How To Survive Poison

While a lot of animals can sequester toxins, it’s done most iconically by monarch butterflies. Their beautiful orange, black, and white wings contain some nasty chemicals. When a bird takes a nip out of a monarch wing, that’s guaranteed to make it ill; the butterflies can survive a damaged wing, and the birds can learn they’re not worth eating. Anurag Agrawal at Cornell University studies this, and Phil Sansom asked him where and how the monarchs pick their poisons...

Anurag - The monarchs are the quintessential example of a butterfly that gets its poisons from its food. The monarch caterpillar feeds on the milkweed leaves and the milkweed leaves are producing poisons called cardiac glycosides

Phil - Cardiac glycosides, you said?

Anurag - Yeah - they bind to a universal animal enzyme and they stop it from functioning, which is what makes them poisonous to most animals.

Phil - What's the enzyme?

Anurag - The enzyme is the sodium-potassium pump and every animal cell, whether it's our human bodies or an insects body, uses this enzyme to shuttle salts across the cell membrane - it's a very critical cellular function. And without that, basically, the cell starts to have either too much salt inside or not enough, which basically causes the system to crash.

Phil - Sounds like a nasty poison!

Anurag - Nasty poison - and very general in the sense that all animals use these pumps so it's going to be very poisonous.

Phil - I just have to ask, you said they were called cardiac though. That means heart, right?

Anurag - Great question yeah. The name cardiac glycoside comes from the fact that these compounds have been used historically in traditional cultures to treat congestive heart failure. There've been several really interesting intersections of societal happenings with cardiac glycosides. And one of them is that Vincent van Gogh, as I assume all the listeners will know, in the last two years of his life and in his paintings, they took a turn. His paintings started having much more yellow, and halos around the lights that are so famous in starry night or in the sunflower paintings. Van Gogh was being treated for epilepsy at the time with extracts of the foxglove plant, which have cardiac glycosides. What we now know is that a side effect of too much of this medicine is yellow vision and seeing halos around bright objects.

Phil - That's amazing. Now I assume the monarch butterflies aren't having their cells unable to take salts in and out, and they're not getting their heart conditions treated. How do they not have all this stuff happen to them?

Anurag - The monarch butterfly has three specific mutations that we're aware of in the genes that code for its sodium potassium pump. Quite remarkably, those three single base pair changes alter the physical structure of that pump, making it about 200 times less likely that a cardiac glycoside will bind and stop that pump from functioning. There probably are other little changes, but there's three main ones that really change the shape of that sodium potassium pump.

Phil - But then the butterflies and the caterpillars go beyond that don't they? Because you said that they actually not only get resistant to the poison, but start to use it themselves.

Phil - Absolutely. Yeah. I think one of the most fascinating things about monarch butterflies is they are themselves poisonous and they advertise it with that highly contrasting orange, black and white coloration. The monarch brings those compounds into its body, packs them away in its wings primarily, and that gets used then as the monarch's defence against predators like birds.

Phil - How sort of physically is it doing that?

Anurag - That's a great question. I'd say we don't have all of the answers. So some of these chemical compounds have chemical attributes that allow them to move throughout the body very quickly crossing membranes. So that would be a passive mechanism of chemical movement into the caterpillars body. The average milkweed plant, however, has, you know, 20 different forms of these cardiac glycosides. And some of them would not be naturally moving passively through the body. And the caterpillars, the monarchs, actively use transporters to move them around to particular places in their body.

Phil - Do you know what genetically is going on in the butterflies that has allowed this to happen?

Anurag - I would say that's one of the big mysteries that we are trying to unravel. From the passive part, it's certainly possible that once an organism becomes tolerant of the compounds, some of them end up in the body accumulating. In experiments we've done with Drosophila the fruit fly we've altered the genes, those same three genetic changes, once they become tolerant of cardiac glycosides small amounts of them already start to accumulate in their bodies.

Phil - You know, it all sounds like a lot of effort to go through when you could just eat a plant that's not poisonous.

Anurag - No question - it's a lot of effort! But one of the consequences is you've got that resource largely to yourself. You know, one of the axioms in nature is that specialisation is beneficial. A jack of all trades is master of none. But we can't really think of it just as the Monarch butterfly deciding to specialise in eating the milkweed. What really more likely happened is that the monarch butterfly ancestor made initial steps towards feeding and specialising on milkweed. In response to that, the milkweed reciprocally evolved a host of defences to try to push the monarchs away. We call that coevolution when two species are going back and forth, evolving in response to each other.

Humans can become resistant to poisons via the body’s inbuilt adaptability. Eating small amounts of them is sometimes successful; and the technique is called Mithridatism, after a famous figure from classical history called Mithridates who pioneered the technique. Historian Adrienne Mayor described the man to Phil Sansom...

Adrienne - Mithridates was a powerful king of a small kingdom on the black sea. He was born in the second century BC. He was quite a successful rebel against the Roman Republic.

Phil - When did he first start taking poison?

Adrienne - I think he began experimenting even as a young man. When he took over the kingdom, he poisoned his mother and brother, and then he began experimenting himself with poisons and antidotes because he was always in danger of poisoning himself. His mother, even when he was a child, attempted to poison him. Poisoning was pretty rife in that time and place. He experimented on himself and his friends at first, and then when he became a powerful king, on condemned criminals and even allies and enemies. So he goes down in history as the world's first experimental toxicologist.

Phil - Wow. What kind of poisons are we talking about?

Adrienne - Well, there were myriad poisons known in antiquity from toxic plants to snake venoms. There was even poisonous honey in his territory made by bees that fed on toxic plants and then made honey that was a neurotoxin. And there were also many minerals in his kingdom that were highly toxic, such as arsenic.

Phil - Instead of using an antidote, did he actually build up a resistance to them just from taking the poison itself?

Adrienne - Yes. Arsenic was probably the most common poison in those days and it was sometimes called the powder of succession. It's odourless, doesn't have a flavour, but highly toxic. So that would have been the first poison that Mithridates sought to defend himself against because he had used it to poison so many people in his family and other enemies. Now arsenic interferes with metabolism. If you take small doses, however, very tiny doses of it, your liver produces enzymes that will inactivate the arsenic. And if you keep taking these small doses, it allows the liver to produce more of those enzymes that allow you to survive what would normally be a lethal dose. So Mithridates first achieved that. And then in his toxicological experiments with plants and other poisons, he was essentially investigating whether a similar process might work with plant poisons and venoms and other toxic minerals. That's a real scientific method that he was using. And we're talking about the first century BC. So it is quite an incredibly scientific approach to finding an antidote.

Phil - At the same time, it sounds like it's a really dangerous one, right?

Adrienne - Yes. I think it would be dangerous, but he had access to all kinds of resources. It's possible that he even had Hindu treatises on antidotes and poisons. He was able to speak more than a dozen languages. And of course it was risk-taking, but he felt it was worth trying to find a universal antidote. And he finally did come up with a concoction that later became known as the Mithradatium. But Mithridates' invention, you might say, was to not just include beneficial substances, but to also include tiny amounts of poisons or toxins as I said. We do have all of this documented in ancient sources, the problem is we don't know the exact recipe of his concoction that has been lost. On the other hand, physicians of the Roman emperors after the death of Mithridates claimed that they had the recipe of the Mithridatium and every Roman emperor thereafter took a concoction that they believed was the Mithridatium. All royalty throughout Europe took it - I believe up through Elizabeth the first.