a whopping $9000 per millilitre.1What are the ingredients of this deadly stew, and why does it represent such a redoubtable foe to both our health and wealth?
Evolution is essentially a long-drawn design problem, one with clear specifications and an ample timeframe for experimentation. Scorpions, like many venomous animals, employ their venom for two primary purposes – incapacitation of prey and resistance against predation. Most species range in size from 4 to 12 cm2 and so must subsist on prey within said spectrum – insects, spiders, small vertebrates and occasionally other scorpions.3 The evolution of venom is often inextricably linked to the physiology of both predator and prey, and in this case even the heavy artillery possessed by the former is woefully inept at digesting the sturdy exterior of the latter.3 Therefore, part of the venom’s function is to facilitate the liquefaction of the prey’s innards. Additionally, scorpions are active hunters, unlike web-building spiders for which protracted paralysis is presumably the primary objective. Their venom must thus act quickly, preventing terrestrial or aerial escape. Finally, it must be able to deter predators, often far larger than the scorpion, inducing sufficient pain and suffering to prevent an attempt at capture in the first place.
Across millions of years of natural selection tailored to these specifications, each species of scorpion developed a unique mixture of chemicals suited to its own ecological circumstances. Nevertheless, the general template remained the same: varying proportions of water, mucosa, amino acids, enzymes, biogenic amines, nucleotides, mucopolysaccharides, mucoproteins, histamine, serotonin, heterocyclic components and numerous miscellaneous compounds.4 Each of these performs a distinct function once the venom has entered the bloodstream, but the precise purpose of some of these compounds remains moot.
Ion channels are proteins that allow for selective inflow and/or outflow of ions, generating potential differences across membranes and stimulating action potentials. A remarkable feat of evolution is the seemingly orthologous presence of these channels in all living cells5 – fortifying the presumption that they represented, and remained, the most efficient method of transmitting signals. However, this also created an easier target in the development of venom; most toxins appear to set their sights on impairing channel function. Scorpion venom is no exception, with short-chain peptides attacking K+ channels and long-chain peptides focussing on Na+ channels, often by inhibiting their necessary deactivation.4 The ubiquity of ion channels is a fortunate twist of fate for those that wield venom, for it implies that toxins designed to dispatch small organisms i.e. prey need not be significantly altered in a functional capacity in order to work on much larger creatures i.e. predators. The size of these peptides is significant with regards to the rapidity of action – shorter peptides have been linked to easier membrane penetration in cone snails, for instance.6 Liquefaction, on the other hand, is achieved not through the primary toxic components of venom but through a series of extracellular digestive enzymes such as chitinases.7
Having ticked all the checkboxes over many years of evolution, scorpion venom is one of the most efficient weapons in nature. In humans, stings can lead to severe corporeal and psychological ailments, sometimes including death. While about 1475 of the 1500 known species of scorpion are innocuous8, the remaining two dozen odd species present considerable peril – more than 3000 people die every year from scorpion stings.9 Fatalities are most often due to unfavourable time and place, and may be precipitated by something as simple as not checking footwear for minute marauders.
In characteristically human fashion, though, interest in the action of venom has allowed us to tip the scales in our favour. We have not only managed to develop direct remedies for its symptoms but also to go above and beyond, forming connections between the deadly functions of toxins and desirable pathological outcomes. From the earliest folklore suggesting scorpion venom to be a powerful aphrodisiac10 to more recent research detailing its potential in cancer treatment, the general scientific outlook towards venom has only become progressively more sanguine. The very peptides that fatally inhibit Na+ channels may be leveraged to alleviate pain, those that target K+ channels modified to act as immunosuppressive agents, and virulent apoptotic and antiproliferative compounds recruited in the gruelling battle against cancer (4). Previous studies have also highlighted its efficacy in the management of epilepsy, diabetes, cardiovascular disease, microbial infections and even malaria.4 Interestingly, genes for certain enzymes from scorpion venom have also been injected into viruses designed to eradicate pestilent caterpillars.11
As for its prohibitively high cost, the rationale is surprisingly straightforward. Scorpions are small animals, and their stingers have evolved to deliver paltry doses of venom (< 2 mg)1 to account for the high energetic cost of its production.12 When the host of benefits and high demand are weighed against the almost impossibly low supply, value is bound to skyrocket.
