Poison sausages and platypus venom
looks at the weird history of poisons turned medicines
When researchers develop new medicines, eye of newt, adder’s fork and blindworm’s sting don’t come close. Drugs based on venoms, toxins and poisonous blood sausages are medical mainstays. Now, the venom from a creature that 18th century naturalists believed was a hoax might lead to new treatments for a common, deadly disease.
We’ll begin in 1793 in the village of Wildbad, southwest Germany, where 13 people fell ill after eating blood sausage. Six died. Blood sausages caused several other outbreaks of fatal food poisoning around the same time; so between 1817 and 1820 the German doctor and poet Justinus Kerner investigated a ‘fat poison’ he extracted from ‘sour’ sausages. Despite killing several animals with the extract, he tested the ‘fat poison’ on himself. A few drops on the tongue caused marked drying of Kerner’s mouth and throat. In 1869, John Müller, another German physician, coined the name botulism, from
botulus, the Latin for sausage. We now know that botulinum toxin kills by excessively relaxing and paralysing muscles; but in tiny doses, it is invaluable for treating, among other conditions, spasticity, excessive sweating, chronic migraine, bladder problems and, of course, reducing the appearance of wrinkles. Yet just a gram of inhaled crystalline botulinum toxin would kill more than one million people.
Botulinum toxin isn’t an isolated example of a poison turned medicine. In the 1970s, researchers discovered that extracts of the venom of the Brazilian pit viper ( Bothrops
jararaca) inhibited angiotensin converting enzyme (ACE), a
The platypus sank its spurs into his right arm and held on
protein that helps control blood pressure. The discovery led to the development of captopril, the first of a now widely used group of drugs called ACE inhibitors. More recently, a toxin from a marine cone snail – which fires a venomladen harpoon at its prey – led to ziconotide, which often alleviates otherwise intractable pain.
Meanwhile, drugs based on venoms from other species help treat diabetes, which causes about 24,000 premature deaths each year in England alone. Insulin isn’t the only hormone that controls blood sugar levels. Your gut, for example, produces a protein called glucagon-like peptide-1 (GLP-1) that has several anti-diabetes actions. However, GLP-1 is rapidly broken down: about half the amount in the blood is gone in just two minutes or so. This short action means that human GLP-1 isn’t any use as a drug for diabetes. Then, in the early 1990s, researchers extracted a protein called exendin-4 from the venom of the Gila monster ( Heloderma suspectum). Exendin-4 triggers the same biological pathways as GLP-1. But the sequence differs. Human GLP-1 is usually 30 amino acids long. Amino acids are, of course, the building blocks of protein. Imagine sticking 30 bricks together: that’s human GLP-1. Now switch 15 bricks. That’s how much exendin-4 differs: half its amino acids are different from human GLP-1. The differences make exendin-4 resistant to DPP-4. So, it’s broken down much more slowly and the person with diabetes benefits for longer. Exenatide – synthetic exendin-4 – is now a mainstay of diabetes treatment. But it’s not the only unusual potential source of new diabetes treatments. A recent study suggests that future drugs for diabetes might trace their heritage to venom from the duck billed platypus ( Ornithorhynchus anatinus).
When a dried platypus arrived in London in 1799, the eminent naturalist George Shaw wondered if it was a “colonial prank”. After all, Asian taxidermists regularly stitched the head and trunk of a monkey to a fish tail to create a ‘mermaid’. There are, however, three families of living monotremes; the longand short-beaked echidnas and the platypus. In common with reptiles, amphibians and birds, but unlike most mammals, the alimentary and reproductive tracts share an exit – thus the name monotreme, from the Greek for one hole. Monotremes also lay eggs, which pass through the same opening as urine and fæces. The male platypus has a sharp spur in the ankle of its hind legs connected to a venom gland behind the knee. Some fossil mammals from the Mesozoic (252 to 66 million years ago) have similar structures. Such characteristics led some authors to describe monotremes as primitive. Yet they are remarkable survivors and masters of their environmental niches. After all, an ancestor of today’s monotremes lived in Argentina, just after the demise of the dinosaurs, and they are still around – as some people, and dogs, found to their cost.
In 1816, the Irish surgeon John Jamison shot a platypus in New South Wales. When the overseer picked the injured animal up, the platypus sank its spurs into his right hand and held on until it was killed. The overseer’s arm swelled “prodigiously” and he exhibited symptoms similar to those of a bite from a venomous snake. By massaging the animal’s hind legs, Jamison found the platypus ejected poison from the spur. In 1869, a platypus spiked a fisherman in the finger. The pain was intense, the man’s entire arm swelled and he developed symptoms reminiscent of snakebite. Although painful, platypus venom doesn’t seem to be fatal to humans. However, several dogs died after being spiked. Nevertheless, the amateur naturalist Augustus Simson, who experienced excruciating pain after being spiked, reported that some indigenous people would rather hold a snake than a platypus.
Recently, researchers from the University of Adelaide’s School of Biological Sciences discovered that monotremes express GLP-1 in their intestines and venoms. Platypus GLP-1 differs in about a third of the amino acids from humans, including the site at which DPP-4 cleaves the hormone. Again, it’s resistant to the rapid degradation normally seen in humans. In the platypus gut, GLP-1 regulates blood glucose. But it’s also in their venom, used to fight off other males in the mating season. This probably triggered the evolution of a stable form of GLP-1. These findings could lead to a new diabetes drug. Yet we’re just scratching the surface of venom’s pharmacological potential. After all, venom from a single species can contain hundreds or even several thousands of chemicals. And biologists have studied few venomous animals in detail. I’m waiting for the first drug based on the venom of the Mongolian death worm…
2 MARK GREENER is a medical writer, FT contributor and clinical editor of Pharmacy Magazine.