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Harvesting from Natural Molecular Space: An Old Human Story

August 16, 2011

In the previous post, the current theme of ‘Natural Molecular Space’ was considered from the point of view of its sampling by animals for the purposes of self-medication, or zoopharmacognosy. Now, it is time to move beyond this, to the human use of the huge and highly diverse resource of natural biomolecules. Unlike other mammals, humans can use their intelligence to greatly expedite the profitable sampling of Natural Molecular Space, and in one form or another, this has been practiced from the earliest times across all cultures. The manner and nature of this ‘harvesting’ is the topic of the present post.

Early human pharmacognosy, and continuing

It is clear that since sampling and application of natural bioproducts do not require any awareness of the physical nature of drugs themselves, the process of useful molecular discovery can (in effect) take place long before the definition of a molecule. ‘Discovery’ here is thus defined  in a loose sense as the identification of a natural source which contains a useful molecular species. Only within the last century can we apply the more rigorous definition which includes the purification and full characterization of the active constituent(s) in molecular terms. Obviously, early humans had no accurate picture of the nature of material reality, and even more obviously this applies as well to animals involved in zoopharmacognosy (as discussed in the previous post). Indeed, the very concept of a molecule as a precise group of atoms (held together in a very specific manner by the rules of chemical bonding) is of extremely recent vintage in historical terms.

It is unlikely that any human cultures have never used accessible environmental materials for health-related reasons, and many such natural sources contained active constituents which proved enduringly worthwhile. Examples of these are not hard to come by, particularly from local plant sources. Some well-known cases are the anti-malarial drug quinine, derived from the bark of South American trees of Cinchona species, anti-pyretic / analgesic salicylates from willow bark (related to aspirin), cardiotonic digitalis (digoxin) from foxglove, narcotics (morphine and derivatives) from the opium poppy, and anti-psychotics (such as reserpine) from Rauwolfia species. Apart from human disease management, other traditional uses for environmental pharmaceuticals include preparations for control of insect pests and animal diseases. This extensive fund of traditional knowledge about the usefulness of local biotas has been termed (in the most general terms) ethnobiology, or (when focusing on the active compounds found within traditional medicines), ethnopharmacology. In a majority of cases (albeit not exclusively), the sources of such medicines are plants, and the fund of long-standing plant-derived cultural medicinal lore is accordingly termed ethnobotany.

Obviously the biodiversity of the environment within reach of a specific culture will have a bearing on the range of potential tribal medicines, especially since most such treatments derive from plant sources. At extremes one can compare the scope of botanical sources available to polar Inuit peoples with rain forest dwellers; indeed jungle regions such as the Amazon have been particularly rich sources of biopharmaceuticals. So there is obviously no question that humans across the board have been skilled at finding medically useful materials from their environments. But how systematic has this been, and how comprehensive?

When it comes to finding edible and nutritious foodstuffs, it has been noted that human cultures which have long inhabited specific geographic regions have identified essentially all plants which can become dietary items. Apart from much practical field experience and observations in support of this proposition, if a tribal group have lived in a relatively small region for thousands of years, it would seem quite reasonable to accept ipso facto that their knowledge of the food value of local plants would be highly advanced, and close to completion, if not quite at a literal 100% level. (One factor complicating the sampling of foods is where certain plant materials possess initial toxicity, which can be removed by specific processing steps. Clearly, it will take longer to gain such knowledge than by simply tasting plant products for their agreeability).

But the acquisition of plants with medicinal value, as opposed to worthiness as foods, is not the same thing. Could we expect that a tribal people in a resource-rich environmental (such as a tropical rain forest) would have identified all potentially useful medical plant (or other biological) sources after thousands of years in a similar location? If ‘all potentially useful’ is taken literally to mean beneficial to all humanity, then the answer is clearly in the negative. This is obviously the case, given the simple observation that human medical afflictions are far from geographically homogeneous. While modern transport systems can now spread infectious diseases rapidly around the globe, infections and parasites were historically often relatively local in the extent of their reach. Although this is patently obvious, even potential treatments for genetic conditions would not be sought if such problems did not exist within a relatively small tribal population. (Genetic diseases occurring at a low frequency would only tend to be noted on average within large population groups). It then goes without saying that no tribal people could search for a treatment for any pathological condition outside their frame of reference, any more than even the most sophisticated modern screening and drug design methods can be used against a novel disease which has not yet ‘emerged’. So, natural landscapes may harbor drugs whose usefulness is not yet definable even in the present day.

