Artemisia annua Prospects, Applications and Therapeutic Uses

Edited by Tariq Aftab M. Naeem M. Masroor A. Khan

Internationally, scientists are making unstinted efforts to improve the understanding of malarial biology and to develop more effective malaria treatments. Malaria remained the major scourge of mankind until the Chinese introduced artemisinin to the world as a remedy. The antinialarial drug artemisinin was discovered by Tu Youyou, a Chinese scientist, who was awarded half of the 2015 Nobel Prize in Medicine for her discovery. Since the discovery of artemisinin, treatments containing artemisinin derivatives (artemisinin combination therapies, or ACTs), have been standardized for the treatment of Plasmodium falciparum malaria worldwide. Artemisinin is certainly one of (he most promising natural products investigated in the past couple of decades. The plant has potent therapeutic potential beyond its (antimalarial activity, including anticancer, immunosuppressive, anti-inflammatory,! antihypertensive, antioxidative, antimicrobial, antiparasitic, and antiviral activities. However, artemisinin-derived drugs are not available (o millions of the world’s poorest people because of the low yiekl (0.1%-0.5% of dry weighl) of artemisinin in naturally grown Artemisia plants. The present demand for artemisinin far outstrips supply; therefore, researchers around the world are working toward improving the artemisinin content of the plant by various means.

The editors' efforts, in the form of this comprehensive volume, delail recenl updates to the applications, current research, and future prospects of Artemisia annua. Since the intact plant contains artemisinin in very low concentrations, its commercial extraction requires huge amounts of plant biomass to be processed. Massive demand and low yield of artemisinin from the plant has led to exploration of alternative means of production, including the cultivation of A. annua on scientific lines. Considering the significant benefits of various properties of the plant to human health, we present this exclusive volume entitled Artemisia annua: Prospects, Applications and Therapeutic Uses. As per (he rationale, this volume focuses on various scientific approaches, namely, agricultural, pharmacological, and pharmaceutical aspects, in vitro technology, and nutrient management strategies, as well as omics technologies for the regulation of artemisinin biosynthesis in A. annua. The ^book also contains a plethora of information about various scientific approaches to| the cultivation of this medicinal plant. Also, it includes information about the plant's survival under conditions of environmental stress.

The book comprises 14 chapters, most of them being reviewed articles written by experts from around the globe. We are hopeful that this volume will meet the needs of all researchers who are working or have interest in this particular field. Undoubtedly, this book will be helpful to research students, teachers, ethnobotanists, oncologists, pharmacologists, herbal growers, and anyone else with an interest in this plant of paramount importance.

We are greatly thankful to the CRC Press, Taylor & Francis Group. USA, for their expeditious acceptance and compilation of this scientific work. Sincere thanks are expressed to the team members of the Taylor & Francis Group for their dedication, sincerity, and friendly cooperation in producing this volume. With great pleasure, we

extend our sincere thanks to all the contributors for their timely response, outstanding and up-to-date research contributions, support, and consistent patience.

Lastly, thanks are also due to the well-wishers, research students, and authors* family members for their moral support, blessings, and inspiration in the compilation of this book.

Tariq Aftab M. Naeeni M. Masroor A. Khan

Aligarh Muslim University, Aligarh, India

This chapter explores whether, and how, the enormously rich and rewarding biomedical research into the antimalarial efficacy of artemisinin, contained in A. annua plant materials, might be useful for textual scholarship.1 Admittedly, such a project is fraught with problems, as social historians working with pre-twentieth century medical texts are apprehensive of any attempt to identify the referential meanings of the terms translated. Malaria, for instance, is a modern scientific nosological term for which there is no equivalent in the

premodern Chinese medical texts. Modern scientists have translated malaria into the Chinese niieji 瘧疾.which derives from a term that occurs in premodern Chinese texts~just as malaria is derived from premodern terminology, maVaria ([caused by] bad air). However, neither niieji nor maVaria referred to malaria as a disease category in these texts. The pre modern Chinese had notions of bing 病(disorder), hou 候(conditions, “syndromes”X zheng 證(evidence, patterns; patterned evidence), and (he like, as perceived through the prisms of morality, ^idhoc (magical) intervention, and legal practice, among others. The premodern| Chinese term niieji was a bing or a hou and not a “disease” in the modern scientific sense. Yet, today, it is used as the standard term into which the biomedical disease category “malaria” is translated.

