Toxins as tools
Toxins are functional ecomolecules. Tools are functional artefacts. Pharmacological biodiscovery is the process of turning toxins (and other active molecules found in nature) into tools.
Homo habilis - the "handy man". Once upon a time, we believed tool use was a unique trait of the hominid lineage. 20th century studies of animal behaviour (ethology) debunked this fairy tale of human exceptionalism. Image: Thomas Goodgame.
If you’ve been following the Australian Venom Research Unit’s blog series, by now you have some idea of what a “toxin” is. Nonetheless, let’s have a quick recap. In the biological context, toxins are molecules that organisms use to mediate antagonistic interactions with other organisms. These are ecological molecules – ecomolecules – designed by evolution, which one organism deploys against another, typically to either deter that organism (which may be a predator or a competitor) or to subdue it so that it can be consumed. Secretions that contain toxins are generally referred to as “poisons”. Since this (like “toxin”) is a widely used word, we once again have to narrow in on its more specific biological meaning. In biology, we typically segregate toxic secretions into two categories – “poisons” and “venoms”. Venom, as discussed here, is that subset of biological poisons which is actively delivered, generally by a bite or a sting. Venoms, therefore, are often used offensively, in prey subjugation, whereas in biology we typically reserve the term “poison” for secretions which are passively delivered (e.g. when a predator attempts to eat the poisonous organism). Thus, biological poisons are typically used defensively. In either case, toxins are the molecules within the secretion that actually confer its toxic effect – they are functional molecules designed to interfere with the normal physiological processes of the target organism. In this context, “normal” is a synonym for “healthy” – toxins are molecules that make you sick.
Tools – not just for humans
So much for toxins. How about “tools”? A typical dictionary definition for “tool” is “a device or implement used to carry out a particular function.” Once upon a time, we humans believed that we were the only species that used tools. Indeed, tool-making was considered one of the unique and defining synapomorphies (shared derived traits) of the hominid lineage (us and our extinct relatives). Evolutionary thinking is the antidote to this fairy tale of human exceptionalism. Don’t get me wrong, humans are pretty exceptional, but when we view humanity through an evolutionary lens it becomes clear that all our “exceptional” attributes have their roots in traits and behaviours that are widely shared across the animal kingdom. In evolution, things do not appear de novo – you can’t get something from nothing. Everything exists on a spectrum of transitional forms. Often, our sense of uniqueness simply stems from ignorance of the activities of our “cousins”. So it was with tool use – in the second half of the twentieth century the use of “devices or implements to carry out particular functions” was revealed to be widespread. Apes and monkeys use tools, of course, but so do birds, pigs and other animals. We’re special, we’re just not as special as we often think we are.
Capuchin monkeys use stones to crack hard-shelled nuts. Image: Luca Antonio Marino.
Most tools are just things animals find lying around in their environments – rocks, sticks and the like. These are co-opted into functional behavioural complexes with specific goals. Although most animals do not fashion their tools, they do select them to be fit to purpose. Thus, bearded capuchin monkeys (Sapajus libidinosus) look for large, fixed boulders to use as anvils and smaller, manipulable stones to use as hammers for cracking hard-shelled nuts. By trial and error, they select the best hammer stones, which then become prized objects within a troop. Chimpanzees (Pan troglodytes) and Caledonian crows (Corvus moneduloides), on the other hand, do fashion their tools. Chimps use a variety of tools – stones and sticks for cracking nuts, but also grass stalks for extracting termites from their mounds. These grass stalks are selected and picked, then intentionally modified by removing the leaves and splitting the end to form a “brush” in which termites are trapped. This is not just tool use, but tool making. Similarly, Caledonian crows not only select and snap off twigs but trim them to an appropriate size before using them to extract insect larvae from tree trunks. Even “metatool use” is known for Caledonian crows, in which one stick may be used to reach and collect another. Incredibly, experiments have demonstrated that this kind of behaviour can be used to solve completely novel problems set for crows and parrots in a laboratory environment (similar results exist for parrots, primates, and even octopuses). This indicates that such tool use and manufacturing is not “merely instinctual” but involves the use of complex cognitive processing to respond to unique challenges.
Finding something in the environment and turning it to a purpose for which it was not designed is a kind of exaptation. Rocks weren’t really designed for anything – they have no purpose but may have been shaped by arbitrary physical processes into forms that make them fit for purpose. It takes an organism with evolved cognitive capacities to recognise this fit and transform a rock from an epiphenomenon (a “random” or undirected by-product of some process) into a functional artefact. As you may recall from earlier AVRU blog articles, this kind of exaptation is a core process in the evolution of novelty in general – new functions typically arise from the redeployment of pre-existing materials. This very often happens within organismal lineages, as when a toxin is “recruited” for an exophysiological function (in the body of another organism) by the exaptation of a molecule with an endophysiological function (in the body of the organism that produces it). In the case of tool use, however, the exaptation occurs between an organism and a component of its environment. A fairly important component of the environment of any organism is other organisms (this is what ecology is all about), which leads to the possibility of “interlineage exaptation”.
