22 December 2009

Why are pufferfishes deadly and not dead?

Pufferfishes contain tetrodotoxin, among the most powerful natural toxins known. Cooking does not neutralise it and 2 milligrammes can kill a human. Tetradotoxin attacks nerves that are found in many animals including the pufferfish itself. How is it that the toxins in a pufferfish that make it deadly doesn't kill the pufferfish itself?
Milk-spotted pufferfish (Chelonodon patoca)
Pufferfishes are sometimes seen on our shores.

In particular as the toxins are not made by the fish. Evidence suggests the fish gets it from tetrodotoxin-producing bacteria that is found in its food. For instance, pufferfishes artificially raised in filtered, bacteria-free water, are nontoxic.

So, why aren’t pufferfishes dead?

Whatever Doesn’t Kill Some Animals Can Make Them Deadly
Sean B. Carroll, New York Times 21 Dec 09;
Have you ever tried to think up the worst meal you could imagine? How about blue-ringed octopus, floral egg crab, basket shell snails and puffer fish.

Sure, some people may think these are delicacies, and puffer fish is certainly treated as such in parts of Asia. But each dish has something more important in common: they are all deadly. Each of these animals is chock full of a powerful neurotoxin called tetrodotoxin.

First isolated from the puffer fish, tetrodotoxin is among the most potent toxins known. It is 100 times as toxic by weight as potassium cyanide — two milligrams can kill an adult human — and it is not destroyed by cooking. Just half an ounce of the fish liver, known as fugu kimo in Japan and eaten by daring connoisseurs, can be lethal. When ingested, the toxin paralyzes nerves and muscles, which leads to respiratory failure and, in some cases each year, death.

In 1975, the Kabuki actor Bando Mitsugoro VIII ordered four fugu kimo in a restaurant in Kyoto, claiming he could resist the poison. He was wrong.

Tetrodotoxin is found in more than just marine creatures. It is present in high concentrations in the skin of certain newts in North America and Japan, and in several kinds of frogs in Central and South America and Bangladesh. The widespread occurrence of tetrodotoxin poses some intriguing riddles. First, how is it that such different animals, belonging to separate branches of the animal kingdom, have all come to possess the same deadly poison? And how is it that they are able to tolerate high levels of tetrodotoxin while others cannot?

The questions are particularly interesting because, in general, animal toxins are distinct and specific to each group. For instance, the venoms produced by snakes and scorpions are made of different kinds of toxins. But the tetrodotoxin found in each dish of that deadly buffet is identical.

One explanation could be that each of these animals has independently found a way to synthesize tetrodotoxin. But the toxin is a rather complex molecule that requires several chemical steps to assemble. It seems very unlikely that the molecule would be invented many times over in different animals. Rather, the evidence suggests that animals do not make the toxin themselves.

For instance, when puffer fish are raised in aquariums with filtered, bacteria-free water, they are nontoxic. Similarly, when Japanese newts or Panamanian frogs are raised on special diets, they lose their toxicity. These experiments indicate that tetrodotoxin-bearing animals obtain the toxin from the food chain. Indeed, several species of tetrodotoxin-producing bacteria have now been isolated from puffer fish, the blue-ringed octopus, certain snails and other animals. It appears that the animals become toxic by sequestering the bacterially produced toxin in their tissues.

While those discoveries solve the mystery of the source of tetrodotoxin, they do not quite explain how so many kinds of animals exploit it. Tetrodotoxin attacks an ancient feature of the animal kingdom, blocking channels that normally control the movement of sodium ions across nerve and muscle cell membranes and halting their electrical activity. All animals have these sodium ion channels, and the part of the channel that tetrodotoxin fits into and blocks is generally very similar among them.

This fact raises a simple question: Why aren’t puffer fish dead? How are tetrodotoxin-bearing animals able to withstand high levels of a substance that attacks their nervous systems?

One clue is that not all 120 or so species of puffer fish are toxic or resistant to tetrodotoxin. Toxic species can withstand about 500 to 1,000 times the concentration of tetrodotoxin compared with nontoxic puffers or other fish. The flower egg crab is similarly resistant, and the Japanese newt can withstand an even greater relative concentration of toxin. Most other crabs and newts are sensitive to tetrodotoxin. There must be something different then about toxic, tetrodotoxin-resistant species.

That difference becomes clear from examining their sodium channels in detail. Puffer fish have eight versions of these channels encoded by eight separate genes. Manda Clair Jost and her colleagues at the University of Texas at Austin and the University of Chicago have discovered that in toxic puffer fish, most or all of these channels have evolved resistance to tetrodotoxin and different groups of puffer fish appear to have independently acquired resistance. Toxin-resistant channels have also been identified in a Japanese newt.

So the most plausible chain of events for the evolution of high-level toxin resistance is that mutations initially occur that afford some protection and that the continuing presence of tetrodotoxin in the environment selects for animals bearing additional mutations until, over time, many or all channels are highly resistant. In this sense, what does not kill the evolving animals makes them stronger, and deadly.

In most cases, tetrodotoxin is an effective defensive weapon. But in the game of natural selection, victory is rarely total or permanent. Predators could evolve resistance via the same path that made prey toxic, and this is exactly what has happened in some snakes in the western United States that now feast on highly toxic newts.

Unlike most snakes that are immobilized, sickened or killed when they try to ingest these newts, members of three species of garter snakes are able to dine on the toxic amphibians. A team of researchers led by Edmund Brodie Jr. of Utah State University and his son Edmund Brodie III of the University of Virginia found that the species have independently evolved tetrodotoxin-resistant sodium channels. Indeed, some snakes from California are so resistant that the dose of toxin needed to immobilize them is sufficient to kill 900 people.

Remarkably, some of the same channel gene mutations responsible for conferring partial resistance to tetrodotoxin have occurred in different snake species. Moreover, some of these and other mutations have also occurred repeatedly in puffer fish channels.

These precise parallels in channel evolution among species reveal a surprising facet of evolution that biologists had no inkling of before the ability to pinpoint adaptive changes in DNA — namely, that evolution is more reproducible than previously thought. The simple explanation for that profound insight is that given similar agents of natural selection (tetrodotoxin in this case), very different species living in different places on the planet will evolve similar or identical adaptations.

It follows then that evolution is somewhat predictable. Given the prevalence of tetrodotoxin-producing bacteria and the many known uses of the toxin as a defensive weapon strategy, we should expect to find more toxic animal species.

With luck, the discoveries will not be made at dinner.

Sean B. Carroll, a molecular biologist and geneticist, is the author of “Remarkable Creatures: Epic Adventures in the Search for the Origin of Species.”

More about pufferfishes (Family Tetraodontidae) on our wild shores.

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