Opinion: Why Traditional Knowledge is Important in Drug Discovery

Recent decades have seen some intense debates concerning the alleged wholesale misappropriation of traditional knowledge by the pharmaceutical industry. Many within the industry counter that scientific and technological advances make traditional knowledge irrelevant in drug discovery, and bioprospecting a waste of time and money: it may have been important in the past, but that does not make it important today or tomorrow. This article shows, through a number of historical and present-day examples, that traditional knowledge is a potentially valuable source of leads for drug discovery and that overlooking it is not in the interests of industry or the public.

To some people, the pharmaceutical industry almost literally preys on indigenous peoples, patenting their knowledge and making billions of dollars without sharing a cent with them. Many people in the industry, while not denying the past importance of traditional knowledge, profess to have no interest whatsoever in it as a source of leads for new pharmaceutical applications and entities, and consider it to be worthless for their line of business.

Both views, that traditional knowledge substantially subsidizes the pharmaceutical industry, and that traditional knowledge has no relevance for present and future drug discovery, are incorrect. The traditional knowledge champions tend to rely too much on their analysis of a small number of high profile cases. As for the detractors – to whom this article gives most attention given the journal’s readership – it is suggested that the error arises from adhering to a conveniently simple but inaccurate assumption that pharmaceutical research and development invariably follows a purely linear, unidirectional pathway starting with a single discovery, followed 10–15 years later, if at all, by a product. In the paradoxical real world, progress in pharmaceutical research goes backwards as well as forwards and along winding complicated pathways often with no obvious beginning or end. Alternatively, one might suggest the complexity of research progress has more in common with trees having many spreading branches than with thoroughfares. This is tacitly acknowledged by industry when, perfectly legitimately, it invests in the discovery of second uses of known drugs and in incremental improvements, and by legislators and judges when they allow these to be patentable. Arguably, then, industry is hardly unaware of the reality, whether or not the traditional knowledge-related implications are ever contemplated. The error is also partly a result of the misleading assumption that rapid scientific and technological advances are inevitably making natural-product research unfeasible.

What is traditional knowledge anyway? We only speak of traditional knowledge at all because there is knowledge in the world that we assume to be radically different from ‘our’ knowledge. The latter we prefer to label as ‘modern’ or ‘scientific’ knowledge. Holding to a traditional–modern epistemological dualism as if all knowledge is either all of one or all of the other is in fact simplistic, misleading and unhelpful. For convenience, let us just take traditional knowledge to mean the knowledge that predominates in past and present societies living close to the land whose livelihoods are relatively unaffected by industrialization and the mechanical and chemical outputs of modern industry.

There are two conventional wisdoms about traditional knowledge regarding its value for the pharmaceutical industry. Put plainly, one ‘wisdom’ is that the pharmaceutical industry has always needed traditional knowledge relating to bioactive substances such as medicinal preparations and toxins of plant, animal and mineral origin, and continues to do so. The other is that the pharmaceutical industry does not need traditional knowledge. According to the first wisdom, traditional knowledge is so important that not to use it would have substantial negative impacts on the industry as reflected in decreasing rates of drug discovery and development and lower profits from sales [1].

Given the audience for this article, and in the interests of being constructively provocative, we will focus critically on the second wisdom. At its most extreme, the view here is that traditional medicines are crude and unsophisticated preparations delivered on the basis of incorrect theories and practices that mostly do not work or else rely on a placebo effect. Consequently, observing traditional use of plant extracts, animal extracts or minerals is of little use in drug research and development either in providing helpful clues, raw materials or intermediates, or as finished articles.

This article argues that the relationship between drug discovery and traditional knowledge is real, yet more complex than most industry insiders and critics suppose. This complexity does not make it easy for the antibiopiracy critics to score political points against the industry for making vast profits from the free use of traditional knowledge (though it does justify calls for greater respect for traditional knowledge holders and fair benefit sharing) [2]. However, it also means industry needs to be more aware of the major role traditional knowledge has played in drug discovery and its potential for contributing to commercial success. Such awareness is, I argue, in the best interests of an industry whose productivity rates in terms of getting new chemical entities to market has diminished in recent years; but is also a matter of justice.

