Can you imagine a circumstance when it would be beneficial to eat something poisonous? Perhaps you could see the benefit if, in low doses, it also acted as a medicine by poisoning parasites, as in the cases of fruit flies (and humans) consuming alcohol or other drugs. Many of our pharmaceuticals are toxic in moderate doses. But under no circumstance would you want adaptations that kept those toxins around in your body, where they could do you harm, right? Turns out, this biological phenomenon is common enough it has a name: sequestration. Specifically, sequestration is the evolved retention of specific compounds, which confers a selective advantage through chemical defense or another function.
As implied by the above, toxins are just chemical compounds that interfere with the normal biological processes of cells. Because of the wide diversity of cell types and the high specificity of toxins, some toxins may be dangerous only to some targets and not others. However, many toxins are broad in their ability to attack cellular targets. For example, a toxin called tetrodotoxin blocks voltage-gated ion channels in skeletal muscles, preventing the propagation of the action potentials required for motion and causing paralysis in nearly all vertebrates. Sequesterers take advantage of these broadly toxic molecules by stealing toxins synthesized by animals or plants in their diet (to which they are necessarily tolerant). This could be less energetically expensive than synthesizing toxins themselves from nontoxic precursors, or they may lack the evolutionary pre-adaptations necessary for said synthesis. It could be assumed that resistance or immunity to the sequestered defensive compounds (SDCs) is an evolutionary prerequisite for sequestration, but for SDCs with highly specific targets, segregation of these toxins from their targets in the sequesterer’s body might be sufficient.
Sequestration spans a continuum from simple accumulation of toxins in unmodified tissues to the evolution of specialized delivery systems. It has been studied extensively among invertebrates, but relatively few examples of vertebrate SDCs have been documented. In a newly-published review article in the journal Chemoecology, Alan Savitzky and colleagues chronicle the biology of amphibians and non-avian reptiles that sequester toxic compounds from their prey. They also lay out a framework for exploration and discovery of new SDC systems within Tetrapoda (refresher course), which they predict will result from collaboration between field biologists and natural product chemists, and may lead to exciting new ecological, physiological, biomedical, and evolutionary discoveries.
Our current knowledge of sequestration in tetrapods is organized around three types of systems: tetrapods that eat toxic arthropods, tetrapods that eat toxic mollusks (or molluscs if you prefer), and tetrapods that eat other toxic tetrapods, especially toxic amphibians. It’s worth noting that, in each of these systems, the possibility exists that SDCs are moving across two or more trophic levels (that is, the arthropods, mollusks, or amphibians in question are themselves sequestering toxins from plants or fungi), although no one has yet conclusively shown this to be the case.
In fact, it’s not surprising that so little is known about SDCs. It was only in 1994 that they were discovered by the late chemist John Daly in Neotropical dendrobatid frogs (more popularly known as poison arrow or poison dart frogs), although Daly had been collecting and cataloguing poison dart frog toxins since 1964, under the assumption that they were being synthesized by the frogs themselves. In a series of experiments, Daly and his colleagues have shown that poison dart frogs lack toxins in captivity, that they can acquire them when given access to toxic prey, and that toxin profiles of wild frogs vary over time, in conjunction with variation in diet. Sequestration is now known to have evolved independently in five different lineages of frogs, all of which sequester lipophilic alkaloids from their diet of arthropods, including ants, beetles, millipedes, and oribatid mites. They also share a variety of other convergent traits, from small body size to aposematic coloration and diurnal activity, despite being found in places as disparate as Cuba, Australia, South America, and Madagascar.
It wasn’t until the year 2000 that confirmation of SDCs in other vertebrates arrived, with the discovery that the feathers of two genera of passerine bird from New Guinea contained nearly the same toxins as the skin glands of Neotropical poison frogs. Hints at this SDC system extend as far back as 1990, when University of Chicago PhD student Jack Dumbacher noticed burning in his tongue and lips from sucking on a cut after handling hooded pitohuis entangled in his mist nets. The exact source of these SDCs has yet to be proven beyond a doubt, but the most likely candidate is melyrid beetles of the genus Choresine, which contain the batrachotoxins and are eaten by the hooded pitohui and related species of toxic New Guinea passerine. These are the same chemicals that Neotropical poison frogs sequester from their arthropod prey.
In 2004, Becky Williams and colleagues published a paper documenting the first known instance of SDCs in a non-avian reptile. The Common Gartersnake (Thamnophis sirtalis) preys upon the Rough-skinned Newt (Taricha granulosa), which contains the neurotoxin tetrodotoxin (TTX) in the skin. Gartersnakes harbor sufficient amounts of active toxin in their own tissues to incapacitate or kill avian and mammalian predators for several weeks after consuming a newt. Because many people mistakenly call venomous snakes ‘poisonous’ (to a biologist, venoms are actively injected, whereas poisons must be passively ingested), Williams et al. took pains in their title to emphasize that they were in fact describing a poisonous snake.
