Medicinal Plants Past, Present, and Future Paper.pdf

The Plant Cell, January 2013, www.plantcell.org ã 2013 American Society of Plant Biologists. All rights reserved. TEACHING TOOLS IN PLANT BIOLOGY™: LECTURE NOTES Medicinal Plants: Past, Present, and Future Plants are amazing chemical factories. Like other organisms, HISTORICAL USES OF PLANTS AS MEDICINES they produce a shared set of small-molecule metabolites, referred to as primary metabolites, which in plants probably Prehistory through the Middle Ages number ,10,000. Collectively, organisms in the plant king- Throughout most of human history, plants have been important dom also produce a vast array of at least 200,000 specialized sources of medicines. Herbal remedies came about by ob- metabolites that are not conserved but instead are usually serving nature and by trial and error and were passed down from restricted to a single plant family, genus, or species (metabolite generation to generation over hundreds or thousands of years. number estimates are from Pichersky and Lewinsohn, 2011). Very early uses of plants as medicines are revealed by archeo- These specialized metabolites (formerly called secondary logical data. For example, 77,000-year-old bedding material found metabolites) are the most rapidly evolving aspect of plant in South Africa included leaves from a plant still valued for its metabolism, and the compounds often have defensive or toxicity to mosquitoes, Cryptocarya woodii, and an analysis of signaling functions. Many of these specialized compounds have biological chemicals isolated from 50,000-year-old Neanderthal teeth activities toward microbes and invertebrate or vertebrate suggested that the individual consumed chamomile (Matricaria animals. Among these are some of the most important recutita) or related medicinal plants prior to death. medicines used for the treatment of human illnesses or di- The earliest written record of plant medicine comes from seases. Many of the drugs we use today come from plants, Sumerian clay tablets that date from ;4000 years ago, which some of which have been used for healing purposes for include descriptions of the medicinal use of opium (Papaver hundreds or thousands of years. Plant-derived medicines are somniferum), thyme (Thymus spp), licorice (Glycyrrhiza glabra), often grouped together with medicinally active compounds willow (Salix alba), fig (Ficus spp), and many other plants. Assyrian derived from microbes, fungi, or animals into the category and Babylonian artifacts include similar descriptions. “Herbals” of natural compounds (to differentiate them from synthetic are texts that contain the names, descriptions, and medicinal uses compounds), but here we limit our discussion to those derived of plants, descriptions of where they can be found, methods for from plants. Furthermore, we exclude most of the health- storage and shelf life of the harvested materials, along with re- promoting phytonutrients found in food and focus on those cipes for extractions, tinctures, or potions. One of the best plants and compounds ingested to treat ailments. (The many known and most complete of the ancient herbals is the Egyptian food plants that can contribute to disease prevention are Ebers Papyrus, a 70-foot-long medical scroll discovered in described in Teaching Tools in Plant Biology 21: Plants, Food, the 1870s. It lists 800 recipes and refers to the use of aloe and Human Health.) (Aloe vera), wormwood (Artemisia spp), peppermint (Mentha x More than half of the top 150 prescribed drugs in the United piperita), henbane (Hyoscyamus niger) for worms, castor oil States have at least one compound derived from plants, and (Ricinus communis), mandrake (Mandragora officinarum), garlic ;80% of the world’s population depends on plants or plant (Allium sativum), juniper (Juniperus spp), frankincense (Boswellia extracts as their major source of healthcare. There is a keen spp), senna (Senna spp), elderberry (Sambucus nigra), bayberry interest in screening plants for potential medicines, but with over 250,000 species of flowering plants alone, the task is (Myrica spp), onion (Allium cepa), opium, thyme, and honey, just immense. Some scientists have turned to traditional healers to name a few. and folklore to help identify plants that might be medicinally The practice of traditional medicines in China dates back at least active, and others are looking at plant families that are 4500 years. The Shen Nong Ben Cao Jing (previously sometimes particularly rich in medicinal compounds. New approaches, written Pun-Tsao) is considered by some as the oldest list of such as metabolomics, metabolic engineering, and systems medicinal herbs. This herbal describes the gathering, preparation, and synthetic biology, are contributing toward the identifi- and use of medicines derived from 252 medicinal plants, 67 cation, characterization, and production of plant-derived med- medicinal animals, and 46 mineral drugs. It describes thousands icines. This article looks at the history of medicinal plants, of herbal cures, including the use of Chaulmoogra oil from the ongoing efforts to identify novel medicinal compounds from Hydnocarpus genus to treat leprosy and the use of ma huang plants, herbal remedies in traditional and contemporary med- (Ephedra spp, Chinese ephedra), which contains ephedrine, to icine, and the regulations and policies that govern the use of improve circulation, reduce fevers, and treat lung disorders. plant extracts as medicines. The Rig Veda is a 3500-year-old collection of Hindu sacred verses that forms the foundational works of Ayurveda, or traditional Indian medicine. These descriptions include location of plants and www.plantcell.org/cgi/doi/10.1105/tpc.113.tt0113 methods for storage and shelf life of the harvested material. 