Venom: Nature’s Deadliest Weapon

STUDYING VENOM is a risky business. Ask Bryan Fry: he’s been bitten by venomous creatures 27 times — mostly by snakes on land and at sea, and by box jellyfish and stingrays. He’s also amassed 23 broken bones, 400 stitches and three concussions, once breaking his back in three places and spending months in hospital relearning to walk.

But the herpetologist — the branch of zoology dealing with reptiles and amphibians — is no masochist: it’s just that to study venom, you have to go into the wild to collect the critters in their native habitats. And not only can venomous animals be dangerous, they often live in remote locations, prefer to stay hidden and, when found, can be devilishly difficult to ensnare.

It may be dangerous, but it is necessary, because without venom, you can’t make antivenom. And no antivenom works across all species: each antivenom needs to match the toxins of a particular species. To make matters worse, toxins can vary widely even within the same species, depending on its environment and prey. And without a detailed understanding the toxins in a venom, you can’t predict how the human body will react, what organs will be affected and how to treat a patient.

“There is a global database of antivenoms maintained by the World Health Organisation, but it’s based on what is known about each species of snake,” says Fry, who runs Venom Evolution Lab at the University of Queensland (UQ) in Brisbane, Australia. “How well these have been tested against the full geographic range of any particular snake, or how it performs against snakes that are close relatives and may therefore have some cross-reactivity, we just don’t know.”

Understanding what toxins make up the venom of the world’s venomous creatures, the sometimes-sizeable toxin variability between geographic ranges of the same species, as well as what elements of one antivenom might work across related or unrelated species — known as ‘cross-reactivity’ — takes up a lot of his lab’s time. For this, they rely on the most diverse venom collection in the world — spanning Antarctic octopuses, king cobras, Komodo dragons and vampire bats — collected during Fry’s 20 years of fieldwork.

And knowing what’s in those venoms is essential, since being bitten by a venomous animal, known as envenomation, is a global problem. Some 5.4 million people each year are bitten by venomous snakes alone, and between 81,000 and 138,000 die. Venoms not only kill, but can cause paralysis, bleeding disorders, kidney failure and tissue damage, all which can lead to permanent disability or limb amputation. Children suffer more severely because of their smaller body mass.

Fry, considered one of the world’s venom specialists, is the author of almost 250 scientific papers and a leader of 40 expeditions. Which is why he gets calls from all over the world, sometimes in the middle of the night, asking for help.

“I get phone calls at two in the morning from researchers who are assisting doctors to treat bite victims,” he says. “I recently consulted on a bite in Brazil — somebody who kept a pet cobra illegally — and one of the veteran researchers asked, ‘What’s this cobra’s venom likely to do?’ It was one we’d worked on, so I said, ‘Ok, in addition to the paralysis, for which they’ll need artificial respiration, this cobra’s venom also affects the muscles. So, you need to monitor for muscle breakdown … and [possibly] kidney failure.”

But it is the promise of venoms to advance modern medicine that is now exciting scientists. The complex cocktails found in venoms have a dazzling array of functions, most of which are completely unknown. And as scientists begin to unravel them, they are finding not only a host of new and more effective drugs, but also rewriting the textbooks on how our bodies work at the molecular level.

WHY DID VENOM arise in nature? It’s principally used for two things: to attack and subdue, or kill, prey; or to defend against attack. And it’s found in an astonishing variety of wildlife: spiders, scorpions, jellyfish, octopuses, squid, fish, bees, wasps, ants, centipedes, snails, molluscs, corals, frogs, salamanders, moles, bats, shrews, some hedgehogs and rats, the male platypus, and even primates — the slow loris. It’s estimated that at least 15% of all animals are venomous.

Venom did not first evolve in one species long ago and pass those genes down the millennia: it’s evolved independently almost 100 times, an example of ‘convergent evolution’ — when creatures develop similar solutions to the same challenges, and natural selection for the most useful adaptive traits does the rest. Eyes and flight are often used as examples of convergent evolution, but venom outshines these by a country mile.

