Rising numbers of exotic snakebites reported in the UK

Exotic snakebites recorded in the UK have "soared" over the course of a decade, as numbers of the exotic pet increase -- a peer-reviewed study in Clinical Toxicologyreveals.

In 11-years, 300 patients with exotic snakebite were registered by the UK National Poisons Information Service (NPIS). This included 72 children aged 17 years or under and among those, 13 were aged just 5 years or less. No children had severe injuries.

Nine patients were bitten twice and one patient, some three times.

The new study, which included an audit of enquiries registered by the NPIS between 2009 and 2020 by experts from leading institutions across the UK, shows a total of 321 exotic snakebites from 68 different species.

Of those bitten, 15 had severe symptoms. This included a reptile conservationist who had previously survived a bite from an eastern green mamba but died after being bitten by a king cobra.

The World Health Organisation (WHO) considers more than 250 species of poisonous snake worldwide as medically important -- most native to Asia, Africa, Latin America and Oceania. But the possibility of encountering these dangerous species is no longer limited by geography. In recent years, snake ownership has increased in popularity in the UK. It is estimated that around one in 100 households now own a pet snake.

"The prospect of being bitten by an exotic (non-native) snake (in the UK) is still remote, with bites typically occurring in those keeping such snakes as part of their occupation or hobby," states lead author Pardeep Jagpal, from the National Poisons Information Service (Birmingham Unit). "Rapid access to expert clinical advice and the availability of appropriate anti-venom are important considerations when these accidents occur."

Advice to NHS healthcare professionals on managing exotic snakebites is available in the UK on a 24-hour basis through the NPIS. The authors examined all telephone calls involving snakebites that were received by the service between January 2009 and December 2020. They excluded enquiries about the European adder -- the only species of poisonous snake native to the UK -- or where the identity of the snake was unknown.

Of the 321 exotic snakebites in 300 patients:
 

• 207 (64.5%) of bites occurred in males -- and 10 people were bitten on more than one occasion.
• 72 (22.5%) of bites occurred in children -- 13 of whom were aged five or under.
• 184 (57.3%) of bites were inflicted by snakes of the family Colubridae, including hognose snakes, king snakes and false water cobras.
• 30 (9.3%) of bites were by Viperidae species, including western diamondback rattlesnakes and copperheads.
• 14 (4.3%) of bites were by Elapidae species -- most commonly by Indian cobras, monocled cobras and king cobras.

The majority of these exotic snakebites resulted in either no symptoms or mild to moderate symptoms. However, fifteen bites caused severe symptoms -- all of which were caused by front-fanged Viperidae or Elapidae. In total, seventeen people received antivenom treatment.

"Our results show an overall increase in the number of exotic snakebites reported to the NPIS compared to previous figures," says co-author the University of Oxford's Professor David Warrell, a world leading figure in tropical medicine, and the founding director of the Centre for Tropical Medicine and Wellcome Trust-Mahidol University Oxford Tropical Medicine Research Programme, Thailand.

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To keep up with evolving prey, rattlesnakes tap genetically diverse venom toolbox

In the evolutionary arms race between rattlesnakes and their prey, rodents, birds and other reptiles develop resistance to the snakes' deadly venom to survive. But new research led by the University of Colorado Boulder and University of Texas at Arlington sheds light on how snakes manage to keep the upper hand: They maintain a broad and diverse toolkit of genes that encode snake venom, allowing them to adapt as local prey and conditions change.

The findings, published today in Nature Ecology and Evolution, help explain how rattlesnakes have kept up with prey species evolving resistance to their venoms over millions of years. This research overturns decades of thought on what factors shape venom gene evolution and venom variation, and sheds new light on why developing effective antivenom treatments for snakebites remains so challenging.

"We found these rattlesnakes had a more diverse venom repertoire, more genetic tools in the toolkit, than their venom composition alone might suggest," said Drew Schield, lead author on the paper and postdoctoral fellow in Ecology and Evolutionary Biology at CU Boulder.

Snake venom, an evolutionary adaptation, is made up of different enzymes and toxins that enable snakes to capture their prey. For decades, biologists have thought that co-evolution between predator and prey would drive snake venom to become highly specialized: the venom evolving to effectively kill specific prey and unused venom gene genetic diversity disappearing along the way. Known in evolutionary biology as "directional selection" this process is like the sharpening of a knife -- while the weapon gets more deadly, it loses a bit of itself in the process.

The new study proposes that instead, "balancing selection" is the mechanism at play, an evolutionary process where multiple versions of a gene -- in this case, genes that encode venom proteins -- are maintained instead of eliminated. This could be the key to how snakes prevent themselves from going down evolutionary dead ends.

