The Insane Biology of: The Poison Dart Frog

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Deep in the forests of Central and South America, some of the world’s deadliest organisms lurk. These creatures contain such toxic chemicals that only a tiny dose is needed for them to kill a full-grown human. Poison dart frogs might be bright, cute, and minuscule amphibians, but they are absolutely nature’s version of “find out the hard way.” Just 0.2 micrograms of poison could kill a human, making this organism 100 times more lethal than the deadly inland taipan snake. There is absolutely no antidote to their poison, and no treatment to save you from a painful death.

These frogs are not exactly trying to sneak up on anyone through camouflage; in fact, they are downright flamboyant. Their colors serve as a warning to would-be predators. The deadliest of the family of poison dart frogs is known as the golden poison dart frog, which has enough poison on its skin to kill more than 20,000 mice. This little creature, which only grows up to 47 mm in size—smaller than your thumb—is absolutely covered in batrachotoxins. This alkaloid poison causes complete muscle paralysis, shutting down the heart, diaphragm, and everything else within minutes.

Their deadly secretions have been used by indigenous people for poisoned blow darts since pre-Columbian times, which is what initially gave the frogs their name. These poison darts are enough to drop monkeys and birds in their tracks. Nerve paralysis is almost instantaneous.

Today, there are several hundred species of poison dart frogs spread across tropical forests in Central and South America. Besides the golden poison dart frog, some of the other notable species include the strawberry poison dart frog, which has a variety that is considered to be wearing blue jeans, and the green and black poison dart frog, which looks like a chocolate mint. The dying poison dart frog gives off a sort of sour vibe. Other more deadly species include the splashback poison frog, the granular poison frog, and the fantasmal poison frog.

Among the hundreds of species are hundreds more types of alkaloids, many of which are deadly, some of which were unknown to science before researchers started studying these frogs. Poison dart frogs don’t make these toxins themselves; they collect them from their prey, such as arthropods like ants, mites, and millipedes.

But how is it that they can eat things that are full of such brutal poisons, and how do these frogs avoid poisoning themselves? Poison dart frogs are the only vertebrates we know of in which coloration, toxicity, and diet specialization all work together. The combination of bright colors and poison is known as aposematism. Essentially, the frogs evolved to be as bright as neon signs at the same time as they evolved to harbor toxic chemicals. Their coloration is a warning: “Eat me, and you’re in for a bad time.”

Interestingly, when the frogs are raised in captivity and fed a diet of fruit flies, they don’t develop any of the toxins. If wild frogs are brought into the lab and fed a non-toxic diet, they gradually lose their poison. Most toxic species of animals, like snakes or jellyfish, have the ability to produce the dangerous substances on their own, a trait known as endogenous biosynthesis. The ability to eat something toxic and harvest those substances for one’s own protection is called sequestration, which is pretty uncommon in the natural world. That’s what poison dart frogs do, and they manage it in ways we don’t completely understand.

These frogs have two types of glands on their skin: mucus glands and serous glands. It’s the second of these two glands that contain the toxic alkaloids. Alkaloids themselves are organic compounds that contain nitrogen, and they’re not always toxic. Things like caffeine, nicotine, and quinine are all alkaloids, and we’ve found plenty of uses for them. However, the alkaloids on the skin of poison dart frogs range from making them taste bitter to mild poison to absolutely lethal poison.

Only 10% of the known alkaloids on their skin have had their sources identified. In cases where researchers have found a source for the toxin, it’s been through the frog’s diet. One study found that strawberry poison dart frogs were getting a lot of their poison from orrited mites. These tiny mites are related to spiders and scorpions but are only about 1 mm in size. To defend themselves from being eaten, they have their own toxic alkaloids. Unfortunately for the mites, those toxins are just what the strawberry poison dart frog is looking for. The frogs collect the alkaloids from the mites and move those same poisons to their skin. The more they eat, the more poison they collect.

Other alkaloids have been traced to certain other arthropods, such as tricyclics from certain beetles, and the most deadly of all, batrachotoxins from melid beetles. In some cases, the accumulation of toxicity for the frogs isn’t linearly additive; sometimes, the frogs supercharge the poison they are collecting by modifying the structure of the alkaloids to make them more potent.

When some species of frogs eat arthropods that have a specific alkaloid called pumiliotoxin, they can selectively hydroxylate it by adding an O group, forming a new alkaloid called alop pumiliotoxin, which is five times more toxic than the original alkaloid. However, the exact mechanism for how they move these toxins around their body is still a bit of a mystery. What we do know is that they have poison glands near the surface of their skin and ducts that open up to carry the alkaloids to the surface of the skin.

When a frog is attacked by a predator, and if the predator ingests the poison, death comes swiftly. Many of the dangerous alkaloids in the frog’s skin are neurotoxins that kill by permanently blocking nerve signal transmission to the muscles. Normally, nerves work by generating electrical signals that transmit information. This electrical signal is created by the flow of ions across their plasma membranes. At rest, the inside of a neuron has a negative charge, created in part by positive sodium ions being pumped out of the cell. When a stimulus occurs, the sodium channels briefly open because there are many more positive sodium ions on the outside than on the inside of the neuron. Sodium ions rush into the neuron, the cell rapidly depolarizes, and fires an action potential, meaning the neuron fires its neurotransmitters.