There is an important difference between the venomous and the poisonous: an animal or plant is poisonous when its toxins are used passively — like the warty skin of a cane toad or the leaves of poison ivy — and gets into the body via swallowing, inhaling or absorption through skin. Venom, however, is directly injected via a bite or sting, and its target is the bloodstream. Some animals can be both venomous and poisonous, like the blue-ringed octopus, which has a venomous beak, but it is also poisonous if ingested.

There are five types of venom effects: neurotoxic, attacking the brain and nervous system; coagulopathic, targeting the cardiovascular system; myotoxic, incapacitating muscle tissue; proteolytic, breaking down cell structure in muscle, lungs, heart and blood vessels; and cytotoxic, causing cell damage or cell death. An animal’s venom can have one of more of these effects on its victims, and effects vary from species to species.

Venoms tend to be a cocktail of toxins which have carefully evolved to be most effective against the prey they target; but those same toxins can affect non-prey species too. Which is why a box jellyfish sting can cause cardiac arrest and death in a matter of minutes; and one drop of marbled cone snail venom can kill 20 people. The venom of the funnel-web spider, considered the world’s most deadly, can kill a human in just 15 minutes — yet has little effect on dogs, cats or birds.

“Funnel-web venom is only deadly to invertebrates and primates,” says Glenn King, a biochemist at the Institute for Molecular Bioscience in Brisbane. “It didn’t evolve to kill humans, it’s just an accident of evolution.” The venom has opposite effects on the two groups: its paralyses insects, but leads to respiratory and heart failure.

“But then, some Queensland whistling tarantulas cause no problems to you and me, but they are lethal to dogs and cats. It’s serendipity — a lot of these spider venoms are designed to kill insects, but it just so happens that that receptor they target in that insect and ours are similar enough to affect dogs, or affect us.”

No-one knows when venom first evolved, since venom glands don’t fossilise. But it’s thought venom first appeared in the sea among Cnidarians, the animal phylum that includes corals, sea anemones and jellyfish, whose earliest fossils date back 580 million years. Genetic studies — using molecular clock analysis of mitochondria, the power packs inside cells which mutate at predictable rates over time — suggest they may have emerged some 741 million years ago.

The first effective antivenom was developed in 1894 in France by injecting horses with small amounts of cobra venom and then harvesting the resulting antibodies from their blood. Since cobras are immune to their own venom, the researchers thought, perhaps immunity could be ‘learned’ by the body. They were right: the horse antibodies, when injected into a human bite victim, immediately bound to the venom, alerting the body’s immune system to recognise the venom and disable it.

Today, antivenom is still produced in much the same way: rabbits, horses or sheep are injected with small doses of a particular venom over time; the antibodies to the venom created by the animal’s immune system are then extracted and the blood serum, or plasma, is concentrated and purified into pharmaceutical grade antivenom.

But the resulting antivenom is only 100% effective against the particular cocktail of toxins in the venom injected into the host animal. Hence, you need the venom to make an antivenom.

There are 46 laboratories producing antivenoms globally, mostly public institutions in Asia and the Americas, and one in Australia and they mostly produce snake antivenoms, since snakes account for most of the world’s cases of envenomation. But antivenoms also exist for species of scorpions, spiders and even marine animals, although the latter are often less serious or less common worldwide.

In Australia and many other wealthy nations, researchers have developed a ‘polyvalent’ antivenom; this is produced by generating, in the blood plasma of host animals, antibodies to all five major groups of Australian land species of snakes. Hence, one polyvalent antivenom generally works against most Australian snakebites. Depending on the amount and toxicity of the venom, a bite victim may need several injections to completely neutralise the venom.

However, if the snake species that caused a bite is known, ‘monovalent’ antivenom for that species is used. This is because antivenom can trigger severe side effects, like ‘serum sickness’ (a kind of allergic reaction that can bring on a shortness of breath or nausea, vomiting and shock), and polyvalent antivenom — which is given at higher volumes — can make it worse. As a result, antivenom is only used when envenomation leads to muscle tissue breakdown or profuse bleeding caused by venom toxins hampering the blood’s ability to coagulate.