The rest of this article attempts to justify this in-between view on the basis of the empirical evidence. It seeks to demonstrate, without exaggeration, traditional knowledge’s continuing commercial importance as a source of biological information worth investigating. It also emphasizes the continued relevance of traditional knowledge at a time when the industry is broadening its range of drug-discovery strategies in the face of a persisting failure to increase the rate of developing new molecular entities (NMEs), which includes taking an intensified interest in natural products.

Why traditional knowledge still matters

There are three reasons why traditional knowledge matters more than people may think. First, because the learning trails that have led from traditional knowledge to some highly profitable drugs and classes of drugs can be so long and winding that they become hard to retrace with lengthy sections disappearing from most people’s sights. Rediscovering these trails may show past traditional knowledge connections to some of today’s best-selling drugs. Second, because the pharmaceutical industry, for all its investment and acquired expertise in new biological technologies and synthetic chemistry, is surprisingly dependent on the re-engineering (or ‘renewing’, as I call it) of past discoveries, some of which will definitely have traditional knowledge origins. The third reason is that natural-product research continues, despite the promise of new chemical, biotechnological and screening technologies, to be absolutely essential for the industry. Where the natural products have plant or animal origin, traditional knowledge has a good chance of being relevant. Admittedly the first reason may seem rather academic, but this is not the case when we consider that learning trails are potentially endless.

Losing track of the learning trails

The first reason requires us to reject the repetitive cliché that drug research and development is a linear one-way process in which one molecule in 10,000 will enter the market 10–15 years after its discovery; the discovery of the successful molecule marking the start of the trail and the end being the placement of the approved drug on the market.

In reality, the ‘learning trails’ from the initial find (or set of initial finds) to a product or class of pharmaceutical products is usually long and complex with the likelihood that the trails will fade away in the course of time. Enormous lengths of time may elapse between finding or rediscovering some early clue, such as a reported use of a plant for a particular purpose by an indigenous group, and the marketing of a pharmaceutical product whose therapeutic use may in fact be quite different. Trails have no obvious end, since one product leads to another. Trails may branch off in some very fruitful directions, possibly before any product has been developed, and also merge with others. Of course every accession in a natural-product extract library has a past and an origin. But there is no particular reason why a pharmaceutical scientist should be aware of the history and geography of any given extract’s usage unless such information is reported in the recent scientific literature.

Arguably, the patent system encourages this neglect of history and geography. As technology historian George Basalla once put it, “a patent bestows societal recognition on an inventor and distorts the extent of the debt owed to the past by encouraging the concealment of the network of ties that lead from earlier, related artifacts”[3]. As I have argued elsewhere, one could go further than Basalla and suggest that a patent tends to legally sever the ties leading to related artifacts developed not just in the past but also at the same time, whether in the same place or in a faraway location. Arguably, this view holds even if such ties are acknowledged in the specification, since a reference to the work of others does not amount to a sharing of rights or an admission that they are co-inventors [4]. Obviously, it is never likely to be the case that the originators and holders of traditional knowledge inspiring the discovery of a pharmaceutical compound in one of their medicinal plants would themselves have known how to isolate or describe it chemically. Even so, the logic of treating a description of the traditional knowledge as part of the public domain and owned by nobody, and the isolation and chemical description, no matter how creatively and expensively achieved, as a patentable invention subject to private ownership, is unlikely to appear just or reasonable to the indigenous traditional knowledge-holding group. This is especially so if group members actually assisted the researchers. In this context, it is worth noting that while the names of plants containing a pharmaceutical chemical are usually mentioned in patents, traditional knowledge leads are frequently not.

