1Abstract
In the past hundred years, synthetic drugs had gradually replaced plant-derived drugs, except for antibiotics and antitumor drugs. Due to the development of experimentation with molecules, new openings and perspectives appear for natural products. Progress in biotechnology, biochemistry and research on metabolism are also the cause of renewed interest in natural resources.
This interest is based on growing awareness that a large number of secondary metabolites playing a significant role for the prevention of diseases are also present in our food. The food-processing industry is heavily investing in this branch, which results in an improvement of the overall quality of our diet, including the development of functional food and neutraceuticals.
This contribution was also published in Phytotherapy Research

Introduction

2Pharmacognosy was for the first time defined as a pharmaceutical discipline in 1815 by Seidler (Through A. Tschirch, 1909). Tschirch gave the following definition (translated from German): "With the name Pharmacognosy we mean the science which has the task to learn everything about drugs originating from plants or animals in all aspects, except the physiological effect, to describe them correctly and under a general vision connect this knowledge". During the 19th century it was by far the most important pharmaceutical discipline, the "mother" of all present day pharmaceutical disciplines. But 100 years ago (1899) the first signs for a new era became obvious with the introduction of a very successful synthetic drug: Aspirin (Viktorin, 1999). The first example of using nature as lead for a new synthetic drug. Despite some obvious failures, such as heroin, gradually synthetic chemistry became more important for developing new drugs. The wish to have pharmaceutical formulations with single pure compounds with well defined activities was an important driving force in this trend.

3Pharmacognosists have always been very keen in introducing new technologies into their discipline. In the 19th century microscopy was introduced for the quality control of pharmaceutical preparations from plants. However, for too many years pharmacognosy remained with these methods, and with the rapidly decreasing number of herbal preparations in the pharmacy, the discipline had great difficulties in holding their prominent position in the pharmaceutical curriculum in the sixties and seventies. Fortunately, some visionary pharmacognosists were able to open up new directions. The development of thin layer chromatography by the well known pharmacognosist professor Egon Stahl is probably the best example (Stahl, 1967). But also in the field of gas chromatography and high pressure liquid chromatography, pharmacognosists were among the pioneers in the analysis of plant materials. For studies of the active compounds in plants, these chromatographic methods became important tools. Moreover, in the seventies the spectrometric methods such as MS anc NMR became commonplace for the pharmacognosists in their search for new biologically active compounds in plants. But in that period developing new drugs from plants was not as easy as with synthetic drugs, as the pharmacological test systems, mainly in vivo animal experiments and in-vitro isolated organs, are not suited for bioassay-guided fractionation of active compounds from plant extracts. That requires methods that can readily measure large numbers of samples in a short time. Only for activities for which simple test methods were available, natural products remained a major source for new drugs. This is clearly illustrated by the fact that most of the antibiotics and antitumor drugs are natural products (Cragg et al., 1997). These activities can be easily tested in in-vitro systems based on cell cultures. So in the period from 1983 to 1994 of all new approved drugs, 78% of the new antibiotics and 61% of the new antitumor drugs were natural products or natural products derived.

4Currently, there is a rapidly increasing interest in pharmacognosy and natural products research. A number of new international scientific journals in the field illustrates this trend. The increasing interest was also clearly reflected in the meeting of the four major international societies in the field of pharmacognosy and natural products research. This joint meeting, a 5-yearly event, in July 1999 attracted more than 1100 scientists from all over the world to Amsterdam, the largest number ever in this field and almost double the number of the previous meeting 5 years ago.

5There are several reasons which can be mentioned to explain the increased interest in natural products and pharmacognosy:

• search for new leads for drug development
• biotechnology for the production of pharmaceuticals
• health claims for food (nutraceuticals)
• validation of traditional medicines
• increased interest in phytotherapy

6With this development in the past decade presently we can distinguish three major areas of interest for the pharmacognosist:

• studies of new biologically active natural products
• production of drugs from natural origin, including new methods such as biotechnology
• quality control of drugs from natural origin.

7The two first aspects I should like to discuss in some more detail. The studies for new active compounds have two major aspects: finding new leads for drug development and studies on the validation of traditional medicines. Traditionally the pharmacognosists have focused on plants as the source for new compounds, whereas work on microorganisms has mostly been in the hands of industry or academic chemistry groups. Here I will also mainly deal with plants.