Over the course of hundreds of thousands of years, humanity has managed to gauge, adapt to, and dramatically transform the environment for its own benefit. It is perhaps organisms like the scorpion that serve to remind us of what insignificant specks we are on the grand timescales of evolution, evoking well-deserved awe at their impeccable blueprint – efficient to a fault and engineered to kill.
1. Tang DA Abby. Why scorpion venom is the most expensive liquid in the world [Internet]. Business Insider. 2018 [cited 2022 Jun 6]. Available from: https://www.businessinsider.com/scorpion-venom-most-expensive-liquid-in-the-world-2018-8?r=US&IR=T
2. Rein J. The Scorpion Files – Frequently Asked Questions (FAQ) [Internet]. http://www.ntnu.no. [cited 2022 Jun 6]. Available from: https://www.ntnu.no/ub/scorpion-files/faq.php#:~:text=The%20smallest%20scorpions%20are%20found
3. Culin J, Polis GA. Scorpion | arachnid. In: Encyclopædia Britannica [Internet]. 2018. Available from: https://www.britannica.com/animal/scorpion
4. Tobassum S, Tahir HM, Arshad M, Zahid MT, Ali S, Ahsan MM. Nature and applications of scorpion venom: an overview. Toxin Reviews. 2018 Dec 20;39(4):1–12.
5. Channeling the past [Internet]. eLife. 2020 [cited 2022 Jun 6]. Available from: https://elifesciences.org/digests/52828/channeling-the-past
6. Nisani Z. Behavioral and Physiological Ecology of Scorpion Venom Expenditure: Stinging, Spraying, and Venom Regeneration. Loma Linda University Electronic Theses, Dissertations & Projects. 2008 Jun;
7. Fuzita FJ, Pinkse MWH, Patane JSL, Juliano MA, Verhaert PDEM, Lopes AR. Biochemical, Transcriptomic and Proteomic Analyses of Digestion in the Scorpion Tityus serrulatus: Insights into Function and Evolution of Digestion in an Ancient Arthropod. Gibas C, editor. PLOS ONE. 2015 Apr 15;10(4):e0123841.
8. Brown W. Scorpions – How poisonous is a scorpion and can it kill you? [Internet]. Texas A&M AgriLife Extension Service. Available from: https://agrilifeextension.tamu.edu/library/insects/scorpions/
9. Cheng D. Scorpion Envenomation: Background, Pathophysiology, Etiology. eMedicine [Internet]. 2021 Oct 15 [cited 2022 Jun 6]; Available from: https://emedicine.medscape.com/article/168230-overview#:~:text=The%20estimated%20annual%20number%20of
10. Nunes KP, Torres FS, Borges MH, Matavel A, Pimenta AMC, De Lima ME. New insights on arthropod toxins that potentiate erectile function. Toxicon. 2013 Jul;69:152–9.
11. Connor S. Scorpion’s gene used to engineer pesticide: Venom introduced into virus kills caterpillars more quickly and highlights alternatives to chemicals [Internet]. The Independent. 1994 [cited 2022 Jun 6]. Available from: https://www.independent.co.uk/news/uk/scorpion-s-gene-used-to-engineer-pesticide-venom-introduced-into-virus-kills-caterpillars-more-quickly-and-highlights-alternatives-to-chemicals-1393514.html
12. Evans ERJ, Northfield TD, Daly NL, Wilson DT. Venom Costs and Optimization in Scorpions. Frontiers in Ecology and Evolution. 2019 Jun 6;7.
Article written in June, 2022