When David Julius needs a fresh batch of venom, he usually calls an Australian. Which makes sense—the continent is literally crawling with poisonous critters. Julius has hundreds of samples; boxes upon boxes of vials milked from spiders, snakes, scorpions, and the occasional platypus. A humming gray refrigerator in his San Francisco lab keeps the whole collection chilled to -80 degrees Celsius.
Over the past decade, Julius and his team at UC San Francisco have been combing through a vast chemical library of animal venom to discover new toxins. Not because they want to poison anybody—quite the opposite. Julius is a physiologist studying pain, and the toxins in those venoms make you hurt in different ways. By looking at how and where those toxins attack different parts of the nervous system, Julius and his lab might find some that could be used to develop better painkillers.
Pain is your nervous system's reaction to certain stimuli. And there are so, so many ways to feel pain. There's the pain that comes when you burn yourself, or take a plunge in icy water, or eat a ghost pepper. Scientists classify those as thermal pain. There's chemical pain, like when lactic acid builds up in your legs during a run or your cells get damaged. There's the pain of having a giant, bristling tarantula sink its fangs into your hand—mechanical pain. And then there's the big slug of venom that spider delivers straight to your nervous system, a searingly painful combination of any of the three prior types.
Terrifying and badass, yes. But venoms are especially useful for pain research because they're filled with hundreds of toxins designed to bork nervous systems of all kinds, combined and honed over millions of years. Many of those toxins are knotted strings of amino acids that nestle into some specific nook of a pain receptor—a terrible case of things fitting perfectly into other things, but useful for pinpointing locations on nerve cells that feel certain types of pain. Julius wants to figure out where those spots are and how they work. "Basically, they're finding new ways to inflict pain," says Chris Ahern, a biophysicist at the University of Iowa.
Now, Julius and his coauthors have published the latest results of their search in today's Nature. They isolated two kinds of toxins from the venom of a tarantula called Heteroscodra maculata, and discovered it causes mechanical pain. That's what you feel when your body gets pinched or strained or prodded, and it also underlies chronic pain in afflictions like irritable bowel syndrome. When the scientists injected mice's paws with small doses of the toxin, they became much more sensitive to getting poked.
The keys here are sodium channels. Molecular structures on the membranes of neurons that allow those cells to send electrical signals—bzzt! bzzt!—and trigger all sorts of nervous system responses. Including pain. And since sodium channels are so important for normal nervous system functioning, many venoms evolved to target them. Some latch on to sodium channels and don't let them close, which overloads the nerves with electrical signals. Other toxins, like tetrodotoxin in pufferfish, simply shut down the channels and cause paralysis.
The tarantula venom, though, has two toxins that target a very specific type of sodium channel. And once scientists figured that out, they deduced that those sodium channels control mechanical pain.
That link could be key to developing new painkillers. Scientists had sort of overlooked sodium channels before, says Ahern, ignoring the nuances between the types—each is big and complex, and the nine types of channel aren't all that structurally different. But those nuances turn out to be very important. "It's kind of a renaissance for sodium channels," Ahern says. And drug companies would love to target specific sodium channels to get at some types of pain and not others.
Case in point: The local anesthetics doctors use now, like lidocaine, block all sodium channels. That shuts down all nerve communication in an area for a short period of time. Which is fine if you're getting a root canal, but not so great for recurring ailments like back pain. "The pharmacology of pain is still pretty primitive," Julius says. And the medicines that treat chronic pain—opiates, mostly—aren't too swell either. "Opiates are embarrassingly blunt," says Jeremiah Osteen, a post-doc in Julius' lab who led the Nature study. "They don't do anything to the pain signal itself, they just dampen the body's response to it."
So, more knowledge of what controls different types of pain could mean better pain meds. And those channels might be helpful in targeting other, non-pain conditions. For instance, the sodium channels targeted by the Heteroscodra maculata's toxins hadn't really been studied before in the context of pain, but scientists had previously discovered that mutations on that channel often cause epilepsy. Julius and his team suggest the toxins they found could be fruitful starting points for epilepsy researchers to develop drugs.
In pursuit of pain
Julius's lab didn't pull those tarantula toxins out of a hat. With hundreds of venoms in their library to sort through, they've developed a systematic, laborious process to home in on the interesting ones. "We're screening pretty much continuously," Osteen says. They test every new venom they get by applying each to mice and rat nerve cells in a dish. If a subset of the cells lights up—showing up neon blue against a purple background, thanks to a calcium dye—it's a sign that the venom is targeting some pain receptors and not others.
Of the venoms they test, about 15% turn up promising. From there, it's a matter of winnowing out the toxins they find interesting. The trickiest parts, Osteen says, are figuring out what exactly each toxin is and where exactly it's targeting. The lab separates out the promising venoms into their individual toxins, in almost imperceptibly tiny droplets. ("They're very potent," Osteen says.) To determine what's what, they use mass spectrometry, sequence proteins, analyze genes in the animals' venom sacs, and synthesize the toxins. Sometimes, they call in specimens of the venomous animals themselves to collect RNA (molecules that show which genes are being expressed and when). Then, the scientists throw out the toxins that have been studied extensively, and delve into the rest.
The lab isn't stopping at a couple of toxins that may be medically promising, however. Julius and his colleagues are intent on figuring out how the entirety of pain works, doing what Osteen calls "curiosity-based science." Of course, they'll look closely at any serendipitous medical discoveries that might branch from their research, but they're mostly researching this stuff because, well, it's cool. Why wouldn't you want to learn all about venom?
Still, their work is eminently practical. Pain is universal, Julius points out, and it's something everyone is viscerally interested in. "On a fundamental level," he says, "it shapes how we experience the world." Though the experience of a debilitating tarantula bite might be one you'd want to stay a world away from.