Leadfinding

8Nature is an almost infinite source for drug development. The number of organisms that exist in the world is not so easy to assess. Pimm et al. (1995) made an effort to express biodiverstity in numbers. The total number of species is estimated to be between 10 100 million. The largest diversity is in insects (total of arthropods estimated as high as 30 million species), algae, prokaryotes and fungi (each about 1,5 million species). Plants are in fact a relatively small group with about 250000 species, of which about 6% has been studied for one or more biological activities, and about 15% has been studied phytochemically (Verpoorte 1998). All of these organisms produce a number of secondary metabolites which are connected with the interaction of the organism with its environment. During evolution this has resulted in a large chemodiversity (Harborne, 1978).

9What are these secondary metabolites? The number presently known is about 139000. Each year about 4000 new structures are reported. NAPRALERT and the Dictionary of Natural Products are the two main databases for natural products (Corley and Durley, 1994). The first one collects and abstracts all papers on natural products and their biological activity, as well as ethnopharmacological data. The Dictionary of Natural Products (Chapman and Hall, 1999) is a compilation of all known compounds and has now about 139000 entries. As you can learn from Table 1, the major group is that of terpenoids, the second major group is that of the alkaloids. Particularly the latter group contains a large number of medicines. This is due to their special characteristic of a water soluble compound under acidic conditions and lipophilic properties under neutral and basic conditions. In fact quite a large proportion of all medicines do contain a tertiary nitrogen.

Table 1. Number of secondary metabolites as present in the Dictionary of Natural Products (Chapman and Hall, 1999)

10Despite the enormous structural diversity, nature just uses a few building blocks to create this chemodiversity (Luckner, 1990; Verpoorte and Alferman, 1999). The basic building blocks are the acetate (C₂), isoprenoid (C₅) and phenylpropanoid (C₉) units. The acetate unit is used in the polyketide biosynthesis, particularly well developed in microorganisms. The isoprenoid pathways leads to all terpenoids by coupling two or more C₅ units. The terpenoids are found in all organisms. The phenylpropanoid pathway is most typical for plants, it is based on phenylalanine and tyrosine and via cinnamic acid this pathway leads to among others lignin and lignans. In combination with three acetate units the C₉ unit leads to the flavonoids and the anthocyanins, well known for their role in flower colours. With the building blocks mentioned, and some amino acids most organisms make more or less similar basic structures. The diversity is the result from various "decorating" enzymes found in each species, that introduce new functionalities, such as hydroxy-, epoxy-, methoxy-groups. Oxidations (cytochrome P450 enzymes, peroxidases en dioxygenases) and reductions are the most common reactions. Biological activity is sometimes altered by adding one or more sugar molecules to the basic structure. In fact, the trendy combinatorial chemistry of the synthetic organic chemists is nothing new, it is as old as evolution. Combinatorial chemistry has even been called the chemists surrogate for the rain forest (Hogan, 1997).

11For exploring nature's chemodiversity, the situation has changed dramatically in recent years by the introduction of high-throughput screening (HTS) methods (for several reviews see Bohlin and Bruhn, 1999). By using molecular targets, large number of samples(up to 100000 in 24 hrs) can be screened for a single activity. Obviously, synthetic chemists are not able to produce such numbers of new compounds. Their answer was the development of combinatorial chemistry and testing mixtures of compounds obtained through this novel solid-phase chemical synthetic methods. About 10 years ago a synthetic chemist in pharmaceutical industry made about 8 new chemical entities (NCEs) per year; in the near future it is expected to reach 50 per year (Valkema, 1999). However, the structural diversity from synthetic chemistry will never match nature, a novel active compound like paclitaxel, having 11 asymmetric carbons, will never be designed in a synthetic laboratory.

12Thus HTS offers new possibilities for natural products. It allows rapid screening of large number of extracts, and it is very suitable for bioassay guided fractionation, which in the past was the major bottleneck in studies of active compounds in plant extracts. Powerful chromatographic methods in combination with HTS are now a very efficient way to new leads for drug development. A project sponsored by Astra, in which the Australian biodiversity is screened for new leads is a successful example of this new approach (Quinn, 1999). In the coming years, technological developments will further improve the rate in which new active compounds can be isolated and identified from natural sources. For example, recently HPLC online methods have been developed for determining biological activity (Oosterkamp et al., 1997a, b). We have for example developed such a method for the detection of acetylcholinesterase inhibition in plant extracts (Ingkaninan et al., unpublished results). By using prefractionation methods, the chances of finding novel compounds will be increased and dereplication, the rapid identification of known active compounds or false positives, will take less time.

