Half of the 2015 Nobel Prize in Physiology or Medicine was awarded to Chinese phytochemist Tu Youyou for her role in the discovery of the natural compound artemisinin, which is produced by the traditional Chinese medicinal herb qinghao (Artemisia annua, Asteraceae), also known as sweet wormwood. Artemisinin derivatives are commonly used in the treatment of malaria, one of the world’s oldest and deadliest diseases.1-3
The other half of the Prize was awarded to Japanese microbiologist Satoshi Ōmura, PhD, and Irish-American biologist and parasitologist William C. Campbell, PhD, for their discovery of avermectin, a natural anthelmintic compound (i.e., one that expels worms and other parasites from the body). Avermectin is produced by the bacterium Streptomyces avermitilis, and its derivatives have dramatically reduced the incidences of parasite-induced diseases, such as river blindness and lymphatic filariasis.3
Both halves of the Prize are a triumph for the field of pharmacognosy (the study of medicines derived from plants and other natural sources) and, according to many, Tu’s half is also a win for China. Tu, who was born in 1930 in Ningbo, a port city in Zhejiang province on the eastern coast of China, is the first citizen of the People’s Republic of China (PRC) to be awarded a Nobel Prize in the sciences. (Five Chinese-born scientists have won the Nobel Prize in Physics, but none were citizens of the PRC.1) Some people in China view the win as confirmation of the strength of Chinese science and medicine, while some traditionalists view it as a reminder that Chinese medicine is ignoring its heritage by using methods similar to those used by Western pharmaceutical companies.4
In truth, the discovery of artemisinin, which also involved ethnobotany, the study of people’s historical uses of plants, may be a prime example of traditional Chinese medicine (TCM) and Western practices complementing each other.
The discovery of artemisinin is considered one of the most important advancements in the treatment of malaria since the isolation of quinine in 1820. Quinine is a natural compound found in the bark of South American trees in the genus Cinchona (e.g., C. officinalis, Rubiaceae). These trees are native to the rainforests of the Andes Mountains, and extracts of their bark had been used to treat fevers caused by malaria at least as far back as 1632.2,5-7
Artemisinin derivatives are the most effective of all current antimalarial drugs.8 In April 2001, the World Health Organization (WHO), which directs and coordinates international health within the United Nations (UN) system, first recommended the use of artemisinin-based combination therapies (ACTs), which combine an artemisinin derivative with another, longer-lasting antimalarial drug.9 Since then, ACTs have saved millions of lives.10
History of Artemisinin
The discovery of artemisinin can be traced back to 1967, during the tumult of the Chinese Cultural Revolution, when many Western-trained Chinese scientists were being persecuted by the Communist Party. At the same time, the Vietnam War was escalating, and many North Vietnamese soldiers were falling victim to malaria that had developed resistance to chloroquine (a synthetic analog of quinine) and other drugs.1,11 Communist North Vietnam, an ally to China, asked for China’s help to find a new treatment for malaria, which was also afflicting many people in southern China, as well as thousands of American soldiers who were fighting against North Vietnam. (The US Department of Defense undertook its own drug hunt, which eventually produced mefloquine, another synthetic analog of quinine.)1,2,11
In response to North Vietnamese President Ho Chi Minh’s appeal, Chinese Premier Zhou Enlai and Chairman Mao Zedong set up a secret military project called Project 523 (because of its starting date, May 23, 1967) to find a solution. Progress was slow at first, despite the fact that the initiative reportedly involved the efforts of about 500 scientists working at about 60 laboratories and institutes in China.1,12 Though the project was kept covert, and some details of its history remain foggy even now, information flowed freely at joint meetings among the different research groups involved. Three new malaria treatments were produced by 1969.
Until the late 1960s, according to one source, the antimalarial remedy of choice in China, perhaps by default, was changshan. The term “changshan” generally refers to the root of Dichroa febrifuga (Hydrangeaceae), rather than to the complex mixture that traditionally contained the root as a central component. Changshan was mentioned in the Canon of the Divine Husbandman’s Materia Medica, which was written circa 200 CE, as a treatment for fevers. However, changshan has an intense emetic effect, which is compounded when the active alkaloids are used in isolation from the rest of the plant, and when the plant itself is used without the offsetting effects of the other ingredients traditionally used in the mixture (e.g., ginger [Zingiber officinale, Zingiberaceae], licorice [Glycyrrhiza glabra, Fabaceae], and betel nut [Areca catechu, Arecaceae]). This effect led to the eventual disuse of drugs derived from the root, and perhaps further necessitated the finding of a new, more palatable treatment option.13
Tu, who graduated from the Beijing Medical University School of Pharmacy in 1955 (she has no postgraduate degree or research experience abroad, neither of which was possible during the Cultural Revolution), did not become involved with Project 523 until January 21, 1969 when she was sent to Hainan Island off the southern coast of mainland China. Tu, 38 at the time, was working at the Academy of Traditional Chinese Medicine in Beijing when she was given the daunting task of searching nature for a new malaria treatment.
