Environment

How, or Why, Cobras Evolved Tissue-Destroying Venom

En route to answering this question, a new study shows that some components of snake venom can be used for defensive purposes also.

Black-necked spitting cobras not only have bright body banding but also red warning colours. Credit: Randy Ciuros

Black-necked spitting cobras not only have bright body banding but also red warning colours. Credit: Randy Ciuros

Animals do the most amazing things. Read about them in this series by Janaki Lenin.

Cobras are an extraordinary family of snakes. Even though they have enough venom to knock down a herd of oxen, they’ve developed defensive displays in a league of their own. They unfurl the elongate ribs of their necks to form hoods. Some like spectacled cobras startle predators with eye-like markings. Others can shoot venom with varying degrees of accuracy from considerable distance at their assailants’ eyes.

For a long time, scientists thought spitting cobras’ venom have more toxins that induce pain and destroy tissue than the venom of non-spitting cobras. These are the cytotoxins or cardiotoxins, a class of proteins. When the venom of spitters hits their antagonists’ eyes, it has an immediate reaction. Therefore, these cobras need to have more cytotoxic venom, the thinking went.

Rinkhals, closely related to cobras, advertise their cytotoxic venom with bold body-banding. Credit: Giuseppe Mazza

Rinkhals, closely related to cobras, advertise their cytotoxic venom with bold body-banding. Credit: Giuseppe Mazza

Other cobras possess cytotoxins to digest their preys’ innards even as their predators begin the cumbersome process of swallowing them whole. A similar process causes human victims of cobras to suffer skin and tissue damage, often permanently debilitating them. Despite the damage they cause, these toxins are not as potent as neurotoxins that attack the nerves.

Why do snakes that already have deadly neurotoxic venom evolve less lethal cytotoxins? A team of 26 scientists from five countries sought the answers in a new study.

“Evolution has one innovation come on to the scene at a time,” Bryan Grieg Fry, the lead scientist of the study, told The Wire. “Spitting as an innovation would not evolve in the absence of something worth delivering.”

By tracing the ancestry of cobras and using statistical models, the researchers discovered that cytotoxins evolved after cobras developed hoods. Despite the name, king cobras are not close relatives of cobras. They also independently evolved to spread their hoods and sit upright, facing their antagonists. Puffing up to look large is a common defence mechanism in the animal world. Soon afterward, the venom of cobras and king cobras developed cytotoxins, say the researchers.

In cobras, the tissue destroyers are tiny peptides called 3-finger toxins. King cobras developed L-amino acid oxidase to perform the same job.

By opting for different lifestyles, a few African species like the water (Naja annulata), tree (Naja goldii), and burrowing cobras (Naja multifasciata) opted out of this defence strategy and lost their ability to hood. Consequently, the cytotoxicity of their venom dropped.

The Malayan population of king cobras, with a bright orange throat, has the highest cytotoxicity of king cobras tested in the study. Credit: Kevin Messenger

The Malayan population of king cobras, with a bright orange throat, has the highest cytotoxicity of king cobras tested in the study. Credit: Kevin Messenger

What if the hooding bluff fails to deter? The most recent ancestor of cobras and rinkhals was probably a drab snake that could hood. Like the Egyptian cobra (Naja haje), its hood may not have had any markings and its venom was possibly moderately cytotoxic. When confronted, the ancestor perhaps behaved like its modern day lookalike – fleeing after striking nervously.

Three clans of closely related snakes – African cobras, Asian cobras, and rinkhals – developed a new weapon as plan B. They fine-tuned their venom delivery kit so they could shoot a fine jet of venom from a distance at the eyes of their assailants. The opening in the fangs of these snakes became narrow and migrated from the tip to squarely face the front, the better to target the eyes. Their venom became less viscous for greater reach. In addition to using their venom to inject and subdue prey, spitting cobras also used it in defence.

“Defensive venoms are characterised not by lethality but by pain,” says Fry, University of Queensland, Australia. “Predatory venoms however are selected for their potency. So these are mutually exclusive strategies. Thus predatory venoms are not selected as defensive plan Bs.”

Supplementing their already potent arsenal with non-fatal peptides allowed these snakes to stand their ground. After all, no animal wants to call the snakes’ bluff and suffer the searing pain caused by tissue-destroying venom in their eyes.

While many African cobras aim accurately, Asian cobras, likely being more recent innovators of this technique, are not as proficient. Some like the Chinese cobras (Naja atra) and monocled cobras (Naja kaouthia) spit only on rare occasions. Unlike Sumatran spitting cobras (Naja sumatrana) for instance, they didn’t develop special adaptations for spitting.

Many others didn’t go the spitting route or lost it later. Instead they developed startling eye-like markings on the back of their broad and round hoods like our spectacled and monocled cobras (Naja naja and Naja kaouthia).

The researchers tested the potency of the cytotoxins against healthy and cancerous cell lines. “We wanted to focus on the toxins that were indiscriminate killers,” says Fry. “So we looked for congruence between the two cell types as the guide for the truly potent cytotoxic activity.”

Red-spitting cobras dispense with markings in favour of a scarlet coloration. Credit: Wikimedia Commons

Red-spitting cobras dispense with markings in favour of a scarlet coloration. Credit: Wikimedia Commons

Indochinese cobras (Naja siamensis) and snouted cobras (Naja annulifera) developed startling black and white bands that serve the same purpose as the warning hood marks. Similarly, the more scarlet the snake, like red spitting cobras (Naja pallida), the more startling to predators. All these species that possess warning markings, bands, and colours have high cytotoxicity. Among king cobras, the Malaysian population that has a bright orange throat has more tissue-destroying toxins than other populations.

Across the board, whether they spat or not, Asian cobra venoms are highly cytotoxic. In contrast, drab, patternless African cobras that didn’t spit have lower cytotoxicity than ones with warning markings, bands, or colours.

All of this raises the question: Why don’t king cobras spit venom? After all, they already possess tissue-destroying factors in their venom. Unlike cobras, the cytotoxic elements of king cobra venom are large and globular that cannot easily attack the exposed surface of the eyes. So they never developed this weapon.

This study, perhaps the first, shows that some components of venom can be used for defensive purposes.

“I think it’s an excellent example of bringing multiple methods together to reveal a fascinating evolutionary story,” Rick Shine, a professor at the University of Sydney, Australia, told The Wire. “One of the aspects that fascinates me is the notion of ‘honesty in advertising.’ You might think that warning colours would help any snake to discourage predators, so those colours might evolve in fairly harmless species as well as deadly ones. But in fact this paper shows that a warning colour is generally a reliable indication that the snake does, indeed, possess a venom potent enough to cause major problems for any predator silly enough to attack it.”

However, cobras, rinkhals and king cobras aren’t the only venomous snakes to have cytotoxins. Many viper species that don’t spread hoods or spit venom possess them, too.

Fry says his team is conducting “a followup line of research with other snakes with significant warning displays, e.g. rattlesnakes, which have non-rattling ancestors.”

While cytotoxins cause a lot of human misery, they can also help us. They attack cancer cells with as much virulence as they do normal tissue. In the future, they may become the source of frontline drugs to treat cancer. “Anything that kills cells is a good thing in the search for new cancer medicines,” says Fry. “So our next step is to purify individual components out of the venoms and see if by fluke one happens to be more specific for cancer cells than healthy cells.”

The study was published is the journal Toxins on March 15, 2017.

Janaki Lenin is the author of My Husband and Other Animals. She lives in a forest with snake-man Rom Whitaker and tweets at @janakilenin.