Confront: Bull ant takes on echidna in evolutionary battle

By Karen McGhee

April 21, 2022

Queensland scientists have identified a toxin in bull ant venom that cleverly evolved and developed specifically to target short-beaked echidnas, the main predator of ants in the Aussie bush.

But there is even better news. This breakthrough could help treat human pain.

The discovery that Australian bull ants and echidnas share an intertwined evolutionary history began about four years ago when Dr. Sam Robinson, a molecular biologist and expert on animal toxins at the University of Queensland, was handed a container of these stinging insects.

There are 93 species in the group we know as bull ants – the genus Myrmecia – and all but one are endemic to Australia and its islands. The short-beaked echidna is also a special Australian animal, not found anywhere else in the world.

Sam’s research now indicates that these two are engaged in a lengthy evolutionary struggle for survival, with the ants using pain to prevent echidnas from raiding their nests.

Australian bull ant coming out of its nest. Image credit: Doctor Sam Robinson

Seriously annoying stingers

Bull ants is just one of the common names for these ants: they are also known as bulldog ants, jack jumpers and inch ants. “They’re all big ants and probably the most characteristic thing about them is their large jaws,” explains Sam.

“Another thing about them is that although many ants use ‘scent’ [chemical trails] to get around, these ants are very visual.”

Watch them for a while and you may notice that they send semaphore-like messages to each other by waving their antennae.

“And the other thing we know is that they sting, and it hurts,” adds Sam.

Get bitten by one of these things and you know it!

It’s the poison that stings and that’s what Sam wanted to investigate when he first got his hands on that container of ants.

“We generally knew very little about what was in ant venom at the time,” Sam says. “And I thought this was a really cool place to start, with one of these really charismatic Australian ants.”

Doctor Sam Robinson.

Obsessed with pain

Sam had been studying poison for several years by then.

“I had already looked at a lot of different ones at that time,” explains Sam. “But my broader research program is focused on isolating things that cause pain and the specific toxins in venom that cause pain.

“I want to understand how those work on the human body and use that information to almost rewrite the book on pain at the molecular level.”

The reason for doing that is that if you can understand how pain — which is an extremely complex physical response in the human body, triggered by a dizzying array of triggers — you’ll be in a better position to develop ways to relieve it.

Researchers in Australia have been successfully extracting and collecting venom from snakes and spiders for decades. But those techniques don’t work with ants. To investigate what’s in ant poison, Sam first had to figure out a way to safely collect it.

“And that was to basically just have them poke on a little waxy paper strip and then collect the droplets from that,” he says. “Then we figured out what was in that venom by using some pretty complicated techniques.”

Australian bull each litter. Image credit: Dr. Sam Robinson

World first

Sam’s team then published a paper characterizing an ant venom for the first time, essentially breaking down its chemistry.

It gave a complete picture of what is in the venom, making it possible to determine the structure of any molecule it contains.

“This allowed us to see how it worked,” says Sam, explaining that most of the molecules have been shown to be related to and act in a manner similar to the main toxin in honey bee venom — melittin.

These toxins punch tiny holes in cells and when they do that in a nerve cell – a neuron – it activates it. “It’s a pretty common mechanism of action for pain-causing toxins,” says Sam. “But there was one standout that was structurally very different from the rest of these toxins.”

Sam’s team tested that toxin in lab mice, but got no pain response from it.

They couldn’t even get any reaction to it, so it was put aside and forgotten about for a while until Sam was stuck in COVID quarantine and decided to take a much closer look at that anomalous molecule.

Short-beaked echidna. Image Credit: Shutterstock

Identify a connection

After comparing the molecule with a huge database of other molecular structures, something unusual appeared.

Sam was looking for molecules with a similar structure and “one thing that struck me was that the things at the top of the list were actually these hormones from Australian marsupials”.

This can’t be a coincidence, he thought. “There is an ant that is endemic to Australia and we are getting a strong signal for Australian animals,” says Sam.

He then looked at the scientific literature — outside of his usual molecular focus and in more ecological areas — and realized that the thing that probably exerted the strongest selection (evolutionary) pressure on these ants was the echidna.

“It’s the only Australian animal known to actually dig up ant colonies — to eat their larvae and eggs — and I thought if that’s the animal that’s attacking them, maybe this toxin mimics a hormone in the echidna to create a ​​or other reason related to pain,” Sam says.

“So I looked at the echidna genome, which was only published a few years ago, and I found this hormone sequence there indeed and it was the most closely related thing to this toxin that we had seen.

“It was pretty strong evidence that there was a link between bull ants and the echidna and that the toxin had evolved to target a receptor in the echidna.”

Previous studies had suggested that this particular receptor may be involved in pain hypersensitivity. The team then repeated its lab experiments, this time not just injecting the bull ant toxin into mice, but followed up by applying pressure to the area being injected.

“We just took a thread and pressed it against the mouse foot and just measured when it started to recoil,” explains Sam. “It wasn’t painful; only a measure of sensitivity.

“And what we found was that the mice had become extremely sensitive to mechanical or thermal stimuli within a few hours.”

The researchers continued to measure and found that this increased sensitivity lasted for about a week.

“So what we think is going on is that if an echidna is to say attack a bull ant colony, it will be stung by a lot of ants, like anyone who interferes with a bull ant colony, and it will be a large dose of this poison ,” says Sam.

“If it later returns to that colony to raid it again, or to a neighboring colony, it will probably avoid that because it will be a lot more sensitive to the pain of the experience.

“So, it probably reduces the length of time an echidna can stay in a bull ant colony or the frequency with which it starts targeting bull ant colonies.”

Not surprisingly, echidna foraging studies show that they tend to eat other ants, not those of the bull ant genus.

“These ants make up a small percentage of what echidnas eat — maybe just 5 or 10 percent,” says Sam. “They’ll focus on things that are a lot simpler.”

Perhaps this shows that the ants’ strategy has worked? “We don’t have direct evidence for that yet, but you would assume it is. I mean, if you were an anteater and had a choice of two different ant colonies and one of them would hurt a lot more, you’d probably avoid it!”

For Sam, the most remarkable aspect of this work to date has been to see how closely the structure of ant toxin mimics the hormone in echidnas. “It’s pretty amazing,” he says.

And clearly, he agrees, it’s a wonderful example of evolution in action.

Help for human pain

However, there is so much more to this discovery than the wonderful light it sheds on understanding the natural history of Australian animals.

There is the potential it could have in the long term for treating some forms of pain.

Pain is a complex phenomenon that manifests itself in many different ways: one is chronic hypersensitivity, and this is seen in certain diseases such as certain types of migraines and some cancer-related pain.

“The most important thing in the context of pain is that, by highlighting a receptor involved in hypersensitivity to pain, the bull ants have revealed a potential new drug target,” Sam says. And that, he agrees, is really one of the main goals of his research.

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