2 The Plant Cell Ayurveda medicine is still practiced by up to 80% of the Indian printed in Europe, many based on ancient texts, and botanical, population. medicinal, or physic gardens were founded by monasteries, medical The origins of Western medicine start with the Greek physician schools, physicians, and apothecaries (pharmacists). Herbal med- Hippocrates and later Galen, whose writings refer to the use of icines were an important part of medical treatment, but, starting in more than 300 plant species. Another Greek, Theophrastus, has the early 1800s, herbal medicines began to fall out of favor as been described as the father of botany, and his book “Historia advances in chemistry opened the door to purified drugs. Plantarum,” which describes the natural habitats, geographic distributions, collection, and preparation of medicines, spices, and perfumes, was used for over 2000 years. “De Materia Case Study: Digitoxin and Cardiac Glycosides Medica” was written by Pedanius Dioscorides, a Greek physi- cian traveling with the Roman army and is one of the most The use of glycosides purified from foxglove (Digitalis purpura) influential herbals ever written. This five-volume book, consid- as treatments for cardiac problems originates with its use as an ered to be a precursor to modern pharmacopeia, described herbal remedy. Early studies were performed by William ;4740 medicinal usages, from aromatic oils, salves, and ointments Withering, who was a medical doctor and a botanist. He was to narcotics and poisons. Furthermore, Dioscorides recognized active in the late 1700s, a time when rationalism and science that plants’ medicinal properties are affected by cultivation and were applied to all of life from agriculture to politics. Prior to his harvesting practices. For example, he observed that opium poppy studies on Digitalis, he wrote the first natural history of British latex collected in early morning is more potent than that collected flora that used the Linnaean system of classification. According later in the day. to legend, Withering observed the successful treatment of Evidence of medicinal plant use in other parts of the world is a patient with a heart condition by a woman using an herbal scarce due to the scarcity of written records. The earliest Aztec therapy. By virtue of his botanical knowledge, Withering recog- herbal written by a native physician, Martin Cruz, was published nized that of the 20 or more herbs used in the medicine, the active in Mexico around 1552. In 1570, a Spanish doctor recorded constituent was probably from the plant foxglove. From 1775 to around 1200 medicinal plants used by Aztecs, many found in 1784, he studied and standardized the preparation of foxglove for large Aztec botanical gardens. Tobacco (Nicotiana tabacum) medicinal purposes, culminating in his book published in 1785, was mentioned in a number of texts describing its use in recipes “An Account of the Foxglove, and Some of its Medical Uses.” to cure health problems from gout to stomach upset. Although Withering’s work preceded the advances in chemistry Numerous medicinal texts were written in the Arab world, that were to follow, and he did not purify the active chemical combining their herbal and pharmacological knowledge with compounds from the plants, he laid the foundation for the science those of the Greeks, Romans, and Asians. The Persian Avicenna of medicinal phytochemistry. The active ingredients, cardiac Ibn Sina (980 to 1037) produced one of the most famous medical glycosides, were later purified, and they continue to be prescribed encyclopedias of this period, The Canon of Medicine (1025), and for the treatment of heart problems. a second book based on plants and their healing properties. These books introduced clinical trials, randomized controlled FROM 1800 TO THE PRESENT: THE QUEST FOR trials, and efficacy tests, becoming the basis of today’s clinical ACTIVE COMPOUNDS pharmacology. They were used as medical authorities for the next 500 years both in the east and west. Beginning early in the 19th century, many drugs and medicines Herbalists from the time of Dioscorides through the mid 1600s used the purified active compounds isolated from medicinal ascribed to the “Doctrine of Signatures,” which stated that plants rather than the complex extracts or decoctions. One of a plant’s shape, texture, and color could indicate what part of the most famous was the extraction of salicin from willow bark in the body it might heal. Mandrake and ginseng have roots the 1820s. Willow had been used for centuries as a painkiller, shaped like men (or women) therefore could be used to treat any antipyretic, and anti-inflammatory agent. Improvements to number of human sicknesses. Plants were given “signatures,” lessen salicin’s adverse physiological effects eventually led to names to indicate what part of the body they might treat (e.g., the production of aspirin, which was the first major medicine spleenwort, boneset, brighteyes, and maidenhair fern). The sold in tablet form. Swiss physician Paracelsus, “the father of chemical pharma- Many drugs are compounds that are purified from plants, or cology” (1493 to 1541), popularized this notion. derivatives of the natural products, of which several are ex- amined more closely below, but first it’s worth considering the question, “Which is better, a plant extract or the purified Age of Herbals and Physic Gardens compound?” There is no simple answer. The plant extract can include more than active compound and have a multifactorial After the fall of Rome, herbal manuscripts were maintained, effect that can’t be replicated by a single compound. Plant translated, and copied in monastery libraries, and monks and extracts are usually cheaper than pharmaceutical-grade med- nuns gathered and raised herbs that they used to treat the sick. icines. However, there is also a problem of batch-to-batch Charlemagne (742 to 814) is credited for commanding that his variation in potency and the possibility of contaminants, and royal gardens contain medicinal plants, therefore establishing there can be supply shortages. Furthermore, medicinal plants the basis for later botanic and physic gardens. From the 15th are routinely overharvested, and several are endangered. Purified through 17th centuries, numerous herbals were published and compounds are chemically defined and provide consistent supply January 2013 3 and precise dosages. Purified compounds can also be starting Case Study: The Antimalarials Quinine and Artemisinin points for the production of more effective drugs or drugs with fewer side effects (such as aspirin from salicin). However, the extensive Malaria is a deadly disease that has affected humans since our testing and clinical trials needed for regulatory approval of a new earliest written records and occurs in tropical and swampy compound mean that these drugs can be prohibitively expen- regions all over the world. Malaria kills about a