Researchers at the University of Maryland have identified a promising new way to treat venomous snake bites by taking advantage of the snakes’ own natural defenses. Their approach uses toxin-blocking proteins that Western rattlesnakes evolved to protect themselves from venom.
By combining specific proteins found in the blood of rattlesnakes, the researchers achieved unusually strong protection against the venom of several dangerous snake species.
The study was led by distinguished university professor of biology Sean B. Carroll and published in the Proceedings of the National Academy of Sciences. The findings could help researchers develop more powerful antidotes for deadly snakebites, which remain a major health threat in some regions of the world.
“This is one of those great stories where nature has already solved a problem we’ve been dealing with for decades,” said Carroll, who also holds the Andrew and Mary Balo and Nicholas and Susan Simon Chair at UMD.
The global snakebite challenge
Snakebite is considered one of the most neglected tropical diseases in the world. According to the World Health Organization, venomous snakes kill between 80,000 and 140,000 people a year, while hundreds of thousands of survivors are left with permanent disabilities. Many of those affected live in rural areas where it can be difficult to obtain an effective antidote.
Existing antidotes save lives, but they also have significant drawbacks. They are usually produced by exposing large animals to snake venom and then collecting the antibodies those animals generate. These treatments can be expensive to manufacture, their quality and effectiveness may vary, and they may not work equally well against the different toxins found in the venom of different species of snakes. They can also cause serious immune reactions.
Those limitations have pushed scientists to look for better options. In this case, researchers turned to the snakes themselves for clues.
“We’ve known anecdotally for 100 years that vipers tend to be resistant to their own venom,” Carroll said. “But for a long time no one knew exactly what was circulating in their blood and what protected them.”
A natural defense hidden in a rattlesnake’s blood
In 2022, Carroll’s lab found part of the answer: a protein called FETUA-3. The researchers found that it could block the activity of many metalloproteinase toxins found in western rattlesnake venom. It could also bind to and inhibit toxins from the venoms of several other rattlesnake species.
“This was evolution’s way of snakes protecting themselves from accidental self-poisoning,” he said, prompting a follow-up question. “Why trust horse antibodies when nature has prepared an effective antidote right there in the snake?”
For the new research, co-authors, including Elda Sánchez, director of the National Natural Toxin Research Center at Texas A&M University-Kingsville, examined what each FETUA protein contributes to poison resistance.
The team found that individual proteins could counteract certain effects of the venom. One could reduce bleeding, for example, while another could interfere with enzyme activity. However, none of the FETUA proteins alone were able to completely prevent death from venomous bite.
Protein combinations dramatically increase protection
The results changed when the researchers combined several FETUA proteins. These mixtures were much more effective at blocking the harmful effects of the venom than the individual proteins alone.
Finding the best combinations is difficult because snake venom is extraordinarily complex. A single venom can contain around 100 toxin proteins belonging to multiple protein families, and the composition of the venom differs from one species of snake to another.
“The ingredients are there,” Carroll said. “We just have to keep trying various mixes.”
In laboratory experiments, the optimized protein combinations were approximately 10 times more potent than the current sheep-derived rattlesnake antivenom. The mixtures completely neutralized the lethal effects of rattlesnake venom and also provided broad protection against the venom of multiple species of vipers, including species separated by millions of years of evolution.
“The fact that parts of these inhibitors have been perfectly conserved over 50 million years of snake evolution indicates how real the risk is to these animals,” Carroll said, noting that how snakes become poisoned is not well understood, whether through oral tissue during a bite, by eating poisoned prey, through cannibalism or all of the above.
Towards a new generation of antivenoms
The present study focused on metalloproteinases, an important family of poisonous toxins. Researchers are now using the same general strategy to target other families of toxins.
“We are getting remarkably close to having effective solutions for the three major families of toxins in snakes,” Carroll said. “What we have learned here, together with the research we are doing now, gives us real confidence that nature-based recombinant technology [lab-produced] “The antidotes are within our reach.”
Carroll hopes that the first commercial applications of “nature’s antivenom” may be in veterinary medicine, with treatments for human snake bites later to follow.
He envisions future antidotes that protect against a broader range of poisons while being safer, less expensive and easier to manufacture on a large scale than many current treatments.
“We could make train cars out of this material and help solve a huge global health problem,” Carroll said. “Many of our most important medicines come from nature. I’m delighted that the components of a better-than-commercial antivenin were in these snakes from the beginning.”
Along with Carroll, UMD co-authors included Department of Biology visiting specialists Fiona Ukken and Yetunde Ayinuola.
The research was funded by the Howard Hughes Medical Institute and the Viper Resource Center (Grant #P40OD01960-22). This article does not necessarily reflect the views of these organizations.