Spiders are radical. Eight legs, plural eyes, armored bodies, silk-shooting butts, and best of all: venom. Delivered through stiletto-sharp fangs, spider venom shuts down a victim's central nervous system, rendering it paralyzed---or dead---so the spider can turn its innards to mush and gulp down the organ soup.
But spider venom's origin story has vexed biologists for years. Unlike snake and lizard venom, the origins of the venom deployed by arthropods like spiders and centipedes are still a scientific mystery. Also, snake and lizard venom all trace back, evolutionarily, to a single species. But venom in arthropods evolved in multiple ancestors, from different genetic pathways that converged on similar chemical toxins. Figuring out how all that happened isn't just academic; the toxins in venom can also be used to make new types of pesticides and novel drugs. A new study, published today in the journal Structure, solves some toxic mysteries in a venom shared by several species of spider and centipede.
When people talk about venom, what they are usually talking about are the toxins within venom. "These are very complicated in terms of biochemical composition," says Jessica Garb, an evolutionary biologist specializing in toxins at the University of Massachusetts Lowell, who was not an author of the paper. Most basically, toxins can be proteins, peptides (short chains of amino acids), or other molecules that attack cellular functions in another organism. (Scientists are still figuring out the functions of other venom ingredients, though some might be used to soften up tissue so the toxins can do their dirty work. The jury is still out about whether these are the same enzymes spiders use to digest their prey's innards.)
Researchers generally think the toxins slot into the same structures on the outside of a neuron that those nerve cells use to communicate---with each other, and with muscles and organs. Those molecular antennae---ion channels that open and close to expose the guts of a cell to the outside world, and receptors that pick up chemical signals from the surrounding environment---are a key to bodily functions. But venom hacks the network, shutting down intercellular communications. Result: paralysis and death.
In arthropods, the origin of venom is tricky to track down because of the way the toxic molecules fold. Recently however, scientists figured out that the peptide toxins in spider venom are part of a bigger biological family originally found in crustaceans---crabs and lobsters.
As dismaying as it may seem to find a biological connection between crabs and spiders, they're actually close relatives. These "ion transport peptide/crustacean hyperglycemic hormones" control things like molting, eyestalk growth, and organ development. In humans and other vertebrates, similar hormones control the relative concentration of fluids inside cells and organs and also the release of insulin---which is what turns carbohydrates into sugar. That's the "hyperglycemic" part.
This is where the new research comes in. The question is, how did these useful, sugar-digesting hormones get toxic? In the study, the scientists traced back a single peptide using recombinant DNA techniques. "We simply instructed E. coli bacterium to make a copy of the native spider and centipede toxins," writes Glenn King---a structural biologist at the University of Queensland in Australia and author of the study---in an email. They made sure this toxin was identical to the naturally-produced toxin by checking the structure with high-tech magnification techniques. And they made sure it killed bugs by testing it on nasty little parasites called sheep blowflies.
The spider and centipede toxins only shared about 22 percent of the same genetic source material, but structurally---and functionally---they are the same. Because they were so unique, the researchers put them in a new class: HAND toxins. That's short for Helical Arthropod-Neuropeptide-Derived, not because it chokes the life out of its prey. At a genetic level, HANDs are distinguished from the ITP/CHHs they evolved from by their lack of a single helix bond.
"The thing is that we don’t know is the specific mechanisms of action of these HAND toxins," says Garb. The cellular surface structures that toxins attack are still very hard to visualize, so it could be a long time before scientists untangle these interactions. But the researchers did figure out the genetic structure, and along with the larger scale function---conking out prey---they could proceed with figuring out from whence the toxins came.
For this, they searched for both the HAND toxin and its precursor hormone in a number of other spider and centipede species. After mapping the presence or absence of one or both hormones on species of each creature family, and then comparing the evolutionary relationship between each species, they were able to figure out approximately when the precursor hormones to HAND toxins became weaponized.
The scientists believe this happened---in both spiders and centipedes---sometime in the last 140 million years (around the same time flowering plants emerged and massive long-necked sauropods walked the earth). Their hormonal precursors---the ITP/CHH's---had more divergent origins, popping up around 410 million years ago in spiders and 250 million years ago in centipedes.
"Our work shows that spider and centipedes recruited [the precursor] hormones into their venom hundreds of millions of years ago," writes King. "We don't know why." One theory is that these precursor hormones found their way into some members of the ancestor species, and the bites of these individuals were in some way damaging to prey. Over time, the hormone became more and more weaponized. "They no longer possess the original hormonal function but are instead potent neurotoxins." There's no way to know for certain exactly how non-toxic hormones became harmful, but technical innovations, like those in microscopy that biologists are using to view the structure of cellular ion channels and receptors, could bring us closer.
And this is important, not just because venom is radical. Understanding the ways spider and centipede toxin work could help health care. Pharmacologists have shown that ion channels like the ones targeted by spider venom might also be the bullseye for drugs that treat pain, epilepsy, bipolar disorder, and depression. And even without therapies, it is fascinating to think about the deep-time evolutionary pressures that turn an innocent metabolic chemical turn into a neuronic killer.
