The Toxin Resistance Tango (part 1)

Perhaps the most vivid illustration of venomous and poisonous animals coevolving with their predators and prey (i.e. target organisms) is the existence of toxin resistance. This is a big subject, so this week we'll be introducing it in general terms before highlighting specific examples in future posts. Get ready for the Toxin Resistance Tango!

Animals and plants use toxic secretions – poisons and venoms – ecologically. This means that the function of these secretions is to mediate interactions with other organisms – poisons are used for defence against predators, whereas venoms are used to both deter (as in defence) or subdue (as in predation) target organisms. It’s fun to coin new terms, so let’s call these intrinsically ecological secretions “ecosecretions”. Secretions are typically composed of a mixture of molecules, and poisons and venoms are no different. The “active” components of these toxic ecosecretions – the molecules that confer the functional activity to the secretions as a whole – are called “toxins”. Thus, toxins are molecules that mediate interactions between organisms – ecomolecules!

Strawberry poison frog

The bright colouration of this strawberry poison frog (Oophaga pumilio) is "aposematic" - warning colouration. The fact that many poisonous animals "advertise" their toxicity is another example of the fundamentally ecological role that toxic secretions play as molecules that mediate interactions between organisms. Image: Marsal Hedin, Wikimedia Commons.

Wherever there is ecology, there is the possibility of coevolution – the evolution of each organism in the interaction may have an effect on the evolution of the other organism(s). Evolution by natural selection is change mediated by selection pressures exerted on organisms by their environment, and a big part of that environment is other organisms. This means that organisms are evolving together – hence “coevolution”. As you might expect, toxic ecomolecules exert strong selection pressures on the target organisms against which they are deployed. These selection pressures drive the evolution of toxin resistance. Resistance to a defensive toxin can result in a predator gaining access to a food source for which there is little competition from other (non-resistant) predators. This is a big win, in evolutionary terms! Resistance to a predatory venom, on the other hand, might be the difference between being on the menu and living to fight another day. Either way, it’s easy to see the advantages that toxin resistance can confer, and this is exactly the way that the “selection” component of natural selection works.

The antagonistic coevolutionary dynamics between toxic organisms and their targets (predators or prey) are often referred to as a “chemical arms race”….because that sounds a lot cooler than “antagonistic coevolutionary dynamics”! A characteristic of coevolution (and “arms races”) is reciprocal selection – toxins exert a selection pressure on targets, and the evolution of resistance that results exerts a reciprocal selection pressure on the toxins (or the secretions they comprise) that drives them to evade that resistance. Such arms races have been likened to the situation of the Red Queen in Alice and Wonderland, who keeps running as fast as she can but never gets anywhere. Similarly, reciprocal selection pressures can theoretically fuel an arms race in which there is no winner – every time toxin resistance evolves, a way of evading that resistance evolves and the antagonistic coevolutionary dynamic is reset. This is a nice metaphor, but it doesn’t always work this way – sometimes it seems that one of the competitors gets ahead and stays ahead.

There is another colourfully named hypothesis – the “life-dinner principle” – which suggests that in predator-prey arms races the selection is stronger on the prey than on the predator. This is because the prey is fighting for its life, whilst the predator is only fighting for its dinner. Such a view predicts that prey animals should be able to get ahead and stay ahead in the arms race, but this is not what we seem to see with chemical arms races, in fact it often looks like the opposite is true – if anyone is winning, it’s the predator, and this seems to be the case both for defensive poisons (in which the prey animal is the toxic species) and predatory venoms (in which the predator is the toxic species). We don’t fully understand why this should be the case, but part of it may be due to the fact that poisons tend to be simple mixtures – often with only one principle toxic molecule – whereas venoms are often complex, comprised of many distinct forms of toxin.

Wolves bison

The "life-dinner principle" suggests that selection pressures should be stronger on prey animals - which are fighting for their lives - than predators - which are fighting for dinner. Although this makes intuitive sense, its predictions do not always match the data concerning "chemical arms races" between toxic animals and their predators/prey. In this image, bison and wolves are in a stand off in Yellowstone Park. This stand off recalls another coevolutionary hypothesis - the "Red Queen" - in which organisms have to keep evolving in order to remain on level pegging with their antagonists, which are evolving in parallel. Image: By MacNulty DR, Tallian A, Stahler DR, Smith DW - Influence of Group Size on the Success of Wolves Hunting Bison. PLoS ONE 9(11): e112884. doi:10.1371/journal.pone.0112884, CC BY 4.0,