“The work was the top priority so I was certainly willing to sacrifice my personal life,” Tu told New Scientist in 2011. While on the island, Tu observed firsthand the toll malaria was taking on the population, and this was the beginning of a decade of work.1,10 “I saw a lot of children who were in the latest stages of malaria,” she said. “Those kids died very quickly.”
Tu also visited TCM practitioners across China and compiled a notebook: “A Collection of Single Practical Prescriptions for Anti-Malaria.”1 Back in Beijing, Tu and her team investigated more than 2,000 traditional Chinese herbal preparations.10 According to a 2011 written account by Tu, her team “identified 640 hits that had possible antimalarial activities. More than 380 extracts obtained from [about] 200 Chinese herbs were evaluated against a mouse model of malaria. However, progress was not smooth, and no significant results emerged easily.”29
According to the same account, the turning point came when an extract of A. annua, or qinghao, initially “showed a promising degree of inhibition against parasite growth.” But this observation was not reproducible in subsequent experiments. Tu and her team scoured the TCM literature looking for a possible explanation and found one in physician Ge Hong’s medical text A Handbook of Prescriptions for Emergencies, which was written circa 340 CE (some sources say the text is called Emergency Prescriptions Kept Up One’s Sleeve).29,30 One passage in the text described a method of preparing qinghao to be used for the treatment of “intermittent fevers,” one of the most telltale symptoms of malaria. The passage reads: “qinghao, one bunch, take two sheng of water [about two liters] for soaking it, wring it out, take the juice, ingest it in its entirety.”30
Interestingly, the text 52 Prescriptions contains the earliest known mention of qinghao being used as a treatment, but in this case for hemorrhoids. The text was compiled sometime between 1065 and 771 BCE, but it was sealed in a tomb in 168 BCE and was not discovered until 1973 (shortly after artemisinin was discovered), during the excavation of the Mawangdui archeological site in Changsha, Hunan, China.8,31 The earliest known mention of qinghao being used to treat a disease resembling malaria is contained in Zhang Ji’s text On Cold Damage, which dates to about the second century CE. The text recommends treating “fevers with sweating and jaundice” with a mixture containing boiled qinghao.8
Ge’s instructions to take a juice wrung out of the entire fresh plant (rather than an herbal tea prepared by pouring hot water onto dried plant material) probably resulted in an emulsion of water, flavonoids, and aromatic oils, with higher quantities of artemisinin than some other methods recorded in the Chinese literature.30 These instructions also gave Tu the idea that the heating involved with their original extraction method was probably destroying the primary active components of the plant.29,30 “Indeed, we obtained much better activity after switching to a lower temperature procedure,” Tu wrote.29 This method was similar to the method Ge described, but involved diethyl ether as the solvent.30 Organic solvents (i.e., solvents that contain carbon), such as diethyl ether, generally are better-suited for extracting hydrophobic compounds (i.e., compounds that are not soluble in water), such as artemisinin. Diethyl ether, however, is highly flammable.32
Tu wrote that they separated the extract into its acidic and neutral portions, and that, on October 4, 1971, they obtained a nontoxic, neutral (pH of 7) extract that proved to be 100% effective when administered orally to mice that had malaria caused by parasites of the species Plasmodium berghei and monkeys with malaria caused by P. cynomolgi.