Let us consider the example of curare, a name originally applied to certain plant-based preparations from South America. It is admittedly rather easy to retrace the link from curare the surgical muscle relaxant, to curare the Amazonian arrow poison despite the long period of time between the observation by Europeans that some Amazon Indians used certain plant extracts to asphyxiate their prey and the use of curare in surgery, which began in 1942. However, to suggest that the learning trail ended in 1942 is false for two reasons. First, curare inspired the discovery and development of better surgical muscle relaxants. Second, and more important, scientific investigation of curare from the 1930s was incredibly fruitful. Using curare as a research tool proved the essential role of chemicals in channeling messages within the brain and from the brain to the rest of the body, thereby radically enhancing our understanding of physiology and brain function. This led directly to the subsequent development of numerous spin-off drugs including the b-blockers, antidepressants such as Prozac and treatments for Parkinson’s disease, asthma and diarrhea [5]. Needless to say perhaps, the trail from curare the arrow poison to Prozac is hardly an obvious one, which of course is testament to the considerable amount of scientific research conducted over a long period that began with no more than an observation made by a few curious European explorers. Who knows where else this particular trail will lead in the future?

Similarly, the willow bark extracts used to treat fevers and inflammation in ancient Greece and Rome became aspirin, the synthetically produced mass-consumption pharmaceutical product at the end of the 19th century. Willow tree bark’s antipyretic properties were rediscovered in the 18th century by English clergyman Edward Stone, whose search was inspired, at least indirectly, by the Peruvian Indians’ use of cinchona tree bark extract (quinine) to treat fevers like malaria, and by the European doctrine of signatures, often attributed to Paracelsus but that has much earlier roots, which led him to search for such a product in the known source of fevers, marshy ground. Aspirin, as a treatment for mild fevers and headaches, is far from being the end of the story. It was the first of a class of drug (i.e., NSAIDs). It would be going too far to suggest that aspirin inspired the development of all NSAIDs that followed. Ibuprofen, for example, was discovered in an effort to find alternatives to cortisone, the first hormonal anti-inflammatory drug, which has some very unpleasant side effects. Nonetheless, it was research on aspirin that demonstrated the mode of action of this whole class of drugs and underlines the long-term importance of aspirin as a product, the first of a class of product and as a research tool for future discovery.

Renewing the old

Industry has in recent years been responding to the present shortfall in the number of new chemical entities entering the market by, among other activities, returning to known substances to identify undiscovered properties. They are, as I put it, seeking to ‘renew the old’. Since old products are more likely to have some kind of traditional knowledge connection, it follows that traditional knowledge will most likely continue at least indirectly to provide a source of leads for ‘new’ uses for old drugs for as long as companies are doing this. This is not widely appreciated, given the common assumption that modern technologies such as high-throughput screening, genomics and combinatorial and synthetic chemistry are reducing the need for natural-product research and, hence, for traditional knowledge.

What is the evidence? It is no secret that the number of NMEs entering the market has been disappointing in recent decades despite the ever-growing research and development expenditures. As they continue to be hard to identify, scientists often go back to earlier substances. There is nothing inherently wrong with this. Even as innovative a scientist as Sir James Black knew that looking forward often meant looking back first. As he put it: “the most fruitful basis for the discovery of a new drug is to start with an old drug” [6]. Nowadays, though, discovery seems often to end with the old drug too.

Out of 1264 new drug applications submitted to the US FDA between 1993 and 2004, 68% were not NMEs [7]. Of the 961 that were approved, 67% were non-NMEs, meaning that each was one of the following types of drug: a new salt, formulation or indication of a previously approved drug; a new combination of more than one drug; a duplication of an already marketed drug or an already marketed drug that had not previously been approved by the FDA, such as a very old drug (e.g., aspirin) [7].