Evolving resistance to a single toxin seems relatively “easy”, and if the poisonous animal has no way of modifying the toxin or “recruiting” additional toxic ecomolecules to its poisonous ecosecretion, it may become the permanent “loser” of the arms race. This doesn’t mean its poison is useless of course, because it may still provide protection against many non-resistant potential predators, but it may provide no defence at all against resistant predators, which are often specialised for feeding upon their toxic prey. Venoms, on the other hand, being more complex mixtures, may be much harder to evolve comprehensive resistance to. After all, even if a prey animal is “lucky” enough to develop resistance to a single toxin, this may not be much help if half a dozen other toxins in the venom subdue it anyway. In such cases the resistant mutation may not even be “fixed” in the population by selection but may disappear in a single generation. However, resistance to venoms does evolve, and some organisms are resistant to multiple toxins. This is possible because encounters between venomous organisms and their predators or prey are often not nearly as cut-and-dry as we often imagine – sometimes venom just provides a relatively small advantage by weakening or being painful to the target organism. The effect of venom is strongly dose-dependent too, so organisms that only receive a small amount of venom in a typical encounter with a venomous organism may have a better chance of evolving resistance. Once again, the “life-dinner principle” is refuted by nature – whilst there are certainly examples of prey species that have evolved resistance to the venom of their predators, many of the best characterised examples of venom resistance are possessed by predators of venomous organisms. There is evidence from a number of venomous lineages that less venom is injected in defensive than offensive encounters, and this may be part of an explanation for this pattern, but the factors influencing the outcome of encounters between venomous organisms and their predators (and prey!) are understudied and likely complex.

blue-ringed octopus

Resistance to tetrododoxin, which makes the greater blue-ringed octopus (Hapalochlaena lunulata) both poisonous and venomous, is widespread amongst marine organisms. Image: Rickard Zerpe, wiki commons.

Regardless, there are four primary pathways through which toxin resistance is acquired. Two of these are common, whereas the other two are less frequently observed (and are really variants of the first two). The more common varieties are molecular inhibition and alterations to the target molecule. In the former, the resistant organism possesses molecules that bind invading toxins and inhibit their mechanism of action. This form of resistance is often directed against enzymatic toxins, because every enzymatic pathway within an organism’s physiology (including ours!) already has inhibitory molecules associated within it that act to regulate the pathway so that it doesn’t get too excited and start to mess things up. Since enzymatic toxins are recruited from normal, “endophysiological” pathways, the complementary inhibitors of these pathways can be rejigged to specifically bind and inhibit the toxin versions. Alterations to the target molecule, on the other hand, result in toxins being unable to bind their intended targets, or being able to bind them but not modulate their activity. The possible ways in which a target can be altered to confer resistance are limited by the fact that the target (e.g. a receptor) must continue to be able to bind its endophysiological interaction partners (ligands). A variation on inhibition is the “molecular cage” strategy, in which multiple molecules bind a toxin from all sides, preventing it from being able to interact with targets. A variation on altered targets is alternate targets, in which another receptor in the target organism’s body evolves a greater affinity for the toxin than the intended target. Thus, the toxin does not inflict its intended toxic effect but modulates some other pathway. In the case of the grasshopper mouse, which feeds upon scorpions, toxins in the scorpion’s venom designed to inflict pain apparently end up causing pleasurable sensations by binding an alternate target. The mouse not only gets a meal but actually enjoys being stung by the hapless scorpion!

grasshopper mouse

The grasshopper mouse (Onychomys leucogaster), depicted here feeding on its namesake, is not only resistant to the toxins of the scorpions it feeds on, it might even enjoy being stung! Painting by Louis Agassiz Fuertes.

One last important thing to mention in this introduction in resistance to autotoxicity. It's not only target organisms that have good reason to evolve toxin resistance - it's also important not to poison yourself! Sometimes it might be easy to avoid autotoxicity simply by ensuring that appreciable quantities of a toxic secretion never enter the bloodstream of the producing animal. On the other hand, if your venom delivery system is in your mouth, there's always a risk of biting yourself and if your toxins are particularly toxic even at very low concentrations, you had better make sure you're resistant to them! This is exactly what we see with many venomous snakes, who are quite resistant to their own venoms and even the venoms of other species. An even more fascinating and convoluted example of toxin resistance occurs in poisonous animals that do not produce the toxins they use defensively themselves. This is more common than you might think - many poisonous animals actually steal their toxins from other organisms! Clearly, if you're going to consume another organism and "sequester" its poison for your own ends (cheeky!), or if you're going to encourage toxin-producing microbes to live inside your body and grant you their poisonous secretions for your protection, then you need to be resistant to these toxins yourself. Nature is absolutely full of these sorts seemingly fantastical scenarios, making toxin resistance a treasure trove of wonderful examples of evolutionary innovation.

This is part one of a series on the tango (it takes two!) of toxin resistance. In future instalments we’ll be looking at each of the aforementioned mechanisms in more detail and illustrating them with examples. Next time around, we’re going to focus on toxin resistance (and the lack of it) in evolutionary arms races between predatory snakes and amphibian prey (frogs, toads, newts and salamanders). This will include a detailed discussion of the impact that cane toads have had on Australian snakes, most (but not all) of which lack resistance to their toxins.

- Tim

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Dr Timothy Jackson