“During the Cultural Revolution, there were no practical ways to perform clinical trials of new drugs. So, in order to help patients with malaria, my colleagues and I bravely volunteered to be the first people to take the extract,” Tu wrote. After personally confirming the safety of the extract, Tu went back to Hainan Island with her team to test its efficacy in patients infected with both P. vivax and P. falciparum. “These clinical trials produced encouraging results: patients treated with the extract experienced rapid disappearance of symptoms — namely fever and number of parasites in the blood — whereas patients receiving chloroquine did not,” she wrote.29
“We had just cured drug-resistant malaria,” Tu told New Scientist. “We were very excited.”1
In 1972, Tu and her team identified a colorless, crystalline substance as the active component of the extract, and named it qinghaosu (artemisinin).29 Artemisinin, whose structure was determined in 1975, is most abundant in the leaves of A. annua, but the compound has also been found in other species of Artemisia: A. apiacea and A. lancea, and in small quantities in A. sieberi and A. scoparia.30,33 In fact, in polymath Shen Gua’s Dream Pool Essays, written in 1086 CE, it is suggested that A. apiacea, not A. annua, was the species the Chinese literature intended when referring to qinghao. A passage in the text reads: “In the depth of autumn, when the other hao are yellow, this one [A. apiacea] alone is blue-green; its smell is quite aromatic. I guess [this is] the one the ancients used, they considered this one the preferred one.” For this reason, it has been suggested that the name qinghao (“blue-green hao”) should be reserved for A. apiacea and that huanghauhao (“yellow blossom hao”) should be reserved for A. annua.34 (Other species in the genus Artemisia have historically been used to treat malaria, including but not limited to A. absinthium and A. abrotanum in Europe, A. afra in Africa, and A. argyi in China.35)
In 1973, artemisinin was altered to produce the semisynthetic derivative dihydroartemisinin (DHA), from which other important and widely used derivatives are produced, such as artesunate and artemether. “During evaluation of the artemisinin compounds, we found that dihydroartemisinin was more stable and ten times more effective than artemisinin,” Tu wrote. “More importantly, there was much less disease recurrence during treatment with this derivative.”29 Furthermore, unlike artemisinin, DHA is water soluble.30
Solubility is an important property of drugs, and one that often poses challenges to drug formulators. Drugs that are hydrophobic have a low dissolution rate in the aqueous gastrointestinal fluids when administered orally, resulting in reduced bioavailability (the proportion of the administered amount of a drug that is available at the site of physiological activity).36 On the other hand, drugs that are extremely hydrophilic also are poorly absorbed because they are unable to cross lipid-rich cell membranes.37
In the 1980s, several thousand patients in China were successfully treated with artemisinin and its derivatives, and news of their efficacy attracted worldwide attention.29,38 However, the WHO would not recommend the use of ACTs until April 2001, almost 30 years after artemisinin was identified. This hampered the efforts of aid agencies, which could not buy drugs that were not approved by the WHO. Even after the WHO’s recommendation, the drugs would not become widely available until 2006, according to The New York Times.2,9
There were several reasons for this delay. China’s isolationism certainly played a role. In addition, under communism, patent law was nonexistent in China, and the country took out no Western patents. This meant that anyone could use artemisinin, which prevented pharmaceutical companies from being able to exclusively produce and market the drug. There was also some general skepticism about artemisinin, as there is with most new drugs. Whatever the reasons, hundreds of thousands of African children were dying each year as artemisinin idled, causing some to call the delay “genocidal.”2
The case of artemisinin exemplifies how complex legal, economic, and political landscapes can impede drugs from coming to market. It may also signal the need to minimize these barriers to entry to allow people to receive the care they need.
Lasker-Debakey Award and Nobel Prize
In 2011, the prestigious Lasker-Debakey Clinical Medical Research Award was given to Tu by the Lasker Foundation, which celebrates “the contributions of scientists, clinicians, and public servants who have made major advances in the understanding, diagnosis, treatment, cure, or prevention of human disease.”2,39 The Foundation named Tu “the discoverer of artemisinin,” which caused controversy in the scientific community. Some said it was unfair to credit the discovery to one individual, and named others they thought were equally deserving, but Tu is widely credited with having had a major hand in almost all of the events that led to the discovery.