But one can put this high-level issue of generality to one side, and restrict tribal medicine to matters which would be of direct concern to them. Yet here, too, there are problems. From first principles, it could not be automatically assumed that a molecular solution to a given medical problem will necessarily exist anywhere on Earth. And by the same token, a useful molecule within Natural Molecular Space might indeed exist, but not necessarily within the accessible environment of any given tribal group. (If it ain’t there, you can’t find it). This is a kind of counterpoint to the above point noting that a local biota might harbor drugs for as yet undefined purposes – it might also lack useful drugs for specific applications, which are naturally available elsewhere. Consider an example with respect to the ancient enemy malaria: Long endemic in Africa, one of the best natural solutions (at least until the acquisition of parasite resistance) was native to South America in the form of the Cinchona plant (more of which below). Thus, early African peoples obviously had no means for arming themselves against malaria with this particular weapon.

The other problem with identification of useful biological medications is the complexity of doing so in a systematic manner, when faced with knowledge limitations, a vast array of potential environmental sources, and the range and variation within human medical problems. Despite their familiarity with their biological surroundings gained over very long time periods, many tribal peoples, especially in tropical environments, certainly suffered from a high burden of infectious and parasitic disease before access to modern medicine. It can be accordingly inferred that evidently either no solutions to such pathologies existed in their environments, or potential solutions existed, but they had not yet found them (or they had not discovered how to use them in a productive way).

 Sifting the Environment for Medicinals

What other factors might be involved in the growth of tribal medical lore? Is it possible to come up with some kind of formula as a rough guideline for the likelihood that a particular culture would develop, purely by trial-and error sampling from its available environment, a useful treatment for a specific medical condition? This question can be rephrased in the following manner: An early tribal people have lived in a forest area for many generations. During this time, some of them have become ill from a previously unknown disease. Their shamans try treating their sick patients with a whole range of available plant materials. What are the chances that they might find something genuinely useful? What factors influence whether there is no hope at all, or whether there is a real prospect of success, perhaps given an element of good luck? For the present purposes, ‘genuinely useful’ means a bioproduct which directly or indirectly alters the pathogenic state in a favorable manner. And such beneficial effects need to be objectively measurable.

Since time immemorial, human patients have been given real comfort from healers of any description who could deliver a placebo effect through their ministrations. Yet although shamanic medicine has a radically different view of reality to modern chemical and pharmaceutical science, there is no question that traditional healing practices have found many therapeutically useful biological materials. Indeed, this very fact has led to the development of ethnobotany as a science in its own right.

While it is not possible to produce a quantitative formula for the likelihood of finding useful local environmental bioproducts by traditional medicines, we can think about the relevant factors involved, and for convenience represent them as R, D, B, C, and t; explained as follows:

R denotes the ‘druggability’ of the specific biological need in question, in terms of the probability of ‘solutions’ available within Natural Molecular Space. In brief, this refers to how well-suited are target molecules (relevant to a specific disease process) to interaction with drug-like compounds found among the gamut of natural biomolecules. This is influenced by the complexity of the illness or disease symptom itself, and what kind of molecular targets it offers for outside intervention. A complex multicellular parasite will contain a large number of proteins vital to its own functioning (but foreign to the host) which are potential sites of action for therapeutic drugs, while a viral infection which hijacks the machinery of the host cell presents fewer targeting options. If the disease stems from some internal physiological malfunctioning, the susceptibility of relevant target molecules to drug action is uncertain in the absence of specific information or empirical evidence. For example, perturbation of protein-protein interaction surfaces has historically been regarded as a difficult proposition, in contrast to the ‘drugging’ of protein clefts and pockets (which usually include enzymatic active sites).