"The existence of these resistance mechanisms in prey led us to wonder: If there's selection pressure imposed back on the snakes, then it might make sense evolutionarily to have a more expanded venom arsenal," said Schield.

As rattlesnakes prey on a variety of animals, including mice, voles, birds and lizards, selection over time may not only maintain, but proactively select for a greater venom gene diversity, something no research has shown before.

"Our findings help explain decades of seemingly contradictory theory and evidence for what drives the extreme variation observed in snake venoms. It turns out that the arms-race between snakes and prey ends up favoring the constant re-shuffling of venom variants that are favored, leading to the retention of lots of venom variants over time, some of which are ancient," said Todd Castoe, co-author on the study and professor of biology at the University of Texas at Arlington.

Population level insights

During his work as a graduate student and postdoctoral researcher at the University of Texas at Arlington in 2019, Schield and his colleagues figured out where the venom genes reside in the rattlesnake genome, which up until that point was mostly a mystery. Now knowing the genetic architecture of venom as a trait (published in Genome Research), he realized scientists could investigate what evolutionary mechanisms have been operating on the venom genes.

Snake venom is a popular study subject, a promising model for understanding the origins of gene novelty. But previous studies in this field have not explored how selection has shaped this trait within closely related populations, so the researchers focused on select populations of rattlesnakes in Colorado, Montana, California and Idaho.

After scouting out locations where these snakes live, Schield and his co-authors traveled to a series of sites over several years in late spring and early summer from 2017 to 2020, where they collected 68 rattlesnakes belonging to two different species occupying the western United States in order to sample their blood, venom and take physical measurements.

They sequenced and analyzed genomes from these rattlesnake species, investigating genetic variation in regions of the genome housing venom genes. They found striking genetic diversity and strong evidence for natural selection maintaining multiple forms of different venom genes, adding to a growing body of evidence that balancing selection is more pervasive in nature than previously thought.

Based on the new study, Schield suspects that while directional selection may have driven the origins of venom, in more recent timescales, there may be an equilibrium shift towards balancing selection favoring diverse venom repertoires.

This may be one reason that snakebite is notoriously difficult to treat.

"These evolutionary mechanisms ramp up the complexity that you're contending with when you develop antivenoms, as venom composition within the same species but in different geographic regions might be totally different," said Schield.

Understanding how diverse venomous snake genomes truly are -- from rattlesnakes to cobras and coral snakes -- can inform advances in anti-venom therapeutics and save lives around the world, Schield said.

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Indiana Jones was right all along: Research shows the smaller the scorpion, the deadlier

Researchers in NUI Galway have shown, for the first time, that smaller species of scorpions, with smaller pincers, have more potent venoms compared to larger species with robust claws.

The scientists tested the theory from Indiana Jones and the Kingdom of the Crystal Skull, which warned of the dangers of small scorpions, and that "when it comes to scorpions, the bigger the better."

While this may have simply been a throwaway movie line from the adventurous archaeologist Indiana Jones, the research shows there is truth to it.

The team of scientists at NUI Galway's Ryan Institute put the quip to the test by analysing 36 species of scorpions to show that larger scorpions have less potent venoms and really are better in terms of avoiding a nasty sting.

The results of the research have published in the international journal Toxins.

It shows the smallest scorpions in their analysis, like the Brazilian yellow scorpion, where over 100 times more potent than the largest species they studied, such as the rock scorpion.

The potency pattern was not just about body size, but also pincer size, with venoms found in species with the smallest pinchers, including the South African thick-tail scorpion, which is more than 10 times more potent compared to species with the largest and most robust pinchers, such as the Israeli gold scorpion.

Dr Kevin Healy, Lecturer of Zoology at NUI Galway and senior author of the study, said: "Outside of entertaining movie trivia there are good evolutionary reason to expect the results and important medical implications for such patterns."

The researchers highlighted that while scorpions use both their venomous sting and their pinchers to capture prey and for defence there is an evolutionary trade-off between these weapons. Energy used to make bigger pincers means less energy is available for its chemical arsenal. This results in larger scorpions which can use their physical size are less reliant on venoms, while smaller species have evolved more potent venoms.

Dr Healy added: "When we look at the most potent, and dangerous, scorpion venoms we find they tend to be associated with species such as the deathstalker which are relatively small. In contrast, the biggest species such as rock scorpions have venoms that are likely to only cause slight pain."

Alannah Forde, an NUI Galway graduate student and lead author of the study, said: "Not only did we find that bigger is better -- when it comes to people being stung -- we also found that bigger pincers are better when it comes to assessing the danger level of a scorpion. While species such as large-clawed scorpion might be small to medium in size, they mainly rely on their large pincers instead of their relatively weak venom."

Scorpion stings are a global health problem with more than 1 million cases and thousands of deaths every year. Identifying the species involved with a sting is vital for treatment, hence general rules such as "bigger is better" are often used to help with treatment.

