In 2001, after working up to it for years, Tim Friede finally allowed himself to be bitten by a snake.
He started with venomous cobras because they're dangerous — and because they're what he had on hand at the time.
"My first couple bites were really crazy," he says. "It's like a bee sting times a thousand. I mean, you can have levels of anxiety that goes through the roof."
Friede has been fascinated with snakes for as long as he can remember. He used to hunt garter snakes growing up in Wisconsin.
As an adult, his obsession turned to venomous snakes — and the harm they cause people globally. He felt the most dramatic way to raise awareness of the issue was to allow himself to be bit, repeatedly.
He admits it's been "a rocky road," however. Right out of the gate, he says, "I was put in ICU after two cobra bites and I dropped in a coma for four days."
Friede recovered and with time, became more careful. To date, he estimates he's willingly been bit some 200 times by all manner of venomous snakes — black mambas, taipans, cobras, kraits and many others.
These snakes may be dangerous but he's often found them easier to understand than people. The relationship is clear. "They want to kill me," he says. "I want to survive."
Friede's motivation evolved to see if he could develop immunity to this swirl of toxins — so that his body might provide a roadmap to making a broad kind of antivenom.
Now, in a new paper in the journal Cell, researchers say they've done just that, thanks in large part to the antibodies that Friede has developed over nearly a quarter century of self-envenomation.
Venomous snakes are a global health problem
Every year, venomous snake bites kill tens of thousands of people globally and permanently disable several hundred thousand more, according to the World Health Organization (WHO). "So they might lose a limb, they might lose function in a limb, they might end up having to have huge surgeries, skin grafts, that kind of thing," says Stuart Ainsworth, a molecular biologist at the University of Liverpool who studies snake bites, antivenoms and the role that antibodies can play in helping create more powerful antidotes.
This is a particular problem in low- and middle-income countries and also countries in the tropics. These places "have huge snake bite burdens," says Ainsworth.
Specific health risks vary depending on the region of the world and the kinds of snakes found there. For example, in Papua New Guinea, most of the snakes produce neurotoxic venom. David Williams, a scientist who evaluates antivenoms for WHO, says the biggest risk to people who are bitten by these snakes is paralysis, "which can prevent them from being able to control their airway and breathing and they can potentially suffocate and die as a result of that."
Other venoms can affect the blood and cause it either to fail to clot or to form clots too readily, "which can lead to basically the patient stroking out or having a clot lodge in the vessels of the heart and cause a heart attack," says Williams. Some venoms cause intense pain while others cause no pain at all.
Such diversity in venom form and function is a big reason why the creation of a broad universal antivenom has been such a challenge.
A new approach
For decades, antivenoms have come from the antibodies generated by animals like horses that have been injected repeatedly with small amounts of venoms, says Williams. Their manufacture has improved substantially but Jacob Glanville, CEO of the biotech company Centivax, wondered about a different approach.
Some years back, after working on the problem of developing a universal flu vaccine, he began thinking about how to create a universal antivenom that could defang the venom of all venomous snakes. Glanville wanted to find a shared molecular site across multiple venom toxins from different snake species that he could target.
Rather than using a horse, Glanville figured that a person who'd been repeatedly exposed to lots of different venoms might have human antibodies that could target such a site to interfere with the toxins.
"I was calling vivariums hoping for a clumsy snake researcher," he says, but he was coming up empty-handed.
And then he found Tim Friede.
Friede remembers Glanville saying to him: "You're the guy I'm looking for. We need your blood. We need your antibodies." And Friede accepted.
"If anybody has broken through the problem of getting the immune system to focus," says Glanville, "it's this guy, by this repeated stimulation with all these snakes."
Once Friede agreed to participate, Glanville scanned his blood for its immune memory. He searched the troves of antibodies for those that netralized the neurotoxins of multiple snakes.
"And we found the ultra-broad antibody that had this very remarkable ability to go bind right on the conserved site that the neurotoxin uses to cause paralysis," says Glanville.
The antibody provided mice with full protection against five snakes — the black mamba and a mix of cobras. So Glanville and his colleagues wrote the journal Cell to gauge their interest in publishing the research.
"A really smart editor said, 'Look, antibodies are wonderful, but I think we could actually go further,'" recalls Peter Kwong, a structural biologist at Columbia University and one of the researchers. "And she proposed something like a working cocktail," one that would take on even more snakes. The team agreed it was worth a try.
They added a small molecule called varespladib that had already been shown to work against some venoms. "And some additional species were suddenly covered, some completely and some partially," says Glanville.
The team also went back to Friede's blood and found a second broad-acting antibody. "And so we added that in and that's when we suddenly saw this coherent protection that was happening across this large panel," Glanville says.
This cocktail of three components offered mice complete protection against 13 species and partial protection against six more — representing a set of genetically diverse venomous snakes from Asia, Africa, Australia, North America, and more.
There are other antivenoms that can neutralize a broad set of snakes, says Ainsworth, who's not involved in the study, but this is the first to do so using synthetic antibodies.
Slithering forward
"It's definitely a step in the right direction because it's answering some of the questions we have about how to properly design universal antibodies," says the WHO's Williams, who wasn't involved in the research.
But he cautions that further developing this cocktail into a truly universal antivenom will inevitably have its challenges, including doing human trials and expanding its coverage to vipers, which make up about half of the venomous snakes.
Ainsworth agrees that the findings are solid, though he's eager to see how the antivenom works in people, especially given that venoms are complex chemical formulations. "There are lots of different components in venoms," he says. "This, you're only neutralizing two components. We don't know if we just neutralize the key components in the venom, what will the other toxins do? This is why it's very important to do clinical trials."
The team at Centivax says their next steps include testing the new cocktail in dogs that have been bit by venomous snakes in Australia. And as they continue to develop their antivenom for an even wider array of snakes, they plan to incorporate vipers as well.
Glanville hopes to get philanthropists or foundations to help pay for the clinical studies and manufacture in order to make the resulting antivenom affordable globally. He estimates there's a market of $600 million per year, but it's currently split across a few dozen antivenoms. A single antivenom would allow Centivax to own most of the market.
For Tim Friede, who's now the director of herpetology at Centivax, it's about helping the people impacted by venomous snakebites worldwide. When he heard that his antibodies had helped create this new antivenom cocktail, he says he was happy.
"I couldn't believe it. I really couldn't believe it," he says. "I know I'm doing something for humanity and giving back to science."
Upon Glanville's recommendation, it has been several years since Friede last allowed himself to be bitten by a venomous snake. But he admits to missing it, mostly in terms of "just knowing where you can take your mind," he says.
"To know you can beat that and keep your calm and keep your cool, it's a wonderful thing."
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