This ‘R factor’ can be viewed as a kind of general bias factor for small molecules in Natural Molecular Space towards the common range of protein folds. (This aspect of natural bioproducts as a very non-random selection of general chemical space has been considered in a previous post). But on the other hand, compounds modulating protein-protein interactions (as opposed to intraprotein folds) appear to be harder to find within the same natural set. To illustrate this further, consider the following hypothetical situation:

A series of human medical needs are compared, assuming complete knowledge of the underlying problem and the best protein molecule(s) which should be targeted for therapeutic improvement. These problems are grouped into two broad classes: In one type, the best target solutions involve clefts or pocket-like regions on a single protein; in the other, relatively flat protein-protein interaction surfaces present the best possible targets. Humans undertake a search of available biotas for natural products with therapeutic value for both types of pathological conditions. In principle, it does not matter whether tribal shamans or biotechnological operatives are involved, although of course the former act in complete ignorance of the underlying reality (biotechnologists may or may not possess full detailed target information in advance of their search). It can be then predicted that a preponderance of useful ‘hits’ for the cleft/pocket targets would be obtained from Natural Molecular Space, over the protein-protein surface type.

It should be noted though, that the R factor here is not at all intended to represent an absolute measure of druggability, only what Natural Molecular Space tends to define as ‘druggable’.  Thus, the druggability of protein-protein interactions, once believed to be intractable, is now seen as solvable in many (if not all) cases through ingenious artificial design approaches. The central ‘take-home’ message is that not all diseases and not all molecular targets are created equal, and as a consequence some have a higher likelihood of being vulnerable to a therapy based on a naturally available low-molecular weight drug than others.

D refers to the diversity of the total potential set of biomolecules accessible in the human environment. (‘Accessible’ here means that which is available for the normal geographical range of the human group. Nomadic groups may often cover different environments and thereby increase their exposure to diversity, but possibly at the expense of the time factor as below). The assumption here is that the higher the diversity, the higher the probability that beneficial biomolecules will exist in the environment, and indeed a rainforest has far more potential as a pharmaceutical source than an arctic tundra. (But note that although arctic and other environments with extreme conditions have lower biodiversity, they are nonetheless useful for bioprospecting in specialist roles. The adverse conditions which restrict diversity in the first place also mean that life in these regions has special adaptations which can be useful for biotechnology, such as ‘antifreeze’ proteins. The same observations also apply to other extreme environments, including the opposite pole of very high temperatures.) How does one define and measure diversity, anyway? In molecular terms, one must have yardsticks for comparing molecules with each other, in order to assess their relative dissimilarities. A large number of such ‘descriptors’ have been devised, including molecular structures, shapes, and chemical and physical properties, which must be rendered into mathematical representations for formal modeling purposes. But a working definition of a diverse library of molecules is one which spans a chemical space in a non-redundant fashion, by means of covering a wide and continuous range of properties. A large group of molecules can thus be less diverse than a smaller set, and a set which only included members at extreme ends of property values would have reduced diversity in comparison with a set whose members possessed properties covering a wide dynamic range. Even so, no absolute standard for assessing diversity exists, although many sophisticated approaches have been developed.

But to return to out environmental considerations, an implicit assumption is that the higher the D value, the greater the odds that the total collection of environmental compounds will include one which is fortuitously useful for a human requirement, even if this is totally unrelated to the function for which the compound was originally derived by natural selection. But this D value is clearly not a random portion of chemical space, since the environmental biomolecules of inherent value are far from randomly generated (as discussed in a previous post). The ‘druggability’ factor R noted above already addresses a general bias of Natural Molecular Space towards a relatively limited set of protein folds found in nature (compared to the huge potential size of protein sequence space). But there are more direct factors which may also bias the prospect of success towards a given biomolecular target, and this is the basis for considering a specific bias element (the B factor raised above).

