Finding opioid alternatives in cone snail stings

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ven as a boy plucking cone-snail shells from tide pools near his home beside Manila Bay, in the Philippines, Baldo­mero ­Olivera knew that grabbing a living one could mean death. The magician’s cone, whose sting can cause extreme swelling, is the shape of a pointed hat; a tulip cone can trigger blurred vision and uncontrollable drooling, but it has ­ornate petal-like swirls. Mishandling a live geographer cone could stop his heart within minutes. But it looks like a Persian rug! Snagged. “We knew even as kids,” Olivera says, “that this snail was ­capable of killing humans and that it has a 70 percent fatality rate.” It’s a foggy morning in Salt Lake City, and Olivera is near a bank of fish tanks in his lab at the University of Utah. Inside one aquarium, a white-and-brown snail is burrowed in the sand beside a small ­goldfish. The invertebrate extends its thick snorkel-like siphon and lightly sniffs the fish’s underbelly. Olivera, now 77, grew up to be a chemist but never shook his love for these slow-moving assassins. He’s now the lead scientist at a 25-person lab that studies cone-snail venom. His job is to figure out how it works, and, in turn, transform it into drugs that could soothe and save human lives. So far, his lab has isolated several promising molecules, including a few painkillers, and a fast-acting insulin that could let diabetics quickly ­control their blood sugar. Among the former is Prialt (for primary alternative to morphine). Aside from being the first federally OK’d drug to come from a lethal snail, it works on different receptors than opioids to alleviate chronic pain in cancer patients. In other words, it’s non-addictive. But it will never be a primary replacement for morphine because it needs to be pumped into a patient’s spine. These days, Olivera and his colleagues are trying to isolate a snail toxin that could be turned into a new class of painkillers that target different pathways than what’s now on the market. If successful, it could offer a substitute to addictive narcotics like oxycodone (which kills upward of 14,000 Americans a year) as the go-to medication for millions of chronic-pain sufferers.

Meanwhile, in the aquarium, the snail shoots a tiny ­harpoon-shaped tooth from its proboscis. Bam!—the mollusk lances its prey, squirting a toxic cocktail that makes the finned creature thrash like it’s been tasered. Its gills are still twitching when the predator emerges from its pretty shell and pulls the victim into its mouth.

Venom is nature’s drug industry. Each one is a soup of proteins that can hijack the molecular machinery animals use to modulate their respiratory, muscular, nervous, and every bodily system in between. Rather than tightly regulate those systems, the chemical weapon aims to send them into lethal tailspins. But with modern bioengineering techniques, the right molecule at the right dose can be used for good.

Today, researchers spend entire careers trying to pluck a worthwhile drug from poisonous creatures that range from spiders to vampire bats. It wasn’t until 1981 that the first such drug hit the market as Captopril, a vasodilator used to treat hypertension. The drug is derived from a peptide in viper venom that causes blood pressure to plummet. It’s saved millions of lives, earned billions of dollars, and led a wave of researchers to start combing venoms for drug leads. Cone snails happen to be singularly potent.

“Their sting is the equivalent of getting bitten by a ­cobra and eating a lethal dose of pufferfish,” Olivera says. Parts of the sea bug’s artillery home in on nerves, sniffing them out and interfering with them. A typical snail venom can contain 200 or so distinct peptides, mini proteins that all play a role in that sabotage. With little molecular overlap among the venoms of the 700 known cone-snail species, the medical potential of these predators is so expansive that Olivera talks about it in celestial terms. Each toxic family of venom proteins affects a “constellation” of physiological targets, opening up myriad possibilities for cures. The National Institutes of Health sees the potential: Since the 1990s, it has given Olivera’s lab millions of dollars to support his work. In 2016, the Department of Defense kicked in $10 million more.

On this May morning, most of the researchers have not yet arrived, and Olivera’s lab is quiet. “This is really kind of an amazing snail,” Olivera says. He’s wide-shouldered, broad-faced, and mustachioed. In his library, holding a shell with such quiet affection, it’s easy to imagine him as a boy by the sea. It’s the geographer cone, the species that launched this project.

Back in the 1960s, Olivera was doing his postdoctoral research in DNA synthesis in a Stanford lab that had, as he puts it, “all the equipment.” When he returned home to work at the University of the Philippines, the place had “no equipment whatsoever.” So Olivera used what tools he had to investigate how his favorite childhood creatures kill. In the Philippines, there’s a trade in geographer cone snails; so he bought them from a local vendor and extracted their venom. Through some careful molecular parsing, he teased out “very many more toxic components than we expected,” he says. He then jury-rigged an experiment to try to figure out what each one did.

First, he borrowed some mice from the medical-­school laboratories. He placed them upside down on a mesh (mice will cling to mesh for more than 10 minutes at a time). Then he injected them with fractions of individual venom components. “It was incredibly crude science,” he admits. It was also ingenious. By measuring how quickly the drugged mice fell, he identified two components that caused paralysis.

But by the 1970s, the Philippines had grown violent ­under the regime of dictator Ferdinand Marcos, and ­Olivera fled, eventually landing in Salt Lake City and the University of Utah. Here, in 1979, a 19-year-old undergrad asked him: What about all the other compounds he had identified? What did they do? Nothing, as far as ­Olivera knew. The student persuaded Olivera to let him and a few other undergraduates inject those peptides directly into mice’s central nervous systems via needles to the brain. Each one elicited a distinctive behavior: continuous head swinging, running in circles, 24-hour naps.