VENOMS ARE “one of the most diverse, versatile, sophisticated and deadly biological adaptations ever to have evolved on the planet,” write biologists Ronald Jenner and Eivind Undheim in their book, Venom: The Secrets of Nature’s Deadliest Weapon (Smithsonian Books, 2017). “A venom acts more like a battalion of snipers than a machinegun loaded with one type of bullet. Because the most complex venoms contain hundreds or even thousands of distinct components, they are able to overcome the defences of almost any victim. Moreover, venom toxins act as self-guided bullets.”

That complexity makes venom attractive for scientists seeking to better understand how the human body works, and how to tweak its internal machinery to correct problems, fight disease and improve health. That’s because the body has astonishing galaxy of components — multitudes of proteins and enzymes, fatty acids like lipids, vitamins, salts such as sodium and potassium, trace elements and signalling molecules that all interact with each other and genes, both DNA and RNA. And all of them work in mostly unknown or little understood ways.

Having evolved over millions of years to alter or subvert the molecular machinery of so many species in a dizzying array of pathways, venoms represent a treasure trove of potential insights. And you can clearly see that potential being exploited at Australia’s — and perhaps the world’s — preeminent centres of venom research in Brisbane.

It’s a four-minute walk from the concrete-and-brick Gehrmann Laboratories where Fry’s Venom Evolution Lab is housed, to the sweeping curves of glass, steel and sandstone of the Queensland Bioscience Precinct. In the midst of this US$100 million showpiece, completed in 2002, stands the Institute for Molecular Bioscience, fringed by palm trees.

Between the two locations are some of the most sensitive, most fancy (and most expensive) scientific instrumentation in Australia, designed to coax insights from the tiniest fragment of a molecule. At the institute are 21 high-tech microscopy facilities, and an auditorium-sized mass spectrometer able to do 100 scans per second to a resolution of less than 1 part per million, identify 1,200 proteins an hour and map the plethora of peptides in a venom. All of this is backed by high-powered, graphics accelerated computers for image processing and visualisation.

In this hive of 21st century scientific bravura, some 400 scientists probe the genetic and molecular basis of living things, seeking to apply their findings to design new drugs or develop new treatments that improve health, combat disease or make cities and food more sustainable.

“This is the centre of the world in terms of venom research,” says King, a slender, affable fifty-something with a thin, stubby grey beard. “There are other places doing excellent work in anti-venom research, and groups in Belgium and Melbourne doing great work on venom toxins, but in terms of research breadth across drug development, pharmacology, chemistry and structural biology, we’re definitely the leaders.”

It was his interest in insects while at Hurlstone Agricultural High School in Sydney that brough him into the field. Later, studying insecticides at the University of Sydney in 1995, he was asked by a colleague at Deakin University in Geelong, the late Merlin Howden, to look at the structure of an interesting molecule in funnel-web spider venom, which eventually led to a paper in Nature Structural Biology.

“And I thought, ‘Wow, this spider stuff is cool’,” he recalls. “I asked him for venom to look at it in more detail. He said, ‘Sure, I’ll send you some.’ Next thing I know, I get glass pipettes with freeze-dried venom in the mail. It’s hilarious. You couldn’t do that today.”

He used liquid chromatography to separate out the venom’s compounds — substances with different elements that are chemically bound together. He was expecting the machine to spit out two or three peaks, from which he could discern the active peptides — short strings of amino acids that carry out essential functions in biology.

“But the peaks just kept coming and coming — there were hundreds of compounds,” he marvelled, his eyes lighting up. “And I thought ‘My goodness, this is all completely uncharacterised, nobody knows what most of this stuff is.’ We now know the venom of the funnel-web alone contains more than 3,000 peptides. We think it might be the most complicated chemical arsenal in the natural world.”

That diversity is found across venoms, says his colleague, Irina Vetter, director of the Centre for Pain Research at the institute. “Nature has provided us with this amazing library of millions and millions of compounds, and they all do something,” she says with a slight German accent, her hazel green eyes alight with fascination. “And if you’re looking for tools to help you understand how sensory nerves function, or how to affect them, venom is just a treasure.

