Venom: Nature’s Deadliest Creatures

Animals have been evolving toxins for millions of years, perfecting the art of paralyzing prey, killing targets, and deterring predators. While poison is either ingested or inhaled, venom is toxin delivered directly into the target’s circulation by means of a bite, sting, or other rudely penetrative means. Even the more mild venoms from tiny insects are impressively efficient; a bee can create havoc in an animal hundreds of times its own mass (a 1/10 gram bee compared to a 70 kilogram human).

Despite the fact that some of us experience complete mental breakdowns the minute a venomous creature passes by, humans have been harvesting and utilizing animal venom for hundreds of years. The key to many of these toxins is their astonishing specificity; they bind to an exact spot on a specific protein in only certain types of cell to achieve an precise, and devastating, effect. This incredible feat is far beyond our own ability to engineer, and so we study these toxins, altering them for use in life-saving therapies and medicines. In order to celebrate these amazing chemicals (and because venomous animals are too cool to pass up), let’s see how some of the deadliest venoms work.

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Arachnids

I will shamelessly admit I suffer from arachnophobia and have the embarrassing propensity to scream at the sight of any eight-legged, skittering creature. It doesn’t help that spiders are some of the most proficient venom-users around. Spider venoms are complex, with up to hundreds of different components in a single type and a vast range between species. Spiders will catch their prey and deliver a bite with their rather grotesque mouthparts, called chelicera (the different types of chelicerae are disturbingly called jackknife, scissor, and 3-segmented chelate), paralyzing their target and allowing them to chow down at their leisure. Spider venoms are often species-specific; they are incredibly toxic to a targeted type of insect, but may be completely harmless to others. This allows them to be extremely useful in studying targeted insecticides [14].

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If only they all looked this cute. Photo by Scott Thompson (baby jumping spider)

The Guinness Book of World Records has declared the world’s deadliest spider to be the Brazilian Wandering Spider, the genus Phoneutria. Also known as armed spiders and banana spiders (for their tendency to hang out in clumps of bananas), they are found in Tropical South and Central America. There are eight species in the genus, and they can get to a whopping leg span of 13 to 15 cm. They don’t bother with webs as they can leap 40 cm to deliver their devastating toxin in one bite. When startled, these spiders lift their bodies up and stick their front two pairs of legs in the air before swaying from side to side in a bizarre defensive dance. If you see a spider striking this pose, watch out as it often precedes an attack. There were 2,687 cases of bites in humans in 2006 [2].

Phoneutria venom varies between species, but a couple of the component toxins have been well studied, one being a neurotoxin called PhTx3. This is a broad calcium channel blocker that prevents calcium influx and subsequent glutamate neurotransmission in synaptic terminals of neurons [2]. What does that mean?  Calcium is essential to our nervous system; when neurons signal to each other, the communication is based on the release of chemicals known as neurotransmitters. A nerve impulse or action potential triggers this communication by opening voltage-gated calcium channels at the end of the nerve (basically, your neurons are kept at a specific voltage by controlling the concentration of charged ions inside relative to outside the cell. An action potential is a traveling wave of depolarization, or positive change in voltage, that transiently moves down the neuron. This positive charge opens channels that allow calcium ions to enter the cell). The calcium then causes the release of packets of neurotransmitters from the nerve, which trigger a signal in the next nerve. Glutamate is one of these neurotransmitters, known as an excitatory neurotransmitter because it causes action potentials in the subsequent nerves (incidentally, glutamate is very important for memory and learning).

In effect, PhTx3 prevents excitatory nerve communication from occurring, specifically between nerves and muscles. In envenomed victims, high concentrations can result in a loss of muscle control (nerve signals used to trigger muscle movements are blocked), leading to paralysis and asphyxiation due to the breathing muscles being paralyzed. Additionally, the toxin has an excitatory effect on the serotonin receptors in your sensory nerves, resulting in severe pain and the release of chemicals triggering inflammation. Oddly enough, it also causes priapism in humans: erections that can last for hours. Before you get any ideas, these are quite painful and can lead to impotence (however, one component of the venom is being studied for erectile dysfunction treatments) [15].

The species responsible for the most bites is Phoneutria nigriventer, whose venom also contains Toxin 1 (Tx1). This toxin actually blocks voltage-gated sodium channels in neurons, which are important in creating the depolarization that makes up an action potential. Consequently, this toxin also inhibits communication between neurons, specifically between neurons and muscles resulting in a paralysis[9].