This controversy resurfaced in October 2015 when it was announced she would be awarded part of the Nobel Prize in Physiology or Medicine. Tu, who, because of the nonexistent patent laws in China at the time, has never financially benefitted from the commercial use of artemisinin, said in a 2007 interview, “I do not want fame. In our day, no essay was published under the author’s byline.”10,40 In fact, Tu was one of four anonymous authors of the original 1977 paper on artemisinin.2
Shortly before accepting the Nobel Prize in December 2015 in Stockholm, Sweden, Tu, 84 at the time, responded to the controversy in an interview with The New York Times: “Everyone is entitled to his opinion. We all believed in collectivism. All I wanted was to do good work at my job. Of course, I’d be nothing without my team. Foreign countries, like the United States, care a lot about which individual should claim credit. Foreigners read historical records and picked me. Chinese awards are always given to teams, but foreign awards are different. This honor belongs to me, my team, and the entire nation,” she said.40
In a different New York Times article, Tu is quoted as saying, “Artemisinin is a gift for the world people from the traditional Chinese medicine.”41
Chemistry of Artemisinin and Its Derivatives
Artemisinin belongs to a class of compounds known as sesquiterpene lactones, which contain 15 carbon atoms (three isoprene units with five carbon atoms each) and a lactone ring.
“Sesquiterpene lactones come in different types of classes, with the class also defining the stereochemistry of the molecules [i.e., the relative spatial arrangement of atoms within the molecules],” said Eloy Rodriguez, PhD, the James A. Perkins Endowed Professor of Environmental Toxicology and Medical Ethnopharmacognosy at Cornell University and member of ABC’s Advisory Board (oral communication, February 24, 2016). Rodriguez is an expert on this class of compounds, and has identified 30 or 40 novel structures with his colleagues and students. “Stereochemistry is very important in biological activity. … The degree of oxygenation, or the degree of oxygens in the molecule, is [also] very important in determining biological activity,” he said. He also said that these compounds rarely contain nitrogen or chlorine and that they tend not to affect the central nervous system.
“[Sesquiterpene lactones have] been around for hundreds of millions of years,” Rodriguez said. “And what makes the sunflower [Asteraceae] family so unique is the fact that it makes this incredible array of sesquiterpene lactones.”
With more than 5,000 structures identified to date, sesquiterpene lactones are probably the largest class of secondary metabolites found in plants. These compounds display a wide range of biological activities, including antitumor, anti-inflammatory, analgesic, antiulcer, antibacterial, antiviral, antifungal, insect deterrent, and, of course, antiparasitic.33
“These molecules evolved primarily as a defense, as insecticide, as repellent, against herbivores, things that like to eat plants, or like to infect plants, such as bacteria, fungi. So, these molecules, not only did they evolve, effectively, to knock out enzymes in insects and other predators, it’s not surprising that [some] also have the same effect against Plasmodium, because, as far as the molecule is concerned, Plasmodium is just one big caterpillar inside of your body. It kills it the way it would kill a caterpillar,” Rodriguez said.
According to one source, artemisinin and its derivatives are the most potent and rapidly acting antimalarial drugs ever discovered.35 They are highly active against and most commonly used for infections of P. falciparum, the deadliest species in humans, but some sources suggest they work as well, if not better, against P. vivax, the most geographically widespread species.42,43 These drugs, however, do not affect all stages of the parasite’s life cycle equally. They are inactive against the pre-liver stage (sporozoites) and liver stages. (Since symptoms do not manifest until the blood stages, diagnosis at this point is seemingly impossible anyway). In fact, they are inactive against all extra-erythrocytic forms, which also includes merozoites. Late-stage ring parasites and trophozoites are generally more vulnerable to artemisinin and its derivatives than are schizonts or small rings.43,44
The inhibitory effects of artemisinin and its derivatives against trophozoites prevent the progression of the disease and reduce the formation of gametocytes, the dormant sexual forms of the parasite.45 This is important because eliminating gametocytes in the human host prevents the parasite’s life cycle from restarting in the mosquito host, in the event that a female mosquito in the genus Anopheles were to take a blood meal from the infected human. Stage specificity is an important consideration with antimalarial drugs, especially for patients with severe malaria. Since severe malaria is usually fatal within 48 hours after symptoms present (i.e., the time it takes P. falciparum, P. vivax, and P. ovale to complete one asexual multiplication cycle within an infected erythrocyte), it is mainly the parasites present at the time the patient presents for medical care that will determine whether the patient lives or not.46