“Sometimes it’s really unexpected where it can take you. You can actually learn a lot about how pain-sensing nerves work, how the channels are activated, and new ways to modulate them — and hopefully, create new treatments.”

Venoms have already given the world six new drugs, such as Ziconotide in 2004, derived from a species of marine cone snail that is highly effective against severe chronic; another nine are undergoing clinical trials. Vetter says that while Ziconotide proves venom-derived peptide painkillers are possible, it has to be injected into spinal fluid, “which is less than perfect”. Her team hopes to develop easier-to-use painkillers that could be taken once a week or less.

An area of the institute’s focus are the nine different sodium channels in humans, multi-layered biological switches that create and respond to the body’s electrical signals. They are implicated in a variety of diseases including epilepsy, irregular heartbeat and nerve pain caused by trauma, surgery, disease or chemotherapy. One subtype is predominantly in the heart, another almost exclusively in skeletal muscle, and three subtypes are only found in pain sensing nerves. But Vetter’s team has discovered, thanks to scorpion venom, that a subtype for touch sensing also plays a part in pain.

“In pain research, we’re at a stage where cancer research was maybe 30 years ago, where people started to realise, ‘It’s actually way more complicated than we thought’,” she says. “If you have cancer, I can chop out a bit of the cancer and study it. If you have pain, I can’t really chop out your pain sensing nerves to understand what’s going on. So, it’s really difficult to correlate pain you’re describing to a molecular mechanism.”

In a room behind a double steel door underground is an insectary where some 100 rectangular plastic trays and round take-away food containers are each filled with a little soil and a single spider. There are various species of huntsman, tarantula, wolf, trapdoor, funnel-web and mouse spiders — just some of the 50,000 named species — and a collection of venomous centipedes and scorpions.

Samantha Nixon, a chirpy fresh-faced PhD student of King’s, shows me how she milks venom for research: she places a small container with a single Sydney funnel-web (Atrax robustus), and puts it at the centre of a larger tub. Taking a long pipette with a thin, hollow extender, she gently pokes the spider around the head, triggering its attack mode, and then swiftly drains its venom gland with one squeeze. Not bad for someone who, as she admits, was once an arachnophobe (or one who fears spiders).

And it’s not just spiders, snakes and cone snails that yield venom: researchers are exploring plants too. Back in Vetter’s office, a fuzzy-leafed Gympie-Gympie sapling is perched by the window. Vetter, a genial woman with amber hair and feline grace, picks it up to show me the dense hairs on the surface of the leaves which, if touched, act like hypodermic needles and inject a potent neurotoxin.

In a study published in the journal Science Advances in September 2020, her team discovered toxins that had only been seen before in the venom of spiders and scorpions, although their chemical composition is very different. Yet, they cause pain the same way — by modulating sodium channels in pain-sensing nerves — but do so in a way that makes pain that can last for days or even weeks.

Why would a plant evolve a neurotoxin? She has no idea. But being a pain researcher means she’s interested in the mechanisms of pain and how we feel it, so she can develop new treatments. That occasionally means being on the receiving end, as she was with the Gympie-Gympie: “You get redness and weals, it starts to burn; the pain becomes wavelike and can radiate to your lymph nodes, and you get a deep aching sensation in the shoulders. It’s very strange,” she recalls.

Despite working on venoms, apart from plants, she stays away from venomous things. “I don’t go out and collect things — I’m an arachnophobe,” she grins.

FRY, WITH HIS SHAVED scalp and athletic features, speaks with an earnest American accent while his grey-blue eyes, girdled by comfortable over-sized glasses, peer alertly at you. With undergraduate degrees from Oregon, he came to UQ for his PhD and followed with fellowships in Singapore and Melbourne before settling down in Brisbane again to head up his own lab.

And it’s quite a space: buzzing with bright doctoral students from all over the globe, and brimming with a panoply of high-tech equipment — like the world’s fastest, most reliable blood clotting analyser that is the only one in a research lab in the country. It’s christened ‘Dracula’ — “We like to name our machines,” he smirks. Another is a massive glass cube housing a robot with three arms, the heart of a US$1.6 million biosensor facility — the only one in the Southern Hemisphere — that measures the binding of molecules down to the size of two hydrogen atoms. It’s dubbed ‘Skynet’, after the giant super-intelligent computer network in the Terminator movies.

