Matt Lewin waited for the paralysis to set in. Two anesthesiologists and an emergency-room doctor monitored his vitals while the mivacurium moved through him. Mivacurium paralyzes skeletal muscles the same way a cobra bite does, with the venom’s most deadly effect: It causes the diaphragm to stop contracting, and the victim suffocates. The doctors had chemically immobilized Lewin, like a snake would, to see if they could reanimate him with a new snake-venom antidote.
It was an antidote Lewin himself had developed: a nasal spray of the compound neostigmine. Doctors first described neostigmine’s ability to undo snake-induced paralysis in 1972, but it is usually injected, and administered by doctors in a hospital. Lewin wanted to create a first-aid–style, no-supervision-required version that a person could stick up her nose after a cobra bit her. But his Afrin-like version had never been tested against snakebites—not even in mice, rats, chimps, or the other lab-test favorites that usually precede humans.
Courtesy Matt Lewin.
Lewin, prone in the research room, was the first test subject. (A known antidote to mivacurium waited right next to him, just in case.) At first, the effects of mivacurium felt relaxing, the ultimate shavasana. Then, Lewin couldn’t see. His breathing got shallower. He had trouble swallowing, couldn’t lift his head. Speech departed.
He felt impatient and dependent, like a child whose well-being depends on others. “Even though I knew I was being monitored intensely, they appeared to me very casual,” he says, “because they couldn’t experience what I was experiencing.” And what he was experiencing was a slow, staggering walk toward death (metaphorically, since he couldn’t even wiggle a toe). He could only hope that his antidote would grab his hand and lead him back.
“Everything that was going on was just in my head,” he says, “which was, give me the drug. Stop talking about Hank Williams, Jr.”
Underneath his anxiety, though, he knew that the doctors were confident and focused, playing out the scenario they had dress-rehearsed and planned for months. When he heard them approach his nose with the antidote, he got so excited that his heart monitor began beeping like crazy before the mist even entered his nasal cavity.
The effects were almost instantaneous. The muscles under his face jerked awake and reordered themselves. It felt cartoony, like CGI of a human morphing into an animal. Minutes later, the rest of his body worked. He rose from the bed like Lazarus.
“It worked!” he said.
His words came out slurry and garbled. He cried.
* * *
Lewin, a wilderness physician, first began thinking about snakebite treatments after he became a fellow at the California Academy of Sciences. As part of his duties preparing for the 2011 Hearst Philippines Biodiversity Expedition—which sent 94 people in search of new land and sea species in the Coral Triangle, which is full of venomous snakes—he created a snakebite treatment kit.
He started reading about treatments and discovered how big a problem snakebites are worldwide—and how many problems the solutions have. Scientists make antivenom by injecting an animal—like a horse or a sheep—with venom, harvesting the antibodies they produce to fight it, and then packaging those antibodies for injection into humans. It works well, but it is fairly snake-specific. The bitten person must know what bit him and get to the hospital, where the antivenom must be kept refrigerated. The right serum must be on hand, as well as personnel who know how to administer it and how to monitor the sometimes deadly side effects. But, on the plus side, the technology to produce antivenoms exists already.
More general than antivenoms and less explored, antidotes (sometimes called biotherapeutics) are small molecules that treat the symptoms of snakebite—the paralysis itself, for instance, rather than the specific poison that caused it. That’s how neostigmine works. Most antidotes don’t need to be refrigerated, but these, too, usually require professionals to inject a victim. And while antivenoms will help reverse most if not all the symptoms of snake venom, a given antidote usually works on just one symptom. In the case of neostigmine, that’s paralysis.
Snakes bite about 5 million people per year, and 2 million people end up with venom in their bloodstream. Of these, hundreds of thousands are injured, and between 94,000 and 125,000 die. For the most part, these “envenomations” happen in poor, remote areas. It’s often hard for victims to reach a hospital, let alone get to one quickly.
Based on his reading, Lewin included injectable neostigmine—a standard treatment recommended by the World Health Organization—in the explorers’ snakebite kits, but he wanted to do better. He soon became obsessed with the idea of creating an inexpensive, foolproof, snake-agnostic antidote. He continued to work with neostigmine, came up with the idea of nasal spray, and tried to get development money. But potential funders didn’t think his plans felt solid enough.
Lewin was flailing at that time, dissatisfied with his life personally and professionally. A friend dragged him to a house party in Marin County, California, just across the Golden Gate Bridge from San Francisco, where people like George Lucas live. Lewin made himself a wallflower. But the wall of this house was more interesting than most. Stuck to it was a newspaper clipping with the headline “Jerry Harrison Makes People’s Visions Happen.” Harrison is a founding member of the Talking Heads and now a music producer, and a friend of the party’s hosts. As if in some kind of belief-straining movie orchestration, Harrison happened to be at the party, and Lewin heard him ask, “Does anybody have any crazy ideas that are lying fallow?”
