A Man Who Survived Hundreds of Snakebites Helped Scientists Develop a Potent Antivenom

Growing up in a remote village nestled in the Guatemalan highlands, computational immune-engineer Jacob Glanville frequently heard of snakebite incidents in the area. With the nearest medical center being hours away, locals could not access life-saving medicines. As an adult, Glanville realized that the problem was widespread beyond his own village.

The Global Challenge of Snakebite Envenoming & Antivenom Innovation

Snakebite envenoming affects almost two million people globally each year and kills almost 100,000 people. Conventionally-used antivenoms employ animal-derived antibodies which can trigger serious allergic reactions and may not efficiently target diverse snake venom toxins.¹

This motivated Glanville to start Centivax, a biotechnology company which, among other things, focuses on developing universal snakebite treatments.

“Antivenom had always fascinated me,” said Glanville. He wondered whether antibodies built up in somebody who had survived snakebites could neutralize some snake toxins. In his quest to identify such people, he serendipitously found an ideal donor.

Now, using antibodies from the serum of a man with a unique snakebite history, Glanville and his team have developed a potent antivenom against toxins from some of the world’s deadliest snakes.² Their results, published in Cell, pave the way toward a universal antiserum that may offer protection against diverse snake venom toxins.

“The study is very well-executed and planned, and they have got some really nice antibodies,” said Kartik Sunagar, a venom researcher at the Indian Institute of Science, who was not involved in the study.

Timothy Friede's Unprecedented Self-Immunization Against Snake Venom

For their study, Glanville and his team contacted Timothy Friede, a truck mechanic, who had been undertaking an unusual side-project since 2000. As an amateur snake collector constantly at risk of envenomation, Friede, now a herpetologist at Centivax, started milking his snakes for their venom and repeatedly injecting himself with it, hoping to develop immunity.

A few months after Friede began his experiment, he suffered accidental back-to-back cobra bites—he spent four days in a coma. “That was a big mistake,” he admitted. After his near-death experience, Friede continued his experiments with a renewed purpose: He wanted to help other snakebite victims. Over the next 17 years, he endured the bites of his snakes, including taipans, mambas, and cobras over 200 times, and injected about additional 500 doses with a syringe. “[Snakebites] are very painful; like a bee sting times a thousand,” said Friede.

Once he had built sufficient tolerance, Friede attempted contacting scientists, although unsuccessfully. Glanville found out about Friede’s dangerous snakebite experiments in 2017 and got in touch with him to request a blood sample. “And his answer to that was, ‘I’ve been waiting for this call for a long time,’” recalled Glanville.

Unlocking Potent Antivenom: The Scientific Breakthrough

Equipped with Friede’s presumably hyperimmune blood, the researchers embarked on their first experiments. “We wanted to start someplace, so [we thought] why don’t we start with the ones that are most prevalent?” said Peter Kwong, a structural biologist at Columbia University and study coauthor.

The team focused on venoms from 19 of the world’s deadliest snakes belonging to the elapid family, which contains roughly half of all venomous species including mambas, cobras, taipans, and kraits.

The researchers extracted DNA that encoded antibodies from Friede's immune cells. Using phage display to insert these genes into phages, they generated a library of about two billion antibodies. Incubating this library with venom toxins helped them isolate the antibodies that specifically bound to the toxins.

These antibodies bound their respective toxins with a high affinity. When the researchers studied the crystal structures of the antibody-toxin complexes, they observed that the antibody blocked a site on the toxin that engages with target neuronal receptors in hosts. This site is conserved among other snake neurotoxins, suggesting that the antibody could broadly neutralize neurotoxins from other snake species.

“That, for me, was a very exciting moment,” said Glanville. “A universal antivenom is now tractable, within reach, and we have the tool, and we just need to keep turning the crank to find it.”

Promising Antivenom Efficacy: In Vivo Study Results

Glanville and his team next studied the effects of the antibodies in vivo. They injected the venoms of one of six snakes of black mamba or cobra species into mice and treated the animals with the antibodies. While all untreated mice died within a few hours, most of the mice that received the antibody against the long-chain neurotoxin survived.

To strengthen the antivenom further, the researchers treated envenomed mice with an antibody against short-chain neurotoxins and the small molecule varespladib, which counteracts enzyme toxins found in some snake venoms.³ A cocktail of the two antibodies and varespladib offered total protection against 13 of the 19 tested venoms, with all the mice surviving envenomation. It protected the mice partially against the remaining six venoms by extending their survival for a few hours.

“Once [the mice] started living, that was really exciting,” said Kwong. “I was like ‘Oh my god, we actually have something that could actually work,’” he recalled.

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The Future Landscape of Universal Snake Venom Antidotes

“The findings add to the repertoire of monoclonal antibodies against snake venoms that are already there,” said Sunagar. While the findings are promising, he noted that the next step is to take these into clinical trials.

Glanville noted that the in vivo model, where mice were administered a controlled dose of venom, has some limitations. “In the wild, you don't get a controlled dose,” he said. The researchers next aim to study the effect of their antivenom cocktail in larger animals.

Friede has stopped self-immunizing since 2018 once he had donated blood for studies. “In the future, I might do it just for me personally,” he said. “Because I enjoy knowing that when I inject myself with some venom, that somebody's going to be saved because of it.”

However, Sunagar expressed concerns about the approach of self-immunizing against snake venoms. “It's dangerous,” he cautioned. “It carries a lot of risk to life.”