million people sive for most people. Clearly, both plant extracts and purified a year, mostly children, and millions more are chronic sufferers compounds are needed in global healthcare. of its debilitating effects. It is caused by a plasmodium protozoan, which is carried from human to human by mosquitoes. Malaria is treatable by drugs that target the protozoan, and the two most effective treatments, quinine and artemisinin, come from plants. Case Study: Morphine and Other Opiates Quinine comes from the bark of the Cinchona tree (Cinchona Opium, which is a complex mixture of alkaloids isolated from the spp) native to the Peruvian region of South America. In the 17th seed capsules or other parts of the poppy Papaver somniferum, century, Spanish priests observed the indigenous Indians using has been used as a pain reliever (analgesic) and sedative since the powdered bark as a remedy for fevers, and they brought it before recorded history. Morphine, one of several biologically back to Europe. The effectiveness of this treatment led to a great active alkaloids present in opium, was the first medicinally active demand for it, which threatened the natural Cinchona forests. In plant compound to be purified and the first to be sold as 1820, the active compound, an alkaloid called quinine, was a commercial product. Morphine was purified in 1805 by a young isolated by the French chemists Pelletier and Caventou. More pharmacist, Friedrich Sertürner, who is also credited for naming than 100 years passed before a method was developed to his new compound after Morpheus, the Greek god of dreams. synthesize it. The first synthetic pathway, published by Woodward in Sertürner’s work laid the groundwork for the subsequent purification 1944, was inefficient in part because the product was a mixture of of many other plant alkaloids, such as codeine and noscapine, stereochemical isoforms. In the 21st century, improved methods to which are effective cough suppressants. Derivatives of these synthesize the active stereoisoform were published, but in each natural compounds are also important medicines. Diamorphine, case, the synthetic route was not economical compared with the commonly known as heroin, is a more potent synthetic derivative purification of the natural product from the bark. Furthermore, of morphine, and oxycodone is a derivative of the alkaloid strains of plasmodia resistant to quinine and other antimalarials thebaine that is used as a time-released painkiller. have emerged, so alternate drugs are often used. Morphine is the best of drugs and the worst of drugs. Its pain- Records in China dating back nearly 2000 years describe qing relieving properties are unmatched. It is the most widely used hao, also known as sweet wormwood (Artemisia annua), as treatment for pain, with more than 230 tons of morphine used a treatment for fevers or malaria. The active compound, an medicinally each year. During a ceremony honoring Friedrich endoperoxide sesquiterpene lactone named artemisinin, was Sertürner, a celebrant said, “Without morphine I would not want first purified and characterized in the 1970s by Chinese scientists. to be a physician.” However, opiates can be highly addictive Artemisinin has proven to be an effective therapy against malaria, substances. Morphine and other opiates act by binding to but it is usually provided as a combined therapy with other drugs neurotransmitter receptors. With prolonged opiate use, the to slow the rate at which the protozoan develops resistance to it. activity or amount of receptor produced by the target cells can The amount of artemisinin extracted from plants is variable decrease, so more medication is needed for pain relief. Users but usually low. The worldwide demand cannot be satisfied from can develop a dependency or addiction and suffer debilitating the gathering of wild plants, so it is cultivated throughout Asia withdrawal symptoms. and Africa. Nevertheless, the supply of artemisinin is sometimes The potential for misuse means that these drugs are limited, and prices are often prohibitively expensive. Further controlled substances and that there is an active illegal trade in enhancements in artemisinin production are needed. Two them. In most countries, it is legal to grow poppies but illegal to approaches are being followed to address this issue: plant harvest opium from them. Although synthetic methods have breeding and synthesis. been established for the production of these alkaloids, they are not The yield of artemisinin from a plant depends on the plant commercially viable, and most opiates are derived or derivatized genotype and the environmental conditions in which it is grown, from plant extracts. (Methadone, used to treat opiate dependency, and these can vary tremendously. Plants producing consistently is a structurally dissimilar synthetic opioid.) Most of the opiates higher yields are being developed through selective breeding. used medicinally in the United States come from plants grown One approach is to take advantage of natural genetic variation to and harvested legally in India or Tasmania, but the black market identify gene loci correlated with increased production of artemisi- demands for opioids means that poppies are also grown for illicit nin. For example, as artemisinin is produced in glandular trichomes purposes. Safer poppies have been developed, such as the on the leaf surface, selecting plants with more trichomes or larger thebaine poppy that carries the thebaine oripavine poppy1 leaves may increase yields. Genes encoding steps in the bio- mutation that blocks the production of morphine and codeine, synthetic pathway can also contribute to the natural variation in so that the plants accumulate thebaine and oripavine, precursors artemisinin production. Another approach may be to target specific for the production of painkillers. Other studies have used viral- genes, such as the biosynthetic genes for a metabolic engineering induced gene silencing and RNA interference methods to approach in transgenic plants. manipulate the production of secondary metabolites in poppy A different approach has been to identify synthetic methods and to investigate further this unique biochemical pathway. for artemisinin production, which can allow artemisinin to be 4 The Plant Cell produced year-round and on demand. The greatest success so traditional Chinese