Lewin blurted out, “Nasal spray for snakebite!”
Harrison was intrigued. He hooked Lewin up with a patent lawyer and has been involved with the project planning ever since. His enthusiasm gave Lewin a boost, and Lewin plunged into the work. But Harrison didn’t provide funding, and no one else wanted to invest the big money necessary for biomedical research and development. Without it, Lewin couldn’t run the trials necessary to test the new antidote formulation. He felt frustrated that his vision for a world safe from venomous snakes had stalled. He describes his mindset as “very nihilistic.”
Then one day, Lewin was driving across the Golden Gate Bridge (a historically bad place to be when in a nihilistic state of mind) with anesthesiologist Philip Bickler. Lewin lamented the lack of money for proper studies. He couldn’t just hide behind a bush, wait for someone to be bitten by a snake, and then spring out and stick his concoction up the poor guy’s nose.
Bickler, the cables of the bridge whizzing past his window, said, “We could just paralyze you.”
Lewin didn’t say yes right away. But he did say yes.
* * *
They worked for six months to get approval for their experiment from the Committee on Human Research at the University of California–San Francisco (UCSF), where Bickler works. “We never mentioned the word snake or the word paralysis in the application,” says Lewin. “We said nasal spray and muscle relaxation” (which the committee understood as code words). They used as precedent two studies from UCSF anesthesiologists John Feiner and Tim Heier, who had previously paralyzed people with mivacurium to find out how residual muscle relaxation affects patients’ breathing after they leave the operating room. It was the procedure Bickler was thinking of when he brought up the idea, and the procedure they later followed.
And that is how, in April 2013, Lewin came to be on the anesthesiology table, unable to move or speak or breathe or do anything but exist and hope that his antidote would be the thing to save his life, and the lives of others around the world.
Later that month, Lewin gave a talk to the American Physician Scientists Association in Chicago. He hadn’t planned to talk about the nasal spray, but he gushed about it anyway. This yanked awake a young scientist named Stephen Samuel, who worked at Trinity College Dublin and was fighting jetlag. Samuel had grown up in India and knew the magnitude of the snakebite problem. He caught Lewin after his lecture to talk about a collaboration.
With just a few emails to their relationship history, Samuel became totally committed to the project, like a novice Internet-dater. In what Lewin calls a “clinical leap of faith,” Samuel traveled to India to prepare the stage. He spent two months working with hospitals in Krishnagiri to figure out how to do a clinical trial in this real-world setting, on real people with real snakebites who staggered into real emergency rooms. They hope to eventually use what they learned in a trial of an antidote.
While Samuel was there, Lewin traveled to India to meet him and do a mouse study. Typically, researchers would drug mice long before they drugged a human. If a treatment works in mice, it might work in humans. Smiling, Lewin says of their backward method, “The fact that it worked in me suggested it would work in mice.”
Photo by Tom Brakefield/iStock.
In the mouse trial, the rodents received actual Naja naja venom, from the mouths of cobras. Then scientists shot atomized neostigmine up their tiny, twitching noses. It saved 67 percent of the mice that had received 2.5 times the lethal dose of venom. The rodents who received 5 times the lethal dose survived 196 minutes compared to 45 minutes in untreated mice, and those that got 10 times the fatal dose lived 175, as opposed to 30, minutes. It wasn’t a panacea, but it was a start. With these initial successes, Lewin’s ambition grew.
* * *
Neostigmine probably only works against snakes that paralyze their victims like cobras do, although no one has funded a proper study on even that since the 1970s. What if a kind of snake that kills in a different way—like a krait—bites you? And, as David John Williams of the University of Melbourne and the CEO of the Global Snakebite Initiative points out, “snakes very rarely have venoms that contain only one type of toxin.” Their fangs deliver cocktails of deadly components. An antidote like neostigmine helps against a major one and buys the victim time, but it’s not going to help every snakebite victim. Williams says that Lewin’s nasal-spray neostigmine could save the lives of people bitten by snakes whose venom it works against and “should be promoted specifically for species that meet this definition,” after full clinical trials, but it’s not universal.
Courtesy Matt Lewin
Lewin steered his next project toward finding a more widely applicable treatment. Now he thinks he’s found a biochemical pathway that many venoms’ deadliest effects have in common. More importantly, he also claims he’s found a way to shut that pathway down.
When I met him in November at his medical practice—in a Marin office building that also houses a law firm and a beauty salon—the weather was uncharacteristically rainy. He showed up on a bicycle, his cargo shorts drenched. He unlocked his office door, slipped his soaking shoes off, and set them by the furnace. Soon after he sat down, a FedEx deliverer arrived with a round Styrofoam container.