Furthermore, regarding plant identification, ethnobiologists have demonstrated that the modern species-concept is just as historically evolved and socially constructed as modern biomedical terms of human pathology. However, since the mid-20th century, elhnobiologists have attenuated their cultural relativist claims by demonstrating that (he plant world is cross-culturalIy considered to be marked by

discontinuities, some of which can be reproduced with great constancy; this is in stark contrast to the worlds of sickness and disease (Hsu, 2010).

Textual scholars do not profess to have deep medical understanding, and they often rely on their colleagues in medical schools, and commonsense biomedical understandings of disease and the body. The Cartesian view of body and mind, which provides the foundations for the biomedical understanding of the body, has given rise to a prevailing assumption in textual scholarship that plots an underlying “nature,” which is real and of the body, against “culture，” which is constructed and of the mind. Currently, recipes in premodern materia medica texts tend to be read either in an almost naive realist way, where premodern terminol-|ogy is imbued with contemporary scientific meanings (niieji means malaria), or| in a cultural constructivist way, where they are read as consisting of a somewhat random assemblage of information on how to treat rather arbitrary, culturally constructed，states of misfortune and bodily dysfunction. More recently, however, some medical anthropologists have been inspired by Merleau-Ponty's ([1945] 1962) Phenomenology of Perception to demonstrate that these culturally specific terms need not be entirely arbitrary and incommensurable with others in cross-cultural comparisons. The key concept that will be mobilized here is Merleau-Ponty’s notion of physiognomy, which draws on and further develops the Gestalt psychologists’ notion of Gestalt.

As argued here, it is particularly research applied to individual cases, with practical implications and easily perceived immediate effects that enable a textual scholar to undertake critical comparisons across time and space. Recipes or formulas (fangji 方劑）and recipe texts are meant to have practical effects and can be tested on individual patients, as can the application of materia medica (in the sense of “herbs” or “medicinal drugs” 藥）and materia medica literature (ben cao 本草>.Since these texts often present therapeutic procedures with perceived immediate effects' they qualify as a genre worth investigating here. Their practical significance makes it possible for us to test a physiognomic reading.

1.2 PHYSIOGNOMIC READING OF A RECIPE TO TREAT INTERMITTENT FEVERS WITH QING HAO

Let us start by reading the famous physician Ge Hong's 葛洪（284-363 CE) prescription against “intermittent fevers” ("tie 辑）in his Zhou hou bei ji fang 肘後備急方 (emergency prescriptions kept in one's sleeve). Let us first ask whether he considered these fevers malarial, which would make his prescription an herbal anlinialarial. and second, query what might make the reading of his formula (or recipe) physiognomic.

Another rccipc: qing hao, one bunch, take two sheng [2x0.2 liters] of water for soak-4 ing it, wring it out, take the juice, ingest it in its entirety (you fang: qing hao yi wo yi | shui er sheng zi, jiao qu zhi, jin fu zhi又方青蓄一握以水二升漬絞取汁_服€). (Zhou hou bei ji fang, juan 3, **Zhi han re zhu niie fang” 治寒熱諸篇方16: 734-407)

If we ask whether he recognized the intermittent fevers as a sign or symptom caused by what today is malaria, the answer has to be “no.” Although he used the term qing hao, we cannot be certain that Ge Hong used what today is considered the Chinese herb or drug, or more aptly, the Chinese materia medica, called qinghao; that is, plant materials of the species A. annua L. As the practice of zhongyi 中醫， Chinese medicine, is a living tradition, there is no guarantee that any term in use today designates the same taxon as it did in Ge Hong's time. From a biomedical perspective, we also know that intermittent fevers are a symptom not only of malaria but also of other diseases. We can be quite certain that intermittent fevers, read as a symptom or sign of a biomedical disease category, occur in many more conditions than those caused by malarial parasites.

