MEDICINAL PLANTS FOR HUMAN HEALTH: ROLE OF MODERN TECHNOLOGIES FOR HIGHER EFFICIENCY
V. S. RAMA DAS
Formerly: Dean and Rector, Sri Venkateswara University, Tirupati
Senior Professor of Life Sciences, University of Hyderabad, Hyderabad
Director, Institute of Himalayan Bioresource Technology (CSIR), Plampur, Himachal Pradesh
Introduction
Please let me begin by saying that plants are nature's finest organic chemists producing more than 200 thousand small molecules (less than 500 daltons) many of which being secondary metabolites are also useful as medicinal compounds. Not only that what I have said plants being organic chemists they also perform an extremely difficult and an astonishing oxidation chemistry not matched in any other biological systems by splitting water into oxygen electrons and protons (not ionization). The oxygen released by the entire green mantle of the earth is estimated to be 1011 tons annually. It is this oxygen that sustains aerobic life on this planet besides the photosynthetic reaction resulting in production of carbohydrates (and not hydrocarbons) and other primary metabolites including proteins and fats. By our singing laurels on the extraordinary powers of plants the human intelligence is not yet adequate to understand intricacies of the plant way of life. This year being an International year of planet earth it becomes all the more important to understand the functioning of the green mantle, the biodiversity of which is extremely important and the dependence of man on the green plants.
It is not precisely understood when perhaps the single celled bacteria, the earliest living organisms started using sun light to make food in the photosynthetic process. Chlorophyll development was mot important evolutionary consequence for releasing through photosynthesis free oxygen into the atmosphere. Presumably, cyanobacteria the earliest chlorophyll using organisms appeared 3,500 million years ago. Another very startling event in evolution is the acquisition of terrestrial habit by the plants from their ancestral oceanic home which has to possess many adaptive features for survival on land. It is interesting to note that a recent study on the genomics of very popular moss, Physcomitrella patens which has a genome size of 35,000 potential genes. The size is apparently larger than that of first higher plant, Arabidopsis whose genome has been sequenced. Some 10,000 genes are perhaps specific to moss for its evolution in movement to land.
What I spoke so far, is my invocation for plants; I shall move to medicinal plants:
A working definition of medicinal plants consists of all those species used in traditional medical systems of healing and also those which formed to the source of inspiration for several major pharmaceutical drugs. It is estimated that approximately 50,000 species are considered to be useful medicinally, which means that one in every six of all known higher plant species (estimated 300,000 are expected to be used in medicine). It is also that modern drugs apparently derived from only around 100 plant species. Medicinal plants actually are used to maintain or augment health – physical, mental and spiritual but also for specific ailments.
What cam be the main issues concerning the medicinal plants? In this context the most important factor seems to be conservation of species while harvesting from the wild. The harvest from the wild is known to cause loss of genetic diversity and habitat destruction. An alternative is to cultivate the wild plants particularly to avoid misidentification of genetic variability and instability of extracts and sometimes toxic components and contaminants. Problems encountered in commercial cultivation are the difficulty in predicting which extracts will remain marketable and the likely market preference.
Availability of genome sequences for Arabidopsis and O. sativa and several model species is of considerable help in the improvement of medicinal plants through comparative genetics. Medicago truncatula, a model legume is related to M. sativa which is a medicinal herb. The model plant Populus is the source of aspirin and other medically useful plants.
Several modern techniques which I can list as follows can be used for improvement and maximal utilization of medicinal plants. 1. Biotechnology for medicinal plant cultivation; 2. Metabolic engineering and use of metabolomics; 3. Biofortification and biotechnological principles; 4. Nutrition and health; 5. Molecular farming which is a fast developing technology (a latest example, 2008 is the production of resveratrol through metabolic engineering in several plants by bio-engineering; 6. Use specific techniques like gene silencing through RNA interference (RNAi), a mechanism for post transcriptional gene silencing.
The use of specific knockout of certain genes has been shown to increase morphinan alkaloids. Sometimes over expression of certain genes would also results in increased content of the required medical constituents.