13The availability of sources of biodiversity, however, are presently a major bottleneck. Largest number of species is in 2nd and 3rd world countries which in most cases do not have the resources for conducting an extensive screening of their national biodiversity. On the other hand, negotiations about revenues with pharmaceutical companies interested in screening the biodiversity are not easy, because of the difficulty to define the value of making available biodiversity for screening. Compared with the total process of drug development, the costs of leadfinding are only a relative small part of the total budget. So despite the good intentions of the various international treaties and the Manilla declaration concerning the right of each country to its biodiversity (Baker et al., 1995), presently establishing collaborations between industry, academia and governments concerning exploration of biodiversity might be a difficult task. The fact that biodiversity does not mind political borders, does not make things easier.

14Plant cell culture extracts are an interesting option for screening, as they are easy to scale up in case that an interesting activity is found (McAlpine et al., 1999). Moreover, plant cell cultures can be made from rare plants to ensure the production of compounds from these plants which have shown interesting activities.

15Besides the more or less at random screening of organisms for biological activity, one can also look at ecological leads for a biological activity (Verpoorte, 1998; 1999). E.g. young leaves and seedlings are expected to be more strongly protected against predators by, among others, secondary metabolites, than older parts of a plant. For example, we found very high levels of quinoline alkaloids (quinine and related compounds) in seedlings of Cinchona (Aerts et al., 1990; 1991 a, b) and the highest level of ginkgolides ever found, we detected in seedlinqs of Ginkgo bitoba (Carrier et al., 1998).

16A very different approach to leadfinding is studying traditional medicines. Such studies can serve two goals: validation of the use of traditional medicines, and finding new leads. With the increased awareness of developing countries that their cultural heritage is a great treasure, studies on traditional medicine are getting more attention. They can lead to an efficient use of such preparations, avoiding the need to import expensive western medicine. Moreover, availability directly from the field is a major advantage in remote areas. In fact, it is estimated that about 80% of the world population relies on traditional medicines in the primary health care (Baker et al., 1995). Such studies should not only concern activity, but also toxicity. The compounds being responsible for the activity in traditional medicines do not necessarily lead to new drugs. In many cases it might be already known compounds, or compounds that do not perform better than already known drugs. HTS is the field of industrial research, traditional medicine is mainly studied by academic institutions, and governmental laboratories. In Scheme 1 the different approaches are summarized.

Biotechnology

17Another area which has opened new perspectives in pharmacognosy is biotechnology. Traditionally pharmacognosy focuses on plants, and relatively little attention has been paid in both teaching and research to microorganisms as a source of drugs. The classical biotechnology of production of e.g. antibiotics has been more or less outside the scope of the discipline. However, when plant cell biotechnology emerged as a new possibility for the production of plant secondary metabolites in the mid seventies, the pharmacognosists eagerly moved into this field. The aim was the production of known pharmaceuticals by means of plant cell cultures. In the past two decades such a production of plant derived pharmaceuticals has extensively been studied by a number of groups all over the world. Besides the enormous possibilities of biotechnological production of pharmaceuticals using microbial, plant, insect, or mammalian cells, biotechnology offers also genetic engineering as an important new technology. Genetic engineering can be used to increase yields in an organism producing valuable pharmaceuticals, but also to introduce the production of valuable compounds in other production organisms. For example, one can produce pharmaceutical proteins in microorganisms (e.g. insulin in E. coli) or plants (e.g. human serum albumin or vaccines) (Arntzen, 1997; Cunningham and Porter, 1998; Pen et al., 1993; Ponstein et al., 1996). In Scheme 2 various aims in biotechnology and the possible role of the pharmacognosists (pharmacists) are summarized.

18Below some of these aspects for plant cell biotechnology and genetic engineering from a pharmaceutical (pharmacognostical) point of view will be discussed in some more detail.

Plant cell biotechnological production

19For the biotechnological production of complex natural products plant cell cultures are an interesting option. A cell culture can be obtained from any plant species. In such a culture each cell has all the genes necessary for all the functions of a plant, including secondary metabolism (totipotency). For the application of such in-vitro cultured cells for a commercial production there are two major questions to be answered:

• Is the technology feasible?
• Is the economy of the process competitive?