The team aim to test these evolutionary rules to what makes some species more potent to help develop better medical approaches to scorpion stings.

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Rodent ancestors combined portions of blood and venom genes to make pheromones

 Experts who study animal pheromones have traced the evolutionary origins of genes that allow mice, rats and other rodents to communicate through smell. The discovery is a clear example of how new genes can evolve through the random chance of molecular tinkering and may make identifying new pheromones easier in future studies. The results, representing a genealogy for the exocrine-gland secreting peptide (ESP) gene family, were published by researchers at the University of Tokyo in the journal Molecular Biology and Evolution.

Researchers led by Professor Kazushige Touhara in the University of Tokyo Laboratory of Biological Chemistry previously studied ESP proteins that affect mice's social or sexual behavior when secreted in one mouse's tears or saliva and spread to other animals through social touch.

Recently, Project Associate Professor Yoshihito Niimura led a search for the evolutionary origin of ESP genes using the wide variety of fully sequenced animal genomes available in modern DNA databases. Niimura looked for ESP genes in 100 different mammals and found them only in two evolutionarily closely related families of rodents: the Muridae family of mice, rats and gerbils, and the Cricetidae family of hamsters and voles.

Notably, the Cricetidae had few ESP genes usually all grouped together in the same stretch of DNA, but the Muridae had both that same small group of ESP genes as well as a second, larger group of additional ESP genes.

"We can imagine about 35 million years ago, the common ancestor of Muridae and Cricetidae formed the first ESP genes. Eventually, approximately 30 million years ago, the ancestor of Muridae duplicated and expanded these ESP genes. So now mice have many more ESP genes than the Cricetidae rodents," said Niimura.

To identify the source of what formed the first ESP gene, researchers compared additional genome sequences. They uncovered how random chance copied uniquely functional portions of two other genes, then coincidentally pasted them next to each other.

The DNA sequence of a gene includes portions called exons, which later become the functional protein, and other portions called introns, which do not become protein. Introns and exons are spaced throughout the gene with no apparent organization, introns interrupting essential functional portions of exons. Therefore, if a single exon were randomly copied and pasted elsewhere in the genome, any resulting protein fragment would have no meaningful function.

However, if an exon-only version of a gene were copied and reinserted into the genome, the chances of that new sequence remaining functional become much greater. Cells do create exon-only versions of genes called mRNA as part of the normal process of making protein from genes and cells do possess machinery, likely left over from viral infections, that can copy mRNA back into the DNA strand.

"This is not the normal way of things in cells, but it is a common source of evolution. We guess this is what happened to make ESP genes because the whole functional portion of the ESP gene is one exon, no intron interruption," said Niimura.

Specifically, the research team discovered for the first time that ESP proteins contain an uncommon spiral shape characteristic of alpha-globin, a component of the iron-carrying hemoglobin protein in blood. DNA sequence comparisons revealed that multiple alpha-globin gene exons spliced together show a subtle but distinctive similarity to the ESP gene sequence.

"It doesn't matter that hemoglobin is the source of the ESP pheromone. Any protein can become a pheromone if it is used for species-specific communication," said Niimura.

Regardless of its shape, no protein can function without being in the proper location. In ESP proteins, the alpha-globin-derived portion is attached to a signaling portion, which directs the protein to be secreted from salivary and tear glands. Researchers identified the ESP genes' location signaling sequence as resembling that of CRISP2, a gene expressed in mammalian reproductive tracts and salivary glands as well as the venom gland of some snakes.

The hemoglobin and CRISP genes are both ancient genes that existed in the shared evolutionary ancestor of vertebrates -- all animals with a backbone -- over 500 million years ago. The genetic shuffling that created ESP genes occurs relatively frequently in the cells of all organisms, but for these changes to become inherited evolutionary traits, the changes must occur in the sex cells so they can be passed on to future generations.

"The creation of new genes is not done from scratch, but nature utilizes pre-existing material. Evolution is like a tinkerer, using old things and broken parts to create some new device with a useful function," said Niimura.

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First evidence of snake-like venom glands found in amphibians

Caecilians are limbless amphibians that, to the untrained eye, can be easily mistaken for snakes. Though caecilians are only distantly related to their reptilian cousins, researchers in a study appearing July 3 in the journal iScience describe specialized glands found along the teeth of the ringed caecilian (Siphonops annulatus), which have the same biological origin and possibly similar function to the venom glands of snakes. If further research can confirm that the glands contain venom, caecilians may represent the oldest land-dwelling vertebrate animal with oral venom glands.

