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Defining Useful Molecules

July 12, 2011

This post will have a rather different flavor to its predecessors, since a new theme is introduced, which can be encompassed by the term ‘molecular discovery from natural sources’. To cover this, about five upcoming posts are planned. (But this is certainly not to say that topics relating to biological ‘dark matter’ and general bio-frontiers will not be returned to in the future).

In this context, these posts will also take a look at what can be termed ‘Natural Molecular Space’, or the set of all molecules derived from Earth’s biosphere, especially where they have relevance and utility to humans. It should be noted that while the field covered here (covalently bonded molecules) is very large, it clearly does not include all physical materials exploited for human applications. Thus, simple ionic salts are excluded, and also monatomic metals or inert gases. The great majority (but not all) molecules meeting the present criterion of ‘usefulness’ are carbon compounds.

The Chrestomathy of ‘Chrestomolecules’

 Before looking at some specific areas of Natural Molecular Space in later posts, for the present purposes let’s pause and think about useful molecules in general. This of course goes beyond drugs and also beyond biomolecules themselves, since some natural non-biological molecules can be useful, and certainly an enormous number of artificial molecules which are never found in any known natural circumstances are likewise beneficial. Some thoughts on the notion of general molecular usefulness will consequently be useful in themselves. Utility in this regard is defined as the capacity for providing solutions to human needs, irrespective of the ‘natural’ function of the molecule, if any. But to pin down this sense of ‘utility’ and relate it to true ‘molecular solutions’, we need to consider that such beneficial molecules have economic significance of some form or another. To contract this into a single word for brevity, we can coin ‘chrestomolecule’ where the prefix is derived from the Greek, khrestos, useful. This root is found within the bona fide (albeit rarely used) word ‘chrestomathy’, defined as a collection of literary passages used in the study of language, or literally ‘useful learning or knowledge’.

A chrestomolecule is then defined as any molecule (irrespective of size, structure, or source) which is economically significant to any human culture or cultural subgroup, in the broadest sense. Should this encompass molecules composing human nutrients? Certainly, molecules which compose digestible foods (such as proteins, carbohydrates, and lipids) and vitamins or other cofactors might be thought of as comprising a distinct category, given that they are directly required for survival and are not ‘optional extras’ in terms of human needs. Yet at the same time, it is equally plain that food materials have always been, and will always continue to be, of fundamental economic importance. To resolve this, it should be noted that an implicit presence wrapped up within the ‘chrestomolecule’ definition is human knowledge, at least applied after the fact. Obviously, foodstuffs in enormous variety have always been obtained and prepared by humans from necessity, but it is only in the most recent times (historically speaking) that any conception of the real compositions of foods was derived. One does not need to know anything about protein molecules to satisfy hunger from meat, in the same manner that the benefits of a medicinal plant do not require the slightest inkling of the nature of the active compound, or what a molecule is in the first place. It is only when such knowledge has been laboriously acquired that any definitions of molecular utility can be entertained. And molecular understanding goes beyond merely description, but inevitably moves into synthesis. This is also applicable to general human nutrients – it is perfectly possible to synthesize a variety of digestible substances, potentially including molecules which are completely novel. (As an example, a novel folded protein with an optimal complement of essential amino acids could be produced). Such undertakings are not currently economically competitive with natural foods, but this situation need not always remain the case for the future. Since nutrients are obviously definable at the molecular level, and are by no means exempt from human molecular manipulations, excluding their constituent molecules from the current ‘chrestomolecule’ umbrella seems unwarranted. At the same time, nutrients are clearly in a special category in comparison to all other human needs and desires met by specific molecular entities.

But aside from nutrient value, a chrestomolecule could indirectly affect food production in many ways, such as promoting plant growth or inhibiting insect pests. It is also necessary to consider the aspects of the vast food industry which deal with non-nutritive additives, such as artificial sweeteners and flavors, preservatives, and colorants. Some non-digestible natural molecules occurring in food preparations can be considered in this light as both ‘natural additives’ and chrestomolecules, if they enhance the economic value of a food substance. For example, for some Japanese the suitably-prepared flesh of pufferfish (fugu) is considered a delicacy through the effects of traces of tetrodotoxin, a deadly poison in elevated doses. We must also note that some food molecules can serve both as nutrients and in other roles, in which case their functional status as chrestomolecules overlaps their alternative nutritive use. A classic example of this is the digestible polysaccharide starch, which is a widely-used food, but also has many industrial and domestic applications. And in this context, mention should also be made of ethyl alcohol, the oldest drug and a food (with a specific calorific value) as well.

