Were cone snails ever used as weapons

Poisons: Nature's deadliest weapons

Poisons are extremely complex mixtures

The two locations are home to some of Australia's most sensitive, fancy - and expensive - scientific instruments, which experts can use to examine even the smallest fragments of a molecule. The Institute for Molecular Bioscience is equipped with over 20 high-tech microscopy systems and a huge mass spectrometer. This auditorium-sized device can perform 100 scans per second with resolution less than one in a million; it is also able to identify 1200 proteins per hour and map the abundance of peptides in a poison. All of this is supported by powerful, graphics-accelerated computers for image processing and visualization.

In this center of scientific excellence, around 400 scientists research the genetic and molecular basis of living things and try to develop new drugs or find new applications that promote health, fight diseases or make cities and food more sustainable.

“This is the center of the world in terms of poison research,” says King, a slim, sociable man in his mid-fifties with a thin, gray, stubbly beard. "There is excellent work being done in antotoxic research elsewhere, and scientists in Belgium and Melbourne are doing great research on poisonous toxins, but we are definitely leaders in the breadth of drug development, pharmacology, chemistry and structural biology research."

Even during his time at the Hurlstone Agricultural High School in Sydney, King showed a particular interest in insects. When he was 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 study the structure of an interesting molecule in the funnel-web spider's venom. This led to an article in "Nature Structural Biology", a major journal in this field.

"Nature has made this amazing reservoir of millions of compounds available to us, and all of them have a special effect" (Irina Vetter)

King recalls thinking back then, wow, that spider stuff is cool! “I asked Howden for poison so I could take a closer look. He said: Sure, I'll send you some. At some point I got glass pipettes with freeze-dried poison - don't laugh now! - by post. You couldn't do that anymore today. "

With the help of liquid chromatography, he separated the individual components of the poison from one another. He expected the machine to spit out two or three peaks - signals triggered by a substance each - that would lead him to the active peptides. Peptides are short strands of amino acids, much shorter than most proteins, but often with significant biological effects.

"But the peaks came and came" - there were hundreds of connections, "he explains. “And I thought, Gosh, most of it is unfamiliar stuff. Now we know that funnel snake venom alone contains more than 3000 peptides. We believe it could be the most complicated chemical arsenal in nature. "

From poison to medicine

This diversity can be found in all poisons, says his colleague Irina Vetter, head of the Center for Pain Research at the institute. "Nature has made this amazing reservoir of millions of compounds available to us, and all of them have a special effect," she explains with a slight German accent. "And if you try to understand how sensory nerves work or how you can act on them, then poison is simply gold."

Vetter was sometimes surprised by where the research was leading her. “You can actually learn a lot about how pain-sensitive nerves work, how the channels are activated. We have the chance to find new ways to modulate their activity - and hopefully develop new treatment options. "

Poisons have already brought six new drugs to the world. For example, ziconotide in 2004, which was extracted from a marine species of cone snail and is highly effective against severe chronic pain. Clinical studies are ongoing for a further nine drugs. Vetter says that although ziconotide shows that peptide painkillers can be obtained from poison, it must be injected into the spinal fluid, "which is anything but ideal." Her team hopes to develop pain relievers that are easier to use and only need to be taken once a week or less.

One focus of the institute is on the nine different sodium channels in the human body. These are multilayered biological switches that generate and respond to the body's electrical signals. They are implicated in many diseases, including epilepsy, irregular heartbeat, and nerve pain caused by trauma, surgery, illness, or chemotherapy. One subtype is found predominantly in the heart, another almost exclusively in the skeletal muscles, and three subtypes occur only in pain-sensitive nerves. But thanks to scorpion venom, Vetter's team discovered that a subtype for tactile perception also plays a role in pain.

"In pain research we are at the level where cancer research was perhaps 30 years ago," says Vetter. It was then recognized that it was more complicated than expected. “If you have cancer, I can cut out a piece of the cancer and examine it. When you are in pain, I cannot cut out your pain-sensing nerves to understand what is going on in your body. So it is really difficult to see a connection between the pain a patient describes and a molecular mechanism. "

In an underground room there is an insectarium behind a double steel door. There are about 100 containers of the type in which you get food from the delivery service. In each of them there is a spider sitting in the middle of some earth. Hunter and tarantulas are among them, as well as wolf, trapdoor, funnel-web and mouse spiders; Despite the diversity, only a fraction of the 50,000 known species are represented. There is also a collection of poisonous millipedes and scorpions.