Artemisinin and its derivatives are safe and well-tolerated. Some reported adverse effects include mild gastrointestinal disturbances, dizziness, tinnitus (ringing in the ears), and bradycardia (slow heart rate).42 The greatest concern regarding these drugs is the neurotoxicity that has been reported in some animal studies.45
It should be noted that artemisinin itself is not used as a component in any of the five current WHO-recommended ACTs. This is primarily because of its poor solubility in both water and oil, and because of its poor bioavailability. DHA, artesunate, and artemether are all more potent and have greater oral bioavailability (> 60%) than artemisinin.33,42 Furthermore, since artesunate is more water soluble than other artemisinin derivatives, it can be administered effectively intravenously. It can also be given orally, rectally, or intramuscularly. Since artemether is lipid soluble, it can be administered effectively intramuscularly or orally. Non-oral (i.e., parenteral) administration is often necessary for patients with severe malaria, because they are often unconscious or too ill to swallow.35
DHA is two- to threefold more active than artemether. Artemether, however, is metabolized back to DHA in varying amounts in vivo, depending on the route of administration used. The same is true for artesunate, which is preferred over artemether in the treatment of severe malaria. This is partly because after intramuscular injection, artemether is often absorbed more slowly and erratically than artesunate, which is absorbed quickly and reliably.47
Artemisinin and its derivatives also have potent anticancer effects. They have been shown to target a wide variety of cancer cells (including leukemia, breast, colon, prostate, pancreas, ovarian, hepatic, renal, melanoma, osteosarcoma, central nervous system, and lung cancer cells), with almost no negative effects on healthy cells. In addition, DHA is active against other parasites, including Trichomonas vaginalis and Giardia lamblia, as well as against species of the genera Schistosoma, Toxoplasma, and Leishmania.33
Artemisinin-based Combination Therapies
ACTs combine DHA, artemether, or artesunate with another antimalarial drug that lasts longer and has a different mode of action. The artemisinin component rapidly clears the blood of the vast majority of parasites, while the partner drug eliminates the remaining parasites. ACTs are generally administered over a three-day treatment period.47
The three-day course covers two of the parasite’s 48-hour intra-erythrocytic asexual cycles.47 The artemisinin component alone reduces parasite numbers by about 10,000-fold in each cycle (compared to 100- to 1,000-fold for other antimalarial drugs35), ensuring that only a tiny fraction of the parasites (< 0.0001% of those present at the peak of the infection, according to one source42) remain for the slowly eliminated partner drug to clear. This reduces the potential for parasites to develop resistance to the partner drug, and the partner drug reciprocally reduces the potential for parasites to develop resistance to the artemisinin component.
ACTs are recommended by the WHO as first-line treatment for uncomplicated P. falciparum malaria.48 By April 2006, 60 countries had adopted ACTs into their national treatment policies, primarily as first-line treatment, and by the end of 2013, 79 countries had adopted them as first-line treatment policy.9 The WHO recommends treating P. vivax infections with chloroquine in areas where chloroquine is still effective. In areas with chloroquine-resistant P. vivax, ACTs should be used (except for pregnant women in their first trimester, who should be treated with quinine).47,48 In addition, adults and children with uncomplicated malaria caused by P. malariae, P. ovale, or P. knowlesi should be treated with either chloroquine (where effective) or an ACT.
For severe malaria, the WHO recommends treating adults and children with intravenous or intramuscular artesunate (or artemether, in preference to quinine, if parenteral artesunate is unavailable) for at least 24 hours. Once the patient is well enough to tolerate oral medication, treatment should be completed with an ACT for three days.47
According to the third edition of the WHO’s Guidelines for the Treatment of Malaria, all five recommended ACTs have been shown to result in cure rates of >95% in the absence of resistance.47 ACTs have also been reported to reduce malaria mortality by 20-30% overall.3 Additionally, for uncomplicated P. falciparum malaria, ACTs have been estimated to reduce mortality in children aged one to 23 months by 99% (of the total who received an ACT), and in children aged 24-59 months by 97%, according to the WHO’s World Malaria Report 2015. Furthermore, in sub-Saharan Africa, parasite prevalence among children aged two to 10 years is estimated to have decreased from 33% in 2000 to 16% in 2015, and ACTs are estimated to have been responsible for 14% of that reduction.17
Though the primary purpose of ACTs is to avert severe disease and death, prompt treatment can also reduce the incidence of uncomplicated cases. It is estimated that ACTs averted 139.23 million cases of malaria in sub-Saharan Africa between 2001 and 2015. It is also estimated that, in sub-Saharan Africa, ACTs saved the public sector about $156 million in health care costs between 2001 and 2014, based on the number of cases that are estimated to have been averted during that time period and the estimated number of those cases that would have sought care in the public sector.
