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Poisonous Snakes Can’t Resist Toxic Toad Tucker…or Can They?

The views expressed are those of the author and are not necessarily those of Scientific American.


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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.

Hahnel’s Pale-striped Poison Frog (<em>Ameerega hahneli</em>) from Ecuador. Photo by Andrew Durso

Hahnel’s Pale-striped Poison Frog (Ameerega hahneli) from Ecuador. Photo by Andrew Durso

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.

A melyrid beetle (genus Choresine, left) and hooded pitohui (Pitohui dichrous, right). Photo by John Dumbacher

A melyrid beetle (genus Choresine, left) and hooded pitohui (Pitohui dichrous, right). Photo by John Dumbacher

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.

 

Subadult Rough-skinned Newt (Taricha granulosa) in unken posture, advertising toxicity. Photo by Andrew Durso

Subadult Rough-skinned Newt (Taricha granulosa) in unken posture, advertising toxicity. Photo by Andrew Durso

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.

Tiger Keelback (Rhabdophis tigrinus) showing nuchal glands. Photo by Deborah Hutchinson

Tiger Keelback (Rhabdophis tigrinus) showing nuchal glands. Photo by Deborah Hutchinson

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>

 

Andrew Durso About the Author: Andrew Durso is a PhD student at Utah State University studying toxin sequestration by snakes. You can read more of his writing at his blog, Life is Short but Snakes are Long, or follow him on Twitter @am_durso. Follow on Twitter @am_durso.

The views expressed are those of the author and are not necessarily those of Scientific American.






Comments 23 Comments

Add Comment
  1. 1. Sean McCann 10:51 am 08/21/2012

    That is just great! A fascinating article..Thanks for writing it!

    Link to this
  2. 2. amdurso 2:44 pm 08/21/2012

    You’re welcome! Thanks for reading it!

    Link to this
  3. 3. llaferte 5:00 pm 08/21/2012

    I agree, fascinating. It brings to mind grandmothers stories about chickens eating poison-ivy berries to kill off internal parasites. Thanks.

    Link to this
  4. 4. Bill_Crofut 6:20 pm 08/21/2012

    Re: “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….Sequestration is now known to have evolved independently in five different lineages of frogs…”

    How does the current knowledge of sequestration, based on observation, lead to the claimed knowledge of evolution of the feature which would seem to be unobserved?

    Link to this
  5. 5. egodinez 8:54 pm 08/21/2012

    Very interesting paper. It reveals complex adaptations in several kind of animals related with evolution of the prey strategies. Congratulations!

    Link to this
  6. 6. rcdohare 3:06 am 08/22/2012

    That may be true for human being also.As Eskimose blood have antifreezing molocules which might be coming from sea food/their body is synthesing it, Arebian people have low cholestrol although they are eating red meat.

    Link to this
  7. 7. amdurso 1:07 pm 08/22/2012

    @Bill_Crofut: I’m not sure I understand exactly what you mean, but if you’re asking how it can be that sequestration has evolved at least five times in frogs alone, despite there being only three “types of systems” (arthropod, gastropod, and amphibian-eaters), it’s because all five frog groups are sequestering from arthropods, so they fall within the first of the three systems. We know that sequestration has evolved at least five times in frogs because most frogs don’t sequester toxins, including ancestral frogs like Ascaphus and Leiopelma, but these five unrelated families of frogs do (these are Mantellidae, Myobatrachidae, Bufonidae, Eleutherodactylidae, and Dendrobatidae, although bufonids and dendrobatids are closely related, so it could have been just four times).

    Link to this
  8. 8. Torbjörn Larsson, OM 1:55 pm 08/22/2012

    Thanks, that was putting some AWE into awesome!

    Also, thanks for the reminder on venomous/poisonous distinction. My native language [swedish] doesn’t seem to care about it, so I tend to forget over time, not being a biologist.

    “the quick way is just to taste them, but that only works once.”

    Droll. But we can always educate more biologists, can’t we? At least if they transmit their affinity to biology culturally before passing on. =D

    Link to this
  9. 9. amdurso 2:58 pm 08/22/2012

    @Torbjörn: Thanks for reading! I agree, these systems are completely awesome, and the coolest part is that there are likely many more awaiting discovery. Many of these systems have been discovered as a result of increased investigation thanks to a nasty taste or smell that a biologist noticed.

    Link to this
  10. 10. Bill_Crofut 11:06 am 08/23/2012

    amdurso,

    You inquiry has made me realize how ambiguous my comment is.

    Following is a quote from one of the hyperlinks you provided (“newly-published review article” para. 3):

    “Among the several groups of ectotherms known to sequester prey toxins (Table 1), the earliest and still best known examples involve the poison frogs, five lineages of anuran amphibians that have independently evolved the capacity to store lipophilic alkaloids obtained from dietary arthropods.”

    Sequestration is known in the five lineages noted above because it has been observed. Since there was no human observer present at the outset of the existence of any of the five lineages, how is it known that the feature evolved? How is it known that the feature was not present initially in the gene pool of each of the five lineages?