The key point to be made is that if so many ‘new’ drugs are not in fact new molecules, it becomes more likely that the sources of a significant proportion of drugs currently on the market can be traced to indigenous communities, if one takes the trouble to find out. The fact that aspirin is mentioned in the above-referenced US government report is somewhat telling in this regard, given its traditional knowledge connections, although one should not overstate the case since recent drugs that are completely synthetic can turn out, upon further examination, to have therapeutic applications different from those previously envisaged. Of course, even completely new drugs may have origins in traditional knowledge, as we will see, but non-NMEs are far more likely to. Let us now consider some examples of old traditional medicines being turned into new products or at least being the subject of new discoveries.

Again, aspirin is relevant. Since John Vane worked out its mode of action in 1971, aspirin has been found to have therapeutic applications other than relieving pain and fever. Indeed, patents relating to new uses of aspirin are still being granted. To turn from a plant to a mineral, arsenic was both a drug and a poison in Ancient Greece and Rome and it is used currently in Chinese traditional medicine. Although it was never a treatment for cancer (and in fact has been known for almost two centuries to be carcinogenic), it is used to treat trypanosomiasis as it previously was for syphilis, and Chinese scientists have even investigated its potential use as a treatment for leukemia [8].

Perhaps the best renewing cases are those where traditional knowledge offers a direct lead to a (supposedly) new product. Artemesinin’s antimalarial activity was documented in Fourth Century China. In the 1960s, the Chinese military conducted research into medicinal plants, and in 1972 found a substance known as artemesinin in the leaves of the Artemisia annua (wormwood) plant. Structurally modified artemesinin, used in combination with other products, is now the most effective antimalarial available. Despite this, its mode of action has still not been fully established. Nonetheless, numerous methods for converting, extracting and making analogs have been discovered and patented. Many more are likely to follow.

Nicosan (or Hemoxin) is another traditional medicine, this time from Nigeria, which shows effectiveness as a sickle cell anemic treatment. Though not yet on the market, except in Nigeria, it has orphan-drug investigational status in the USA and Europe. A recent article describes Nicosan as “a mix of plants that came from native-healer information” and can thus be classified as a “true ethnobotanical preparation” [9]. This circumstance gives rise of course to benefit-sharing implications.

Going back to nature – as if we never left

Dependence on nature has not gone away. Recent evidence suggests that it is not diminishing by any means. A comprehensive empirical investigation by Newman and Cragg of the US National Cancer Institute demonstrates convincingly that, as indicated in previous studies, “natural products play a dominant role in the discovery of leads for the development of drugs for the treatment of human diseases” [9].

Despite this, scientific and technological advances suggest to many a reduced dependence on natural products. While this may eventually prove to be correct, some advances, including metabolic engineering, appear at least in the short to medium term to enhance the feasibility of discovering, elucidating, optimizing and mass-producing therapeutic substances of natural origin [10,11]. This is significant given common concerns that natural products tend to be complicated, heterogeneous, scarce, difficult to work with and sometimes prohibitively expensive to synthesize. There may be two kinds of scarcity: in terms of the supply of the species in which the chemical resides; and the actual chemical that the relevant species may produce only in minuscule quantities. Thus, some recent trends arguably make natural product research more appealing. Traditional knowledge is a logical starting point as a source of initial leads.

Conclusion

This article shows that while the unrealized pharmaceutical value of traditional knowledge cannot readily be ascertained, it is surely significant: there is enough evidence to demonstrate that loss of traditional knowledge means cutting off access to a potentially huge and priceless stock of complex biological substances that scientists are unlikely to be able to stumble across elsewhere or invent de novo in the laboratory. Consequently, there is a need for efforts to support the ethno-ecological systems that conserve this knowledge through everyday use and generate further knowledge. As for benefit sharing, the 1992 Convention on Biological Diversity places legal obligations on commercial users of traditional knowledge to share the benefits with the holders and their communities in a fair manner.

Finally: a note of caution. One should not overestimate the value of traditional knowledge either. It is relevant to present drug discovery, but it forms just one portion of a very large reserve of available knowledge, including scientific information reported in books and journal articles and inventions disclosed in expired or lapsed patents.

Acknowledgements

The author gratefully acknowledges helpful comments and suggestions made by an anonymous reviewer.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.