His first memory is, at the age of two, being in an isolation ward fighting the bacterial toxins of spinal meningitis, which can cause brain damage, paralysis and stroke. He had to be strapped down to a hospital bed because, in distress, he’d try to rip out the surgically implanted tubes in his temple and ankles that delivered medicine.

“That’s my first memory, being torn apart by toxins,” he recalls. “I remember my little blue blankie and my yellow rubber duckie we brought to hospital — they took those away and incinerated them.” He survived, but lost hearing in his right ear and still has no sense of balance.

It triggered a life-long interest in toxins of all types — what they do and how they do it — which morphed into a fascination for venomous snakes. “I was four when I told my parents that I was going to make the study of venomous snakes my life’s work. And I managed to turn that childhood passion into a career.”

That passion has taken him across the globe searching for venomous creatures. These days, married and with newborn, Fry eschews what he dubs his “crazy pre-marriage past”– or what his wife Kristina calls “travelling to far-off places trying to get himself killed in unusual ways”.

At the lab, he also maintains a ‘pickled zoo’ of preserved venomous animals, and uses a 3D printer to make replicas of their skulls. “We’re interested in the venom glands. With these prints, we can look at changes in skull morphology and relate that to changes in the venom delivery apparatus and the venom itself, because it’s all an integrated weapons system.”

For exotic venoms, Fry still occasionally mounts an expedition but mostly depends on his network of fellow researchers and their forays into the wild. For the more common venoms, he relies on his lab manager Christina Zdenek, a postdoctoral research fellow and former PhD student who just happens to keep some of Australia’s deadliest snakes at home.

At the suburban townhouse she shares with husband Chris Hay — himself a licensed snake demonstrator turned herpetologist — is a den of 21 snakes: coastal taipans, death adders and eastern browns with names like Squishy, El Diablo, Mr Naughty, Lumpy and Casper. Her lithe figure stoops to a glass cabinet, her long brown hair held up by a white scrunchie, while her chestnut brown eyes watch a venomous coastal taipan intently as she uses a hook to prise it up from its cubicle. She holds it for me to see, left hand on the tail, right hand using the extendable hook to gently hold the snake’s head at a distance.

Also an American, Zdenek got her undergrad biology degree in California and came to Australia to study palm cockatoos before doing her PhD at UQ on her first love: snakes. Specifically, the toxicology and conservation of death adders, one of the world’s most venomous land snakes. Ironically, for a creature armed with a deadly neurotoxic venom, death adders themselves are threatened by cane toads: the amphibian eats young death adders, and adult death adders eating the toads are poisoned by the toxic glands on its skin.

Her love of snakes began at age 5, when her older brothers got a pet python — a South American boa constrictor, no less. At 11, she started breeding veiled chameleons, and grew up with all manner of reptiles in the house. “They’re fantastic pets. They’re not noisy, they don’t destroy the furniture and, depending on the species, you can leave them alone for weeks if you’re on holiday,” she recalls. “I would study their behaviour so intently as a little girl. I still love getting my hands on snakes and see them up close, but I’m careful with the venomous ones.”

Zdenek is now studying snake venoms, and most of her research papers arise from venom she milks from the snakes at home. She’s found that snake venoms — even within the same species — can vary by sex, age, geography and even local temperature. She’s also studying how well existing antivenoms work, what active compounds they neutralise and which they don’t, and what elements of one antivenom have cross-reactivity with other venoms.

She hopes the benefits that science and medicine are deriving from venom will allow the public to appreciate that venomous animals, like snakes, not only perform essential roles in nature but are valuable to society.

“Venom is very common throughout the tree of life,” she says. “You’ve got tens, even hundreds of millions of years of evolution which has honed these very special cocktails to enable each species to survive and thrive, that transforms capturing prey from a physical battle into biological warfare. And that’s turned out to be a goldmine for us humans.”

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