There are hundreds of other venomous spiders with their own unique brand of toxins. Additionally, other arachnids, such as scorpions, utilize venom to their advantage. While I won’t delve into any more arachnid details, I did come across one worthy fact to share: there is a venomous species of tick. Ixodes holocyclus is a tick that releases a venom that can cause severe paralysis (while I didn’t find any human paralysis cases, there were mentions of dogs and horses being effected). Like most of the world’s deadliest critters, it lives in Australia.

Cephalopods & Cnidaria

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One of the most venomous cephalopods (octopi, squid, etc) is the beautiful blue-ringed octopus of the genus Hapalochlaena. There are 3 to 4 species that dwell in tide pools and coral reefs in the Pacific and Indian Oceans, ranging from Japan to Australia. Their vivid coloring provides a striking warning for predators that might be eyeing the 12 to 15 cm long octopus for dinner. Their venom, a potent concoction that is between 100-10,000 times as deadly as cyanide (the research papers are surprisingly contradictory), is injected into its prey through its beak. Considering it hunts small crabs, shrimp, and fish, the strength of this venom seems rather excessive. There is no known antivenom. The main component of the blue-ringed octopus’ venom is tetrodotoxin, which is also found in pufferfish, newts, poison dart frogs, and some crabs. These animals do not produce the toxin themselves, but, rather, shelter various bacteria that produce the toxin for them. In the blue-ringed octopus, bacteria live inside the octopus’ salivary glands and lace the saliva with the deadly toxin [4].

Similar to Tx1 of Phoneutria nigriventer, Tetrodotoxin functions by blocking voltage-gated sodium channels in muscle contractile cells. This prevents communication between the brain and body, causing muscle paralysis. The effects are seen within minutes, resulting in respiratory arrest, failure of vagal regulation of the heart rate, a loss of sensation, and cardiac arrest. The cause of death is often by suffocation due to inhibited breathing cutting off the brain’s oxygen supply. To kill a 170 lb human adult, a mere 8 micrograms (0.00002 oz) will do the trick. Paradoxically, the toxin is proving to be a hopeful agent in the treatment of pain [4].

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The deadliest cnidarian is the box jellyfish, specifically the sea wasp Chironex fleckeri. These jellyfish drift along the coastal waters of Australia up to Vietnam. The main body grows to be about the size of a basketball, trailing four clusters of numerous tentacles which reach three meters in length. Eerily, they have four eye-clusters with 24 eyes (though they aren’t very efficient, but they can detect the color red, which is why jellyfish nets around beaches tend to be that color). While box jellyfish use their venom to kill prawns and small fish for food, it is so toxic that a serious sting can kill a human within three minutes. Over seventy deaths in Australia have been attributed to the box jellyfish. Despite the fact that the venom was first characterized over 50 years ago, we still barely understand how the toxin functions [1,7].

All Cnidarians have cnida, which are specialized organelles inside of cells (cnidocytes). In the case of the box jellyfish, these cnidocytes exist on their tentacles and contain tiny spines swimming in a mixture of toxic proteins. The cells contain sensory receptors, and when they detect protein and pressure (a living organism brushing against the tentacle), the cells explode and shoot these spines and toxins into the flesh of whatever unfortunate creature was passing by. The toxin causes extreme pain and rapid inflammation, killing the cells of the skin and causing an initial rise in blood pressure followed by a phase of often lethal low blood pressure. It triggers shock, breathlessness, unconsciousness, and death from pulmonary or cardiac failure within minutes. How, exactly, it causes these deadly symptoms remains mostly unclear. Only a few venom proteins have been identified, and their suggested action is the creation of pores (or holes) in cells, especially red blood cells [1,7].

Fish

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Source: bluereefaquarium.co.uk

Continuing the sea-creature theme, there are, you will be delighted to know, also many types of venomous fish. The deadliest is the Stonefish, Synanceia trachynis. Named for its uncanny camouflage (which is why so many unsuspecting humans step on it), this fish packs a fatal punch. Found in the Indo-Pacific oceans, off the coast of Florida, and in the Caribbean, the dorsal fins of stonefish contain spines through which venom seeps. When threatened, the spines stand erect and will inject an amount of venom proportional to the pressure (so if you do touch one, squeezing tightly is not recommended). Despite the fact that the fish is deadly, it’s quite a delicacy in parts of Asia as sushi and sashimi.

One of the main toxins in stonefish venom is trachynilysin. This toxin binds to motor nerve terminals (nerves that signal your muscles to contract) and forms pores in the cell, causing calcium to enter and release neurotransmitter, in this case Acetylcholine (which normally signals the muscle cell to contract). Consequently, the toxin causes spontaneous muscle contractions and loss of movement control [10,11].