A full discussion of this would become complex and very lengthy, but for the present purposes, consider the notion of functional bias within Natural Molecular Space towards a human need, and consequently specific targets.  ‘Secondary metabolites’ (raised in a previous post) are present as a result of a long history of natural selection processes in response to environmental pressures on the organism in question. In certain cases these influences may strongly bias the repertoire of available biomolecules in a positive manner from the point of view of human needs and desires. For example, a search for an anti-bacterial drug may have far greater prospects for success from sampling natural sources than from a random collection of molecules of comparable size. (Selective pressures have resulted in the generation of anti-bacterial products by a variety of organisms, and in this sense the ‘aims’ of the producer organisms and the human biologist coincide). Conversely, a search in a natural environment for a molecular function absent from the totality of environment’s biology (Such as a low-molecular weight organic catalyst of a non-natural chemical reaction ) will depend on chance alone for its success. To take this kind of functional bias into account, the B factor is therefore needed. (The higher this bias factor, the higher the probability that molecules of the type sought after exist in the natural environment).

Nevertheless, this ‘bias factor’ caveat is not necessarily as limiting as it may first seem, and can actually work in favor of the bioproduct ‘ocean’ as a source of useful molecules. The shared evolutionary origins of life on Earth means that many biochemical pathways of humans and their domestic animals also have analogs in environmental organisms. In some cases receptor proteins between widely evolutionarily separated organisms may have divergent functions but recognizably homologous structures and primary sequences. This means that a search for a biological modifier within a diverse natural environment in many cases may have a higher probability of success than within a random molecular collection of comparable size, and in turn stresses the worth and value of screening for active natural products.

As noted in a previous post, if it were possible to screen an utterly alien biological world, this positive bias factor would disappear, and such evaluation of the alien natural environment would be equivalent to a random molecular library screen. (Alien micro-organisms might generate secondary metabolites for similar selective reasons as for terrestrial organisms, but the chances of an alien ‘penicillin’ affecting Earth bacteria would be very low). Obviously the ‘molecular bias factor’ was not of great concern for tribal peoples, and in any case will often be difficult to predict in advance. But however one defines the chemical diversity of the total available environmental resources of biomolecules, in the context of ‘natural bioproduct space’ diversity alone is an insufficient guideline.

To return the above factors determining the likelihood of a human culture finding useful environmental molecules, C denotes ‘cultural factors’, probably impossible to quantitate but nonetheless real and important in the present context. Not all human groups will find and use biopharmaceuticals at the same rate, and the determining factor here is the shared set of social values referred to as ‘culture’. Within this set of values we will find such qualities as openness to enquiry and resistance to change. All human beings have the same fundamental genetic endowment, and it has even been suggested that the human talent for ‘folk biology’ may be based on an innate neural module facilitating recognition of differing plant forms or other biodiversity. These considerations aside, clearly human societies vary in their tolerance for behavioral experimentation and their willingness to implement new procedures, both of which can influence the rate of identification and adoption of pharmaceuticals from the bioenvironment. It was noted above that we must take care to define utility of a treatment at the outset, since it is also clear that some tribal medicines have little or no real effects on their supposed target diseases. No early pharmacognosy could pass judgements based on proper clinical trials of biomaterials, and the placebo effect would routinely be present on top of any real benefits deriving from administration of candidate preparations to ill individuals. (Given the demonstrated power of placebos in medicine, it is to the credit of tribal human groups that treatments of real effectiveness could nonetheless be identified). The cultural factor of passing on a time-honored tradition can effectively ensure that knowledge of genuinely useful medicines is retained by a group over time, but unfortunately bad memes can be just as transmissible as good ones. A case in point is the continued use of rhinoceros horns for medicinal purposes in some parts of the world, a false supposition whether for fever reduction or as an aphrodisiac.

Finally, t of the formula above is the time factor, on the logical assumption that the longer a group inhabits a particular environment, the greater the opportunities for biomaterial trial-and-error experimentation. We have already noted the potential for duration to have an impact on the diversity factor for nomadic groups, but time is also relevant to the C (cultural) factor, since even the most hidebound and anti-innovative group may eventually stumble on and adopt useful materials if they dwell for a long enough period in the same environment. And cultures, of course, are not static systems but are themselves mutable with time.

