Herpetologists first discovered in 1933 that rattlesnakes are immune to their own venom. Native to the Americas, rattlesnakes are pit vipers, a family of vipers with a heat-sensing pit organ between each nostril and eye.
Venom resistance in snakes comes in two forms: either the targets in their bodies have evolved such that the venom doesn’t attack them, like in cobras, or they possess specific molecules in their bloodstream that serve as “toxin sponges”, like in vipers, Sean B. Carroll, chair of biology at the University of Maryland, U.S., said.
In 1972, Japanese researchers discovered the first example of a so-called toxin sponge — a serum protein dubbed Fetuin-A — from Okinawa habu (Protobothrops flavoviridis), a pit viper endemic to the Ryukyu Islands. Fetuin-A could inhibit metalloproteinases, a class of venom toxins that could cause haemorrhage, damage tissue, and disrupt the coagulation system.
Metalloproteinases are the most abundant toxin family in rattlesnake venoms, and researchers have studied metalloproteinase inhibitors such as Fetuin-A in great detail. However, only recently did they discover that Fetuin-A belongs to a larger family of FETUA proteins.
In a 2022 paper, Dr. Carroll and his team identified four FETUA proteins from the western diamondback rattlesnake (Crotalus atrox).
Curiously, understanding the principles of venom resistance from C. atrox led the researchers to leverage these antitoxins, which had evolved over millions of years, for human benefit.
In a new study in Proceedings of the National Academy of Sciences, the team at Maryland has shown that specific combinations of C. atrox FETUA proteins can fully neutralise rattlesnake venom lethality in mice, with roughly 10-times the potency of commercial antivenom.
‘String of surprises’
On discovering metalloproteinase-inhibiting FETUA-2, 3, 4, and 5 proteins from C. atrox, the research team studied their antivenom potency. By injecting various protein combinations preincubated with C. atrox venom into experimental mice, they found that some combinations successfully blocked haemorrhaging, while some even staved off death.
“Rattlesnake venoms have 10-15 different kinds of toxins,” Dr. Carroll said. “So it was entirely unexpected that just blocking metalloproteinases would block the lethality of the venom.”
The test results that followed were a “string of surprises”. Encouraged by the success of FETUA proteins against C. atrox venom, the team tried them against the eastern diamondback rattlesnake (Crotalus adamanteus), which proved successful. Then they tested them against two Asian snakes: the Malayan pit viper (Calloselasma rhodostoma) and the Chinese moccasin (Deinagkistrodon acutus). The proteins could protect against those as well.
The team then moved to candidates outside of pit vipers. Of the two true vipers they tested against, the proteins protected significantly against the Sochurek’s saw-scaled viper (Echis carinatus sochureki) — but none against the puff adder (Bitis arietans).
“Our surprises ran out, you could say,” Dr. Carroll said.
According to him, an antivenom needs potency and broad reactivity. And not only could these proteins recognise and neutralise the venom of a spectrum of distant species, when tested against CroFab, a commercial antivenom obtained from animals immunised with four pit viper venoms, including C. atrox, the proteins proved tenfold more potent.
The findings are a “real advance” for antivenom development, according to Kartik Sunagar, an associate professor at the Indian Institute of Science, Bengaluru; he was not involved in the study. “The paper shows convincingly that a combination of naturally evolved FETUA proteins can fully neutralise rattlesnake venom lethality by inhibiting metalloproteinases alone.”
However, Dr. Sunagar also pointed out that the study did not exactly measure clinical capacity.
“Every efficacy experiment premixed venom and inhibitor before injection,” he said. “So the study measures neutralising capacity, not treatment of an animal already envenomed, which is the clinically relevant scenario.”
Next-generation antivenom
According to Dr. Carroll, unlike lab-made compounds, FETUA proteins have been tested in nature.
“Rattlesnakes have evolved these proteins for 50 million years, with remarkable specificity and potency to inhibit their own venom, which gives me the sense that it is worth exploring,” he said.
Manufacturability and purity are added advantages, he added: “We can make recombinant FETUA proteins in the lab in unlimited quantities — whereas traditional antivenom requires animals to be immunised, and then the obtained antibodies have to be purified.”
Dr. Sunagar also shared the view that the recombinant and defined nature of FETUA proteins will help sidestep the low purity of animal-derived products.
While the study showed that these proteins can protect experimental mice from venom lethality, toxins other than metalloproteinases will have physiological effects on humans, Dr Carroll said: “What we don’t know is what else we will have to use in conjunction with these proteins to make an antivenom” for humans.
“FETUAs do nothing for the neurotoxins that dominate many medically important venoms,” Dr. Sunagar said. “The honest reading is that these proteins form the metalloproteinase-neutralising component of a next-generation antivenom, but it is not yet a standalone therapy.”
Dr. Carroll also said his team has found a new component that could aid human antivenom development, but did not elaborate on ongoing research.
Implications for India
In countries like India, which host both vipers and elapids such as cobras, FETUA proteins alone cannot provide a complete antivenom solution, Dr. Carroll said.
Although the study revealed partial protection against saw-scaled vipers (Echis carinatus sp.), one of India’s ‘Big Four’ and a major cause of death and disability, partial cross-reactivity need not translate into clinical protection, Dr. Sunagar added.
But India’s bigger takeaway is the strategy: “The logical path for India is to identify and test FETUAs from our own vipers rather than relying on rattlesnake versions, and to pair them with agents covering the neurotoxic elapids the FETUAs cannot touch,” according to Dr. Sunagar.
Nikhil Sreekandan is an independent journalist.
Published – September 17, 2026 09:30 am IST