Samantha Nixon, a PhD student from Glenn Kings, shows me how she milks the poison for research: she puts a small container with a single Sydney funnel-web spider on it (Atrax robustus) in a bigger tub. Then she takes a long pipette with a thin, hollow extension piece and nudges the spider gently on the head, which triggers its attack mode and causes it to empty its venom gland in one go.

In the institute not only spiders, snakes and cone snails, but also plants as sources of poison are researched. Back in Irina Vetter's office, the scientist shows me the thick hairs on the leaves of a small Gympie-Gympie (Dendrocnide moroides), a species of Australian plant. When touched, they inject a strong neurotoxin like hypodermic needles.

In a study that was published in the journal Science Advances in September 2020, Vetter's team discovered toxins that were previously only known from the poison of spiders and scorpions. The chemical composition is very different, but in both cases the poison causes pain by modulating sodium channels in nerves that are sensitive to pain. And in either case, the pain can last for days or even weeks.

How is it that a plant develops a neurotoxin? Irina Vetter has no answer to this question. As a pain researcher, she is interested in the mechanisms of pain and how we perceive pain. In order to find methods of treatment, she sometimes makes a self-experiment, as with the gympie-gympie nettle. She recalls: “You get redness and calluses and it starts to burn; the pain becomes wavy and may radiate to the lymph nodes. And you can feel a deep pain in your shoulders. ”Apart from her work at the institute, Irina Vetter keeps away from poisonous things. "I don't go out and collect things - I'm arachnophobic," she says, grinning.

Brian Fry says in an American accent that after graduating from Oregon with a bachelor's degree, he came to UQ for his PhD and then worked as a fellow in Singapore and Melbourne before moving back to Brisbane to run his own laboratory. It's teeming with doctoral students from all over the world, and there's plenty of high-tech such as the fastest and most reliable blood coagulation analyzer in the world, which is also the only analyzer in a research laboratory in Australia. It is called "Dracula". "We like to give our machines names," says Fry with a smile.

A huge treasure

Another flagship device is a massive glass cube that contains a robot with three arms - the heart of a US $ 1.6 million biosensor system. It is the only one south of the equator and measures the bonding of molecules up to the size of two hydrogen atoms. It is called "Skynet" after the huge, super-intelligent computer network in the "Terminator" films.

Fry's earliest memory is that when he was two years old, in an isolation ward, he battled the bacterial toxins of meningitis, which can cause brain damage, paralysis, and strokes. There he had to be restrained to his bed for trying to pull out the drug delivery tubes in his temple and ankles.

"This is my first memory: that I was torn apart by toxins," he says. “I remember my little blue blanket and yellow rubber duck we took to the hospital. Both were taken from me and burned there. ”He survived but lost his right ear and his sense of balance.

This experience sparked a lifelong interest in poisons of all kinds, in what they do and how. The interest led to a fascination for poisonous snakes. “I was four years old when I told my parents that I would make studying poisonous snakes my life's work. And I've managed to turn this childlike passion into my job. "

Medicines made from poison

Brazilian pit viper, Bothrops jararaca (1981)

Captopril is the first success story of a drug based on snake venom. It was derived from a toxin found in the venom of the Brazilian pit viper and was approved for use in humans in 1981. It lowers blood pressure by suppressing a natural peptide that the body produces to increase blood pressure by narrowing blood vessels. Many other drugs that lower blood pressure - such as enalapril, lisinopril, perindopril, and ramipril - have a similar molecular structure to captopril.

Pygmy rattlesnake, Sistrurus miliarius barbourin (1998)

Eptifibatide is an anticoagulant that stops blood clots in acute coronary syndrome - an umbrella term for the sudden blockage of blood supply to the heart muscle. It is modeled on a component found in the venom of the southeastern pygmy rattlesnake found throughout Florida and much of the southern United States. The drug was first approved in 1998.