medicine (TCM) and is known as xi shu, far has involved a semisynthetic approach in which the reaction meaning “happy tree.” Camptothecin and its derivatives very takes place partly in yeast cells and partly in vitro. Semisynthetic specifically target the enzyme topoisomerase I, which is needed artemisinin is already being produced, and research to increase to relax DNA supercoiling during DNA replication. Due to side yields is ongoing. However, it is unlikely that this approach will effects associated with camptothecin, its two less toxic derivatives, meet all of the needs for artemisinin because it is more expensive irinotecan and topotecan, are used therapeutically. An unexpected than the drug isolated from plants and currently is not being outcome of this research was the discovery that topoisomerase 1 is produced in amounts sufficient to meet the demands. Improvements a good target for tumor-suppressive drugs. As a consequence, in plant yields and semisynthetic production, including perhaps focused studies searching for inhibitors of topoisomerase 1 have using precursor-rich plant extracts as starting materials, may both been performed, leading to the identification of unrelated but be needed to produce the quantities required for the large-scale effective therapies. antimalarial treatments that will decrease the numbers of deaths attributed to this disease. Case Study: Fortuitous Findings of Vinca Alkaloids The anticancer drugs vinblastine and vincristine are very effective Case Study: Taxol and Camptothecin therapies for cancers of the white blood cells like lymphoma, but In the mid-20th century, a phytochemical screening program this property was nearly overlooked. The Madagascar periwinkle was initiated to identify natural products with beneficial health (Catharanthus roseus; formerly known as Vinca rosea) was effects. Through this program, thousands of plant samples were brought to the attention of researchers because it was being extracted, analyzed chemically for certain compounds (e.g., used as a treatment for diabetes by a physician in Jamaica. This steroids), and subject to biological assays to determine their claim was followed by studies in a Canadian laboratory antibiotic, antiviral, and antitumor properties. Some of the plants interested in finding new treatments for diabetes. When rats were selected by random screening, and others were identified from were injected with periwinkle extracts, little effect was observed traditional medicines. Two major drugs that are effective anticancer on blood sugar levels, but instead the animals became susceptible drugs emerged from this program: taxol and camptothecin. to bacterial infections. The animals became sick because their Taxol, later named paclitaxel, was initially characterized from immunologically active white blood cells were killed by the extracts of the bark of the Pacific yew (Taxus brevifolia), which periwinkle extract and specifically by the vinca alkaloids within had been included in a large-scale collection of plant materials it. Because the alkaloids are toxic to white blood cells, they are from the Pacific Northwest. The yew extract showed an un- effective in the treatment of cancers of the white blood cells like usually high level of cytotoxicity against a cell culture derived lymphoma. Previously, other researchers had set aside periwinkle from human cancer cells. Taxol was purified in 1966 and its when their studies showed no effect on blood sugar levels, so structure determined in 1970. Its mechanism of action was the activity of these very important drugs on white blood cell subsequently shown to be through its binding and stabilization production was nearly overlooked. Further studies on this of tubulin that interfered with cell division. interesting and important plant are described below. Interest in taxol’s anticancer properties led to large numbers of trees being harvested annually. At one point in the 1980s, it Not All Conditions Will Be Treatable by Single Compounds was estimated that 360,000 trees a year would have to be harvested to meet the demands for taxol. Taxol is a large, In spite of the successes described above, not all ailments are complex molecule not readily amenable to synthesis, but in 1994, likely to find a single “magic bullet” compound that cures or two groups published a method for the complete synthesis of prevents them. The examples shown above include drugs that taxol. However, these methods are very expensive and produce bind cell receptors (morphine), drugs that target pathogenic low yields. Today, most taxol is produced semisynthetically from agents (quinine and artemisinin), and drugs that affect single a precursor harvested from the needles of European yew (Taxus cultured cells (taxol and camptothecin), which allows them to baccata) that occurs at much higher levels than taxol. The pre- be screened and identified in vitro. The vinca alkaloids were cursor, 10-deacetyl-baccatin III, can be chemically converted into discovered more or less by accident through animal studies. taxol. Thus, branches can be harvested from trees on a yearly basis Diabetes, the condition vinca alkaloids were initially intended to without sacrificing the tree. Another approach uses a plant cell treat, still is without a simple treatment (other than insulin therapy, fermentation process that starts with cultured plant cells. This which is not very effective for type 2 diabetes). Many human ail- method not only protects the trees from overharvesting, but also ments are pleiotropic in nature and involve dysfunction of multiple avoids the use of hazardous chemicals required for the synthetic systems, tissues, cells, and signaling pathways and so may not be route. The cultured plant cell fermentation approach is an example treatable by a single chemical compound. The search for therapies of “green” (environmentally friendly) chemistry, and the company for these ailments returns us to the traditional remedies. Bristol-Myers Squibb that developed it received the Greener Synthetic Pathway award in 2004 from the U.S. Environmental THE BEST OF BOTH: THE PRESENT AND FUTURE Protection Agency. OF PLANT-BASED MEDICINES Another drug that was identified through this phytochemical screening program, camptothecin, was isolated from Campto- Increasingly, medical practitioners, healers, and government theca acuminata, a