Another toxic component is stonustoxin (SNTX), which induces hemolytic activity by causing red blood cells to rupture [12]. The venom also contains verrucotoxin (VXT) which activates β-adrenoreceptors that activate protein kinase A, leading to phosphorylation of calcium channels (all of that means that it causes an increase of calcium in nerves, like trachynilysin, resulting in more neurotransmitter release) [17].

Combined with the other components of stonefish venom, an unlucky encounter with this creature can cause incredible pain, respiratory weakness, arrhythmia, damage to the cardiovascular system, convulsions, paralysis, and death [10,11,12,17].

Insects

The insect order Hymenoptera is full of various venomous critters, including bees, wasps, and ants. Most of us are pretty familiar with bees and wasps, so I thought I’d just briefly highlight their differences (without delving into the plethora of unique parasitoid wasp venoms). In both of these insects, the stinger is a modified ovipositor (for laying eggs), which means that only female bees and wasps can actually sting. In the case of bees, a sting is all or nothing: in stinging a large animal, the barbed stinger often gets lodged in the skin (fatal for the bee, which unfortunately tends to rupture its guts when the stinger is torn loose). Consequently, bees inject a relatively large amount of venom per sting (about 50 micrograms). This continues to seep out from the stinger into the flesh for a good 45 to 60 seconds, so if you get stung by one make sure to remove the stinger asap [3,15]!

Over half of bee venom consist of melittin, a toxin that stimulates inflammation and nerve endings of pain receptors, resulting in pain and a rush of histamine as the body then attempts to flush the area, causing redness and swelling. Bee venom also contains hyaluronidase, a toxic enzyme that breaks down barriers between cells to aid in the spreading of the venom. Luckily for us, the toxin isn’t that potent: the toxic dose is about 8.6 stings per pound of body weight. A healthy, non-allergic 170 lb man would have to be stung about 1400 times to reach that [15].

Wasps are a little nastier. While they do not inject as much venom per sting (about 2-15 micrograms), they don’t lose their stingers and have the tendency to go completely and horribly sting-crazy and get you several times if you can’t swat them or escape. Their venom contains a cocktail of enzymes (including hyaluronidase) that also destroys cell membranes, as well as containing neurotransmitters such as acetylcholine and serotonin. Some components trigger the release of histamine as well. Generally, wasps and bees are only a problem to humans if we’re allergic or hypersensitive, which can lead to hives, swelling, nausea, vomiting, cramps, shock, dizziness, and difficulty breathing. However, social hymenopterans (with colonies/hives) are prolific defensive-stingers and, upon stinging, will release pheromones to attract other members of the colony to come to their aid. So if you do get stung, it’s probably a good idea to vacate the immediate area [15]!

Mammals

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You know, apart from the platypus I didn’t know there were any venomous mammals out there. Needless to say, when I read an article discussing how there were venomous SHREWS I was gobsmacked (incidentally, I also read that some shrews use echolocation. Talk about underappreciated awesomeness). I have shrews in my backyard. My cats bring them to me in what I always assumed were routine, sacrificial offerings. Perhaps my cats have been plotting against me all these years.

Thankfully, there are only about five types of venomous mammals. All of them, minus the platypus, are within the order Insectivora (basically shrews and hedgehogs). Platypuses (Ornithorhynchus anatinus) are one of those animals that really don’t seem to fit anywhere. They feed their young on milk, lay eggs, are covered in fur, and have a beak. Not only that, but the males have venomous spurs on their hind legs. Why, we really do not know; they don’t have many native predators, nor do they use them to hunt. Some researchers hypothesize that it evolved for sexual competition: the gland increases in size during breeding season, so perhaps it is used to fight other male platypuses. Their venom system, known as the crural system, includes a venom gland on the side of their abdomen which feeds into a duct leading to a spur on each hind leg. When a platypus decides to use these spurs, he wraps his hind legs around the victim in a creepy sort of hug, digging the spurs in and pumping up to 4 ml of venom into his victim. While no human fatalities have ever been recorded, platypus venom has killed dogs. If you do manage to aggravate a platypus and receive the unfriendly hug treatment, you will experience pain and swelling in the injection site, followed by nausea, gastric pain, a cold sweat, lymph node swelling, and temporary paralysis. Interestingly, morphine has no effect on dampening the pain from platypus venom. Sadly, we don’t know much about the toxins involved in the venom except that it contains over 19 different components, but only three types have been identified and sequenced, and their functions remain unknown [16].

