Could humans ever evolve venom? It's highly unlikely that people will join rattlesnakes and platypuses among the ranks of venomous animals, but new research reveals that humans do have the tool kit to produce venom - in fact, all reptiles and mammals do.
This collection of flexible genes, particularly associated with the salivary glands in humans, explains how venom has evolved independently from nonvenomous ancestors more than 100 times in the animal kingdom.
"Essentially, we have all the building blocks in place," said study co-author Agneesh Barua, a doctoral student in evolutionary genetics at the Okinawa Institute of Science and Technology in Japan. "Now it's up to evolution to take us there."
Oral venom is common across the animal kingdom, present in creatures as diverse as spiders, snakes and slow lorises, the only known venomous species of primate. Biologists knew that oral venom glands are modified salivary glands, but the new research reveals the molecular mechanics behind the change.
"It's going to be a real landmark in the field," said Bryan Fry, a biochemist and venom expert at The University of Queensland in Australia who was not involved in the research. "They've done an absolutely sensational job of some extraordinarily complex studies."
A flexible weapon
Venom is the ultimate example of nature's flexibility. Many of the toxins in venom are common across very different animals; some components of centipede venom, for example, are also found in snake venom, said Ronald Jenner, a venom researcher at the Natural History Museum in London who was not involved in the research.
The new study doesn't focus on toxins themselves, as those evolve quickly and are a complex mix of compounds, Barua told Live Science.
Instead, Barua and study co-author Alexander Mikheyev, an evolutionary biologist at Australian National University who focuses on "housekeeping" genes, the genes that are associated with venom but aren't responsible for creating the toxins themselves. These regulatory genes form the basis of the whole venom system.
The researchers started with the genome of the Taiwan habu (Trimeresurus mucrosquamatus), a brown pit viper that is well studied, in part because it's an invasive species in Okinawa.
"Since we know the function of all the genes that were present in the animal, we could just see what genes the venom genes are associated with," Barua said.
The team found a constellation of genes that are common in multiple body tissues across all amniotes. (Amniotes are animals that fertilize their eggs internally or lay eggs on land; they include reptiles, birds and some mammals.)
Many of these genes are involved in folding proteins, Barua said, which makes sense, because venomous animals must manufacture a large quantity of toxins, which are made of proteins.
"A tissue like this really has to make sure that the protein it is producing is of high quality," he said.
Unsurprisingly, the same sorts of regulatory housekeeping genes are found in abundance in the human salivary gland, which also produces an important stew of proteins - found in saliva - in large quantities. This genetic foundation is what enables the wide array of independently evolved venoms across the animal kingdom.
From nonvenomous to venomous
In other words, every mammal or reptile has the genetic scaffolding upon which an oral venom system is built. And humans (along with mice) also already produce a key protein used in many venom systems. Kallikreins, which are proteins that digest other proteins, are secreted in saliva; they're also a key part of many venoms.
That's because kallikreins are very stable proteins, Fry said, and they don't simply stop working when subjected to mutation. Thus, it's easy to get beneficial mutations of kallikreins that make venom more painful, and more deadly (one effect of kallikreins is a precipitous drop in blood pressure).
"It's not coincidental that kallikrein is the most broadly secreted type of component in venoms across the animal kingdom, because in any form, it's a very active enzyme and it's going to start doing some messed-up stuff," Fry said.
Kallikreins are thus a natural starting point for theoretically venomous humans.
If after the drama of 2020, Barua joked, "people need to be venomous to survive, we could potentially start seeing increasing doses of kallikreins."
But that's not so likely - not unless humans' currently successful strategies of acquiring food and choosing mates start falling apart, anyway. Venom most commonly evolves as either a method of defense or as a way of subduing prey, Jenner told Live Science. Precisely what kind of venom evolves depends heavily on how the animal lives.
Evolution can essentially tailor venom to an animal's needs via natural selection, Fry said.
There are some desert snakes, for example, that have different venom despite being the same species, just due to where they live, he said: On the desert floor, where the snakes hunt mostly mice, the venom acts mostly on the circulatory system, because it's not difficult for a snake to track a dying mouse a short distance on flat ground. In nearby rocky mountains, where the snakes hunt mostly lizards, the venom is a potent neurotoxin, because if the prey isn't immediately immobilized, it can easily scamper into a crevice and disappear for good.
A few mammals do have venom. Vampire bats, which have a toxic saliva that prevents blood clots, use their chemical weapon to feed from wounds more effectively. Venomous shrews and shrew-like solenodons (small, burrowing mammals) can outpunch their weight class by using their venom to subdue larger prey than they could otherwise kill.
Shrews also sometimes use their venom to paralyze prey (typically insects and other invertebrates) for storage and later snacking. Meanwhile, platypuses, which don't have a venomous bite but do have a venomous spur on their hind legs, mostly use their venom in fights with other platypuses over mates or territory, Jenner said.
Humans, of course, have invented tools, weapons and social structures that do most of these jobs without the need for venomous fangs. And venom is costly, too, Fry said. Building and folding all those proteins takes energy. For that reason, venom is easily lost when it isn't used.
There are species of sea snakes, Fry said, that have vestigial venom glands but are no longer venomous, because they switched from feeding on fish to feeding on fish eggs, which don't require a toxic bite.
The new research may not raise many hopes for new superpowers for humans, but understanding the genetics behind the control of venom could be key for medicine, Fry added.
If a cobra's brain were to start expressing the genes that its venom glands expressed, the snake would immediately die of self-toxicity. Learning how genes control expression in different tissues could be helpful for understanding diseases such as cancer, which causes illness and death in large part because tissues start growing out of control and secreting products in places in the body where they shouldn't.
"The importance of this paper goes beyond just this field of study, because it provides a starting platform for all of those kinds of interesting questions," Fry said.
The research was published online Monday (March 29) in the journal Proceedings of the National Academy of Sciences.