It's a tale as old as time: Newt meets snake, snake eats newt, newt evolves to produce increasingly deadly toxins. Newt kills snake, snake adapts, snake eats newt and — well, that part goes on pretty much forever.

And this tale, like all good tales, involves a campfire with three dead hunters around it. Three mysteriously dead hunters. Three mysteriously dead hunters and a coffee pot with a boiled newt inside.

In the 1960s, the tale of that deadly amphibian inspired biologists to investigate newt toxicity. They eventually realized that newts — many of which produce varying amounts of tetrodotoxin, the same super-deadly poison that pufferfish are famous for — were locked in an evolutionary arms race with garter snakes, which commonly preyed upon them. Wherever these deadly rough-skinned newts co-resided with garter snakes, the local snake populations would evolve impressive resistance against tetrodotoxin. And that prompted the newts to create even more of the toxin, which is 10,000 times deadlier than cyanide. A newt that could easily kill a garter snake from one side of the country might serve as a tasty snack for one on the other.

The latest research, published Thursday in Current Biology, suggests that this arms race began long before newts as we knew them even existed — some 170 million years ago. So the story didn't start with a bunch of dead Oregonian hunters, but if a newt kills a snake in a forest and no one takes that newt to a lab, does it make a research paper?

Edmund “Butch” Brodie Jr. — the scientist first inspired by the tragic campfire tale — along with his son Edmund Brodie III, identified this deadly tug-of-war between newts and snakes and pinpointed its mechanism: Tetrodotoxin (TTX), which works by blocking sodium channels, the proteins that conduct sodium ions through the membranes of nerve cells. A blocked sodium channel leads to swift paralysis and an unpleasant demise, but some garter snakes have changed the shape of their sodium channels to keep TTX from doing its job. The Brodies found that the adapted snakes had mutations on three sodium channels — two on cells found in nerves and one found in muscle.

It was the muscle channel that produced really resilient snakes — so the Brodies wanted to understand where and how that mutation had come about.

"In this new paper, we show that the evolution of resistance in those nerve channels happened way before the evolution of resistance in the muscle channel," said study author and Virginia Tech researcher Joel McGlothlin, who used to do research in the lab of the younger Edmund.

The origin of that initial, nervy resistance is around 170 million years old, predating snakes themselves by at least a few million years. Some ancestral lizard-thing developed this adaptation and "predisposed snakes to be the types of predators that could prey on toxic things like newts," McGlothlin explained.

By sequencing the genes behind these three sodium channels in 82 species — 78 snakes, 2 lizards, 1 bird and 1 turtle — and mapping their trajectory across the evolutionary tree of life, McGlothlin, the Brodies and their fellow researchers determined that the first adaptation in snakes themselves (the second nerve channel adaptation) happened about 40 million years ago, right around the time that newts came on the scene, and then happened again independently in another three snake lineages. The most extreme resistance (the one that results from a mutated sodium channel in muscle cells) only came about around 12 million years ago. Only five species of snake possess this mutation.

Newts, for their part, possessed a resilience to TTX long before they produced it in deadly quantities. So it's not hard to see how this battle began: Snakes slithered into existence with a TTX-resistant toolkit at the ready, making them poised to devour newts — with their low levels of the toxin — from the moment the amphibians evolved. The more toxic the newt, the less appealing, and soon snakes had to up their game.

And that's how a tiny amphibian evolved to carry toxins strong enough to kill three grown men at once. Evolutionary change can be a brilliant and devastating business, especially when two families are at war.

The researchers hope that the development of these traits can be used to help scientists understand other evolutionary trajectories.

"One of the general take home messages of this is that evolution that happens now is building upon millions of years of evolutionary history," McGlothlin said. "Certain pathways that evolution might go down are closed off because the right things didn’t happen in the past, and other pathways are open because the right things did happen."

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