Caecilians are peculiar creatures, being nearly blind and using a combination of facial tentacles and slime to navigate their underground tunnels. "These animals produce two types of secretions -- one is found mostly in the tail that is poisonous, while the head produces a mucus to help with crawling through the earth," says senior author Carlos Jared, a biologist and Director of the Structural Biology Lab at the Butantan Institute in São Paulo. "Because caecilians are one of the least-studied vertebrates, their biology is a black box full of surprises."

"It is while examining the mucous glands of the ringed caecilian that I stumbled upon a never before described set of glands closer to the teeth," says first author Pedro Luiz Mailho-Fontana, a post-doctoral student in the Structural Biology Lab at the Butantan Institute.

What Mailho-Fontana found were a series of small fluid-filled glands in the upper and lower jaw, with long ducts that opened at the base of each tooth. Using embryonic analysis, he found that these oral glands originated from a different tissue than the slime and poison glands found in the caecilian's skin. "The poisonous skin glands of the ringed caecilian form from the epidermis, but these oral glands develop from the dental tissue, and this is the same developmental origin we find in the venom glands of reptiles," says Mailho-Fontana. This marks the first time glands of this kind have been found in an amphibian.

Researchers suspect that the ringed caecilian may use the secretions from these snake-like oral glands to incapacitate its prey. "Since caecilians have no arms or legs, the mouth is the only tool they have to hunt," says co-author Marta Maria Antoniazzi, an evolutionary biologist at the Butantan Institute. "We believe they activate their oral glands the moment they bite down, and specialized biomolecules are incorporated into their secretions.

A preliminary chemical analysis of the oral gland secretions of the ringed caecilian found high activity of phospholipase A2, a common protein found in the toxins of venomous animals. "The phospholipase A2 protein is uncommon in non-venomous species, but we do find it in the venom of bees, wasps, and many kinds of reptiles," says Mailho-Fontana. In fact, the biological activity of phospholipase A2 found in the ringed caecilian was higher than what is found in some rattlesnakes. Still, more biochemical analysis is needed to confirm whether the glandular secretions are toxic.

If future work can verify the secretions are toxic, caecilian oral glands could indicate an early evolutionary design of oral venom organs. "Unlike snakes which have few glands with a large bank of venom, the ringed caecilian has many small glands with minor amounts of fluid. Perhaps caecilians represent a more primitive form of venom gland evolution. Snakes appeared in the Cretaceous probably 100 million years ago, but caecilians are far older, being roughly 250 million years old," Jared says.

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Unravelling the venomous bite of an endangered mammal

Researchers from Liverpool School of Tropical Medicine (LSTM) and ZSL (Zoological Society of London) have worked with a team of scientists from institutions across the globe - to uncover the truth behind the origin of venom in some very unusual mammals.

As outlined in a paper published today in PNAS, the team focused their attention on an unusual endangered species known as the Hispaniolan solenodon (Solenodon paradoxus) - a member of the eulipotyphlan order of mammals, an ancient group of insectivores also including hedgehogs, moles and shrews. Obtaining venom from wild solenodons and unravelling the genetic blueprint of this species enabled the identification of the proteins that make up their venom, revealing that it consists of multiple kallikrein-1 serine proteases. Analysis of these toxins showed they are probably used by solenodons to cause drops in blood pressure in the vertebrate prey on which they sometimes feed.

To their surprise, the team found that the kallikrein-1 serine protease toxins found in solenodon venom had evolved in parallel with those detected in the venom of distantly related venomous shrews. The same building blocks of venom have therefore evolved convergently within solenodons and shrews, despite their divergence from one another over 70 million years ago - when dinosaurs still walked the earth.

Professor Nick Casewell from LSTM's Centre for Snakebite Research & Interventions is lead author on the paper. He said: "These particular proteins are present in the salivary glands of many mammals. Through our research we are able to demonstrate that they have been independently co-opted for a toxic role in the oral venom systems of both solenodons and shrews. These findings represent a fascinating example of how evolution can funnel novel adaptations down repeatable pathways".

The Hispaniolan solenodon is only found on the Caribbean island of Hispaniola (made up of the Dominican Republic and Haiti), and is considered one of the most Evolutionarily Distinct and Globally Endangered (EDGE) mammals by ZSL's EDGE of Existence programme. It is one of the few venomous mammals, producing toxic saliva that it injects into its prey through unique grooves in its lower incisor teeth (which gives the solenodon its name). Solenodons are some of the last few surviving Caribbean land mammals and are threatened today by habitat loss and predation from introduced dogs and cats.

Professor Samuel Turvey, from ZSL's Institute of Zoology and who jointly led the project, said: "This study highlights how little we know about one of the world's most fascinating animals. Unravelling details of the solenodon's previously unstudied venom system helps us to understand the mechanisms behind convergent evolution - and demonstrates the importance of conserving the world's remarkable EDGE species."

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