TUCSON, Arizona — In a small room in a building at the Arizona-Sonora Desert Museum, invertebrate guardian Emma Califf lifts a rock in a plastic box. “This is one of our desert furries,” she said, exposing a three-inch-long scorpion with its tail arched over its back. “The biggest scorpion in North America.”
This furry captive, along with a swarm of inch-long bark scorpions in another box, and two dozen rattlesnakes of various species and subspecies across the hall, are held here by the realm’s currency: its venom.
Efforts to sort out the vast swarm of proteins in the venom — a field called venomics — have flourished in recent years, and the growing catalog of compounds has led to several drug discoveries. As the components of these natural toxins continue to be tested by evolving technologies, the number of promising molecules is also growing.
“A century ago, we thought venom had three or four components, and now we know that just one type of venom can have thousands,” said Leslie V. Boyer, professor emeritus of pathology at the University of Arizona. “Things are accelerating because a small number of very good labs are pumping out information that everyone else can use to make discoveries.”
She added: “There’s a pharmacopoeia out there waiting to be explored.”
It’s a stunning case of modern scientific alchemy: the most evolved natural poisons on the planet are creating an array of effective drugs with the potential for much more.
One of the most promising venom-derived drugs to date comes from Australia’s deadly Fraser Island funnel-web spider, which halts cell death after a heart attack.
Blood flow to the heart is reduced after a heart attack, which makes the cellular environment more acidic and leads to cell death. The drug, a protein called Hi1A, is scheduled for clinical trials next year. In the laboratory, it was tested on human heart cells. It was found to block their ability to sense acid, “so the death message is blocked, cell death is reduced and we see improved survival of heart cells,” said Nathan Palpant, a researcher at the University of Queensland in Australia, who helped to take the test. discovery.
If proven in tests, it can be administered by emergency physicians and can prevent the damage that occurs after heart attacks and possibly improve heart transplant outcomes by keeping the donor heart healthier for longer.
“It looks like it’s going to be a miracle drug for heart attacks,” said Bryan Fry, an associate professor of toxicology at the University of Queensland, who is familiar with the research but was not involved in it. “And it’s from one of Australia’s most reviled creatures.”
The techniques used to process poison compounds have become so powerful that they are creating new opportunities. “We can do trials today using just a few micrograms of venom that 10 or 15 years ago would have required hundreds of micrograms,” or more, said Dr. Fry. “What it did was open up all the other poisonous strains that produce small amounts of material.”
There is a huge natural library for sorting. Hundreds of thousands of species of reptiles, insects, spiders, snails, and jellyfish, among other creatures, have mastered the art of chemical warfare with poison. Also, the composition of the venom varies from animal to animal. There is a kind of toxic terroir: the venom differs in quantity, potency and proportion and types of toxin, according to habitat and diet, and even by temperature change due to climate change.
The venom is made up of a complex mixture of toxins, which are composed of proteins with unique characteristics. They are so deadly because evolution has honed their effectiveness for so long – around 54 million years for snakes and 600 million for jellyfish.
Venom is the product of a biological arms race over that time; as the venom becomes more deadly, victims develop more resistance, which in turn makes the venom even more deadly. Humans are included in this dynamic. “We are made of protein and our protein has little complex configurations that make us human,” said Dr. Boyer, who founded the Venom Institute for Immunochemistry, Pharmacology and Emergency Response, or VIPER. “And those little configurations are targets for the poison.”
The specific cellular proteins that venom molecules have evolved to precisely target are what make drugs derived from them – which use the same pathways – so effective. Some proteins, however, have inherent problems that can make new drugs unfeasible.
There is usually no need to collect poison to make these drugs. Once identified, they can be synthesized.
There are three main effects of the poison. Neurotoxins attack the nervous system, paralyzing the victim. Hemotoxins target the blood and local tissue toxins attack the area around the site of exposure to the venom.
Numerous poison-derived drugs are on the market. Captopril, the first, was created in the 1970s from the venom of a Brazilian pit viper to treat high blood pressure. It has been commercially successful. Another drug, exenatide, is derived from the venom of the Gila monster and is prescribed for type 2 diabetes. Draculin is an anticoagulant from vampire bat venom and is used to treat stroke and heart attack.
Israeli killer scorpion venom is the source of a compound in clinical trials that finds and brightens breast and colon tumors.
Some proteins have been flagged as potential candidates for new drugs, but they have to go through the long process of manufacturing and clinical trials, which can take many years and cost millions of dollars. In March, researchers at the University of Utah announced that they had discovered a fast-acting molecule in cone snails. Cone snails shoot their venom at fish, which causes victims’ insulin levels to drop so quickly that it kills them. It holds promise as a diabetes drug. Bee venom appears to work with a wide range of conditions and has recently been found to kill aggressive breast cancer cells.
In Brazil, researchers have been analyzing the venom of the Brazilian wandering spider as a possible source of a new drug for erectile dysfunction – because of what happens to human victims when they are bitten. “One feature of their poisoning is that the males get extraordinary, painful and incredibly long-lasting erections,” said Dr. Fry. “They have to separate him from his lethal factor, of course, and find a way to dial him back.”
Some scientists have long suspected that important secrets are locked in poison. Scientific interest first emerged in the 17th century. In the mid-18th century, the Italian physician and polymath Felice Fontana added to the body of knowledge with his treatise, and in 1860 the first research to analyze the components of poison was conducted by S. Weir Mitchell in Philadelphia.
The medicinal use of poison has a long history, often without scientific backing. Poison needles are a traditional form of acupuncture. Bee sting therapy, in which a swarm of bees is placed on the skin, is used by some natural healers. Rock musician Steve Ludwin claims to have routinely injected himself with diluted poison, believing it to be a tonic that strengthens his immune system and boosts his energy.
The demand for poison is increasing. Mrs. Califf of the Arizona-Sonora Desert Museum said she had to travel to the desert to find more bark scorpions, which she hunts at night with a black light because they glow in the dark. Arizona, Boyer said, is “poison hub,” with more venomous creatures than any other US state, making it well-suited for this type of production.
Scorpion venom is harvested from the arachnid by applying a small electrical current, which causes the spider to excrete a small drop of the amber liquid at the tip of its tail. With snakes, the venom glands are gently massaged as they bar their fangs over a martini glass. After they deliver their venom, the substance is sent to researchers around the world.
Vipers, including rattlesnakes, have other unusual adaptations. The “pit” is the location of biological equipment that allows snakes to feel the heat of their prey. “You can blindfold a snake and it will still hit the target,” Boyer said.
But it’s not just the poison that is much better understood these days. In recent years, there has been a successful and concerted search for antivenom.
In 2019, the Wellcome Trust created a $100 million fund for the search. Since then, there have been countless research efforts around the world in search of a single universal treatment – one that can be taken to remote areas to immediately help someone bitten by any type of venomous snake. Currently, different types of snakebites have different antivenom.
It has been difficult. The wide variety of ingredients in the venom that benefit new drug research has also made it difficult to find a drug that can neutralize them. A promising universal antivenom, varespladib, is in clinical trials.
Experts hope the poison’s role will lead to more respect for the fear-inducing creatures that create them. The Doctor. Fry, for his work with blood thinners, is studying the venom of the Komodo dragons, which, at 3 meters long and weighing more than 130 kilograms, are the largest lizards in the world. It is also highly threatened.
Working on Komodo “allows us to talk about the broader conservation message,” he said.
“You want nature close by because it’s a biobank,” he added. “We can only find these interesting compounds from these magnificent creatures if they are not extinct.”