    Link to this
  11. 11. amdurso 12:46 pm 08/23/2012

    @Bill_Crofut: Because they are descended from ancestors that did not sequester alkaloids. All I mean when I use the word ‘evolved’ is that the lineages in question changed over time – from nonsequestering frogs into sequestering frogs.

    Link to this
  12. 12. Bill_Crofut 1:58 pm 08/24/2012

    amdurso,

    That leaves open two questions:

    How has descent been determined?

    What caused the change over time?

    Link to this
  13. 13. amdurso 10:40 pm 08/24/2012

    @Bill: Descent (and shared ancestry) is determined by a preponderance of shared, derived characters. Change over time (evolution) is caused by biological processes such as natural selection or genetic drift.

    Link to this
  14. 14. Bill_Crofut 12:45 pm 08/25/2012

    Amdurso,

    There are/were those who disagree:

    “… Darwin considered that the doctrine of the origin of living forms by descent with modification, even if well founded, would be unsatisfactory unless the causes at work, were correctly identified, so his theory of modification by natural selection was for him, of absolutely major importance. Since he had at the time the Origin was published no body of experimental evidence to support his theory, he fell back on speculative arguments. ”

    [Prof. W. R. Thompson. 1956. Introduction. In: Charles Darwin. Origin of Species. Everyman Library No. 811. London: J. M. Dent and Sons. Reprinted with permission. Evolution Protest Movement. 1967. NEW CHALLENGING ‘INTRODUCTION' TO THE ORIGIN OF SPECIES. Selsey, Sussex: Selsey Press Ltd., p. 8]

    and

    “Natural selection acts as regulator of the genotype, performing a function of genetic hygiene. As to its role as effective agent of evolution, this is not certain. In fact, if it had the full power attributed to it, it would soon stop evolution….The role of natural selection in the present world of living things is concerned with the balance of populations; it is primarily of demographic interest. To assert that population dynamics gives a picture of evolution in action is an unfounded opinion, or rather a postulate, that relies on not a single proved fact showing that transformations in the two kingdoms have been essentially linked to changes in the balance of genes in a population.”

    [Prof. Pierre-P. Grassé. 1977. EVOLUTION OF LIVING ORGANISMS: Evidence for a New Theory of Transformation. New York: ACADEMIC PRESS, pp. 121, 170]

    Link to this
  15. 15. amdurso 3:06 pm 08/25/2012

    @Bill: Observations and experiments numbering in the tens of thousands have shown how evolution by NS happens. A few examples germane to toxin immunity in snakes:

    Feldman CR, Brodie ED, Pfrender ME (2012) Constraint shapes convergence in tetrodotoxin-resistant sodium channels of snakes. Proceedings of the National Academy of Sciences 106:13415-13420 http://www.pnas.org/content/106/32/13415.full

    Brodie III E et al. (2005) Parallel arms races between garter snakes and newts involving tetrodotoxin as the phenotypic interface of coevolution. Journal of Chemical Ecology 31:343-356
    http://www.faculty.virginia.edu/brodie/edb3pdfs/Brodie%20J%20Chem%20Ecol%202005.pdf

    Link to this
  16. 16. Bill_Crofut 1:20 pm 08/27/2012

    amdurso,

    Following is a brief assessment of the first reference you provided:

    para 1
    “…where does adaptive genetic variation come from? Three distinct pathways are possible but are rarely tested with respect to naturally arising adaptations.”

    comment
    It seems to me rather curious that only three distinct pathways are possible yet, after tens of thousands of experiments, they are rarely tested.

    para 2
    “…the requisite alleles are already present and available when a new challenge arises…”

    Comment
    What is the source of the alleles already present?

    para 3
    “Garter snakes (Thamnophis) appear to have independently evolved resistance to tetrodotoxin (TTX)…”

    Comment
    “Appear to have” would seem to indicate assertion rather than observation.

    para 4
    “Resistance to TTX appears in both closely and distantly related garter snake taxa, suggesting independent evolution.”

    comment
    This would seem to be an assertion based on observation of a characteristic already present, but not observed in an evolutionary context. Since there was no one to observe the origin of the garter snake taxa, how can any present observer know the characteristic was not in the original gene pool?

    para 5
    “…gene tree comparisons allow us to test whether phenotypic convergence is the result of novel mutations or evolution via existing genetic variation.”

    comment
    A gene tree is a human construct requiring input from intelligent agents. What has that to do with evolution?

    para 6
    “…[T]he oral dose needed to reduce the crawl speed of a large T. atratus (200 g) from this population to 15% of its normal ability would roughly equal 900 human lethal doses.”

    comment
    How was T. atratus able to survive while natural selection was providing the ability to deadly toxin?

    para 7
    “This locus produces a channel-forming protein essential in muscle function that TTX selectively blocks”

    comment
    What is the evolutionary explanation for this process?

    para 9
    “…M→T replacement…was constructed in rat Nav1.4…”

    comment
    “Constructed” would seem to indicate intelligent action.

