Usha Lee McFarling , 2025-05-02 15:00:00
Theirs is an unusual scientific collaboration, to say the least. Jacob Glanville is an immunologist, who worked for the pharma giant Pfizer before striking out to found startups focused on developing therapies that protect against things like coronaviruses, malaria, HIV, and, more recently, snakebites. Tim Friede is a truck mechanic and snake enthusiast from Wisconsin. Between 2001 and 2018, he was bitten 856 times by the world’s deadliest snakes: black mambas, water cobras, and kraits.
On purpose.
He allowed himself to be bitten, and other times injected himself with snake venom, to build up immunity so he’d be protected if he was ever accidentally bitten by one of his many pets. (Warning: Don’t do this at home. Friede has come close to death several times.)
Friede wondered if his blood — with all those antibodies to snake venom coursing through it — might be useful. He hoped a scientist would call. One day in 2017, Glanville did. While musing about venom, he’d come across a YouTube video of Friede’s exploits and called.
“His reaction was, ‘I’ve been waiting for this call for a long time,’” said Glanville. That started a partnership between Glanville’s startup Centivax and Friede. In 2017, Centivax collected 40 milliliters of Friede’s blood, and eight years later, it led to a breakthrough, reported Friday in Cell, in the long and frustrating search for a universal antivenom.
The need for better antivenoms is critical. Snakebite envenoming is considered a neglected tropical disease by the World Health Organization; some 100,000 people die from bites each year, largely in the developing world, while up to 400,000 suffer amputations or permanent disability. Many bites are treated with antivenom collected from horses that have been exposed to snakebites, but that treatment carries the risk of serious side effects, including anaphylaxis.
Yet in recent years, major pharmaceutical companies have stopped pursuing new therapies or even continuing to sell proven ones, seeing little chance for a financial return. A universal antivenom could be more attractive to investors and big pharma; it could be stocked at clinics worldwide as a single product in a market that’s currently fractured because different snakes and regions require different and unique antivenoms.
The quest for a universal antivenom has increasingly attracted some of the world’s top scientists — using the newest technologies. Earlier this year, nobelist David Baker’s group at the University of Washington published a paper in Nature demonstrating how machine learning might help design venom-neutralizing proteins. The work being reported Friday is a collaboration between Glanville and Peter Kwong, a structural biologist who heads the Aaron Diamond AIDS Research Center and helped develop GSK’s RSV vaccine, Arexvy. (The two met, Kwong said, at a Gates Foundation dinner; both had received grants to work on universal flu vaccines.)
Glanville and Kwong teamed up to create a library of the 2 billion antibodies coursing through Friede’s blood. The advantage these had over designed proteins was something called affinity matching — the fact that antibodies get better and better at binding to and neutralizing their targets. Every time Friede suffered a snakebite — repeated envenoming is necessary to keep immunity up — his antibodies honed in more precisely on the toxins in venom.
The challenge? Snake venoms are complex mixtures of toxins, cocktails in themselves — and differ among snakes. (More than 80 of the world’s 650 venomous snakes are considered deadly enough to be medically relevant.)
The team quickly found an antibody that could provide protection against a broad range of what are known as long-chain neurotoxins found in numerous snake venoms. This protected lab mice from dying after being exposed to the venoms of six snake species. But when the team submitted this result to Cell, they were challenged by an editor to do more, and try to come up with a broader cocktail of antibodies that might work even better.
“I said Jake, you have a company, your whole purpose is to get something that works. Let’s take this challenge,” Kwong said. “Let’s see what it will take to actually make a broader antivenom.”
When the team added a second antibody that worked broadly against smaller short-chain neurotoxins, the mice were protected against the venom of nine species.
The final improvement came by adding a synthetic small molecule called varespladib, a one-time candidate for a heart disease treatment known to work as an antivenom because it inhibits phospholipase A2, one component of venom toxicity. The three-component cocktail worked against the venom of 19 snakes from the elapid family, considered the world’s most dangerous. “To actually make something that could be working, that was super exciting,” said Kwong.
“We found one that hits cobra, then a subset that hits black mamba, then a subset that also hits krait,” Glanville said. “How do we build a cocktail? That’s the beating heart of the paper. It’s not just that we have a cocktail — we built a method of the iterative, cyclical deconstruction of venom.”
What they succeeded in doing is creating a cocktail that protects against multiple venoms without including antibodies for each. Key was a finding, detected using X-ray crystallography, that many of the antibodies work on the same receptor of various toxins — the place where the toxins bind to cells, “like a docking port on a spaceship,” said Glanville. “There are always these little Achilles heels on these very diverse proteins and rapidly mutating pathogens,” he said. “They always have some little spot that they can’t change or they can’t do their job anymore.”
While there are 650 species of venomous snakes, “nature’s lazy, there’s only really 10 toxin classes,” he said.
“This is very promising,” said José Maria Guitierrez, a leading antivenom researcher who is now a professor emeritus at the Instituto Clodomiro Picado at the University of Costa Rica. “It’s an amazing piece of work.” He said he liked the iterative approach the team took of trying one antibody at a time to come up with a powerful cocktail and said the X-ray crystallography results showing different antibodies bound to the same region was an elegant addition to the paper.
One concern Guitierrez has is that the price of the new treatment, once developed, could be high. “Will this be available in the countries where snakebites occur?” he asked. “If the price is too high, it won’t be useful in Asia and Africa.”
Most researchers said the paper did not raise ethical concerns because Friede had voluntarily envenomed himself before he was contacted by researchers and because he no longer needs to do so. Glanville said his startup would share any profits generated from an antivenom with Friede.
Another leading antivenom researcher, Andreas Hougaard Laustsen-Kiel, a professor at the Technical University of Denmark who studies antibody technologies, called the study “solid work” and “a great proof of principle” but cautioned, as the authors do, that it will be some time before the work would result in a commercial universal antivenom. There are many challenges to be able to manufacture such cocktails inexpensively, and finding targets for other toxin families is likely to prove more difficult. “It’s not a walk in the park,” he said, based on his own research experiences.
Any new products, he added, need to focus not only on lethality but also on the horrific damage snakebites can cause, including necrosis, the disruption of blood clotting, and pain.
And of course, the therapy needs to be tested in people, not just in mice. The use of human antibodies as treatment is considered quite safe, much more so than using antibodies grown in animals. For now, Glanville is planning to partner with veterinarians in Australia who are looking for better antivenoms for dogs. Snakebites can take time to kill a dog, usually through respiratory paralysis, so the plan is to try the new cocktail first, and if it doesn’t work, then administer the standard antivenom treatment to dog patients, he said.
There’s also the fact that the new cocktail works on only one family of snakes, and has not been tested on viperids, the family that includes the snake thought to kill the most people annually, the saw-snake viper found in the Middle East and central Asia.
Viperids are next, said Glanville. With the bites he’s received from snakes such as rattlesnakes, Friede’s blood likely has antibodies that can neutralize those venoms too.