Saw-scaled viper, Echis carinatus (2000)

Tirofiban is a synthetic antiplatelet agent that prevents cells in the blood called platelets from sticking together and forming a clot that can lead to a heart attack or stroke. It is a modified version of a molecule found in the venom of the sawshield viper, which is native to India and parts of the Middle East and Central Asia. The drug was first approved for use in 2000.

European medical leech, Hirudo medicinalis (2000)

Bivalirudin is a "direct thrombin inhibitor" and belongs to a group of drugs that are used to prevent and treat embolisms and blood clots. It is a synthetic version of the naturally occurring peptide found in the venom glands of leeches. It was first discovered in the European medicinal leech found throughout Europe and Asia as far as Kazakhstan and Uzbekistan. It was approved for use in humans in 2000.

Magical cone snail, Conus magus (2004)

Ziconotide, an analgesic for severe and chronic pain, such as cancer and neurological diseases, is 1000 times as potent as morphine and was approved for use in 2004. It is extracted from a species of marine snail found in the Philippines, off Queensland, and in areas of the Pacific and Indian Oceans. When injected into the spinal fluid, it works by blocking calcium channels in pain-transmitting nerve cells; as a result, they are no longer able to transmit pain signals to the brain.

Gila monster, Heloderma suspectum (2005)

Exenatide is used to treat type 2 diabetes and can be given as a once weekly injection. The peptide is a synthetic version of a hormone found in the venom of the Gila monster, a poison lizard native to the southwestern United States and northwestern Mexico. It was discovered in 1992 and approved for human use in 2005. It is prescribed to diabetics whose blood sugar cannot be well controlled by other drugs.

This passion has led Fry in search of poisonous creatures across the globe. Now he's married with a young child, so he eschews what he calls his "crazy premarital past." His wife Kristina calls it "traveling to distant places to commit suicide in unusual ways".

In the laboratory he also has a “pickled zoo” with preserved poisonous animals and uses a 3-D printer to make replicas of their skulls. “We're interested in the poison glands. With these prints we can look at changes in skull morphology and relate them to changes in the venom delivery system and to the venom itself. Everything works together like an integrated weapon system. "

Fry still occasionally goes on expeditions for exotic poisons, but mostly he depends on his network of fellow researchers and their forays into the wild. For more common poisons, he relies on his lab director Christina Zdenek, a postdoctoral research fellow and former PhD student who keeps some of Australia's deadliest snakes at home.

She shares the town house in a suburb with her husband Chris Hay - himself a herpetologist and former licensed snake presenter - and with 21 snakes: coastal taipans, death adders and eastern browns with names like Squishy, ​​El Diablo, Mr. Naughty, Lumpy and Casper. Zdenek leans over a glass case and picks up a poisonous coastal taipan. She holds the tail in her left hand and a hook in her right to gently keep the snake's head at a distance.

Like Fry, Zdenek is from the United States and received her bachelor's degree in biology in California. She came to Australia to study palm cockatoos before doing a PhD at UQ on her first love, snakes. More precisely, about the toxicology and protection of the death adder (Acanthophis antarcticus), one of the most venomous land snakes in the world. Ironically, dead otters, which have deadly neurotoxic venom, are themselves threatened by cane toads: the amphibian eats young dead otters, and adult dead otters that eat the toads are poisoned by the poisonous glands on their skin.

Her love for snakes began at the age of five when her older brother was a South American Boa constrictor got as a pet. She started breeding veil chameleons at the age of eleven and grew up around the house with all sorts of reptiles. “They are fantastic pets. They're not loud, don't destroy furniture and, depending on the type, you can leave them alone for weeks when you're on vacation. ”She studied her behavior as a little girl. "I still love touching snakes and looking at them up close."

The biologist hopes that, through the benefits that snakes and other poisonous animals have for science and medicine, the public will recognize more strongly in the future that they not only fulfill important tasks in nature, but are also valuable for society. "Poison is very common in the tree of life," she says. “Evolution has produced these special cocktails over hundreds of millions of years that transformed prey capture from physical combat to biological warfare. For us humans this is a huge treasure. "