Now. if we assume that qing hao in Ge Hong’s recipe and qinghao today are constituted of plant materials of the same species* A. annua, we may deduce that Ge Hong and other premodem Chinese physicians sometimes gol it right (when the intermittent fevers were malarial), but not always (not all intermittent fevers are malarial). In line with our progressivist view of humankind, the suggested readying of the recipe reaffirms our conviction that the ancients engaged in science, bul隹 that our modern scientific knowledge is more precise and accurate than premodem knowledge.

However, did the Chinese physicians conceive of intermittent fevers as symptoms or signs of a biomedical disease category? As established in the preceding paragraphs, they did not. So how should a textual scholar relate to the term used for intermittent fevers, niiel Here，Merleau-Ponty’s (1945) insights become important on the theoretical and methodological levels, as this question can be reformulated: how might we read premodern terms that refer to a lived experience of the body, such as that of fevers (hat come and go intermittently? Merieau-Ponty posiled that how we know the world

depends on how we project our body into the world. In contrast to the assumption that the world and the self can be separated from one another, as posited by empiricist

* Writing convention in this chapter: the monosyllabic transcription refers to terms in premodern texts, for example qing hao, but not in modern ones, where qinghao is used.

ARTEMISIA ANNUA: PROSPECTS, APPLICATIONS, AND THERAPEUTIC USES

science grounded in a Cartesian view of mind and body, Merleau-Ponty insisted that the body-self formed an inextricable part of ihe phenomenal field through which it moved. Accordingly, the researchers body is part of the lived world he or she inhabits and aims to research. While a natural scientist, as the subject who does the research, is expected to investigate a research object in a detached manner (even if “objecliv-ily” may be performed in different ways; Daston and Galison, 2007), Merlcau-Ponty stressed that the body has a spatiality that is part of the spatial field around it. I( cannot be disentangled from its surroundings, just like its parts cannot be considered a Iran-dom] “assemblage of organs juxtaposed in space.” Rather, they form a whole, and are, in not entirely arbitrary ways, “enveloped in each other” (Merlcau-Ponty, 1962，p. 98). Merleau-Pon(y thereby provided a basis for critiquing objectivisl disease categories. Accordingly, intermittent fevers are not a symptom or sign caused by the disease of malaria, because any biomedical disease category presupposes an objective description of the world, and its relation to the sign is grounded in cause-effect relations established through objective scientific study.

Following Merleau-Ponly, I suggest instead to read ^intermittent fevers” as a physiognomy of the spatial field. As already said, Merleau-Ponty emphasizes that the body has a spatial dimension inextricably entwined with the phenomenal field of its surroundings. This spatial field has physiognomies that arise from a practical engagement of the self with its surroundings. Merleau-Ponly's philosophical concept. physiognomy, makes “intermittent fevers” an aspect of the spatial field with which the body-self is practically engaged. This practical engagement arises from the body-self experiencing perceived demands from specific configurations in the spatial field to “do” something. The demands affect the self on multiple levels and are responsible for prompting the body-self into action. Intermittent fevers thus become relevant for the patient and physician as physiognomies of a spatial field demanding a practical intervention from ihe body-self.

