A red-necked black spitting cobra. (Randy Ciuros/Courtesy of Bryan Fry)

Like an unhappy marriage, every animal toxin is toxic in its own way. Lick a feather plucked from Papua New Guinea’s pitohui bird, as more than one scientist has done, and the mouth will tingle, burn and go numb. No researcher who orally investigated these birds has perished. If only all toxic encounters stopped at anesthetized lips. Lick an Australian box jellyfish, and a sting from the jelly’s venom-tipped harpoon can stop the heart, twice — once temporarily and then, if untreated, eternally.

Within the cobra family, too, not all toxins are the same. Some cobra toxins are primed to kill. Other cobra chemicals, when spat in the eyes, cause victims to go blind. Or, if delivered via bite, the venom eats away at skin and limbs.

It was a mystery to venom experts how cobras evolved these flesh-eating chemicals in the first place. The toxins seemed of little use except as defensive spittle. Cobras on the hunt inject their meals with strong neurotoxins, knocking out birds and small mammals before consumption begins. Skin-melting agony would have the opposite effect.

“Predatory toxins are honed for killing prey. Defensive toxins are all about inflicting pain,” as Bryan G. Fry, a biologist at the University of Queensland in Australia, told The Washington Post.

But according to a new study that Fry and his colleagues published Monday in the journal Toxins, the development of cobras’ flesh-eating venom was a tale of snakes backing up their bluffs with defensive weapons. First came the snakes’ hoods, used to scare off predators. This was followed by the painful toxins. Finally, three separate times in the cobra family tree, some of the snakes evolved the unusual ability to emit blinding spit at perceived threats.

Venom expert Fry in Pakistan, looking at a cobra. The wide folds of flesh leading up to the snake’s head are called a hood. (Sean McCarthy/Courtesy of Bryan Fry)

The study was “a refreshingly fresh look at the evolution of venom compositions,” said evolutionary biologist Kartik Sunagar, a venom expert at the Hebrew University of Jerusalem, who was not involved with the new research. The relationship between the flesh-eating venom and physical traits, he said, was “very surprising and intriguing.”

This painful flesh-eating venom was something of a biological oddity. “Venom, one of nature’s most complex biological cocktails, is energetically expensive to produce,” Sunagar said. The chemicals, called cytotoxins after their cell-killing properties, are relatively weak — up to 100 times less lethal than the neurotoxic sedatives. Why, then, would cobras waste the energy producing the less-potent stuff?

To trace the origins of snake cytotoxins, Fry and his colleagues compared evolutionary traits of 29 cobra species and their close serpent cousins. In their analysis of the cobra evolutionary tree, the researchers determined that the snakes first evolved hoods or brightly colored warning bands.

These hoods and bands sent a similar message: Don’t tread on me or in my general vicinity. “It’s like the guy puffing up his chest at the bar,” Fry said.

It was inevitable, though, that an eater of snakes would have called the cobra’s bluff. Evolutionary pressure gave way to what Fry called “chemical krav maga”: a liquid cocktail, like the one found in the glands of modern cobras, of painful cytotoxins and lethal neurotoxins. (Snakes need a mixture because too much defensive venom would impede the ability to hunt. Only a few animals, such as cone snails, have the ability to switch their venom between chemical defense and offense.)

The researchers found that cytotoxicity increased in brightly banded or brightly hooded cobras as well as spitting cobras. This was contrary to long-held belief that only spitters produced the painful, but less lethal, venom.

A snake species called the king cobra helped drive the theory home. Although these snakes have cobra-like warning hoods, they are cobras in name only. Thirty million years and a large number of snake species separate the king cobras from the true cobras. By way of comparison, the last time humans and orangutans shared a common ancestor was thought to be some 10 million to 16 million years ago.

But some king cobras shared remarkably similar venom with their namesake snakes. The scientists found a cytotoxin within the glands of Malaysian king cobras, a species with the colorful warning hoods. The king cobra toxin was a completely different sort of molecule — a large enzyme, rather than the smaller cytotoxic protein used by true cobras — but it was there.

A king cobra, which, like most true cobras, has a hood. (Kevin Messenger/Courtesy of Bryan Fry) A king cobra, which, similar to most true cobras, has a hood. (Kevin Messenger/Courtesy of Bryan Fry)

“The red hood found only in the Malaysian population, which was also the most cytotoxic king cobra, nailed it for us,” Fry said. “It was almost too good to be true. It made perfect sense.”

Some aquatic cobras should have had cytotoxic venom, based on their lineage, but didn’t. Even these animals, though, fell in line with the hood-toxin relationship. Aquatic cobras do not have hoods, likely because the elongated hood bones would interfere with swimming. Without the hoods or a need to bluff — as the snakes could simply swim away into the water — they also lacked the need to produce the weaker venom.

On the path from hoods to toxic spit, the evolution of cytotoxity seemed almost obvious in retrospect. To the snake experts, at least. “We were slapping our hands to our foreheads,” Fry said. “How did no one ever work this out? How did we never work this out?”

It should be noted that the study was more than an idle academic curiosity. Although spitting cobras have venom that burns eye tissue, several non-spitting cobras have harmful amounts of the cell-killer toxins, too. And these cobras have a dramatic impact on human health.

On the Indian subcontinent, for instance, snakes bite about 1 million people a year. About 10 percent of the bites are fatal. Of those who survive, nearly 400,000 to 500,000 will have lasting injuries, many from cytotoxic venom.

“The damage they can cause is astounding,” Fry said. Photographs of cobra victims reveal arms with giant patches of skin burned away, exposing red muscle and white pus. In places like India, a lack of awareness of the cell-killing effects can be devastating, particularly if victims seek traditional but ineffective treatments before emergency medical care.

“Time is tissue,” as one of Fry’s aphorisms goes. If a cytotoxic cobra bites someone’s arm, Fry said, within about two days it’s irreparably damaged. Such a bite can plunge an Indian family into poverty, if the family’s breadwinner loses a limb and is no longer able to work.

If there existed an upside to these cell-killer chemicals — a “silver lining to a black cloud” of cobra venom, as Fry put it — it was that this research suggested targets for further investigation as new chemotherapeutics. Fry and his fellow venom researchers are hoping that, by some random chance, certain cytotoxins from the pool of snake chemicals will kill cancer cells more selectively than healthy human cells. A few, albeit very early, laboratory tests indicate that this may be the case.

“We can’t predict where next wonder drug will come from,” Fry said. “We need to keep around the animals that people fear so much.”

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