An Asian relative of the gartersnake, Rhabdophis tigrinus, was conclusively shown to sequester bufadienolide toxins from toads in 2007 by Debbie Hutchinson and colleagues, although it was suspected for years beforehand. Sequestration in Rhabdophis is more sophisticated than in Thamnophis, because of unique glands on the back of the neck, known as nuchal glands, where the toxins are stored. More amazing, in 2008 the same research team showed that mother Rhabdophis are capable of passing SDCs to their offspring. It’s likely that close relatives of R. tigrinus, which also possess nuchal glands, are also sequestering toad toxins. In fact, snakes of the subfamily Natricinae, to which both Thamnophis and Rhabdophis belong, seem to be remarkably resistant to a variety of toxins. Toxins of invasive Cane Toads (Rhinella marina) have proven lethal to many of Australia’s native reptiles, with the exception of the sole natricine species, Tropidonophis mairii.
One thing that seems to come hand in hand with the sequestration of toxins from prey is exhibiting some kind of passive defense, such as aposematism (warning coloration), mimicry, or death-feigning. These passive defenses contrast with active defenses, better known as fighting back or running away, because they seem to expose their user to great potential risk from very brave or stupid predators. This is where the SDCs come into play. If they are noxious, but not lethally toxic, then there is potential for predators to learn to avoid prey that exhibit the passive defense. This has been shown to occur in visually-oriented bird predators, and predators such as mammals, that rely more on olfaction, might also pick up on chemosensory cues. If instead the SDCs are lethal, then natural selection takes over: predators that avoid prey exhibiting the passive defense survive and pass on that trait (assuming avoidance behavior is heritable), whereas predators that don’t avoid those prey are killed by the toxins. In some mammals, avoidance of the passive defense might be transmitted from parent to offspring culturally, rather than by genes.
In many systems involving SDCs, either Müllerian or Batesian mimicry, or both, have evolved as strategies to exploit this highly effective antipredator adaptation. Müllerian mimicry is a form of mutualism, in which different toxic species benefit by having the same aposematic colors or patterns. Batesian mimicry is more exploitative: a model species is truly toxic, whereas other species resemble (mimic) the model but are nontoxic. Whatever costs toxin sequestration incurs, these Batesian mimics avoid them, but reap the antipredator benefits. Sometimes, species thought to be Müllerian mimics turn out to be Batesian mimics, or vice versa, because it takes a lot of careful chemistry to determine which species are toxic and which aren’t. Of course, the quick way is just to taste them, but that only works once.
If you want to learn more, check out the several other papers in the September 2012 issue of Chemoecology, dedicated to John Daly, or some of the other sources listed below.
Daly JW, Martin Garraffo H, Spande TF, Jaramillo C, Stanley Rand A, 1994. Dietary source for skin alkaloids of poison frogs (Dendrobatidae)? Journal of Chemical Ecology 20:943-955. <link>
Daly JW, Secunda SI, Garraffo HM, Spande TF, Wisnieski A, Cover JF, 1994. An uptake system for dietary alkaloids in poison frogs (Dendrobatidae). Toxicon 32:657-663. <link>
Dumbacher J, Spande T, Daly J, 2000. Batrachotoxin alkaloids from passerine birds: A second toxic bird genus (Ifrita kowaldi) from New Guinea. Proceedings of the National Academy of Sciences 97:12970-12975. <link>
Dumbacher JP, Wako A, Derrickson SR, Samuelson A, Spande TF, Daly JW, 2004. Melyrid beetles (Choresine): A putative source for the batrachotoxin alkaloids found in poison-dart frogs and toxic passerine birds. Proceedings of the National Academy of Sciences 101:15857-15860. <link>
Hutchinson D, Mori A, Savitzky AH, Burghardt GM, Wu X, Meinwald J, Schroeder FC, 2007. Dietary sequestration of defensive steroids in nuchal glands of the Asian snake Rhabdophis tigrinus. Proceedings of the National Academy of Sciences 104:2265-2270. <link>
Hutchinson DA, Savitzky AH, Mori A, Meinwald J, Schroeder FC, 2008. Maternal provisioning of sequestered defensive steroids by the Asian snake Rhabdophis tigrinus. Chemoecology 18:181-190. <link>
Mori A, Burghardt GM, Savitzky AH, Roberts KA, Hutchinson DA, Goris RC, 2011. Nuchal glands: a novel defensive system in snakes. Chemoecology 22:187-198. <link>
Saporito RA, Donnelly MA, Norton RA, Garraffo HM, Spande TF, Daly JW, 2007. Oribatid mites as a major dietary source for alkaloids in poison frogs. Proceedings of the National Academy of Sciences 104:8885-8890. <link>
Saporito RA, Spande TF, Garraffo HM, Donnelly MA, 2009. Arthropod alkaloids in poison frogs: A review of the 'dietary hypothesis'. Heterocycles 79:277-297. <link>
Williams BL, Brodie Jr. ED, Brodie III ED, 2004. A resistant predator and its toxic prey: persistence of newt toxin leads to poisonous (not venomous) snakes. Journal of Chemical Ecology 30:1901-1919. <link>