 An Interesting Case Study – Cinchona and Malaria

The pathway towards finding that cinchona bark is an effective treatment for malaria serves to demonstrate the complexities that can impinge upon the time / culture factors, and an interesting example to consider in a little more detail. In historical terms, cinchona was identified as a malarial cure relatively soon after the arrival of Europeans in South America. Since it is generally accepted that the malarial parasite did not exist in the New World prior to the European invasions, cinchona may be viewed as an example of rapid acquisition of a natural medicine. Although Peruvian Indians are often credited with both the discovery of the anti-malarial effects of cinchona and its transmission to Jesuit or other European visitors, most available evidence suggests that it is more likely that Europeans themselves first came to this knowledge. But upon reflection, it is not probable that newcomers would have tested cinchona bark so rapidly without benefiting from the accumulated lore of the original inhabitants. Some sources indicate that native Peruvians used cinchona bark to relieve shivering, which can occur through pharmacological effects of active constituents of the crude bark. Quinine itself can act as a muscle relaxant, and also has inherent anti-pyretic activity, both of which could alleviate unwanted shivering depending on the cause of the problem. In any case, awareness of this on the part of Europeans could easily act as a prompt for testing the bark in malaria sufferers, owing to the intense fevered shivering occurring at certain stages during the disease cycle. Thus in this particular set of circumstances, the relatively rapid identification of the utility of cinchona bark (and thence quinine) is ironically likely to have resulted from a side-effect of the bark not directly related to its ability to kill malaria parasites. Also, it is most likely (though not provable) that it developed from interplay between traditional native Peruvian empirical lore and European activities. While the story of cinchona may be a special case (and it is certainly noteworthy in that it has occurred during historical times, even though much of the specific detail is obscure), the adoption of many other traditional pharmaceuticals may have similarly tangled origins.

All of the factors except C (‘cultural’ factors) are also relevant to modern empirical screening of natural sources. At least, cultural factors are not operative in the same sense as for isolated independent tribal groups. Potentially inhibitory cultural factors no longer apply since the acquisition of new drugs has become effectively a global enterprise, transcending national barriers. On the other hand, the uptake of a new drug in the modern world depends on regulatory agencies, marketing, and commercial competition with rival products, all of which can be considered as ‘cultural’ forces under a broad definition of the word.

By the arguments presented here, a traditional society would have maximal success for finding useful natural molecules for a specific need if all of the above relevant factors were optimal: Highly druggable ultimate target(s) • Rich natural local environment, (such as rainforest) • Highly positive specific functional bias (for example, sought-after treatment could be satisfied by metabolites of diverse fungi or other organisms) • Highly acquisitive culture, highly receptive to innovation • Extensive duration of time for conducting ad hoc empirical testing of environmental resources.

To finish up, a double-barreled offering of biopoly(verse) of relevant note:

Are shamans biology sages

Possessing the wisdom of ages?

Some shamanic insight

In a drug textbook write

Might add some significant pages

 ____________________________________________________

Some chemists consult tribal lore

Seeking botanical info, and more

From suitable plants

They’ll thus take a chance

That good drugs will pay them a score

But where Westerners (especially those with commercial motivations) “consult tribal lore”, the outcome may be an exploitative one-sided affair sometimes termed ‘biopiracy’ – and that will be taken up in the next post, among other things.

References & Details

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

Examples of these [natural bioproducts as medicinals] ….particularly from local plant sources’   See Rates 2001 for a general review, with specific examples.

‘…..other traditional uses for environmental pharmaceuticals include preparations for control of insect pests…..’    See Seyoum et al. 2002 ….’…. and animal diseases. ’ See Schillhorn van Veen 1997.

‘…..jungle regions such as the Amazon have been rich sources of biopharmaceuticals…..’    See Schultes 1994. This author, the late Richard E. Schultes of Harvard University, was renowned for his ethnobotanical studies, including works on plant-derived hallucinogens. In the latter vein, he co-authored a well-known book in 1979 (Plants of the Gods: Origins of Hallucinogenic Use. New York: McGraw-Hill; with revised editions in 1987 and 2001) with Albert Hofmann, the discoverer of LSD.

‘…….human cultures …… have identified essentially all plants which can become dietary items.’   This point has been discussed by Jared Diamond in his well-known book, Guns, Germs and Steel (Vintage Books, 1997).