20The first point was considered as a major constraint. Shear forces in stirred bioreactors were thought to be a major problem for the large vacuolated plant cells. Some studies in the seventies claimed that plant cells grow better and had higher production of secondary metabolites in low-shear bioreactors, such as airlift reactors, than in stirred tank type of bioreactors. However, more recent studies (Meijer et al., 1987; Scragg et al., 1986) showed that plant cells are not very shear sensitive and can easily be grown in stirred bioreactors. The feasibility of the technology is confirmed by reports on the large-scale culture of plant cells in bioreactors, e.g. in stirred tanks of 60 m³ working volume (Westphal, 1990). Cost price calculations for products from a plant cell biotechnology based process have been made by several authors (Drapeau et al., 1987; Fowler and Stepan-Sarkissian, 1983; Goldstein et al., 1980; van Gulik et al., 1988; Verpoorte et al., 1991 ). We have calculated that at a production of 0.3g/l/14d results in a price of $ 1500/kg. A ten-fold improvement of the productivity results in a price of $ 430/kg (Van Gulik et al., 1988; Verpoorte et al., 1991). The most important cost factor is the investments in the bioreactors. Media costs are only about 5% of the costs in the first example, and 20% in the second. Depreciation of the large bioreactor facilities being the major costs. The lower yield level used for these calculations are for example achieved for the production of ajmalicine in Catharanthus roseus cell cultures (for reviews see Van der Heijden and Verpoorte, 1989; Moreno et al., 1995). The 10-fold higher yield has been achieved for berberine in Coptis japonica cell cultures, that are even capable of higher levels, up to 7g/l, the highest production in plant cells ever reported (Fuyita and Tabata, 1987; Sato et al., 1982; 1984). The productivity for antibiotics such as penicillin in cultures of microorganisms can be as high as 30-50g/l. There is no theoretical reason why plant cells should produce less. This statement can be illustrated by productions of secondary metabolites of 20-60% of the dry weight of a plant tissue or plant cells. Examples are the production of tannins and proanthocyanidins in callus cultures of Pseudotsuga menziesii (Zaprometov, 1988a, b) and anthraquinones in Rubia fruticosa cell cultures (Schulte et al., 1984). Plant cells are thus capable of diverting a large part of the metabolic flux into secondary metabolism.

21Some commercial successes have been achieved, such as the production of shikonin (Fuyita and Tabata, 1987), the production of ginseng roots biomass and some polysaccharides preparations (Fu et al., 1999; Hibion and Ushiyama, 1999). However, for the most interesting compounds such as hyoscyamine, morphine, quinine and vinblastine, the productivity was too low, or even zero (Verpoorte et al., 1991 ). Studies to improve the yields first focused on selection of high producing cell lines and epigenetic manipulation. As this in most cases did not result in the necessary increase in yields for commercialization, research moved into new directions, such as the culture of differentiated cells, induction of secondary metabolites by means of elicitors and the use of immobilized cells. However, for the compounds of interest none of these approaches resulted so far in commercially viable processes.

22Products that came close to an industrial process were rosmarinic acid and sanguinarine. But as these compounds eventually did not reach the market, the processes also lost interest from industrial point of view. A successful process was developed for taxol, for which a productivity increase of 10 - 20 fold was achieved if compared with the average Taxus cultures (for some reviews see Fu et al., 1999). However, the product of such a process requires official approval by the registration authorities as a raw material for the production of pharmaceuticals.

23Plant cell cultures may play an important role during the development of new drugs from plants. Plant cells may provide the necessary amounts of a compound during its development, when a agri(horti)cultural production is not yet available. In those cases in which agriculture does not work, plant cell biotechnology might be the final production method.

24In the meantime, plant cell cultures have developed into an excellent tool for studies of the biosynthesis of secondary metabolites and for the cloning of genes of such pathways (e.g. Zenk, 1991; 1995; Hashimoto et al., 1994; Verpoorte et al., 1998). These genes can be used for genetic modification of plants or plant cell cultures for improving productivity (see below) (e.g. Hashimoto et al., 1994; Kutchan, 1995; Verpoorte and Alfermann, 1999).