The rock this sea otter is using to crack a clam's shell was clearly not "designed" for this purpose. The otter, in selecting the rock, conferred the function of "clam-cracker" to it. This is a form of exaptation, in which "unselected" (epiphenomenal) properties of an object (e.g. the rock's size and hardness) are rendered functional by their re-contextualisation. Image: Mario Nonaka.
Function and purpose
Before we unpack that mouthful, let’s return to a basic consideration of toxins. Remember, toxins are molecules that mediate interactions between organisms – they are ecomolecules with very specific functions. They achieve these functions in very specific ways – by interacting with molecules in the body of the target organism in ways which perturb the function of those molecules, and thus upset the homeostatic regulation of the “poisoned” critter. Think back to how we defined tools – they are “devices or implements” with specific functions. Function is the all-important concept here – functional traits, like toxins, venoms, eyes, ears, wings, lungs (etc. etc. ad infinitum) have purposes. They exist by virtue of the things they have been designed (by selection pressures) to do. Let this sink in a moment, it’s a simple point but is often glossed over because of its subtlety – the reasons that organisms possess the traits they do are largely indistinguishable from the purposes of those traits. After various contingencies are taken into account, the “why?” of a trait is its “what for?”. Tools are, of course, the same – their raison d’être (reason for being) is their function – we bring them into being for specific purposes. Tools and functional traits are thus not dissimilar. Indeed, contemporary evolutionary concepts like the “extended phenotype” and “extended mind” suggest that tools are traits.
Eyes have evolved more than 50 times convergently. "Seeing" (their primary function) is their reason for being. This image is of a cuttlefish eye. Image: Alexander Vasenin.
Natural, sexual and artificial selection
In evolutionary theory, we distinguish between functional traits that were designed by impersonal selection pressures (“natural selection”, sexual selection, etc.) and functional traits or artefacts that were designed by intelligent designers. We typically think of tools as functional objects designed by intelligence – artefacts. Darwin used “artificial selection” – selective breeding by humans to maximise desirable traits in domestic animals – as an analogy to explain his concept of “natural selection”. It’s an apt analogy. In both cases, selection pressures are being exerted on organisms by their environments, it’s just that in artificial selection, the most influential force in the environment is the desires (or whims?) of the human doing the selecting. Like tool making, artificial selection is (more or less) intelligent design.
Do not forget, however, that all evolutionary phenomena exist on spectra. In artificial selection, one organism is strongly influencing the evolution of another. This is the norm in biological evolution. We tend to think of natural selection being driven largely by antagonistic interactions, which is true, but even in this case the outcome is some kind of (highly contingent and localised) “improvement” of the organismal lineage being selected. Maybe the predator of the poisonous amphibian becomes more resistant to defensive toxins from one generation to the next (and the next and the next), because the less resistant individuals either die or can’t exploit a readily available food source (the poisonous amphibian) and thus are out-competed by more resistant individuals. Much less arbitrary than humans breeding dogs to be smaller and cuter, but not a categorically different outcome – cute little dogs are “fit” (they have a lot of babies) precisely because humans keep breeding them.
Selective breeding by humans created dogs (from wolves) and has constrained their evolution ever since. There are so many cute and fluffy little dogs (like this Pomeranian) in the world - i.e. they are so "fit" in the Darwinian sense - because another species (humans) has guided their evolution, making them well-adapted to the "small fluffy companion animal niche". Image: Ksmtbwmc.
In sexual selection, members of one sex drive the evolution of members of the other through their preferences. These preferences are not necessarily arbitrary (though some evolutionists have argued that they could be) – perhaps the extravagant plumage of the peacock turns the peahen on because it’s a demonstration of his vigour and virility. Perhaps he is sending the message that “I can survive despite putting so many resources into being beautiful and making myself conspicuous to predators, because I’m just that darn awesome”. This idea is known as “the handicap principle”. Regardless, the preferences of the peahen drive the evolution of the peacock’s plumage in ways that are transparently analogous to selective breeding for more beautiful flowers, or indeed “more beautiful” plumage (think of designer breeds of chickens). Again, we tell ourselves that sexual selection and artificial selection are categorically different….but this may just be another of our little conceits of human exceptionalism. Do we always rationally understand our motivations for wanting dogs to look a certain way? I’m not sure.
The extravagant plumage of the peacock may be an example of the "handicap principle" (first proposed by evolutionary biologist Amotz Zahavi) - an honest signal of the vigour and virility of the bird which has so much energy to spare, and is so adept at escaping predators, that it can devote resources to the creation of such finery. Image: Peter Andersen.