‘……where certain plant materials possess initial toxicity, but which can be removed by specific processing steps….’    A good example of this is the case of cycads of certain Pacific islands. The seeds of these ancient plants carry both nutrients and toxins, requiring pre-treatment by extensive washings and soakings in order to render the seeds edible for humans. This same example also raises another interesting general issue: humans screening their environments for edible plants will reject those that obviously poisonous (or finds ways to de-toxify them), but some plant sources may have toxins which produce subtle damage that is far more difficult to detect. Peoples of Guam and several other Pacific locales have suffered high rates of neurodegenerative diseases (with features of amyotrophic lateral sclerosis, Parkinson’s disease, and dementia, in varying combinations), and a long-standing hypothesis has attributed this disease focus to the local habits of cycad product consumption. (See the book The Island of the Colour Blind, by Oliver Sacks, Picador 1996, for an extended account of these issues). Yet this has been highly controversial, with varying forms of the ‘cycad hypothesis’ proposed and then discounted. It has become clear, though, that an environmental contribution is highly likely, as the disease incidence is in decline, in parallel with dietary changes (see Steele 2005; Steele & McGeer 2008).

‘…..historically infections and parasites were often relatively local….’    For more on this, one can refer to the same Jared Diamond book again as above (Guns, Germs and Steel ; Vintage Books, 1997).

‘…..even potential treatments for genetic conditions…’    It might be thought surprising that solutions to genetic problems could be found within low-molecular weight natural bioproducts, even in principle. A simple answer to this would be, ‘It depends on the nature of the genetic problem’. If a genetic lesion causes the loss of an entire genomic coding sequence for an essential large protein, clearly it is extremely unlikely that this defect will be ‘fixed’ by ingestion of a small natural molecule. But on the other hand, many genetic problems result from premature termination of protein synthesis, or mutations which cause protein misfolding. In the former case, mutations which result in the formation of abnormal stop codons in an mRNA molecule can be suppressed by drugs which induce translational ‘readthrough’, and thereby enable production of the formerly abnormally truncated protein. Although recent clinical successes have used artificially-obtained compounds for this purpose (see Welch et al. 2007), the original definition of the effect was provided by naturally-derived aminoglycoside antibiotics (see Howard et al. 2004). In the case of protein misfolding, certain compounds can interact with and stabilize misfolded proteins in their correct conformations. Natural products (and artificial compounds) have been found with this kind of ‘chemical chaperone’ potential in treating certain specific genetic diseases (for example, see Brumshtein et al. 2007)

‘……natural landscapes may harbor drugs whose usefulness is not definable even in the present day.’    This is a potent argument for the retention of natural biodiversity, and to resist increasing destruction of natural habitats – especially those within resource-rich tropical zones.

‘…..compounds modulating protein-protein interactions (as opposed to intraprotein folds) appear to be harder to find within the same natural set.’    Note that this is not stating that such compounds are entirely absent in Natural Molecular Space. A notable case in point are natural immunosuppressants: cyclosporins, rapamycin, and FK506. These molecules act by promoting the formation of ternary complexes which inhibit the activation of a key transcription factor for T cell activation. For some details, see Mann 2001; Lee & Park 2006.

‘……the druggability of protein-protein interactions, once believed to be intractable, is now seen as solvable.’    For progress in this area, see Dömling 2008.

‘…..a diverse library of molecules is one which spans a chemical space in a non-redundant fashion….’    For background on medicinal chemical diversity, see Gorse 2006.

‘…..no absolute standard for assessing diversity exists, although many sophisticated approaches have been developed….’     See Maggiora & Shanmugasundarum 2011, for a recent mathematical treatment of molecular similarity, which measures the flip side of diversity.

‘…….it has even been suggested that the human talent for ‘folk biology’ may be based on an innate neural module…..’    This was made by Steven Pinker in The Language Instinct (William Morrow & Co., 1994).

‘…..Peruvian Indians are often credited with both the discovery of the anti-malarial effects of cinchona and its transmission to Jesuit or other European visitors, most available evidence suggests that it is more likely that Europeans themselves first came to this knowledge….’     For much information on this on related topics, see Fiammetta Rocco’s excellent book; The Miraculous Fever Tree (HarperCollins, London, 2003).

‘  Quinine ……. also has inherent anti-pyretic activity…’     See Santos & Rao 1998. For some additional background on malaria, see a useful site.

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