Some therapeutic drugs are designed to increase natural concentration of key biological molecules which are depleted in particular disease states (like insulin). The primary objective of pharmaceutical technology is to generate new compounds that can modulate disease, mostly small molecules of less than a size of 500 daltons.
Medicinal Plant Cultivation:
Obstacle to bring medicinal plants into commercial cultivation is difficult in predicting which extracts will remain marketable and the likely market preference. The W.H.O. has estimated that more than 80% of world's population in developing countries is dependent on herbal medicine for healthcare needs. It is also increasing elsewhere and 25% of UK population uses herbal medicines in regular way. In Europe, 10% of medicinal species used are commercially cultivated. Several plants including Piper methysticum and Glycyrrhiza glabra are threatened. Nearly 10,000 medicinal species are endangered. Introduction of sustainable wild harvesting methods is a viable alternative to increase cultivation of medicinal plants. Biotechnology can solve some inherent problems with production of medicinal compounds if plants are cultivated. Cultivation also offers to optimize yield and achieving uniform high quality.
Complete genome sequences for Arabidopsis and O. sativa and several other model species including Medicago and Populus makes it possible for improvement of medicinal species via comparative genetics. The oestrogenic properties of Trifolium are of increasing interest in the context of human health and hormone replacement therapy. Populus is related to salix, the source of aspirin and other medicinally useful compounds.
Pathway Engineering:
Examples of pathway engineering leading to improvement of potential value in breeding medicinal plants are immense. In Hyoscyamus niger a ten fold enhancement in scopolamine was brought about by over expressing two genes encoding rate limiting steps.
Over harvesting is the cause of decline in medicinal plants. Himalayas are famous for high altitude medicinal herbs which are used in Ayurveda, Tibetan medicine and others. Unfortunately massive grazing pressures have denuded the area. FAO defined the use of sustainable harvests as 'the use of plant resources at levels of harvesting and in such ways that the plants are able to continue to supply the products indefinitely" (replenishment at least to match off-take).
The adaptive management prescriptions are periodically reviewed and adjusted.
Metabolic Engineering and Use of Metabolomics:
Plants are fabulously rich source of diverse functional biochemicals and metabolomics is a valuable applied technology. The technology is geared towards providing an essentially unbiased comprehensive qualitative and quantitative overview of metabolites in an organism. Metabolomics is the newest field of functional genomics. Speculative estimations of total no. of metabolites in plant kingdom including secondary metabolites are between 100 thousand to 200 thousand.
Much of plant biochemistry can unfortunately still be defined as unidentified compounds derived from undefined pathways and with unknown function (Oliver Fiehn, UCD, 2005). The quality of crop plants is a direct function of their metabolite content. It also determines in the commercial value like for example flavour, fragrance shelf life and others. Further development of metabolomics is a complimentary technology to transcriptomics and proteomics. As in other areas the limitation of metabolomics is ignorance. Our basic knowledge of many secondary metabolic pathways and our inability to identify the compound is a drawback.
Metabolomics is perhaps the ultimate level of post genomic analysis. Within functional genomics metabolomics emerges as a robust approach to credit gene activity than used for transcriptomic and proteomic approaches.
Plant Metabolomic Research was not common prior to this decade. But now became increasingly widespread. Rice is also the popular metabolomic target. To overcome the current limitations on metabolomic analysis requires an interdisciplinary (cross disciplinary) approach where biologists, chemists, statisticians and instrument manufacturers need to provide an input. Metabolite profiling is being used extensively in studies of environmental perturbations in attempts to elucidate complex shifts.
Transgenic modification:
New opportunities to alter the content of important plant based secondary metabolites including pharmaceuticals, nutraceuticals and plant protection chemicals. Metabolic engineering modifies the amounts or chemical structures of specific metabolites. Alkaloid pathways have been successfully modified by metabolic engineering. Over expression of strictosidine synthase in cell cultures of Catharanthus roseus resulted in increased content of terpenoid indole alkaloids.