tree native to China. This tree is used in agencies are recognizing that the future of medicine brings January 2013 5 together the best of traditional and modern, reductionist practices. from the formulation makes it much less effective, which Ethnobotany and studies of traditional practices, along with plant suggests that there is more than one active compound involved. surveys and screenings, can provide raw materials from which A specific, pharmaceutical-grade formula of these herbs called to search for therapies and drugs. Modern approaches can PHY906 has been developed and analyzed extensively using provide clinical and analytical methods through which traditional modern methods, and it includes more than 100 phytochemi- remedies can be standardized, analyzed for contaminants, and cals. Human clinical trials have suggested that it can reduce the dosages regularized. Applying scientific approaches to increase side effects of an anticancer drug used in the treatment of the safety and efficacy of relatively inexpensive traditional intestinal and pancreatic cancer. Its effectiveness has also been medicines can particularly benefit the nearly 80% of the population shown through animal studies. Mice treated with the antitumor who primarily rely on them for their health needs. In this section, we drug Irinotecan (CPT-11) suffer diarrhea and weight loss because will look at how new drugs and therapies are being discovered and the drug kills the intestinal epithelial cells as well as the tumor how old therapies are being studied and improved. cells. When the CPT-11–treated mice were given PHY906 at the same time, these side effects were reduced. Molecular analysis revealed that PHY906 may act in multiple pathways to reduce Traditional Chinese and Traditional Indian Medicine inflammation and enhance proliferative activity of intestinal cells as well as to enhance CPT-11’s antitumor activity and prevent the TCM is one of the oldest and most widely used forms of conversion of CPT-11 into a more toxic degradation product. medicine. It accounts for ;40% of all health care delivery in Because Huang Qin Tang’s benefits cannot be replicated by China today. Its views of health and the body are different from a single compound, it is being developed as a complex, mul- those of Western medicine and involve a focus on balancing tifactorial drug, with the recognition that the benefits it confers different properties and energies. Many of its therapies are to an organism probably depend upon the concerted action of involved in restoring balance through the use of massage, exercise, several active components acting synergistically. and acupuncture, as well as thousands of different herbal and alternative medicines. Highly trained practitioners are important in TCM to diagnose and treat the malady. Familiar remedies derived from TCM include Ginkgo biloba, artemisinin, and ginseng Case Study: Ginseng (described further below). Globally, ginseng (Panax spp) is the most widely used medicinal Traditional Indian medicine, Ayurveda, is used by up to 80% herb. The two most studied species are Panax ginseng (Asian of the more than one billion inhabitants of India. Like TCM, ginseng) and Panax quinquefolias (American ginseng). Herbal Ayurveda is very holistic in its approach. It includes massage preparations of ginseng involve the dried root, which can be and exercise alongside herbal medicines prepared and dispensed preserved in several ways and sold as pills, powders, teas, etc. by trained practitioners. Traditional Indian medicinal drugs include Worldwide sales of ginseng exceed $300 million. Ginseng is the senna glycosides, derived from Senna alexandrina and related used alone and also as a component of complex preparations. species, which are used as laxatives and in dieters tea for weight Ginseng is said to benefit the cardiovascular system and has loss; curcumin from the plant turmeric or haridra (Curcuma longa); been used for thousands of years to increase resistance to and withafarin A, from ashwagandha (Withania somnifera). stress and boost vitality. It is used therapeutically for its im- munomodulatory, anti-inflammatory, and antitumor activities. The active agents in ginseng are thought to be the ginsenosides, Drugs and Therapies from Traditional Medicines also known as ginseng saponins. There are as many as 40 different ginsenosides. The composition and amounts of these can The use of plants as medicines dates back several thousand vary according to ginseng species, plant age, and environmental years. How well do these remedies stand up to the analytical and storage conditions. Some ginsenosides act as scavengers of tools of modern science? Generally, they fare quite well. About free radicals or stimulate production of antioxidants. Others have half of the traditional remedies examined have shown some been shown in vitro to bind to and act as agonists to mammalian promise in clinical trials. Thus, these long-established remedies receptors, such as the glucocorticoid and androgen receptors. are another good starting point for drug discovery. Traditional Determining the functions of ginsenosides in humans is compli- practices in China alone have identified more than 11,000 plant cated by the low bioavailability of the compounds and metabolic species with medicinal properties, far more than have been processes that affect their activity. Furthermore, different ginseno- pharmacologically analyzed. Many TCMs involve more than one sides have different physiological properties, and the ginsenoside ingredient, which complicates their analysis, but also may be composition of extracts varies with growth condition and extraction key to their efficacy, as seen for the case of Huang Qin Tang. methods, adding a layer of complexity to the analysis of clinical data. Case Study: Huang Qin Tang from TCM to Clinical Trials Wild plants have been overcollected to the point of endan- germent in Asia and North America, a fate shared by many Huang Qin Tang has been used for centuries to combat nausea medicinal plants. Although ginseng is cultivated for medicinal and vomiting. It is a decoction made of four plants: Scutellaria purposes, wild plants command a premium price and continue baicalensis, Glycyrrhiza uralensis, Paeonia lactiflora, and to be overharvested. Production of ginsenosides in cell and Ziziphus jujube. The