Skip to content

Harvesting from Natural Molecular Space: Natural Origins

August 9, 2011

This post continues the current theme of ‘natural molecular space’ and its usefulness. Here, and in the next two succeeding posts, the exploitation of natural biomolecules is considered as a history of sorts. Where does this old, old story begin? When looking at the acquisition of natural products as pharmaceuticals by humans, one might expect to go back to pre-historical times, or even to consider the question in the context of human evolutionary development. And yet it seems we need not stop there. …for the exploitation of natural molecular space can be framed as a general biological issue, and this is the topic of the day.

Zoopharmacognosy – Self-Protection from Threats, Large and Small

There is now a considerable literature describing the use of plant materials by various animals specifically for self-treating their health problems, usually parasitic infections. Many well-documented reports in this area concern apes and monkeys, although some suggested instances of primate self-medication are plausible but based on circumstantial evidence. More controversial findings have suggested that the same kind of phenomena exist in mammalian herbivores.

Since ‘pharmacognosy’ refers to the isolation of pharmaceuticals from natural sources, ‘zoopharmacognosy’ has not surprisingly been coined as a term for the phenomenon of directed animal self-medication. There is a sizable body of evidence, and a reasonable evolutionary rationale, to suggest that zoopharmacognosy is real and worthy of study. At the same time, given the human tendency to anthropomorphize the behavior of animals at the least opportunity, interpretation of animal actions and motivations should always proceed with caution.

If interpreted broadly, ‘self-medication’ can include the ingestion of environmental materials for defense against external predators as well as parasites, whether the latter are microbial or macroscopic. In fact, it has been suggested that the directed ingestion of plants for purposes not directly related to animal nutrition per se may be an ancient practice long predating vertebrates. Consider an insect eating a plant which is non-toxic to itself, but which renders the insect unpalatable to predators. Insofar as such behaviors are innately programmed, they should be subject to natural selection, where an individual with a specific innate eating preference gains a survival advantage. Therefore, variance in genes determining behavior may constitute the raw material for an evolutionary process modifying non-nutritive food ingestion. The patterns of such behavior, though, may be themselves complex. For example, plant self-medication in caterpillars of a specific insect (lepidopteran) species has been observed to occur only in parasitized animals, towards which the ingested plant materials are beneficial.

The use of environmental molecules (natural molecular space) for defense against macro-predators also exists in vertebrates. A very recent example has been reported which amply demonstrates this, and in fact is the only known case of such a phenomenon in placental mammals. The African crested rat (Lophiomys imhausi) has been found to chew roots and bark of a tree (Acokanthera schimperi) which make a compound with cardiotoxic effects on the rat’s large predators. (Chemically related compounds, such as ouabain from the same genus of plants are well-known for their effects on heart function, and have medical applications). This rat then transfers (slavers) the pulped plant material onto specialized hairs which soak up the added material, and these hairs thus become primed to act as toxic delivery systems for any unfortunate predator attempting to eat a Lophiomys individual. An obvious question here: why isn’t the rat itself bothered by the plant toxin? It was suggested by the same group that the rat may produce compounds in its copious saliva which bind and neutralize the toxic principle. Whatever the specific details, in these circumstances the provision for a self-protection mechanism while producing a defense against predators is exactly analogous to the process schematically depicted in a previous post for defense against local competitors.

A purist might argue that acquisition of environmental chemicals for defense against external predation is distinct from true zoopharmacognosy, where the ingested material is ‘aimed’ at fighting internal infections or parasites. There is obviously a distinction between these activities, but splitting the labeling only comes down to a semantic issue. But there is no question that all self-medication phenomena, whether directed against predation or parasites, involve animals sampling regions of natural molecular space accessible within their environments for their own benefits (technically, increased evolutionary fitness).

 Innate vs. ‘Cultural’ Zoopharmacognosy

Still, there is one broad division within the whole field of animal self-medication / zoopharmacognosy: behaviors which are innate (as with self-medicating caterpillars), and those which are learned and transmitted by example, in a ‘horizontal’ fashion rather than ‘vertically’ by genetic inheritance. Horizontal transfer involves  a ‘culture’, in that an different isolate of the same species (with the same genetic background) may not show the same behavior through lack of direct exposure to it. Certainly there are potential complications with this simple dichotomy. For example, a ‘plastic’ behavioral phenotype (variable outcome on behavior through specific gene action) may result in an adaptive (fitness-promoting) behavior being selected for, and subsequently becoming ‘fixed’ in a population through further genetic change. Also, in certain circumstances, an ‘innate’ behavior may not necessarily be manifested in an isolated individual unless it has been ‘primed’ by a degree of maternal or social interaction.

