Snake Collector Let Himself Get Bitten So Many Times, He’s Inspired An Antivenom Previously Thought Impossible

Approximately 100,000 people die each year from snakebites, and many that survive lose limbs or suffer other permanent injuries. Antivenoms could prevent most of this rolling tragedy, but they don’t exist against many of the more than 600 relevant species because the cost of development and production is large, and most victims are too poor to pay much. 

Using current techniques, the antivenom against each snake species (and sometimes different varieties of the same species) needs to be developed separately and put through clinical trials. Medical clinics also need to keep antivenoms against every snake in the area in stock, which is a heavy cost for small clinics, but one team think they’re on the verge of changing that.

The team produced a single antivenom that provided mice with full protection against 13 species of Elapidae snakes, many of them only distantly related to each other. There was also partial protection against the six other species they tried. The authors are confident they are within reach of offering protection against all snakes that use neurotoxic venom alone. That’s about half the world’s venomous species, including everything from cobras to taipans, black mambas, and some sea snakes.

As astonishing and world-changing as it would be to have a single effective antivenom that could be kept everywhere refrigeration exists, the path to this point is possibly more amazing.

The power of one

Tim Friede likes snakes and handles them a lot as a collector. Aware that this carried a risk of being bitten, he took a leaf out of the book of Mithridates VI (or possibly the Dread Pirate Roberts), who legend tells slowly developed immunity against many poisons by training his body with steadily larger doses.

Friede would give himself 24 injections over four months before he was ready to take the venom straight from the snake’s mouth. “You have to start with small dilutions and build your way up to pure venom,” he told IFLScience in 2023. “But in that four-month range, if you can hit pure venom, you’re gonna be crazy immune. And then you can just do maintenance doses.”

Dr Jacob Glanville of Centivax, first author on the paper describing the antivenom, wants to make sure no one takes Friede’s “you” literally. “No one should attempt to copy Tim,” he told IFLScience. “To state the obvious: snake venom is dangerous to humans.”

[Tim] did something remarkable, but now that it has been done, there is no need for anyone to run his once-in-history experiment again.

Dr Jacob Glanville

Friede developed hyperimmunity, as he has demonstrated on his Youtube channel by having some of the world’s most venomous snakes bite him live on camera. Although Friede has now backed off this behavior, and some of his immunity will have waned, at the peak of his exposure his blood could have made an antivenom against many species. At one point, he previously told IFLScience, “I had more specific antibodies in my blood that are directed towards snake venom than most humans just have in their blood – period.” By the time he quit, Friede had immunized himself 654 times against 16 species, and let them bite him 202 times.

There would never have been enough of Friede’s blood to go round to make antivenoms for all, however, so a different path was required. Centivax discovered Friede around the time he retired from his self-experimentation; in collaboration with academic scientists they studied his antibodies in search of that path.

Making an antivenom

Each venomous snake has many toxins in its venom to make it hard for their prey, or predators, to evolve resistance. These venoms evolve faster than the bodies of the snakes themselves, so exist in dazzling variety. Using the antibodies Friede produced and the venoms themselves, Centivax identified certain common features, allowing one antibody, LNX-D09, to block the activity of many venoms. 

LNX-D09 alone provided mice with immunity against six of 19 species tried, Glanville and co-authors previously reported, but the team had bigger goals. Many elapid venoms include PLA2, which unlike most of the other toxins doesn’t require antibodies to stop – it can be inhibited with the small molecule varespladib. Combining LNX-D09 with varespladib was enough to give the mice protection against nine species with very different origins that Centivax tried.

That’s still a long way from universal, so Centivax went looking for another antibody in Friede’s blood and SNX-B03, and added this to LNX-D09 and varespladib.

“By the time we reached three components, we had a dramatically unparalleled breadth of full protection for 13 of the 19 species and then partial protection for the remaining that we looked at,” Glanville said in a statement. “We were looking down at our list and thought, ‘what’s that fourth agent’? And if we could neutralize that, do we get further protection?”

The 19 species were deliberately chosen because they are so distant from an evolutionary perspective. Most other Elapidae species are closely enough related to one of the 19 that protection is likely to extend there, although unusual prey can spur venom innovation, so plenty of testing is required to confirm this.

Medications that work in mice don’t always translate to humans, but the venoms act on pathways conserved among mammals, and antivenom research is one area where rodents make good models.

Needing just three to four molecules allows a much cleaner path to production than injecting a snake’s entire arsenal into a horse to produce antibodies against that species, often with many accompanying impurities that cause serious side effects.

“Monoclonal antibodies are a major class of drugs that have been developed over the biotechnology industry, with hundreds of drugs approved or in development,” Glanville told IFLScience. “They will be produced in large bioreactors.”

Not all snakes

All the snakes in this study produce neurotoxins, but vipers, among others, combine neurotoxins with venoms that work in other ways. “Viper venom causes a lot of tissue damage and coagulation, etc.,” Glanville told IFLScience. That means entirely different molecules will be required. The Viperidae include rattlesnakes and the small-scaled viper, probably the world’s most deadly snake by numbers. The team hope to produce a broad-spectrum antivenom for vipers as well, but Glanville admitted, “The research is not as developed as the elapid cocktail.”

The cost of getting an antivenom through clinical trials is enormous, and would be larger still when testing for multiple species is required, but the market for a broad-spectrum product is so much larger than for a single species finding investors should be possible. Keeping two antivenoms in stock, one against elapids and the other for vipers, should be within the capacity of even very small clinics, and some parts of the world only have one of the two.

Most snakes outside the Elapidae and Viperidae families are not venomous, at least to mammals, but a handful use quite different approaches, such as Africa’s boomslang, so even two snake antivenoms might not prove strictly universal.

Looking beyond snakes, Glanville told IFLScience, “This process could be applied to scorpions/spiders etc, but it would require a different cocktail, given the great evolutionary distance between the organisms.”

In case anyone fancies becoming the Tim Friede of arachnids, or to engage in scientific replication, Glanville has a clear message: Don’t. “He did something remarkable, but now that it has been done, there is no need for anyone to run his once-in-history experiment again,” he told IFLScience.

The study is published in Cell.