Bryan Fry recalls watching a battle unfold in the Australian outback between two arch-enemies: the sand goanna and the venomous western brown snake.
"The brown snake was biting it and really drawing blood, but the sand goanna was totally unaffected and ended up slurping down the brown snake," he said.
The two reptiles were entangled in an evolutionary arms race.
"We know that the big species of goanna feed a lot on venomous snakes, while the smaller species are obviously small enough to be vulnerable to a venomous snake as far as being potential prey," Professor Fry, a toxicologist at the University of Queensland, said.
In this case, the brown snake drew first blood, but evolution equipped the sand goanna with the ability to combat the snake's highly toxic venom.
Professor Fry is part of a team of researchers that has been investigating how some species of lizards have evolved to survive being bitten by some of the world's deadliest snakes, and why others become a tasty meal.
Their research, which was published in the International journal of Molecular Sciences, focused on the interactions between elapids, a family of highly venomous snakes, and varanids, a family of lizards.
Elapids include death adders and cobras, while goannas and Komodo dragons number among the varanids.
The researchers wanted to compare how the reptiles evolved in response to being both predators and prey, Professor Fry said.
"It was really interesting to see how it all shook up, but we never expected it to be so incredibly complex."
Evolutionary arms race
Elapid snake venom contains neurotoxins which interfere with the transmission of nerve impulses by blocking chemical receptors on muscle fibres so they can't contract, leading to paralysis and death.
To understand how different species of lizards responded to snake bites, researchers applied venom to tiny patches of tissue, sourced from dead lizards in museum collections across Australia.
The study found that most large varanid lizards, such as goannas, have inherited neurotoxin resistance to the venom – a trait Professor Fry said was possibly connected to their predatory lifestyle.
"The key is that the lizards are evolving resistance to alpha-neurotoxins, which is a toxin type that is shared across Australian elapid snakes," he said.
Professor Fry said they discovered multiple mutations in the receptors that were responsible for the lizards' resistance, which were passed down to their offspring and future generations.
But not all lizards "shield themselves in the same way", he said.
The study found that two lineages of giant varanids – the Komodo dragon and the perentie – had reduced chemical resistance to the venom, but would use their physical build to armour themselves against the snakes.
"Their thick, bone-filled scales are enough to protect them against snakebite, while their large teeth are used to quickly dismember the fettuccine-like snakes," Professor Fry said.
"Obviously, that's not going to be enough to protect them against a bite, but as they become bigger and bigger, it becomes like chain mail. Eventually, it's going to be to the point where the snakes aren't even going to be able to penetrate [their skin]."
This indicated that size and mechanical defences may reduce the need for chemical resistance – "in essence, evolution has favoured brawn over biochemistry," he said.
It's not just size that counts
Researchers also found dwarf varanids such as tree monitor lizards lost the resistance as they evolved to live above the ground and away from predators.
Other dwarf lineages such as the rusty desert monitor and the short-tailed pygmy monitor re-evolved the resistance when they came down from the trees and evolved to become burrowers.
Uthpala Chandrasekara, a PhD candidate from the University of Queensland who completed the research work as part of her thesis, said the results illustrated the dynamic nature of the evolutionary process – and why researchers framed their observations as "a Russian doll of resistance."
"What this describes is how lizards have evolved their immunity to venom in a complex and layered manner, similar to how these Russian dolls fit one inside another," she said.
"Specific traits can emerge, be lost and re-emerge across different varanid species in response to the changing ecological and biological processes."
The results also suggested the evolutionary battle doesn't always head in one direction.
"Once the lizards evolve, the snakes fire back with even more potent toxins," Ms Chandrasekara said.
"It's a biological arms race where the only constant is change."
The study discovered that some Australian elapid snakes, such as the death adder, have developed highly potent venoms, which are more effective at counteracting the lizards' defences.
When the lizards develop resistance, this then puts a reciprocal pressure on the snakes, "for their venom to become more potent, or more selective, or more efficient because otherwise they're not going to feed," Professor Fry explained.
"It's a classic back and forth, where a change in the venom puts a pressure on the prey, but a change in the prey susceptibility puts pressure back on the venom."
The only way to win, he said, was to not play the game.
"The little lizards that are up in the trees are the true winners because they're completely decoupled from the entire arms race now."
'Deeply fascinating'
Timothy Jackson, co-head of the Australian Venom Research Unit at the University of Melbourne, said the study was "deeply fascinating" and increased our knowledge of how toxin resistance in varanid lizards worked at the molecular level.
"It is also a strong contribution to the literature on the potential for evolution of venom resistance," Dr Jackson, an evolutionary toxicologist with a focus on reptile venom, said.
But he said there were still questions to answer about how ecological factors such as feeding and defence contributed to evolution.
"As is typically the case in scientific investigations, interesting patterns are observed and there is a reasonable desire to conjecture an explanation for those patterns.
"The specific explanations conjectured in terms of feeding and defensive ecology require further investigation."
He clarified that it was important that "evolutionary biologists should make such conjectures".
"Imagining the encounter between predator and prey and the attendant selection pressures is part of what fuels our desire to investigate these fascinating systems."