If deemed of economic worth, a chrestomolecule will be a subject of human transactions, usually involving money but also any other form of trade or bartering. Within this definition, there need be no requirement that a chrestomolecule should be in a pure state, as long as the relevant molecule is ultimately recognized as at least one component of the preparation responsible for the desired function. The reason for making the economic distinction with respect to molecular utility is to focus on real solutions to human needs. To further delineate this point, it could be argued that any distinct molecule synthesized by humans, or isolated from the natural world, is certainly ‘useful’ in the broadest sense, by increasing human knowledge. Previously unrecognized parts of this huge fund of chemical knowledge may ultimately become directly relevant for the production of economic value, which underscores the importance of basic research. But a ‘chrestomolecule’ for our purposes might arise as the culmination of a long series of studies, embodied in a physical molecule of definable economic significance. ‘Intermediates’ along this pathway, or molecules which are never economically valuable, fail to meet the ‘chrestomolecule’ definition. But we should note here, though, that a huge range of compounds are sold as reagents in research specialty markets and are thus still chrestomolecules by the economic criterion. For example, the ZINC database of compounds (especially designed for computational virtual screening) holds over 13 million entries which are commercially available. Another way of looking at this is to consider that modern biotechnological and pharmaceutical companies may spend much time, money and effort in research which yields a variety of novel molecular structures, but only those making it to the marketplace in some form or another will be classifiable as chrestomolecules.

It is also necessary to note that any specific chrestomolecule by definition may have a transient existence, if the need which prompted its use disappears, or if it is replaced by a superior alternative. An example in this regard is the use of certain dyes from marine sources, which have been superseded by synthetic products. By the same token, a formerly ‘useless’ natural product may acquire value through an experimental demonstration of its possession of a beneficial functional property. In being defined by human cultures or groups, ‘chrestomolecule’ can be regarded as an anthropic principle of sorts applied to molecules – a molecule can only be a chrestomolecule if more than one human agrees that it is. This social dimension to the definition is also value-neutral. ‘Economic significance’ in broad terms has no regard for ethics, and different human groups may disagree violently on the worth of some molecules (consider illicit drugs). Synthetic molecules used for chemical warfare or crowd control are another case in point in this respect.

The chrestomolecular definition, though, is satisfied if at least one human subgroup values a molecule economically, irrespective of the higher wisdom of such a preference. In any case, risk / benefit factors are very often present in the economic use of molecules. As a pronounced example, the synthetic compound DDT is clearly a chrestomolecule, but one with significant negative environmental side-effects as well as beneficial insecticidal properties. The full ramifications of this particular cost / benefit equation are still being debated. ‘Useful’ without the neutral economic qualifier can thus become a highly contentious issue. ‘Chrestomolecule’ itself is a neologism, but whether it is also a ‘neochrestologism’ (new-useful-word) or a ‘neocacologism’ (new-bad-word) is of course only a matter of opinion. But the economic significance of molecules, although defined by humans, is an objectively assessable property. In turn, the cost / benefit analysis of a molecule (upon which its economic worth is theoretically based) is at least in principle amenable to rational scientific analysis, although (as with the DDT story and many others) this can involve many complexities and invoke balancing divergent human values and priorities.

With all this in mind, we can then think about where chrestomolecules collectively come from. Both artificial and non-biological natural molecules can serve as chrestomolecules, although relatively few emerge from the non-biological category. Historically, the category of artificial chrestomolecules is of very recent vintage, since it requires the rise of chemistry and biochemistry as well-defined sciences. The figure below represents these points:

Figure: Origins of chrestomolecules in general, where set diagrams are not drawn to relative scales. A subset of general bioproducts, artificial synthetic molecules and non-biological natural molecules fit the chrestomolecular definition. (As an example of the latter ‘non-biological’ category, consider the simple diatomic nitrogen molecule N2, which is obtained from the atmosphere and used for a variety of industrial purposes). All these molecular groups lie within a greater set of chemically feasible molecules.

Chrestomolecules and Biology

But now we can return to the subset of chrestomolecules which are derived from the biological world, the major theme for this new series of posts. Some major categories of chrestomolecules derived from the biosphere, and some of their properties, are provided in the Table below.