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Meanwhile, European water shrews and American short-tailed shrews are also venomous. Their venom is slightly better understood. The main toxin in short-tailed shrews is blarina toxin (BLTX), which floats around in their saliva and is toxic to other mammals. The venom is similar to lizard venom, containing components that break down proteins and paralyze muscles. As these shrews prey upon larger vertebrates including rodents and frogs as well as insects (I also did not know this about shrews, which I now inaccurately envision as venomous serial killers stalking the night using echolocation), they likely use the venom to paralyze their prey for dinner. Luckily, humans are a bit out of their ability to subdue; shrew bites tend to simply cause a local burning sensation and swelling in us. Researchers are investigating one component of shrew venom, soricidin, for pain control and as an anti-cancer drug [8]!

Reptiles

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I’m fairly certain you can find numerous books solely about venomous reptiles and probably volumes on snake venom alone. There is a fascinating spectrum of reptilian venoms, but in an attempt to keep this under 100 pages, I will limit myself to the most venomous snake in the world: the Inland Taipan. Predictably, it resides in Australia (in fact, there are videos of Steve Irwin playing with one). The Inland Taipan (Oxyuranus microlepidotus) is also known as the fierce snake, yet is relatively shy and reclusive. It reaches up to 8 feet and feasts upon rodents, small mammals, and birds. In one attack it will deliver up to 7 venomous bites, averaging 44 mg, which can kill 50 humans! The venom is mostly made up of neurotoxins, taipoxin and various enzymes, and causes neuromuscular damage, relaxation of heart muscles, low blood pressure, and death [5]. Taipoxin causes nerve and muscle degeneration (muscles are completely degenerated within 1-3 hours), resulting in paralysis. The damage results in a reduction, and then complete loss, of acetylcholine release which causes paralysis. In the end, the victim dies due to asphyxiation as the respiratory muscles are paralyzed [6].

References

[1] Brinkman, D. et al. “Venom proteome of the box jellyfish Chironex fleckeri.” Plos One. 2012. 7(12).

[2] Bucaretchi, F. et al. “Systemic envenomation caused by the wandering spider Phoneutria nigriventer, with quantification of circulating venom.” Clinical Toxicology. 2008. 46:885-889.

[3] Danneels, E. et al. “Venom proteins of the parasitoid wasp Nasonia vitripennis: recent discovery of an untapped pharmacopee.” Toxins. 2010. 2:494-516.

[4] Fozzard, H. and Lipkind, G. “The tetrodotoxin binding site is within the outer vestibule of the sodium channel.” Marine Drugs. 2010. 8:219-234.

[5] Fry, B. et al. “Novel natriuretic peptides from the venom of the inland taipan (Oxyuranus microlepidotus): isolation, chemical and biological characterization.” Biochem and Biophysical Research Comm. 2005. 327:1011-1015.

[6] Harris, J., et al. “The neurotoxicity of the venom Phospholipases A2, Notexin, and Taipoxin.” Experimental Neurology. 2000. 161:517-526.

[7] Hughes, R. et al. “A pharmacological investigation of the venom extract of the Australian box jellyfish, Chironex fleckeri, in cardiac and vascular tissues.” Toxicology Letters. 2012. 209:11-20.

[8] Kita, M. et al. “Blarina toxin, a mammalian lethal venom from the short-tailed shrew Blarina brevicauda: isolation and characterization.” PNAS. 2004. 101(20).

[9] Martin-Moutot, N. et al. “Phoneutria nigriventer Toxin 1: A novel, state-dependent inhibitor of neuronal sodium channels that interacts with µ conotoxin binding sites.” Molecular Pharmacology. 2006. 69(6).

[10] Ouanounou, G. et al. “Trachynilysin, a protein neurotoxin isolated from stonefish (Synanceia trachynis) venom, increases spontaneous quantal acetylcholine release from Torpedo marmorata neuromuscular junctions.” Cybium. 2000. 24(3):s149-s156.

[11] Ouanounou, G. et al. “Trachynilysin, a neurosecretory protein isolated from Stonefish venom, forms nonselective pores in the membrane of NG108-15 cells.” Journal of Biological Chemistry. 2002. 277:39119-39127.

[12] Prithiviraj, N. et al. “Bioactive properties of the stone fish Synanceia horrida spine venom.” International J of Pharm. & Biol. Archives. 2012. 3(5):1217-1221.

[13] “Venom from the banana spider could be the new Viagra.” National Geographic. 2012.

[14] Vassilevski, A. et al. “Molecular diversity of spider venom.” Biochemistry (Moscow). 2009. 74(13):1505-1534.

[15] “Wasp Stings.” IPM Education and Publications, UC Statewide IPM Project. 1998. 7449.

[16] Whittington, C. et al. “Understanding and utilizing mammalian venom via platypus venom transcriptome.” Journal of Proteomics. 2009. 72:155-164.

[17] Yazawa, K. et al. “Verrucotoxin, a stonefish venom, modulates calcium channel activity in huinea-pig ventricular myocytes.”

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