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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.
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.
The earth is filled with many types of worms, and the term “planarian” can represent a variety of worms within this diverse bunch of organisms. The slideshow below highlights fun facts about planarians from Oné Pagán’s book, The First Brain: The Neuroscience of Planarians, and provides a glimpse of why scientists like Pagán study these fascinating creatures.
In taxonomic terms, planarians belong to a large class of organisms called Vermes, the Latin term for “worm.” Platyhelminthes, or “flatworms,” represent a phylum within the class of Vermes, though the Platyhelminthes are broken down into four additional categories. One of these categories includes the Turbellarians—flatworms that are free-living and non-parasitic. Turbellarians are then arbitrarily distinguished based on their size, creating two further divisions: the microturbellarians (worms that are shorter than 1 mm) and macroturbellarians (worms that are longer than 1 mm). There are two types of macroturbellarians, the triclads and polyclads. Though “planarian” is a general term used to describe many types of flatworms, it is most often used in reference to triclads.
Triclads are small worms. They do not typically exceed one inch in length, but many of these worms are even smaller than that. Though these planarians can usually be seen with the naked eye, they are often studied under a microscope for closer observation. The two distinctive bumps that you can see on both sides of a planarian’s head, even without a microscope, are called auricles. Though they are commonly mistaken for ears, auricles do not pick up sounds in the environment, and instead contain many chemoreceptors that help planarians sense both nourishing and toxic substances in their surrounding environment.
Planarians are an ancient species. But like other invertebrates, it’s hard for planarians to fossilize because their bodies lack hard bones. Planarians’ tendency to autolyze—or dissolve head first—when they die makes the process of fossilization even more difficult. Though the fossil record for these organisms is a bit scarce, scientists have identified a fully intact turbellarian fossil from the Eocene period about 40 million years ago. Scientists have also found what they interpret as fossilized flatworm tracks from the Permian period (300 million years ago).
Planarians possess the incredible capability to regenerate cells that are damaged or removed. Though the scope of regeneration varies from species to species, many planarians are capable of full regeneration. This means that if you chop up a planarian into several pieces—the current record is 279 sections—each piece can regenerate into a full grown worm, assuming that this piece of the worm is placed in an environment with adequate nourishment. Even the isolated tip of a tail from a planarian can develop into a full grown worm that possesses a brain and central nervous system.
In the early 20th century, scientists began looking for organisms with which they could test the principles of Mendelian genetics. Most people are aware that fruit flies (Drosophila melanogaster) became a common test subject because of their short lifespans and ability to produce large quantities of offspring in a short period of time. However, planarians also became a great model organism for scientists to use. Though the planarian nervous system is simple, these flatworms display an immense array of complex behaviors—making planarians an ideal candidate with which scientists can study how the brains of more complex organisms, such as humans, function.
Planarians are not only test subjects for scientists to study. These are also creatures of popular culture, making appearances in several movies and TV shows. For example, in an episode of Fringe, Dr. Bishop offers Agent Dunham a smoothie with chopped pieces of planarians—a gesture meant to pay homage to the memory transfer experiments conducted by McConnell. Planarians have also appeared in the first movie of the Twilight saga, in addition to episodes of The Big Bang Theory and Dr. Who.
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Images: The first five photos in this slideshow have been used courtesy of Dr. Masaharu Kawakatsu. Photo six is copyrighted (2003) by the National Academy of Sciences, USA and has been used with permission.