Genetic engineering

Proteins

25Nowadays, in principle new genes can be introduced in any organism. That means that for the production of certain valuable pharmaceuticals, such as proteins, one can cross the borders between species, any type of organism can be considered for the production of pharmaceutical proteins. Posttranslational modifications of proteins are an important aspect in choosing the production organism. Plants and plant cells are like mammalian cells capable of protein glucosidations, and should thus be attractive production systems. However, in case of products used for parenteral applications, proving the safety of the product from such a source will be an important bottleneck for the production of mammalian proteins in plants. Despite the fact that plants would be by far the cheapest source, the safety requirements would imply quite extensive toxicological studies, similar almost as to the development of a completely new drug. Human serum albumin (HSA) can be mentioned as an example (Pen et al., 1993). Without any difficulty one can produce this in plants expressing the gene encoding HSA, chemically the protein formed is identical to the human protein, however the purification and subsequent studies necessary to proof its safety hamper further applications. This means that for such proteins one will stay with the production in systems generally considered to be safe. Only for special products a plant production is of interest. For example the production of oral vaccines by means of genetically engineered edible plants (e.g. bananas) is worked at as a cheap way to help vaccination programmes in third world countries (Shahidi et al., 1999). The main restriction for this is that most vaccins do not work orally. A much more promising and revolutionizing application is the production of antibodies in plants (Conrad and Fiedler, 1994; Cunningham and Porter, 1998; Ma and Hein, 1996; Whitelam and Cockburn,! 996). It opens the way for the production of antibodies for a very low price, opening all kind of new applications. The use in caries prevention is an example of the potential applications of such antibodies.

Low molecular compounds

26The genetic engineering can also be applied to improve the yield of low molecular weight compounds in the producing organisms, e.g. penicillin. I will briefly give some examples of genetic engineering concerning plant derived pharmaceuticals. Three possibilities can be envisaged:

• increasing the production of a compound in plant or plant cell culture
• producing plant compound in microorganism
• production of a new compound in a plant or plant cell culture

Increasing the production of a plant secondary metabolite

27The production of secondary metabolites can be regulated in different ways: the flux towards the compound might be regulated through the activity of enzymes involved or by feedback inhibition. The carbon flux may be diverted into competitive pathways. The product level may also be affected by catabolism of the secondary metabolite (Dagnino et al., 1994; Dos Santos et al., 1994; Schripsema et al., 1994). Competitive pathways and catabolism can be blocked by introducing antisense genes for the genes encoding the enzymes concerned.

28By identifying possible limiting steps in biosynthetic pathways, one can subsequently clone the gene encoding the enzyme involved and overexpress this enzyme or use genes from other sources to overcome the limitation. We have shown that it is feasible to overexpress tryptophan decarboxylase and strictosidine synthase, two important genes from the terpenoid indole alkaloids, in cell cultures of various plants. In Catharanthus roseus cell cultures, the overexpression of these endogenous genes leads to increased level of enzyme activity, but only with the latter gene some increase in the alkaloid production was observed (Canel et al., 1998). Expression in tobacco cells results in the production of tryptamine (Hallard et al., 1997; Leech et al., 1999) and after feeding secologanin also in the production of strictosidine (Hallard et al., 1997). These results show that it is feasible to engineer secondary metabolite pathways of pharmaceutically important compounds, however, the increases mainly concern the immediate product of the overexpressed enzyme. A promising option is the cloning of regulatory genes of a pathway and overexpression of these (Grotewold et al., 1998; Lloyd et al., 1992; Martin, 1996).

Producing plant compound in microorganisms

29Genes from a plant can be expressed in microorganisms. The production of a plant secondary metabolite in a microorganism, however, requires the availability of the necessary precursors. As most secondary metabolites are the result of a large number of steps, this approach is thus limited to products which only need a few steps starting from the available precursor, or one should add the necessary precursors. This only makes sense if these are readily available for a low price. A recent patent application we made, concerns an example of such an approach (Geerlings et al., 1998). Strictosidine synthase and strictosidine glucosidase were expressed into yeast. Growing this transgenic yeast on the juice of the berries of Symphoricarpus albus, containing both the sugar for the growth of the y east and secologanin for the production of indole alkaloids, 2 g/l of alkaloid can be produced. Adding further steps of the alkaloid biosynthetic pathways may eventually lead to the production of known commercially important alkaloids, such as ajmalicine or quinine.