    para 10
    “…other replacements at D1277 do lead to minor changes in TTX-binding affinity…”

    comment
    “Replacements” would also seem to indicate intelligent action.

    para 12
    “…the origin of adaptive genetic variation is not generally known…”

    comment
    No comment seems necessary.

    para 13
    “We established the evolutionary relationships…If elevated TTX resistance in Thamnophis has evolved…”

    comment
    The two statements would seem to be contradictory.

    para 14
    “Resistant forms of Nav1.4 clearly arose subsequent to the common ancestor of T. sirtalis and other western Thamnophis.”

    comment
    What, precisely, is meant by “arose?”

    para 15
    “These results do not exclude the possibility that within each taxon (T. atratus, T. couchii, and T. sirtalis), the adaptive Nav1.4 alleles were present as neutral or nearly neutral variants segregating at low frequency until promoted by selection.”

    comment
    Initial presence would seem to me to be reasonable; “promoted by selection” would seem to be an assertion, rather than a factual phrase based on observation.

    para 16
    “Adaptation via the recruitment of standing variation or hybridization may be more commonly observed in situations where polygenetic changes are required, or where adaptive alleles do not have deleterious pleiotropic effects on fitness and are essentially neutral in the absence of the selective pressure that renders them beneficial.”

    comment
    What is an example of adaptive alleles that “…do not have deleterious pleiotropic effects on fitness…?”

    Link to this
  17. 17. smohammadi 4:52 pm 08/27/2012

    @Bill: Go read an evolution textbook.

    @amdurso: Awesome blog!!

    Link to this
  18. 18. Bill_Crofut 6:31 pm 08/27/2012

    smohammadi,

    Tremendous advice! Have you any particular one you’d recommend?

    Link to this
  19. 19. lorin215 11:28 pm 08/27/2012

    Mr. Durso,
    Your blog posting was an excellent overview of how nearly all scientists view the evolution of sequestration. Indeed, Brodie, Jr. and colleagues have provided the basis for much of this work through his gartersnake/newt system. I appreciated being able to read this well-written and informative post. Thank you.

    @Bill_Crofut–I believe that most textbooks used for the college level would be sufficient to answer your questions. A textbook used at my university is: http://www.amazon.com/Evolution-Mark-Ridley/dp/1405103450/ref=cm_lmf_tit_2.

    Link to this
  20. 20. Bill_Crofut 12:21 pm 08/28/2012

    lorin215,

    Thank you for the reference.

    Link to this
  21. 21. amdurso 10:39 am 11/18/2012

    This article is now available in Spanish!
    Este artículo está disponible en español!

    http://dl.dropbox.com/u/10351554/Scientific%20American.pdf

    Link to this
  22. 22. David Marjanović 11:10 am 03/1/2013

    @Bill_Crofut: I’m not sure I understand exactly what you mean

    Bill_Crofut is a creationist often seen on SciAm blogs. Nothing he says makes sense when you don’t take this into account.

    Actually, because he knows so little, much of what he writes doesn’t make sense even then. To wit:

    “… Darwin considered that the doctrine of the origin of living forms by descent with modification, even if well founded, would be unsatisfactory unless the causes at work, were correctly identified, so his theory of modification by natural selection was for him, of absolutely major importance. Since he had at the time the Origin was published no body of experimental evidence to support his theory, he fell back on speculative arguments. ”

    Bill_Crofut doesn’t know that science marches on. He seems to seriously believe that nothing new has been learned in a very long time. He quoted that description of what Darwin thought in 1859 because he thinks you still think that way in 2013. Because “at the time the Origin was published” there was “no body of experimental evidence to support his theory”, Bill_Crofut believes there still isn’t! And he doesn’t even try to find out whether that’s actually the case!!!

    “Natural selection acts as regulator of the genotype, performing a function of genetic hygiene. As to its role as effective agent of evolution, this is not certain. In fact, if it had the full power attributed to it, it would soon stop evolution….The role of natural selection in the present world of living things is concerned with the balance of populations; it is primarily of demographic interest. To assert that population dynamics gives a picture of evolution in action is an unfounded opinion, or rather a postulate, that relies on not a single proved fact showing that transformations in the two kingdoms have been essentially linked to changes in the balance of genes in a population.”

    That was quite an ignorant thing to write as late as 1977. I guess that’s why Grassé is as unknown as he is.

    If all environments were completely stable and had been so for a long time, all natural selection would be stabilizing. That “would soon stop evolution”. But even the deep sea isn’t stable.

    Link to this
  23. 23. Bill_Crofut 10:20 am 08/13/2013

    David Marjanović,

    Re: “That was quite an ignorant thing to write as late as 1977. I guess that’s why Grassé is as unknown as he is.”

    Perhaps Prof. Grassé is only unknown because his peers are unable to refute his arguments and have relegated him to the status of non-existence in order to avoid having to deal with a fellow evolutionist who is occasionally honest.

    Link to this

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