Physiognomies are perceived wholes. Merleau-Ponly points out that to a person for whom meanings are no longer embodied in the world, the world no longer has any physiognomy (ibid, p. 132). Much like the Gestalt psychologists emphasized that the whole is other than the sum of its parts (a saying that is often misquoted as “the whole is greater than the sum of its parts”)，Merleau-Ponty emphasized that perception relies on an organism's ability to perceive wholes in a single instant. The Gestalt psychologists and the philosopher Merleau-Ponty argued against the behaviorists pf the day, against the “empiricists，” “intellectualists，” and “sensationalists，” w

all posited that sensory perception is an additive process. Merleau-Ponty spoke 01 knowing “without thinking'' (ibid. p. 129)，and underlined immediacy in the perceiving of a whole. His concept of physiognomy is important for us here as it refers lo an “immediate practical recognisability”（Morris，2012, p. 25), where the practical is not merely opposed to the intellectual, but directly appeals to our practical capabilities. As ihe Gestalt psychologists emphasized, (lie perception of the practical significance of objects, entities, and events lies nol merely in their functional characteristics, but also in so-called “demand characters” or “appeals，” “attractions,” “exigencies，” and “solicitations” that arise from the perceivcrs unmcdiatcd, often affective relation to

Focusing on a physiognomy of a malarial episode such as “intermittent fevers” as a lived experience emphasizes that its perception and recognition is inextricably related lo the way in which it is enacted and acted upon. This appeal to practical intervention is very important when interpreting prescriptions, recipes, and formulas that arguably include an antimalarial ingredient, qinghao. Rather than assessing malaria as a disease in terms of objectively given structures and functions, we shall ask what is gained if we read recipes including qing hao as providing a practical response to the many different faces of malaria and their physiognomy.

This does not appear to circumvent the problem of reading a retrospective biomedical diagnosis into a premodern text, however. The skepticism of the self-critical textual scholar cautions us. So, might we frame and conceive of the problem differently? Might we be able to explore modes of countering our skepticism by means of an equally rigorous and critical way of thinking about, or rather of doing, science? A physiognomy has practical significance, which asks for, or demands, a practical intervention.

A natural scientifically minded realist will (urn to experimentation. We know beyond reasonable doubt that the chemical substance artemisinin is a highly effective antimalarial and that A. annua plant materials contain artemisinin. We also |know thal today A. annua plant materials make up the Chinese medical materia^ medica called qinghao. As already noted, the qing hao that Ge Hong used some 1500 years ago may not have consisted of the same plant materials, nor can we be certain that they were identical in morphology and chemical composition.

The easiest way to practically assess the effects of Ge Hongs procedures, surely, is (o re-enact them, much in the way current science historians have buill and reenacted significant nineteenth-century machinery to understand how nineteenth-century scientists arrived at their scientific concepts (e.g., Sibum, 1998). This is exactly what an interdisciplinary team of researchers did from January to June 2006; namely, a gardener, who with (he permission of his patron grew a mini-plantation of

A. annua at Hayley House in Oxfordshire; a pharmacognosist and his research team at the Department of Pharmacy of the University of Bradford; and a malariologist and his team at the Swiss Tropical Institute, with a medical anthropologist as tentative initiator, project designer, and go-between (Wright et al., 2010). Our research was written up as a project in which modem science was used to validate the effectiveness of a premodem recipe. Yet in this chapter a proposal is made to “read” and interpret the project differently.

Relevant for textual scholarship is the interpretation of the experiment as one where (he physiognomy of intermittent fevers prompted the enactment of body techniques to make a qinghao juice that affected it instantly. In ocher words, our experi-^rncnt can be framed as one where we treated intermittent fevers in mice (induced| through the injection of P. berghei parasites into their bloodstream several days earlier) as a specific physiognomic phenomenon of practical significance in so far as it demanded a specific treatment, a qinghao juice. We produced this juice through a practical intervention, namely the body techniques of either wringing out plant materials soaked overnight or pounding fresh plant materials on the same day. Our practical procedure had immediate effecls, which were observed in individuals (ihree

practical intervention of administering qmghao\\x\cq, such that they disappeared and the mice recovered.