However, certain toxins can completely disrupt this process. Batrachotoxin, for example, binds to and irreversibly opens the sodium channels of nerve cells. This means sodium ions can freely diffuse between the inside and the outside of the cell, and thus the membrane potential of the cell is removed. At this point, the cell becomes electrically dead, and the nerve can no longer transmit any signals, which means every single muscle becomes paralyzed, including the heart and diaphragm. Once these stop working, the organism is very dead.

Other toxins from poison dart frogs target things like the acetylcholine receptors, which renders a similar effect. What is consistently surprising about these mighty little creatures is how they aren’t poisoned by their own poison. In one case, scientists found that certain frogs protect themselves by changing the configuration of the receptors on their neurons through a single amino acid substitution. This makes it so the toxin doesn’t bind to their receptors, allowing them to continue to function normally.

Researchers have also found that the golden poison dart frog has gene substitutions and mutations that make it immune to the effects of batrachotoxins and dozens of its other dangerous alkaloids. However, what we still don’t know is how they manage to develop defenses against so many types of alkaloids. Pufferfish, for example, only have to deal with tetrodotoxin, while poison dart frogs have immunity to dozens or even hundreds of dangerous alkaloids—toxins that they don’t even produce themselves.

These poisons are so deadly that the golden dart frog is considered to be the most poisonous creature on Earth. Even just touching the golden dart frog could be lethal, especially if you have a cut on your hand. The poison could even be strong enough to enter through your sweat pores, though I don’t think many people are willing to test that out to know for sure.

Considering that this poison is so toxic that it kills any would-be predator the first time encountering it, how do predators learn to avoid this brightly colored death frog? Given the fact that hundreds of species of poison dart frogs evolved to use bright coloration in combination with poisonous skin, it would seem to indicate that it’s a successful strategy.

In one study, scientists looking at color variations among poison dart frogs found that birds were more likely to attack blue frogs than more vividly colored yellow frogs, suggesting that the birds were a bit more worried about the brighter yellow prey. The more conspicuous the frog, the safer it was. But if the poison from golden poison dart frogs is lethal if ingested 100% of the time, how can any animal learn to avoid it?

One possibility is that every frog has a different level of poison. Juvenile frogs, for example, have had less time to accumulate poison and may not kill the predator, instead giving them a highly unpleasant experience. Additionally, a predator does not need to ingest the frog to be harmed by its toxins. A predator with a wet nose that bumps into the frog while sniffing it will likely have a bad time but perhaps not die. These situations could allow the predator to learn from past experience that a bright frog is a bad frog.

Beyond this, for some predators, avoiding brightly colored animals may simply be hardwired genetically. Over millions of years, predators that were more inclined to avoid brightly colored prey survived more often. But what about predators that don’t even have color vision, like the bullet ant and broad spiders? Both of these arthropods are big enough to prey on small frogs and are known to do so on a fairly regular basis. They also don’t rely on color vision when they’re hunting. Do they know to avoid the dangerous frogs?

Researchers presented bullet ants and broad spiders with two species of frogs: the non-toxic Bransford’s litter frog and the toxic strawberry dart frog. Bullet ants would eat juveniles of the strawberry dart frog but not the adults, and the spiders wouldn’t touch any of the toxic frogs, no matter their age, even though they did eat the non-toxic species. These predators still knew which frogs to avoid, likely using means of chemoreception.

However, the poisonous frogs can’t always be certain that they’re safe from predation. One species of snake called the fire-bellied snake has evolved a resistance to batrachotoxins in the golden poison dart frog. It’s the only known predator of this frog, and the royal ground snake, another species in the same snake genus, was observed to attack and kill three-striped poison frogs. This was the first time this behavior has ever been seen in the wild, suggesting an arms race between predators and poison dart frogs.

As dangerous as these frogs might be to predators, they are not invincible. Even with their chemical arsenal, about a quarter of poison dart frog species are classified as endangered or critically endangered due to habitat loss, fungal infection, and the exotic pet trade—all factors that these small frogs can’t fight against with their toxic skin.

Nonetheless, these small frogs punch above their weight class in terms of lethality and show us that even the tiniest, cutest things can be a force to be reckoned with. Unfortunately for us humans, we can’t absorb the poison that we eat and use it as a weapon, but there is something else that we can absorb: knowledge.

By understanding the genetic underpinnings of the poison dart frog’s resistance to poison, we might one day learn how to be resistant to certain poisons ourselves. By understanding the evolution of poison dart frogs, their predators, and their prey, we will better understand how to conserve them. Understanding biology and the math, chemistry, and physics it all entails is the best tool we have to protect ourselves and the incredible world we live in.

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