elimination of any one of these plants root cultures can increase production and may curtail the 6 The Plant Cell overharvesting of wild plants. However, there are also cultural Most people in the world cannot afford to buy pharmaceutically and nonscientific issues involved in the consumption of ginseng produced or extracted compounds but rely mainly or entirely on (and many other medicinal plants). For example, many farmers’ traditional medicines, which are much less expensive. Without livelihoods depend upon the sustainable production of ginseng. significantly raising the prices of these medicines, it is possible The introduction of cell culture–derived ginseng could have to increase their safety and effectiveness. For example, many serious impacts on those who practice traditional production medicines have been found to be contaminated with heavy methods. Furthermore, the shape of the root has traditionally metals or pesticide residues that can be concentrated to toxic been a consideration in its price and its uses; given their long levels upon drying or extracting the plant materials. Relatively traditional associations with the root itself, how would traditional low-cost methods can be used to assay for contaminants, thus healers respond to a chemically identical but nevertheless very making these medicines safer. The World Health Organization different extract from cultured cells? Beliefs and traditions can be has created guidelines of Good Agricultural and Collection powerful allies in the healing process, and understanding these Practices and Good Manufacturing Practices, guidelines for cultural factors is essential for the success of any venture to herbal medicines to encourage more uniformity and safety. introduce new medicines or therapies. Perhaps, like vanillin, there is room in the marketplace for both the traditional (more expensive) and synthetic (cheaper) product. Over-the-Counter Herbal Medicines Many herbal products are sold directly to the consumer as over- Case Study: Use and Abuse of Ephedra the-counter botanical dietary supplements; in 2007, Americans spent nearly $15 billion on nonvitamin herbal dietary supple- An extract of the dried stems of Ephedra sinica (common name ments. Top sellers include G. biloba, St. John’s wort (Hypericum ephedra) has been used to treat colds, asthma, and respiratory spp), garlic, Echinacea spp, saw palmetto (Serenoa repens), and complaints for thousands of years. The plant produces several Kava kava (Piper methysticum). Because these supplements are related alkaloids, including ephedrine, which is an agonist of not required to demonstrate medicinal benefit, there is often little a- and b-adrenergic receptors. By stimulating these receptors, rigorous data to support their efficacy. However, the incidence ephedrine causes an enhanced heart rate, stimulation of the of direct harm is also rare. Unlike traditional practices in which central nervous system, and dilatation of the bronchi and herbal remedies are usually dispensed by trained practitioners, bronchioles. Thus, besides alleviating the symptoms of asthma, over-the-counter products are marketed directly to the con- it also increases energy level and raises the metabolic rate, so it sumer, and confusion and uncertainty about their use is widely became popular both as a performance enhancer for athletes reported. The National Center for Complementary and Alterna- and as a weight loss drug. Unfortunately, several strokes, seizures, tive Medicine, an institute of the U.S. National Institutes of and deaths were attributed to over-the-counter ephedra-containing Health, provides up-to-date, evidence-based information about supplements. Its over-the-counter sale as a weight loss aid has herbal compounds (http://nccam.nih.gov/health/herbsataglance. been banned in the United States since 2004, although it is still htm), as does the European Medicines Agency (http://www.ema. available in the United States from TCM healers. Its use by athletes europa.eu). in competitive sporting events is also banned. Like morphine, ephedra is a potent beneficial drug that offers the potential for abuse. Case Study: Echinacea Echinacea products contain material from any of several species 21st Century Science Can Be Applied to Ancient Medicines of the genus Echinacea, which includes purple coneflower (Echinacea purpurea) and narrow-leaf coneflower (Echinacea 21st century science is being applied to traditional medicines angustifolia). These plants are native to North America and have with several goals in mind. One is drug discovery, with the been used as medicines by Native Americans and First Nations assumption that, like artemisinin, some traditional medicines will for hundreds or thousands of years. Native Americans relied on be based on single compounds that can be developed into oral histories and traditions, so no written records remain before purified drugs. Even complex formulations like Huang Qin Tang their encounters with Europeans, but archaeological evidence can be improved by standardizing the formulations, which is and studies by ethnobotanists reveal many centuries of medicinal important to achieve the level of reproducibility needed for plant use, which continues today. clinical studies. Echinacea is one of the most used herbal remedies, with global As described below, metabolomics and related methods can sales of over $300 million annually. It is thought to contribute to be applied to the medicinal plants, to understand better their enhanced immune responses and is marketed particularly as biochemistry, and also to the animal or human under study, to a therapy for respiratory infections and colds. Clinical data to investigate how it responds to the medicines. For example, the support these roles are mixed; some studies indicate a beneficial transcriptional responses or the changes in small molecule effect, whereas others show no effect. One study pointed to the profiles of cells or animals responding to traditional medicines effects being stronger on people who are sicker, and another can be compared with their responses to other compounds to indicated that the diversity of materials used in different studies identify their modes of action. (different species, different plant parts, and different methods January 2013 7 of extraction) confounded any clear evidence. As yet, there is no thought to