As a brief aside, the innate / ‘cultural’ divide can viewed through the lens of the ‘extended phenotype’ concept. This idea, first developed by Richard Dawkins, proposes that the action and expression of genes (in combination, the phenotype of an organism) do not necessarily stop at the boundary of the organism’s body. Classic examples are beaver dams or directed modulation of host behavior by parasites. But this general concept within evolutionary biology is very often abused and over-extended. A crucial criterion for a true extended phenotype by Dawkin’s definition is that there must be a correspondence between the success or failure of a putative phenotypic extension and the genes which influence the behavior or activity responsible. Gene variants (alleles) which direct alternate forms of a particular phenotypic extension are thus subject to Darwinian selection, according to the success (or not) of the ‘outer’ phenotypic effect. With this in mind, it can be seen that a building is not a human extended phenotype, since the building outcome has no effect on the frequency (relative genetic allele success) of relevant architect or builder’s genes in the total population.

Although innate behavior which drives evolutionarily useful self-medication does not build anything outside an organism’s body, it uses environmental materials (specific molecules, or sets of them) to provide a fitness benefit. Since neither these molecules nor the enzymes which make them are encoded in the genomes of such organisms, it follows that the gene-modified behavior directs the formation of a chemical extension to the organism’s phenotype. On the other hand, a truly ‘cultural’ transmission pattern violates the gene correspondence guideline, since adoption of such a cultural trend among a population does not favor the gene frequencies of the original innovators of the useful behavior. Therefore, this (somewhat simplistic) division of self-medication / zoopharmacognosy can indeed be used to illustrate both real instances of extended phenotypes and pseudotypes thereof.

But wait a minute, you might well ask. Culture is a human attribute. No one would dispute the importance of horizontal spread of information in Homo sapiens, and its continuation across generations by cultural propagation. But where does ‘cultural’ transmission of useful self-medication occur in the animal world? In fact, some work suggests that our primate cousins do share self-medicating activity in part through observation and imitation. (To invoke Dawkins once again, perhaps one could call this transmission of primate memes through aping). Where ‘cultural’ transmission of self-medication is possible, clearly the associated feeding behavior would have the potential to spread at explosive speed relative to natural selection. Clearly, a key factor here is intelligence, and perhaps a primate-level of cognition is necessary for true ‘cultural’ transmission of self-medication information to occur.

Another issue arises: We should also be careful to distinguish true zoopharmacognosy from any animal self-medicative behavior which is motivated by a direct positive reward from the consumed natural material. This is simply because a pleasure response elicited from eating (for example) a particular drug-bearing plant can produce a direct feedback behavioral loop – the consumption of the plant material and the reward ‘kick’ are relatively easy to connect on a cause-and-effect basis. Also, continued self-application of a pleasurable natural drug stimulus will almost always be neutral at best in terms of disease control, and may be generally deleterious for health if abused, or if addiction-related changes occur in the animal.

There is an extensive literature dealing with animal models for substance abuse and addictive behavior. For studying behavioral aspects of addiction, higher animals are usually required, but for the underlying effects of the drugs on neural systems, even invertebrates may do just fine. But where the result of consuming the natural material is alleviation of a health problem, the ‘reward’ (mitigation or elimination of feelings of ill-health) is unlikely to be so closely correlated in time with the original eating behavior, and indeed might often be preceded by even worse symptoms before improvement is noted.

Thus, where specific cases of zoopharmacognosy have been acquired through learning rather than being innate behavior, it might be presumed that the learning process involved may be sufficiently complex to restrict it to primates. (It is presumably easier to come up with an alcoholic rat than one with a true flair for zoopharmacognosy). On the other hand, rats can be quite sophisticated in their ability to use ‘delayed learning’ to determine if sampled foodstuffs are noxious or not. In such circumstances, a rat will sample a novel food and wait for a time (half an hour or so) to decide whether or not the ingestion of the food is associated with any negative outcome. But correlating a positive outcome (such as parasite reduction) with specific food consumption is a much taller order, since the time lag between ingestion and effect will usually be much longer.

Watch Animals and Learn?