In summary. Ge Hong s extraction technique of wringing out the whole plant, which resulted in an emulsion of water, flavonoids, aromatic oils, and artemisinin as contained in the leaves, in particular, is likely to have yielded artemisinin in larger quantities than earlier techniques of preparation recorded in the Chinese materia medica, and this is in all likelihood directly linked to the recommendation of using il for treating acute fever episodes of intermittent fevers (Hsu. 2014). Not just artemisinin, but also several flavonoids, found in stems and leaves alike, have antimalarial properties, and synergistic effects may or may not have played an additional role 丨(Willcox et al” 2004). Furthermore, resistance to (he antimalarial, artemisinin, isj much less likely to occur in whole plant preparations (Elfawal et al” 2014).

1.3 PHYSIOGNOMY OF COMPLAINTS FOR WHICH THE CHINESE MATERIA MEDICA LITERATURE RECOMMENDS THE APPLICATION OF QING HAO

In the Chinese materia medica literature, wherein qing hao is mostly known as cao hao 草蒿.it is recommended fora variety of complaints other than intermittent fevers (for a chronically ordered, comprehensive translation of these recommendations, see Hsu, 2010). Medical historians have been quick in dismissing those as biologically unfounded “culture-bound syndromes，，，“illnesses,” or “sicknesses.” In what follows, we discuss the treatment recommended in the Chinese materia medica from (he first century CE to 1596 for such culture-specific notions in light of the scientifically known biological variations of malaria. If the pathology of malaria in regions where it is endemic need not always manifest as fever bouts, its cultural perceptions may vary accordingly. In what follows, we explore whai is gained by reading these recommendations as a response with practical significance to the solicitations of the physiognomy of the lived experience of malaria’s diverse biologies.

The Chinese materia medica literature is a genre that consists of long lists of' materia medica identified by name and synonyms: by flavor, quality, and other properties, such as whether the materia medica in question has polency/toxicity (you/wu du 有 I 無毒)：by main indications; and sometimes also by “pharmaceutical” information on how to prepare and when to administer them. The first canonical materia medica, which is no longer extant in its original form but has been reconstructed from multiple citations in later works, is Shennong's Canon of Materia Medica (Shennong ben cao jitig 神II本草經presumably compiled in the first century CE. It has an entry on cao hao, the “herbaceous hao:，

The hcrbaccous hao. Its flavor is bitter, cold. It treats jie itchcs, jia itchcs * and ugly wounds. It kills lice and lingering heat between bones and joints. It brightens the eyes.

* jie sao jia yang 济® 挪痒 is an itching that can affect toes and fingers. See, for instance, yiV jia 挤挪 in Ling shu 进樞 10:307. or jie chuang 济瘡 in Zhu bing yuan hou lun 諸病舍候諭 50:1411.

Another name is qing hao% another name is fang kui. It grows in river waste lands.* (Shennong ben cao jinjuan 4: 341)

Al a firsl glance, it appears as though the authors of this text were completely

unaware of the potential antimalarial use of cao hao. They primarily recommended it for treating different kinds of itches, ugly wounds, and lice.f However, joint aches are a common lived experience among patients in regions where malaria is endemic. Likewise, ihe “lingering heat between bones and joints” in Shennong's Canon of Materia Medica may have alluded to this face of endemic malaria.

Shennong's Canon of Materia Medica also recommends cao hao for ^brightening the eyes” (ming mu 明目）.Incidcnlally it is also mentioned in the Materia Medica for Successful Dietary Therapy (Shi liao ben cao 食療本草)of 721-739 among a list of terms indicating enhancement of one's vitality:

I They say qing hao is cold, enhances qi 氣，causes growth of head hair, can make the | 1 body feel light, supplement the interior and prevent ageing, brighten the eyes, and halt ^ wind poison. (Zheng lei ben cao, juan 10:20b)

Chinese medical historians generally do nol consider materia medica that can “brighten the eyes” to be antimalarial. However, if we take into account that endemic malaria causes anemia, which is experienced as lethargy and tiredness, we can see why a materia medica with antimalarial effects might be considered vitality- and longevity-en hancing.