“Flu vaccines! Do you want a flu vaccine?” he asked me, and then told me that journalists aren’t allowed to accept gifts and ferried the container to a back room. He glanced at the print that hangs behind his office chair: A fire blooms from the painting’s upper right edge; a rabbit, an armadillo, a rat, a turtle, and a snake all huddle together at the lower left.
“What’s a snake’s objective?” he asked, then paused for just long enough that I wondered if I was mistaken in thinking he would answer his own question. “To eat,” he continued. “How is it going to eat when it can’t chew and has no legs?”
While any given venom has hundreds of components, only three or four of them are usually responsible for quickly killing the victim. (Some of the others are digestive agents, which eat away at the victim from within to make it easier for the snake to digest, but they work more slowly than the other killers.) The paralyzing agents work fast. These keep victims from running away and also stop their breathing. Many venoms’ enzymes also affect the body’s ability to regulate bleeding and clotting, and they work fast, too. The same mechanisms that clog crucial blood vessels and the kidneys can also cause uncontrollable bleeding elsewhere in the body. “This [is] why you can die of complications of clotting while bleeding out your gums, bladder, and brain,” says Lewin. Combatting venoms that kill this way won’t be as “simple” as fighting those that kill by paralysis, says Robert Norris, a professor of emergency medicine at Stanford University in Palo Alto, California. “That will be an even tougher nut to crack, as the toxins of those snakes are very complex,” he says.
Lewin thinks he has found a common biochemical cause of paralysis and bleeding: He believes enzymes in a family called phospholipase A2 (PLA2), which cause paralysis, interact with proteins called Factors V and X, which help regulate blood clotting. He compiled a list of thousands of medical compounds that are either FDA-approved or have been tested by others but didn’t work well for their original purpose. Maybe, he thought, one of them could block PLA2.
He thinks he has found one that can. He just filed the patent application to lock down the snake-specific use and the therapeutic composition. The research is still in its early stages: It hasn’t yet been peer reviewed or published, and the recipe remains secret. But he says experiments in test tubes and with mice and rats seem to bear it out.
Lewin is, quite rightly, suspicious of his own potential biases. “All the experiments were done by me, a person who has a lot at stake,” he says. “And the experiments all seem to work.” For a year during development, he woke up spontaneously at 3:28 a.m. every day with the bolt-upright fear that he had screwed something up, unwittingly pushed the data in the direction he wanted. Am I being a little nicer, playing soft music to the mice I want to live? he wondered.
His father, a chemist, has long lectured Lewin about reproducibility, and Lewin’s body never cleared itself of the warnings. “Your experiments don’t mean anything,” his father has always told him. “It only matters when somebody else can do it.”
And so Lewin sent the protocol to outside labs for replication. The test-tube data came back—with better results. And the week before we spoke, outsiders had reproduced the animal results, too.
“One hundred percent survival over 24 hours,” Lewin says, grinning, describing the outcome of the limited test. He says his perpetually doubtful father smiled, too, “for the first time in this entire torture.”
Williams, of the Global Snakebite Initiative, still has doubts. If Lewin is right about PLA2 enzymes being a common cause of clotting and bleeding, Williams wonders how Lewin will be able to block the enzymes in snake venom without interfering with the chemically similar PLA2 enzymes the human body uses for its normal functions. “Notwithstanding this, the inhibition of venom PLA2 activity is an area in which a number of researchers have been active,” Williams says, so Lewin isn’t alone in thinking this is a good path to pursue. Time, and tests, will tell.
Lewin has started a company called Ophirex—ophi- meaning snake, and -rex meaning king—to develop and distribute the drug after clinical trials. While he says he began the project as a purely philanthropic venture, his seed investors would like to make some profit (presumably that money won’t hurt Lewin, either). His company has trademarked the word Unidote, meaning an antidote with one ingredient.
The drug has many more obstacles to overcome before it can be proven, approved for human use, and distributed to the remote areas where people are most at risk of snakebite. And while this antidote is a step closer to a universal solution it, like neostigmine, is a cure-some and not a cure-all.
“This is a field of research that is going to take many years, many millions of dollars in funding, and a great many false starts and dead ends, before it yields a therapeutic agent with sufficient potential to be put through as a candidate drug,” says Williams. But he is hopeful that within his lifetime, we will have a suite of options that, in combination, can combat snakebites around the world.
Courtesy Matt Lewin
Lewin, too, is optimistic. He envisions a world where people don’t have to be afraid of what slithers through the grass, and where if they don’t watch where they step, they don’t have to die.
