DEVELOPING COUNTRIES AND NATURAL PRODUCTS RESEARCH

Blue Print
 
Based on the declaration of the AFASSA Coordinating Group held in Addis Ababa, Ethiopia, September 1-3, 2003.

The value of nature for human life is shown by the fact that ten of the top twenty medicinal products in the world come from natural products research (NPR) which has also been the origin of almost 60% of therapeutic anticancer agents. The unmatched molecular diversity of nature has attracted the interest of academics and companies as well. Every big pharmaceutical company has developed activities in the field and Universities in the developed as well the developing world have characterized some natural molecules. Nevertheless, a very small portion representing less than 10% of over 250,000 plant species has been screened in different laboratories to determine their therapeutic potential and no more than 100 plant species are used to obtain clinically important drug molecules*. In clear contrast, between 35,000-70,000 plants species are used worldwide for medical purposes.

Many important developments, which occurred in the last two decades, have affected research in NPR. First of these is the Convention for Biological Diversity which established rules for access to the genetic resources of the world. However, the Convention remains largely unimplemented particularly because there has been a lessening of interests of big companies in the molecular diversity of tropical and subtropical forests.

Since the 90s, new technologies such as high-throughput screening (HTS), bioinformatics, genomics and combinatorial chemistry (CC) have emerged. These are being integrated widely in the field of molecular discovery research offering an apparently strong alternative of synthetic molecular multiplicity to the natural diversity. Modern drug development involves robotic HTS on 96, 384 or 1536 well microtitre plates using multichanelled pipettors and automated reading of results using fluorescence, radioassay or colorometric readers, scores of bioassays being possible with only 1 mg of material.
Better separation and analytic instrumentation has led to improvements in these techniques and permitted the routine identification of compounds isolated in nanogram quantities. The output per scientist has multiplied over 30 fold using these techniques and the demand for samples has increased and cannot be satisfied by natural products. CC, which involves the synthesis of libraries of compounds in multiple sequential reactions, can provide a large number of samples for screening over a very short time period.
Mechanisms of activity have been correlated to receptor and enzyme active sites and bioassays have been developed to target these sites. With powerful computers available at cheap prices, bioinformatics and genomics have allowed the establishment of databases for gene and protein sequencing and the manipulation of data to model disease process and study small molecule activity at receptor sites. These developments have made NPR less necessary for the pharmaceutical industry. Towards the end of the 90s, NPR as a source of molecular diversity for health science and agronomics appeared to be something of the past while genomics-based molecular discovery was the modern and unsurpassable trend.

 At the same time that NPR was losing favour as a source of leading molecules for health and agriculture, a worldwide resurgence of interest in the use of herbal medicinal products was observed. This trend was evident from the greater increase in annual growth of herbal medicines in comparison to pharmaceutical products. In the United States alone, the market of medicinal herbs has gone up to over two billion dollars.

In the South there are additional forces pushing towards the study of medicinal herbs: traditional medicine is of great importance for the health of the majority of the population as pharmaceutical remedies are often beyond their means**. Furthermore, the pressure for the internationalization of patents and strict enforcement of Intellectual Property Rights (IPR) by big pharmaceutical companies have made countries like Brazil intensify their support for research on traditional medicine resources.

Combinatorial chemistry has however not proved as successful as expected, largely because it provides chemical diversity without providing due weightage to biological significance. Secondary metabolites are found to be superior in terms of biological activity when compared with randomly synthesized compounds. Although the outlook for natural products chemistry appeared dismal a few years ago, it has recently regained some of its attraction because of the greater diversity of compounds it generates compared with combinatorial chemistry and the high enantiomeric purity of the compounds isolated. Natural diversity provides more potential for discovering leading molecules for pharmaceutical and/or agronomical purposes.
New developments include the combination of NPR with CC and HTS to magnify the output. This modern trend has been complemented with proteomics. Gene activity is expressed through proteins that regulate vital cellular processes. Because of the co-evolution of human ancestors and plants, secondary metabolites have impressed their mark on proteins and are potential key regulatory tools contributing to control physiological variables in health and disease in veterinary and agricultural science. Isolated metabolites or even plant extracts are been tested in their effects on intracellular molecular signaling, the last frontier in our comprehension of life regulation. 

Life sciences including chemistry in all its forms (analysis, synthesis, etc) together with biology (physiology, pharmacology, molecular biology, etc) and botany have therefore the answers for the development of NRP that can be considered among the most interdisciplinary field of human research activities.

Summarizing the trends in NPR it can be said that natural compounds still have a key role as repository of molecular diversity for life sciences including medicine, agronomy and veterinary. State of the art chemistry and biology are being incorporated in a multidisciplinary approach that is also including complex biological extracts like medicinal herbs.
The developing countries of the South are the richest in biodiversity and they should are in a position to explore and exploit it for their socio-economical progress. The discovery and development of pharmaceutical and other useful agents from NPR can, under appropriate circumstances, promote economic opportunities and enhanced research capacity in the South. NPR should promote the self-sustainability of the research activities, generating income derived from the intellectual property of the scientific discoveries (IPR).