The Materia Medica for Successful Dietary Therapy uses the raw plant, after

soaking it in urine and making it into a powder and pill. It also recommends qing hao as a pickle, and Tao Hongjing (456-536) seems to have recommcndcd it as an unprocessed food supplement in his Notes to [Shennong’s] Canon of the Materia Medica ([Shennong] Bencao jingji zhu [神農]4草經集注)around 500 CE.2

It is everywhere，this one is today's qing hao, people even take it mixed with fragrant vegetables for eating it. ([5/j^/i Ben cao jing ji zhu, juan 5，p. 363)

Although a syntactic reading of the text is that the vegetables were “fragrant.” there is little tloubl (hut I hey were considered such due lo ihe fragrance of qing hao, iwhich in other texts is called “fragrant hao” (xiang hao 香萬）or even “stinking hao'\ \chou hao 臭萬>• As food supplemenl. the presumably fresh and fragrant qing hao may have been seen as a preventive health measure.

Later materia medica texts recommend cao hao (a synonym of qing hao) for treating “bone steaming” (gu zheng 骨蒸）and conditions of “exhaustion arising due to heal/fevers'' (re lao 熱>• Although Chinese medical historians do not generally consider these two terms to describe malarial conditions, with hindsight, knowing that qing hao can be used as antimalarial, it is possible that they sometimes referred to malarial fevers. Furthermore, it is conceivable that the effective treatment of malarial cases of gu zheng and re lao by cao hao may have led to this recommendation.

For treating bone steaming, take one liang 兩[41.3 g.] of urine to soak it overnight,

I dry it, tum it into powder and make a pill. It entirely eliminates exhaustion arising due | to hcat/fcvcrs. (Shi liao ben cao 食療本草 of 721-739，as quoted in the Zheng lei ben * cao, juan 10:20b)

In this context, it is worth noting that a hao is also recommended for a wide range of convulsive disorders including “daemonic qi'' “rigor mortis possession disorder，”* and fu lian} as in the Supplements to the Materia Medica (Ben caoshiyi 本草拾遺）of the eighth century, which recommended, in line with Ge Hong, wringing out the juice from a presumably fresh plant:

Hao controls daemonic qi, rigor mortis possession disorders, fu lian, the blood qi of women, fullness inside the abdomen and [perceptions of] intermittent cold and hot, and chronic diarrhea. In autumn and winter, use the seeds, in spring and summer, use the sprouts, together pound them with a pestle, wring out the juice, and ingest. Alternatively, dry it in the sun and make it into a powder, and apply it in urine. (Zheng lei ben cao, juan 10:20a)

Nolably, cerebral malaria can also present as convulsions, but Chinese medical historians do not associate “daemonic qi:，the “rigor mortis possession disorder,” and fu lian with malaria. Rather, they tend to relegate these conditions into the domain of culture-bound possession behavior or mental illness, and these have rather distinctive physiognomies; for instance, when associated with pollution through contami-P nation with the dead (e.g., Li, 1999). In this case, it is possible but unlikely that qing hao's effectiveness against cerebral malaria motivated its recommendation. Rather, another observation comes to mind: the component qing, in the name qing hao, has a phonoaesthetic that alludes lo lightness, transparency, and purily，and hence it may have been used for treating conditions of pollution. Although the term qing is not given in this quote, it likely was implied. In the highly medicalized formula literature, qing hao is the usual term，but not in the materia medica literature, where we have cao hao in ils stead.

1

An earlier version of this article was published in Wallis (2009).

2

汉澤 is here rendered as “wasteland,” in accordance wilh Bodde (f 1978】 1981). This is Ihe ecological niche of Artemisa apiacea and Artemisia annua, rather than interpreting ze as meaning swanps and wetlands.

f This is a recommendation much in line with the first extant text on the therapeutic use of qing hao in a manuscript unearthed from a tomb closed in 168 BCE near Mawangdui (Harper, 1998: 272-273〉, and it is one that prevailed in the materia medica literature for about one thousand years (Hsu, 2014: table 1).