OK, back to toxins and tools. Remember that the first tools were really just things lying around in the environment that organisms picked up and put to specific uses. Actually, even picking them up is not strictly speaking necessary – when a bearded vulture (lammergeier - Gypaetus barbatus) drops a bone from a great height onto flat, exposed rock, we might argue that the rock is being used as a tool, despite the fact that the bird does not manipulate it. Anyway, as mentioned earlier, the environment is composed of more than sticks and stones (and these aren’t the only things that can break bones), it’s composed of other organisms and their products, including toxins. As discussed here, toxin resistance is a widespread trait amongst the predators of poisonous and venomous organisms (and also the prey of venomous organisms).
Some resistant predators add insult to injury by taking things a step further – they are not only impervious to the defensive toxins of the prey, but they actually take the toxins and use them for their own purposes. This process is known as toxin sequestration and is actually quite widespread. For example, some snakes that feed upon poisonous toads sequester the hapless amphibians’ toxins in their own specialised “nuchal glands”. These snakes are now poisonous to eat and, given that they are also venomous, possess two distinct ecomolecular traits – in one case they steal the toxins from their prey, in the other (the venom) they produce the toxins themselves. Another colourful example is “kleptocnidae” – in which nudibranchs (psychedelic sea slugs) steal (klepto) the stinging cells (cnidae) from their hydrozoid prey. Poison dart frogs from the tropical Americas are another example – they typically get their defensive toxins from the ants they feed upon. Pitohui birds from Papua New Guinea do something similar, even sequestering the same toxins as dart frogs, despite living on the opposite side of the globe. Indeed, stealing toxins and repurposing them is so widespread it will be the subject of a follow-up article (much more on this process in the next instalment of “the toxin resistance tango” – stay tuned).
This tiger keelback (Rhabdophis tigrinus) sequesters the toxins of the toads it feed upon in "nuchal glands". These glands are located under the bright orange and black patterning that the species is named for. Such warning colouration is referred to as "aposematic" - it means "don't eat me, I'm poisonous". Tiger keelbacks are venomous, too, and have been responsible for human fatalities. Image: Timothy Jackson.
Interlineage exaptation and biodiscovery
Hopefully the parallels between toxin sequestration and the early stages of tool use are becoming clear. It should also be clear that toxin sequestration is “interlineage exaptation”. This is when an organism from one lineage (the “sequesterer”) takes a molecule that evolved for a specific function (defence) in another lineage and deploys it for its own purposes. It’s true that in this example defence is the functional role of the molecule in both contexts, but it’s absolutely transparent that organisms typically do not evolve defensive molecules to defend other species (sequestration of toxins produced by endosymbiotic bacteria, as in the blue-lined octopuses, is an interesting case here, however).
We humans have our own version of toxin sequestration – interlineage exaptation – and, as with tool use in general, we have taken the practice to all new levels of sophistication. I am, of course, referring to biodiscovery. Although we do most of our toxin exaptation in pharmacology labs these days, like other forms of tool use this is a genuinely ancient practice for our lineage. The interdisciplinary (part anthropology, part pharmacology) field of ethnopharmacology studies the historical human usage of active molecules produced by plants (ethnobotany) and animals. Humans have been engaging in biodiscovery for thousands of years, from the vast natural pharmacopeia of “herbal medicines”, to darts tipped with frog poison, to the use of psychedelic plants and fungi in shamanic rituals. It is a highly specific form of tool usage. Once again, we are not categorically different from our relatives across the animal kingdom in this regard. Today, certainly, we use highly sophisticated experimental techniques to identify novel lead compounds, but this has not always been the case. Bringing biodiscovery into the laboratory has very obvious advantages, however. In labs, we can tinker with the structure of toxins and other natural molecules, tailoring their activities for our own purposes - perhaps minimising toxic side effects whilst maximising therapeutic action by increasing target specificity. Sounds pretty similar to honing the edge of a stone to make it a more effective axe head, right? Another considerable advantage of bringing biodiscovery into a laboratory environment is the fact that we no longer have to risk death by “experimentally imbibing” various substances. This means that we can investigate natural products that were far too toxic for us to utilise in the past, including venoms. Indeed, a number of highly successful drugs have been isolated from venoms, and a significant percentage of the research funding for toxinology worldwide is devoted to the quest to discover useful molecules within these toxic secretions. Using toxins as tools is nothing new, but today it’s big business.
Whilst in India searching for snakes, I received a painful sting from a burrowing wasp. An Irula tribesman I was with immediately found the plant pictured above (a variety of mustard plant - if anyone knows the precise ID get in touch!) and directed me to snap one its stalks and rub the milky exudate on my sting. The pain disappeared immediately and did not return. This "ethnobotanical" knowledge has existed worldwide since time immemorial. It is the original pharmacology. Image: Timothy Jackson.
As with toxin sequestration, there’s a great deal more to say about biodiscovery, so don’t forget to check the AVRU blog regularly for more articles!
Dr Timothy Jackson