be present in ;20% of plants. They are structurally consensus about their active agents, although echinosides diverse and have diverse biochemical origins. Alkaloids are and alkylamides are generally considered to be the active usually heterocyclic, nitrogen-containing compounds that are compounds and have been shown to have immunostimulatory and alkaline or slightly basic and taste bitter. The monoterpenoid indole antimicrobial properties in cell culture. Echinacea seems to have alkaloids (MIAs) are a family of ;2000 compounds that includes low toxicity, but it is not recommended for children under 12 years the vinca alkaloids and primarily are found in Madagascar of age. The National Center for Complementary and Alternative periwinkle and Rauvolfia serpentina (sarpagandha or snakeroot). Medicine states that any effects are likely to be small but that Benzylisoquinoline alkaloids are a family of ;2500 compounds, consumers’ choices should be guided by “personal values and including morphine, and are found in several plant families. preferences.” In other words, if you have a cold and Echinacea Tropane alkaloids are more widely distributed in the plant makes you feel better, go ahead and use it. kingdom and include nicotine and scopolamine, purine alkaloids include caffeine, and pyrrolizidine alkaloids are widespread in the plant kingdom and generally induced by herbivory. In Finding Sources for New Drugs humans, alkaloids can be stimulants (caffeine, cocaine, nicotine, and ephedrine), pain relievers (morphine), antitumor agents It is thought that many of the more than 250,000 species of (vincristine and taxol), psychoactive agents or hallucinogens flowering plants harbor medicinally important compounds, but (dimethyltryptamine and mescaline), deadly poisons (strychnine, the challenge is deciding which plants to pursue. One approach scopolamine, and coniine), or have any of several other biological is to look at plants in families that seem to be more likely than activities (e.g., quinine). others to produce medically active compounds. A few examples Phenolics are a structurally diverse family of compounds are the Myrtaceae, which includes eucalyptus and clove, defined as having one or more phenol groups; flavonoids, Apocynaceae (periwinkle), Solanaceae (tobacco, nightshade tannins, phenylpropanoids, etc., are all polyphenols. Medicinal [Solanum dulcamara], and pepper [Capsicum annuum]), Papa- phenolics include eugenol, a component of clove oil that is widely varaceae (poppy), and Taxaceae (Pacific yew). used as a treatment for toothache, coumarins (precursors for the Another approach has been to integrate knowledge of synthesis of anticoagulants), and flavonoids and related com- traditional medicines from different regions of the world. When pounds with diverse anti-inflammatory and antioxidant properties, mapped phylogenetically, groups of related plants whose medic- such as the flavonoid epigallocatechin gallate from green tea, inal properties have been discovered independently are revealed. isoflavonoids like genistein from soybeans, tetrahydro-cannabinol The fact that different groups of humans have independently from Cannabis sativa, anthocyanins, and tannins. discovered these properties makes certain plant groups partic- Terpenoids are a very diverse and complex group of ularly attractive candidates for further investigation. compounds made from five-carbon isoprene units. Monoter- Modern analytical methods can be applied to known medicinal penes, C10 compounds, include volatile compounds such as plants to identify chemical or genetic profiles, and these profiles pinene and limonene, and are used therapeutically to aid respiration. can be used as indicators of medicinally active compounds. For Iridoids are also monoterpenes, often found as glycosides example, if a few metabolic pathways involved in specialized (conjugated to a sugar). Aucubin and valepotriates are iridoid metabolism are highly correlated with medicinal properties, glycosides with analgesic and anti-inflammatory properties found high-throughput methods can be used to screen large numbers of in Plantago lanceolata, Valerian officinalis, and other plants. Other plants for these molecular fingerprints and identify good candi- medicinally active terpenoids include ginkgolides (from G. biloba), dates for further study. Although the biochemical diversity of ginsenosides, taxol, and artemisinin. medicinal compounds is immense, they are mostly derived from Phylogenetic studies have revealed that some compounds only a few dozen highly versatile central intermediates that serve that are present in widely divergent species may be the result of as backbones. convergent or repeated evolution. Given that many of these compounds are derived from the highly conserved products of primary metabolism, such as isoprenes or amino acids, it not Classes of Phytochemicals with Medicinal Properties unreasonable to imagine that the ability to synthesis a compound has evolved more than once. In spite of what some medieval botanists believed, plants do not make medicines to serve humans. Many of the medicinally active compounds found in plants are products of specialized -Omics, Systems, Semisynthetic, and Other Methods metabolism and are believed to function for defense against for Metabolic Engineering herbivores or pathogens. A few types of chemicals are pre- disposed toward medicinal properties, allowing researchers to The study of medicinal plants benefits from many exciting new narrow their focus to certain classes of chemicals as they screen breakthroughs in “-omics” approaches (e.g., genomics, for active compounds. The most prominent classes of medicinally transcriptomics, proteomics, and metabolomics) as well as active chemicals are alkaloids, phenolics, and terpenoids. new semisynthetic methods for synthesis. Currently, the ge- Alkaloids are a very large and diverse group of metabolites nomes, transcriptomes, proteomes, and metabolomes of many and contribute the greatest number of known plant-derived medicinal plant species are being investigated, with the goal of medicines. There are ;12,000 known alkaloids, and they are identifying the genes and proteins involved in the biosynthesis 8 The Plant Cell of important compounds. Spatial, temporal, and environmental a separate but related study, genes encoding enzymes that add expression data