However most developing countries have been unable to exploit their biodiversity through NPR. While there has been some research in NPR in developing countries, it is often not directed at the discovery of biologically active substances. The focus instead in many of the lesser developed countries has been on the isolation and structural elucidation of secondary metabolites and that too only of those from higher plants. Successful isolation of active substances is possible only through bioassay directed fractionation, but the maintenance of a number of bioassays in a developing country environment is difficult. Very few laboratories in the developing world have been able to maintain good bioassays, and even then only to a very limited extent.

An alternative would be to carry out some stages of NPR in collaboration with private and industrial enterprises that could provide financial and marketing means, assuring a fair and safe distribution of the royalties and fees accrued by the results of the scientific investigations. Although such private enterprises are found mainly in the North, there are several smaller growing enterprises in the larger developing countries like Brazil and India whose support may be mobilised.

The experience has been that many scientists of the developing world collaborating with multinational drug companies find themselves to be mere volunteers in global programs driven by the multinationals. Sometimes the companies merely buy various natural products obtained by developing country researchers often for a pittance. When compounds are sold in this manner, there are no rights held by the developing country or its scientists. Furthermore, there is no feedback information expected from the buying companies.

When samples from developing countries are sent for various biological assays on a collaborative arrangement, a common response when activity is shown is that the compound was active enough initially to be subjected to a wider battery of tests and the results are enclosed. No further action will be taken. Any compound that promises efficacy, which is as good as the best drug in the market is considered by the profit-driven drug companies as being not good enough for drug development. Even where bioassay guided fractionation has been carried out in developing countries, it has been difficult to arrive at a marketable product. The only worthwhile outcome has been the generation of new knowledge from research. The question may be posed whether the interests of the multinationals have been served when screening and publishing data on NPR on the flora of developing countries.
Why has it been difficult to utilize NPR in developing countries to obtain a product of value for local and/or global health and agricultural demands ? The main academic origin of research, developed in extremely weak financial environments lacking risk capitals, marketing means and even sound industrial partners, partly explain this situation. Being so complex, the later objectives of NPR are beyond the capacities of an individual scientist and should be provided by local and/or regional institutions. However, in most developing countries, governments are unable to provide this support.

Developing countries have different priorities from multinationals and should not neglect a research finding which offers efficacy against malaria or other ailments common in developing countries nearly as good or slightly less than chloroquine.  From the point of view of developing countries, it may be worth pursuing leads that have been shelved aside because of being “unworthy of further investigation” since they do not promise huge profits to drug companies. 

Collaboration in natural products research has predominantly taken the form of North-South linkages. North-South collaboration should focus on training and acquisition of skills that are of the highest level and also relevant to the developing country. Collaboration among institutions in developing countries is rare and should be promoted. There are centers of excellence in the South that have the facilities for performing biological assays and for providing analytical data. Should not there be South-South collaboration in NPR utilizing these centers ?  Although many of these have very good facilities, they have no mechanism to support the large number of graduate students and a few postdoctoral students that are needed to build up a strong research group. It has been argued that training nationals at PhD level in national institutions leads to inbreeding. This is indeed a serious problem, but can be avoided through external postdoctoral experiences, incorporation of sandwich programs into the PhD training and through regional student and staff exchange programs. 
Scientists in the least developing countries often do not even have access to basic equipment for NPR research like separation equipment like HPLC and analytical instrumentation. While programmes for increased funding of research should be initiated, a way out could be through the facilitation of South-South collaboration. To provide the access of every country to the state of the art in the disciplines mentioned above, NPR should be multinational, complementing national research facilities with easy access to International (regional) Research Centers or Scientific networks with leading expertisein particular areas of a given field (e.g.: NMR or genetic engineering).
NPR in developing countries could also gain from the developments in industry worldwide. Microtitre plate based screening, the use of HPLC databases, mode of action studies and bioinformatics are areas which may be developed. Such work will however require some basic scientific infrastructure, which is often not available in many developing countries particularly the least developing countries. If scientists in these countries are to apply modern techniques and work at the frontiers of research in natural products chemistry, a mechanism for some form of training, short term fellowships or periodic attachment at one of the better endowed institutions in another developing country should be formulated.

Some organizations support regional cooperation through outstanding programmes like IPICS, TWAS and the USHEPiA. However, in most cases funds are not available for such South-South collaboration
However even with such support it would only be possible to carry out only the initial steps such as identifying a promising compound with potential as a lead for the development of a drug or a agrochemical as most developing country scientists neither have access to pharmacological or clinical studies nor the facilities to generate the Test data necessary for approval of drugs and agrochemicals. While chemical synthesis can be carried out in some developing countries, facilities for synthesis in most are often restricted to the carrying out of simple synthetic reactions. Formulation expertise is also unavailable in developing countries. Would it be possible to access such expertise through collaboration with companies in the larger countries of the South like India and Brazil ?

Scientists from such countries could also be encouraged to exploit the enormous amount of popular knowledge on the use of local herbs for health and agriculture and work on the development of nutraceuticals (a growing market in the west), the standardization of drugs used in their indigenous medicinal systems and in the development of crude material for local use based on indigenous medicine as non-prescription drugs or for use by farmers as agrochemicals.