University of Maryland researchers have found a new way to fight snakebites by using the snakes’ own blood. The approach relies on toxin-blocking proteins that western diamondback rattlesnakes use to protect themselves from venom.
By combining specific proteins found in rattlesnake blood, the researchers achieved unusually strong protection against venom from several dangerous snake species. In laboratory tests, these mixtures were about 10 times more potent than a current commercial antivenom.
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 antivenoms for deadly snakebites, which remain a major health threat in some regions of the world.
“This is one of those great stories when nature has already solved a problem we’ve been grappling with for decades,” said Carroll, who also holds the Andrew and Mary Balo and Nicholas and Susan Simon Endowed Chair at UMD.
The Global Challenge of Snakebites
Snakebite is considered one of the world’s most neglected tropical diseases. According to the World Health Organization, venomous snakes kill an estimated 80,000 to 140,000 people annually, while hundreds of thousands of survivors are left with permanent disabilities.
Many of those affected live in rural areas where effective antivenom can be difficult to obtain.
Existing antivenoms save lives, but they also have major drawbacks. They are typically produced by exposing large animals to snake venom and then collecting the antibodies those animals generate.
Manufacturing these treatments can be costly, their quality and effectiveness can vary, and they may not work equally well against the many different toxins found in venom from different snake species. They can also cause serious immune reactions.
Those limitations have pushed scientists to search for better options. In this case, the researchers turned to snakes themselves for clues.
“We’ve known from anecdotes for 100 years that vipers tend to be resistant to their own venom,” Carroll said. “But for a long time, nobody knew what exactly was circulating in their blood that protected them.”
A Natural Defense Hidden in Rattlesnake Blood
In 2022, Carroll’s laboratory found part of the answer: a protein called FETUA-3. The researchers discovered that it could block the activity of many metalloproteinase toxins found in western diamondback rattlesnake venom. It could also bind to and inhibit toxins from the venoms of several other rattlesnake species.
“Here was evolution’s way for snakes to protect themselves from accidental self-envenomation,” he said, which prompted a follow-up question. “Why rely on horse antibodies when nature has packaged an effective antidote right there in the snake?”
For the new research, co-authors including Elda Sánchez, director of the National Natural Toxins Research Center at Texas A&M University-Kingsville, examined what each FETUA protein contributes to venom resistance.
The team found that individual proteins could counter certain effects of venom. One might reduce bleeding, for example, while another could interfere with enzyme activity. However, none of the FETUA proteins on its own was able to completely prevent death from a venomous bite.
Protein Combinations Dramatically Boost Protection
The results changed when researchers combined several FETUA proteins. These mixtures were far more effective at blocking the harmful effects of venom than the individual proteins alone.
Finding the best combinations is complicated because snake venom is extraordinarily complex. A single venom can contain around 100 toxin proteins belonging to multiple protein families, and venom composition differs from one snake species to another.
“The ingredients are there,” Carroll said. “We just have to keep testing various mixtures.”
In laboratory experiments, optimized combinations of the proteins were about 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 venom from multiple viper species, 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 tells you just how real a risk this is for these animals,” Carroll said. He noted that how snakes envenomate themselves — whether through mouth tissue during a bite, by eating envenomated prey, through cannibalism or all of the above — isn’t well understood.
Comparing the Two Approaches
The new approach differs sharply from the standard method used to make antivenoms today.
| Feature | Current Antivenom | New FETUA Protein Mixture |
|---|---|---|
| Source | Sheep-derived | Proteins from rattlesnake blood |
| Production method | Exposing large animals to venom, collecting antibodies | Combining naturally occurring toxin-blocking proteins |
| Potency in lab tests | Baseline | About 10 times more potent |
| Protection range | May not work equally well against toxins from different snake species | Broad protection across multiple viper species |
| Cost and consistency | Costly, variable quality | Not yet demonstrated |
The current system has been the standard for decades, but its limits are well documented. The new protein mixtures showed greater potency and broader protection in laboratory tests.
A New Generation of Antivenoms
The present study concentrated on metalloproteinases, one important family of venom toxins. The researchers are now using the same general strategy to target other toxin families.
“We’re getting remarkably close to having effective solutions for the three major toxin families in vipers,” Carroll said. “What we’ve learned here, together with research we’re doing now, gives us real confidence that nature-based recombinant [lab-produced] antivenoms are within reach.”
Carroll expects that the first commercial applications of “nature’s antivenom” could be in veterinary medicine, with treatments for human snakebites potentially following later.
He envisions future antivenoms that protect against a wider range of venoms while avoiding some of the problems of current treatments.
What the Researchers Found
The key discovery is that no single FETUA protein does the whole job. Each one handles a different part of the venom threat.
- One protein might reduce bleeding.
- Another could interfere with enzyme activity.
- None alone completely prevented death from a venomous bite.
- Combined, they neutralized lethal effects entirely.
That combination effect is what makes the finding significant. The mixture outperformed the current sheep-derived antivenom by a factor of about 10 in laboratory experiments.
The work also showed that these proteins have been stable in snakes for an extraordinarily long time. Parts of the inhibitors have been “perfectly conserved over 50 million years of snake evolution,” according to Carroll.
That conservation suggests the protection is essential to the snakes’ survival. It also means the underlying biology is ancient and proven.
The Road Ahead
The researchers are not stopping with metalloproteinases. They are applying the same strategy to other toxin families found in viper venom.
Viper venom contains three major toxin families, and Carroll says the team is close to having effective solutions for all three.
The first real-world use may not be for humans. Carroll expects veterinary medicine to be the first commercial application of “nature’s antivenom,” with human treatments potentially following later.
For human snakebite victims, the wait may be longer. But the direction is clear.
A Different Kind of Antidote
The standard antivenom process has known limits. It can be expensive, inconsistent and can trigger immune reactions.
The rattlesnake blood approach is different. It uses proteins that nature already refined over tens of millions of years.
Carroll’s lab found the first piece of the puzzle in 2022 with FETUA-3. Now the team has shown that combining multiple FETUA proteins produces a much stronger effect than any single one.
The finding is a reminder that some of the best medical solutions may already exist in nature. The snakes that produce these proteins have been protecting themselves from venom for millions of years.
The research team’s job now is to figure out the right mixtures and bring them to practical use.
“We’re getting remarkably close,” Carroll said.
The next steps will involve more testing and more combinations. But the laboratory results so far point toward a new generation of antivenoms that could be more powerful and more broadly protective than what exists today.
For the people in rural regions where snakebites kill tens of thousands each year, that progress cannot come soon enough.
Source: sciencedaily.com