“It meant the snails had discovered combination drug therapy,” Olivera says. They kill by attacking many systems at once, the same tactic doctors use to treat HIV. During those first experiments, one pioneering student with a mass of dark curls, an 18-year-old undergraduate named J. Michael McIntosh, isolated the peptide that became Prialt. “It made the mice shake,” McIntosh says. Now 57, his hair is gray, and he wears it closely cropped. That morning he wore a sweater over a collared shirt.

Almost 40 years after his discovery of Prialt, ­McIntosh still works closely with Olivera, but their roles have changed. Both now run their own labs at the university: Olivera’s team dissects venoms to find physiologically active molecules, McIntosh heads a crew developing a non-addictive painkiller. The project is close to his heart. After graduating from the University of Utah with a biology degree, he studied medicine in California, followed by a psychiatry residency in Colorado. Today, he’s a practicing psychiatrist at Salt Lake’s Veteran Affairs hospital.

“I regularly see clients for PTSD. But I have a fair number who say if they didn’t have chronic pain, they wouldn’t need to see me at all,” he says. “The relief they get from opioids is fleeting, and the side effects can be debilitating.” McIntosh redoubled his efforts to find a better anal­gesic. His break came in 2003, when a competing team in Australia found a peptide that numbed pain in rats, caused no side effects, and was nonaddictive—the ideal painkiller. Except it didn’t work in people at all. Curious why, ­McIntosh went looking for a molecular cousin and found one in the toxic artillery of a Caribbean cone snail. He called it RgIA. The first step to figuring out why RgIA didn’t work in people was learning why it did in rodents.

Drug testing relies on the squirmy truth that people ­aren’t so different from these bewhiskered mammals. If a drug works in rodents, and causes acceptably few side effects, the FDA allows it to be tested in humans. But here’s the thing. Big pharma, the FDA—nobody really cares how a drug works, they need only to know that it does and that it’s safe. “Take aspirin, as one example,” McIntosh says. It was used for many years before its mechanism of action was understood. That one-eye-closed approach to drug development has helped give us the prescription opioid crisis. (Morphine mutes pain, while causing nausea, a slowed heart rate, and addiction.) The FDA still doesn’t require drug developers to know how a medicine works, but today’s most careful researchers want to know as much as possible and use complex chemistry to identify a drug’s exact mechanism of action in animals before they stick it into humans. McIntosh trained under Olivera. Answering the basic question is what produced their first drug. He is a careful researcher.

By 2006, McIntosh had figured out the exact receptor that RgIA targeted in rats. To determine why it didn’t work in people, his team compared the DNA of the rat receptor to the DNA of the human receptor. What they found was a near match, except one key amino acid was off. That was enough. This discovery, as McIntosh interpreted it, was great news. “It meant we could solve the problem,” he says.

What happened next highlights just how far Olivera and his colleagues have come from the mice-on-mesh days. In order to achieve potency in people, McIntosh’s team had to engineer a brand-new version of the peptide RgIA that fit perfectly with both the human and rat pain receptors. The job was like trying to guess the code on two intertwined combination bike locks by changing a single number at a time. It went like this.

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At a workstation littered with beakers, a scientist created cells with either human or rat pain receptors on their surface by injecting their RNA into frog eggs. They would then dribble the synthesized peptide onto the cells, measure their electrical activity to see whether the protein had latched onto the receptors, curse, and order a new peptide from a scientist across the lab. There, using a machine that looks like the offspring of a washing machine and a 3D printer, those scientists would construct a new version of RgIA. Team frog egg would then test it again. And repeat. For eight years they lapped this scientific merry-go-round, engineering more than 100 versions of RgIA. Finally, as they reported in the Proceedings of the National Academy of Sciences in 2017, the zapped eggs showed that the molecule docked with cells from both human and rat receptors. No champagne was popped, no parties thrown. “Now we had to see if it worked in live rodents,” ­McIntosh says.

Sorry about the smell,” Sean Christensen, who runs McIntosh’s animal experiments, says. He presses his thumb onto a fingerprint reader, then enters a room that smells dankly of critter. On a rack inside are around 30 cages wriggling with rodents. He’s come to inflict (mild) pain upon these animals, and then measure whether RgIA dulls it. They do this by injecting the animals with a chemotherapy drug known to cause such extreme sensitivity to cold that being merely chilly hurts. Then they administer RgIA, and set the test subject on a steel table designed to get 1 degree colder every 10 seconds. If the mouse is slower to raise its paw in discomfort, it’s evidence that it’s less sensitive to pain. Therefore, the painkiller works.

“Usually, when they’re grooming, they lick the back of their hands,” Christensen says, scooping up a brown specimen from a cage and dropping it on the table. “When they’re cold, they’ll pick up both paws like this.” He lifts a hand in a way that conjures a kitten dabbing a puddle.

Gather enough data here to prove the peptide’s ­efficacy in animals, and within the next couple of years, McIntosh expects the drug to go into clinical trials, possibly with cancer patients suffering from chronic pain. If that goes well, it could be on the market by 2025, this time, he hopes, as the primary alternative to morphine. ­Olivera’s and McIntosh’s most promising finds, such as RgIA and the fast-acting insulin, have all come in the past few years. But with hundreds of thousands of molecular components still unstudied, there’s more than enough work for researchers all over the world. “Every venom component is a potential tool to manipulate [neural] circuits and help us understand them,” Olivera says.

The mouse is now peeing on the table, and Christensen presses a foot pedal to start chilling the surface. In the background, industrial fans hum, and restless rodents shuffle in their bedding of wood pellets. When the table’s 15 degrees cooler, the tiny patient lifts its front paws. Christensen clicks the foot pedal again. And that’s it. The animal has been mostly unbothered by the cold. Which is a much bigger deal than it sounds.

This article was originally published in the Winter 2018 Danger issue of Popular Science.