Production of a new compound in a plant or plant cell culture

30In recent years one has developed new possibilities for increasing chemodiversity. Recombinatorial biochemistry, also called combinatorial biochemistry, particularly can be mentioned in this context. It concerns the expression of genes in other organisms, thus affecting the biosynthesis of secondary metabolites. Engineering polyketide bioynthesis in microorganisms leading to the production of new antibiotics is an excellent example of this (e.g. Madduri et al., 1998; Salas and Mendez, 1998). This approach is now also in plants being probed.

31An example of opening a new pathway in a plant is the production of salicylic acid (SA) (Verberne et al., 1998; 1999). SA is an important signal compound in the systemic acquired resistance in plants. The biosynthesis of SA is thought to go via cinnamic acid, though the pathway is not yet completely elucidated. In microorganisms SA is produced via isochorismate from chorismate, an abundant precursor in plants and microorganisms for the production of phenylalanine/tyrosine and tryptophan. By introduction of genes from microorganisms (entC and orfd encoding respectively isochorismate synthase and isochorismate pyruvate lyase, combined with the signal sequence for chloroplast targetting from the small subunit of Rubisco and the 35S promoter) into plants we have achieved constitutive production of SA in plants. The transgenic plants show high SA-levels which are correlated with a decrease in necrosis after infection with tobacco mosaic virus. Other examples are the introduction of the gene encoding stilbene synthase into various plants, resulting in the production of the phytoalexin and antioxidant resveratrol (Hain et al., 1990; 1993) and the introduction of hyoscyamine 6-hydroxylase gene in Atropa belladonna, resulting in the production of scopolamine instead of hyoscyamine (Hashimoto et al., 1994; Yun et al., 1992). This proof of principle invites for further applications of this exciting technology.

Conclusions

32From this very brief historical picture, and a short review of some aspects of the present day research, it is clear that pharmacognosy has entered a completely new era. In the professional situation its role for quality control of herbal drugs has decreased. But it remains a very important task, which may help to avoid mistakes as has occurred for example in Belgium where wrong ingredients were used in a herbal slimming preparation, causing severe damage of the kidneys in a number of people. The trend that some European governments want to ban phytotherapy out of the health care system, carries the risk that such disasters will happen again. All phytotherapy should be in the hands of professionals capable of assuring a proper quality control.

33In terms of drug development and production, there are numerous new possibilities for the pharmacognosist. Leadfinding for drug development using biodiversity or traditional medicines is one major area in which one can see a rapidly increasing activity. The other area is that of biotechnology. In terms of the professional situation, quality control is an important aspect of this field, and pharmacognosy can play here an important role. This includes among others the quality control of proteins and also in the case of gene therapy there is a challenging task for the future pharmacists. In terms of research important new possibilities lie mostly in the production by means of plant cell and tissue culture and metabolic engineering, for increasing the production of natural products or even produce completely new ones.

34These new technologies require, of course, also a new type of pharmacist and pharmacognosist. A pharmacognosist should not only have expertise on the botanical aspects of medicinal plants, but also on phytochemistry, advanced seperation methods, proteins, and molecular biology. Particularly the latter two are new to the field. In the field of proteins it will be proteomics which would fit nicely into the expertise of the pharmacognosists. The molecular biology techniques would be important tools in quality control, not only from biotechnological products, but also in characterizing medicinal plants. Vegetal contaminations in plant material could probably be found at very low levels using PCR. DNA-chips open further exciting opportunities, e.g. for studying the effect of medicinal plants one can use proteomics and DNA-chips for comparing changes in expression levels of genes and the resulting effects on protein levels. This might be much more sensitive than the present day pharmacological assays and also detect multiple changes.

35We have exciting times ahead. There are many options for the pharmacognosist, but making choices is necessary, we cannot do all. Finally, despite the enormous potential of the new technologies, one should not make the mistake to make a molecular biologist out of a pharmacist, that would be as deadly for the discipline as the microscopy was for the pharmacognosists. The future is in collaboration between experts, multidisciplinary teams solving scientific (e.g. biological) problems together, rather than monodisciplinary approaches. Making the drugs of the future by biotechnology, or finding new ones through bioprospecting. In this approach the pharmacognosists have their contribution with their strong points: natural products isolation, separation and identification, from low molecular weight compounds to macromolecules, including the expertise on biosynthesis of such compounds.

Scheme 1. Different approaches of finding new biological active natural products (leads) for drug development

Scheme 2. Role of pharmacognosist in pharmaceutical biotechnology