Two issues relating to zoopharmacognosy are of special interest: did tribal humans in the past learn the value of certain plants from watching animals, and is it profitable at the present time to observe wild animal feeding behavior for obtaining new pharmaceuticals? Unfortunately, the biological source and mode of preparation of the majority of tribal medicinal preparations have been handed down through a long tradition which renders accurate knowledge of the origin of such practices impossible to obtain. Yet while we cannot be certain, it is certainly conceivable that at least some such lore was derived from animal observation, and some ‘living examples’ have been claimed. Is this relevant for drug development today? If self-medicative behavior is a significant factor in maintaining group health in primates, in theory the nature of the consumed plants could be identified by careful observation of the animals in the wild, with the possibility that the active constituent of the identified plant could be a useful pharmaceutical. Recently this has been claimed to be correct, with new candidate anti-malarials and other potentially useful drug candidates resulting from original observations of chimpanzees in Uganda.

To conclude, a relevant musing from biopoly(verse) once more:

 Throughout the natural world, I surmise

Instinct can render an animal ‘wise’

And if self-learning can train

A higher animal’s brain,

Is ‘animal pharma’ any surprise?

References & Details

(In order of citation, giving some key references where appropriate, but not an exhaustive coverage of the literature).

‘……a considerable literature describing the use of plant materials by various animals specifically for self-treating their health problems….’      Engel, C. Wild Health: How Animals Keep Themselves Well and What We Can Learn From Them (Houghton Mifflin, 2002); also Larkins & Wynn 2004; Raman & Kandula 2008.

Many published reports in this area concern apes and monkeys….’    See Huffman 2003; Huffman & Hirata 2004.

‘…..some suggested instances of primate self-medication are plausible but based on circumstantial evidence.’      For example, see Carrai et al. 2003. This study of sifakas (prosimian primates from Madagascar) found a group where pregnant females eat a tannin-rich diet compared to other females and males. Females eating the tannin-rich plants had fewer pregnancy failures than those from another group with a diet lacking the tannin loading. Thus, it was inferred that the tannins assisted the pregnancies, possibly by acting as anti-parasitics. But it was not proven that the tannin-eating sifakas directly benefited from their diets, as other environmental factors (such as reduced stress) might have been the underlying cause. See also a New Scientist article on this topic.

More controversial findings have suggested that the same kind of phenomena exist in mammalian herbivores.’     See Hutchings et al. 2003; Gradé et al. 2009; Villalba et al. 2010.

‘…..it has been suggested that the directed ingestion of plants ….may be an ancient practice long predating vertebrates.’    See Huffman 2003.

‘…..recently plant self-medication in caterpillars of a specific insect (lepidopteran) species has been observed to occur only in parasitized animals……’     See Singer et al. 2009. This phenomenon has been suggested to be a special case of behavioral ‘adaptive plasticity’.

The African crested rat …..has been found to chew roots and bark of a tree …..with cardiotoxic effects on the rat’s large predators.’    See Kingdon et al. 2011.

‘…..a ‘plastic’ behavioral phenotype …..subsequently becoming ‘fixed’ in a population….’     See Ghalambor et al. 2007 for a discussion of this general topic.

‘…… the lens of the ‘extended phenotype’ concept….’     See Dawkins’ book, The Extended Phenotype – The Long Reach of the Gene Oxford U. Press, 1982.

‘…..a building is not a human extended phenotype……’     This example paraphrased from Dawkins 2004. Obviously, the same genetic argument applies to any other human artifact, including computers, despite the latter often being portrayed as extended phenotypic examples.

‘…..some work suggests that our primate cousins do share self-medicating activity in part through observation and imitation….’    Huffman 2003; Huffman & Hirata 2004.

‘…..an extensive literature dealing with animal models for substance abuse and addictive behavior…’    See Gardner 2008.

‘…..for the underlying effects of the drugs on neural systems, even invertebrates may do…’     See Wolf & Heberlein 2003.

‘…..easier to come up with an alcoholic rat than one with a true flair for zoopharmacognosy.’    The propensity to become dependent on alcohol in rats is genetically determined; for example, see Murphy et al. 2002.

‘…..rats can be quite sophisticated in their ability to use ‘delayed learning’..…’     This is based on the work of Paul Rozin (See Rozin, P. 1976. The Selection of Foods by Rats, Humans, and Other Animals. In Advances in the Study of Behavior, Vol 6, Eds J. Rosenblatt, R. A. Hide, C. Beer, and E. Shaw. (NY-Academic Press). PP 21-76.). For a lively discussion of this area, see also Michael Pollan, in his book The Omnivore’s Dilemma Bloomsbury Publishing 2007; (Start of Ch. 16).

‘……some ‘living examples’ [of tribal medicine learnt from animal behavior] have been claimed….’    See Huffman 2003.

‘…..new candidate anti-malarials and other potentially useful drug candidates resulting from original observations of chimpanzees….’     See Krief et al. 2004; Krief et al. 2006.

Advertisements
No comments yet

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s