are also being analyzed because many specialized halides (e.g., Cl and Br) to Trp were introduced into Madagascar metabolites are synthesized only in certain tissues or cells (e.g., periwinkle hairy root cultures, with the result that these plants trichomes) or only under certain conditions. In some cases, different synthesized halogenated tryptamine, and subsequently pro- enzymes in the biochemical pathway are expressed only in different duced halogenated MIAs. Thus, the already diverse family of cell types, which may be important for the regulation of production MIAs that periwinkles can produce has been made even more of the metabolite. The vast amounts of data being assembled diverse, which one writer summarized as “gilding the periwinkle.” require new methods for integration and analysis, and the de- velopment of new systems biology methods is being driven in part by the need to interpret these very diverse metabolic pathways. Recognizing the Value of Biodiversity Information about the biosynthetic pathway is invaluable for Much of the world’s biodiversity can be found in tropical regions, the design of methods to enhance the synthesis of the desired but financial gains derived from this biodiversity often have not compounds, often referred to as metabolic engineering. In some benefitted the people living in these regions. Increasingly, efforts cases, metabolic pathways can be introduced wholly into are being made to encourage the preservation of biological bacterial or yeast cells for large-scale fermentation production. diversity by ensuring that those who protect it benefit from the As described earlier, genes from A. annua have been introduced ultimate commercialization of products derived from it. The into yeast for artemisinin production, and several groups have Convention on Biological Diversity, laid out in 1992, has been reported the successful production of various terpenoids, signed and ratified by most of the world’s countries. One of the phenolics, and even some alkaloids in microbial cells. Alterna- key objectives of the Convention on Biological Diversity is “fair tively, part of the pathway can be introduced into yeast or and equitable sharing of the benefits arising out of the utilization bacterial cells along with a precursor derived from the plant, of genetic resources,” which was elaborated further on in the 2010 sometimes referred to as a semisynthetic method. Nagoya protocol. It is hard to know how successful these efforts Although plant cells can be more difficult to manipulate than have been. Without the ratification of the United States, the leader microbial cells, there are some advantages to their use for in pharmaceutical research, the effect may be small. Nevertheless, specialized metabolite production. For example, plant cells a few companies have voluntarily signed agreements to ensure that often already make the precursor molecules needed. Increasing their bioprospecting efforts benefit the host countries. the expression of a desired product can be as simple as in- creasing the expression level of a single enzyme, obviating the need to engineer the entire pathway. Plant cell cultures or hairy HEALTH CARE FOR ALL root cultures have been demonstrated to be effective systems for the production of several important metabolites (for some The high cost of research and development means that phar- examples, see Leonard et al., 2009; Roberts, 2007; Dixon maceutical companies focus their efforts on diseases that affect et al., 2012). Metabolic pathway can be manipulated in whole the most affluent segment of the population, who can afford plants as well. Examples of these efforts include the production to buy the medicines they develop. The World Health Organi- of reduced caffeine coffee by RNA interference–mediated zation noted that ,1% of the new drugs developed in the past silencing of a biosynthetic enzyme, the morphine-free thebaine 25 years target diseases of the poor, and 90% of research poppy described earlier, and sweeter-smelling lavender pro- and development spending goes into diseases that affect the duced by elevated expression of an enzyme involved in richest 10%. Bringing a drug from herbal remedy to patented pill terpenoid production. is a hugely expensive undertaking, and private pharmaceutical companies cannot afford to pursue it unless they have a strong indication that they will recoup their expenses, through marketing Case Study: Metabolic Reengineering of Madagascar it in the markets that can afford to buy it. Periwinkle For the majority of the world’s population, prescription drugs are prohibitively expensive. Many rely primarily on herbal and Madagascar periwinkle produce a family of ;130 MIAs derived traditional medicines. Implementing evidence-based practices from a single precursor, strictosidine. Strictosidine is produced can maximize the benefit of traditional medicines. In cases in by the action of the enzyme strictosidine synthase, which which the active compound is known, the potency of traditional conjugates the condensation of tryptamine (derived from the medicines can be batch analyzed and standardized. In cases amino acid Trp) and secologanin. Madagascar periwinkle can be where the active compound(s) cannot be identified, the standard- propagated in cell culture or hairy root culture for large-scale ization of cultivation conditions can contribute to a more uniform metabolite production, and genes can be introduced stably by product. DNA barcoding techniques and mass spectroscopy are Agrobacterium rhizogenes–mediated transformation, making inexpensive methods that can confirm the identity of the plants this plant amenable to metabolic reprogramming. In one study, in a medicine, and inexpensive analytical tests can screen for a variant of the key enzyme strictosidine synthase with altered toxins and pesticides. As seen for artemisinin, scientific ap- substrate specificity was identified through a mutagenesis and proaches can contribute to ensuring that the medicine is screening strategy in yeast. The gene encoding the variant available in sufficient supplies to meet demand. The benefits enzyme was reintroduced into the plant, and hairy root cultures of evidence-based medicine ought not to be restricted to the expressing it were shown to synthesize novel products. In wealthy. 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