Chemical warfare in terrestrial flatworms

Biologically-produced toxins include some of the most interesting substances in nature. As advanced as the chemical sciences are, nothing beats nature in terms of the wide variety of structures with specific biochemical properties. Toxins are one of the most effective mechanisms of defense or predation, generally used by organisms lacking traits like sheer size, strength, fast speed, agility, the ability to fly, or the capacity of technological intelligence (yes, this last one is us). I find this one of the most fascinating aspects of biology. As I said in the very first paragraph of my PhD dissertation:

“Nature is the best chemist. During the course of evolution, through literally millions of years, a wide variety of organisms have developed substances used for defense against predators, or to become predators themselves. As part of the evolutionary process, chemical structures beneficial for the survival of the organism are conserved; many of these molecules include small organic toxins.”

If you think about it, it is amazing how many different organisms use chemical compounds as a survival strategy. Such compounds represent the difference between survival and death in these organisms. Once we realize the true extent of chemical diversity in nature, it is no wonder that this embarrassment of riches is used by life. For example, plants and microorganisms account for about half a million unique compounds. According to Richard Firn in Nature’s Chemicals, plants alone are estimated to produce about a million tons (!) of chemical compounds every year.

One of the best-known, and paradoxically least understood toxins is called tetrodotoxin (TTX). This is a rather mysterious molecule. It was originally discovered in a species of pufferfish, of fugu fame (a delicacy in Japan) in 1909, but the toxic properties of pufferfish have been known since at least the 1700s. Its mechanism of action entails the blocking of certain ion channels that control neuromuscular function. There is no antidote. TTX is present in quite a few other types of marine organisms, including the blue-ringed octopus, several crab species as well as a variety of worms (including polyclad flatworms), snails and starfish among many others. Remarkably, amphibians like certain frogs and newts also possess TTX. The most likely mechanism through which organisms acquire this toxin seems to be symbiotic bacteria, but this has not been demonstrated in every single case, especially in terrestrial species. To add more complexity to the matter, there are at least twelve “versions” of tetrodotoxin.

Up until very recently, despite the widespread distribution of TTX in nature, it was never observed in any known invertebrate species. Here’s where flatworms come in.

Some of the most interesting invertebrates include land planarians, many of which display a distinctive “hammerhead” morphology. All known species of land planarians are predators and many land planarians are considered invasive species and agricultural pests because one of their preferred prey are earthworms.

Like many planarians, the land variety displays rather sophisticated “hunting” behaviors. Upon encountering an earthworm, the flatworm performs a maneuver called “capping” where it covers the earthworm’s head region, minimizing its escape behavior, even in individuals significantly larger than the flatworm. In fact, upon capping, the earthworm frequently seems to be paralyzed, which hinted at the presence of a toxin.

These observations ignited the curiosity of Dr. Amber N. Stokes, of the Department of Biology at California State University and collaborators, who hypothesized that the toxin in question was TTX, based on the behavioral response of salamanders that were fed with certain land planarians. In a recent paper, they reported that the planarian toxin seems to be TTX in the two species of land planarians studied, Bipalium adventitium and Bipalium kewense. Their results suggest that these flatworms use tetrodotoxin for both predation and defense. In addition to the documented paralysis-like state that the planarians induced in earthworms, the authors observed that salamanders offered these planarians as food tended to reject them and that in the case of B. adventitium, TTX accumulates in their egg capsules. Research is underway to conclusively demonstrate that tetrodotoxin is the actual toxic agent in these flatworms.

This is just one example of the usefulness of planarians as experimental organisms beyond their traditional use in regeneration and developmental biology research. These fascinating worms are experiencing a “scientific renaissance”, particularly in the areas of pharmacology, toxicology, and the neurosciences. They are ideal, tractable subjects to investigate aspects of these disciplines in an integrated way, as they can be easily examined from the molecular to the behavioral level.

These are exciting times in planarian research!