Notes for Table: Varieties of biomolecules of economic significance to humans (chrestomolecules). MWt denotes molecular weight. ‘Examples’ denotes specific purified or processed products within each category. Natural contraceptives (such as gossypol) may be loosely slotted into the ‘Therapeutics’ category. In accordance with the value-neutral position for ‘economic significance’,  naturally-derived psychoactive drugs (commonly regarded as drugs of abuse among many social groups) are included. A far more objectionable (though relatively minor) value-neutral use category of chrestomolecules is the potential application of natural products as chemical agents of war or terrorism. Nutrients are included here as a special category, as discussed above. The biosphere has by necessity been the source of human nutrition and the corresponding array of molecules large and small which can be processed for the consumer’s benefit to provide energy, structural materials, or catalytic assistance to enzymes (essential nutrient cofactors).

This will extended in the next post. Meanwhile, a biopoly-verse comment on neologisms, which are not always welcomed by some people:

 A new word for molecular use

Is hopefully not seen as obtuse

A newly coined word

May not be absurd

If its meaning is clear, and not loose

References & Details

(in order of citation)

‘…‘molecular discovery from natural sources’…’    While molecular discovery was an important theme within my book Searching for Molecular Solutions, the topics covered here are outside its ambit and have not been previously published by myself.

‘……does not include all physical materials. Simple ionic salts are excluded, and also monatomic metals or inert gases….’    A great many simple salts find a vast range of applications – for example, think of chloride, sulfate, carbonate, and bicarbonate salts of sodium. The range of metals and their alloys (effectively solid solutions) need no introduction in terms of their vast utility since the Bronze and Iron ages. Through the nature of their electronic configurations, inert gases resist chemical bonding and normally remain in a monatomic state, with exceptions for xenon and krypton which can be coaxed into compound formation in special cases. Many applications in industry exist for inert gases, and helium and especially xenon have roles in medicine as effective anesthetics (see review by Harris & Barnes 2008).

It should also be noted that some covalent compounds behave as ionic solutes in aqueous solution (consider hydrogen chloride gas as a covalent molecule vs. aqueous dissolved HCl, or hydrochloric acid. So the some compounds can classified as having covalent or ionic character depending on the specified conditions. Only in the former state will they be classifiable as chrestomolecules by the definition used here, if they are indeed economically useful in the covalent state.

‘……..Such undertakings are not currently economically competitive with natural foods, but this situation need not always be the case. ‘ In this context, consider efforts towards ‘artificial meats’ grown in cell culture. (See New York Times and Time Magazine articles). While these projects use natural (stem cell-derived) animal muscle cells, in principle cells engineered to express modified or novel nutrient proteins could be used. Obviously, in such circumstance safety concerns and consumer attitudes would become major issues.

‘……..the use of certain dyes from marine sources, which have been superseded by synthetic products.’    The historically famous example is the preparation of a purple dye from certain marine mollusks (Murex and Thais species), the origin of which is attributed to the Phoenicians, but later adopted by other Mediterranean peoples, including the Romans. (The expense and prestige of this dye led to restrictions on its use to garments worn by the rich and powerful; hence the source of ‘called to the purple’ as referring to the ascension to the emperor’s throne in imperial Rome). A variety of substitute purple dyes have been used over the ages, but the first synthetic purple dyes were produced and marketed by William Perkin in 19th century Britain (for more details, see the excellent book Bright Earth – The Invention of Colour, by Philip Ball (2008); Vintage Books, London).

‘……a molecule can only be a chrestomolecule if more than one human agrees that it is.’    In other words, no individual can proclaim a chrestomolecule without the concurrence of his or her fellow humans. There is an old joke about one philosopher saying to another, “I think solipsism is the only true philosophy, but of course, that’s just one man’s opinion”. To build on this to make a relevant point: One philosopher says to another, “I’ve found an amazing chrestomolecule. No-one else in the world agrees with me, but of course, I’m a solipsist”. In principle, single individuals in complete isolation could discover useful molecules – for example, by curing themselves from a disease. But unless this discovery then involved transactions with other humans, it could not be defined as economically useful.

‘……the synthetic compound DDT is clearly a chrestomolecule, but one with significant negative environmental side-effects …… ramifications of this particular cost / benefit equation are still being debated.’     See (for example) Rogan & Chen 2005Sadasivaiah et al. 2007.

Natural contraceptives (such as gossypol) may be loosely slotted into the ‘Therapeutics’ category.‘   Gossypol is a polyphenolic compound derived from cotton. In addition to its role as a potential male antifertility treatment, it has several additional bioactivities which may be therapeutically useful. See Wang et al. 2009.

‘……the potential application of natural products as chemical agents of war or terrorism.’    For more information, see Henghold 2004 and Zapor & Fishbain 2004.


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