Morphinan:
Morphinan alkaloids are produced from Opium poppy, Papaver
somniferum. These include morphine, codeine, oripavine and thebaine. Genetically modified poppies with increased morphinan alkaloid production are reported.
Sirtuins:
The magnificent seven types, function, metabolism and longevity have been studied. The sirtuin family of histone deacetylases named after their homology to yeast gene information regulator. Sirtuin biology has come a long way from original description as Yeast class III HDAC that control yeast life span. Sirtuins might play important roles in some diseases. It can be predicted that therapeutic interventions at activating or blocking sirtuins will become helpful in the treatment of human diseases.
Resveratrol is produced by certain plants including grapes and peanuts. It is a major health promoting compound in red wine and functions as an anti oxidant. Consumption of resveratrol extends the life span of yeast, fruit fly, roundworm and fish, the mechanism of which is unclear.
Resveratrol biosynthesis involves deamination of phenyalanine and produces cinnamic acid which is hydroxylated to form 4-coumaric acid. Next 4-coumaroyl-CoA condenses with 3 molecules of malonyl-CoA to produce resveratrol. Sirtuins are implicated in several cellular processes like apoptosis, adipocyte and muscle differentiation and in malignancy and cancer.
Metabolic engineering related to resveratrol is done in many organisms with recent reports on longevity effect of resveratrol in some animals and attracts press coverage.
Biofotrification and Biotechnological Principles:
Deficiencies of micronutrients including iron, zinc and Vitamin A affect nearly three billion people (1/2 of world's population) disease stricken. The deficiency increases morbidity and mortality rates, loss of work productivity and impairment of cognitive development. Current programmes for food fortification and supplementation programmes have shown to be sustainable to live healthy and productive lives. Humans require at least 50 known nutrients in adequate amounts.
Staple cereal grains contain factors (tannins, poly phenols and heavy metals) which can inhibit bioavailability of micronutrients.
Plant based diet could limit intake of calcium. Osteoporosis is one of the most prevalent nutritional disorders and causes patho-physiological conditions. By engineering carrot and other vegetables to contain increased calcium levels may boost the uptake and reduce deficiency. The creation of genetically modified plants with increased nutritional benefits is an expanding field. The term "Nutritional genomics" is used to describe studies involving pint biochemistry, genomics and human nutrition.
Nutrition and Health:
Food nutrition is by definition aimed at maintaining human cell, and organ, homeostasis. The concept of nutraceuticals and bio-protective foods continue to attract attention. Biofortification has several examples induing golden rice with enhanced provitamin A, lycopene rich tomatoes, lysine rich corn and ferritin rich lettuce.
Adding More Life to the Years than Years to the Life:
Nutrigenomics is a science growing rapidly and tries to link nutrition and genome. Although the food health link is still ambiguous, human health is the major driver to innovate in food industry. The current trends in global population and so called graying of the society it has been predicted that social security systems will not be able to survive without having healthier elderly
people.
Molecular Farming:
Production of substances of industrial importance through genetically modified plants is referred to as molecular farming. The company known as Meristem Therapeutics markets a gastric lipase in open field production using maize.
Fighting Cancer with plant expressed pharmaceuticals: Plant made pharmaceuticals (PMPS) are important in the humanitarian problem of cancer. The advantages of plant system for expression of veterinary and pharmaceutical proteins are the low cost of cultivation, high biomass production and fast gene to protein time.
Specific Technologies:
RNAi for engineering plant gene functions (RNA silencing or RNA interference): This is a double stranded RNA and this can cause silencing of any particular gene. With the Nobel Prize award for medicine in 2006 to Fire and Mello for discovery
of RNAi, its use has become wide spread. The double stranded RNA (dsRNA) which is processed into RNA duplexes of 21 to 26 bp called small interfering RNAs. RNAi is used in applied plant biotechnology where reverse genetics is difficult due to lack of suitable mutants. RNAi is also a popular approach for validating the function of candidate genes.
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