From 2005 to 2014, the number of ACT treatment courses procured from manufacturers increased from 11 million to 337 million (almost a 3,000% increase). The WHO African region accounted for almost 98% of manufacturer deliveries of ACTs in 2014. Furthermore, in 2014, 223 million ACTs were delivered by manufacturers to the public sector and 169 million ACTs (about 50% of those procured) were distributed by national malaria control programs (NMCPs; i.e., domestic funding mechanisms) through public sector facilities. International sources (including aid organizations like the Global Fund to Fight AIDS, Tuberculosis and Malaria; The United States President’s Malaria Initiative; The World Bank; and UNICEF) spent $403 million on ACTs in 2014.
There are at least three main reasons artemisinin derivatives are combined with partner drugs. First, though they are the most effective of all antimalarials, they are the most rapidly eliminated, with half-lives (i.e., the time it takes for half of the administered amount of a drug to be eliminated from the bloodstream) on the order of one hour.42 “You don’t need a long life for it to work,” Rodriguez said. According to him, predators trying to consume the sweet wormwood plant would have almost immediately been met head-on by artemisinin. “I don’t think [the plant is] going to put that much energy into making a molecule that’s going to be as solid as a rock,” he said. That being said, it is estimated that for a three-day combination treatment course, the half-life of at least one component should exceed 24 hours. Piperaquine, for example, which is combined with DHA, has an estimated half-life of two to three weeks.42
Second, artemisinin derivatives, when used as monotherapy (i.e., without a partner drug), have relatively high recrudescence (i.e., relapse) rates of about 10%, and they need to be administered over about seven days for radical cure.8
Third, combination therapies prevent the development of resistance. “It’s kind of difficult to develop resistance to multiple weapons, compared to one,” Rodriguez said. “That’s always been my argument why, in the long run, plant-derived mixtures work. The plant mixture might not be 100% effective, like a pure compound, but it will be more difficult for bacteria or parasites to develop resistance over a short period of time to a mixture.”
For this reason, the WHO vehemently discourages the use of artemisinin monotherapies. In January 2006, the WHO issued a press release urging pharmaceutical companies to stop marketing and selling monotherapies. The press release cautioned that once-popular antimalarials, including chloroquine and sulfadoxine-pyrimethamine, became widely ineffective due to the development of resistance.49
“Our biggest concern right now is to treat patients with safe and effective medication and to avoid the emergence of drug resistance. If we lose ACTs, we’ll no longer have a cure for malaria, and it will probably be at least ten years before a new one can be discovered,” Arata Kochi, PhD, the former director of the WHO’s malaria department, is quoted as saying in the press release. (That was 10 years ago, and nothing more effective than ACTs has become available.)
By 2015, artemisinin-resistant P. falciparum had been identified in Cambodia, Laos, Myanmar, Thailand, and Vietnam.17 According to Rodriguez, that’s not too surprising. “Some of them [the parasites] probably already were resistant to it, but as more and more of the resistant strains take over the population, then you have resistance,” he said. “[Plasmodium] is in a battle, and it wants to live too. It doesn’t want to die, so resistance is going to be around forever.” Encouragingly, as of November 2015, of the 78 national health authorities that need ACTs, 49 have taken regulatory measures to withdraw the marketing authorization of oral monotherapies and 22 have never registered them, leaving just seven that still allow the marketing of these therapies.50
The five current WHO-recommended ACTs are artemether/lumefantrine, artesunate/amodiaquine, artesunate/mefloquine, DHA/piperaquine, and artesunate/sulfadoxine-pyrimethamine.47 Artemether/lumefantrine, known as Coartem (Novartis; Basel, Switzerland), was the first ACT and the one that finally got the ball rolling in terms of making these drugs broadly available.2
Factors to be taken into consideration when choosing the appropriate ACT include local data on the efficacy of the ACT, local data on drug resistance, the adverse effects of the partner drug, availability, and cost.47
As with other medicines derived from natural sources, there are challenges related to the sustainable supply of artemisinin. First, A. annua generally yields low quantities (between 0.01% and 0.80%) of the compound.51 Plants yielding higher quantities are chosen for cultivation, but large amounts of dried plant material still are required for relatively small amounts of artemisinin.
Long lead times also contribute to the challenge. Artemisia annua takes about eight months to reach full growth, at which point leaves are harvested and sent to extraction facilities that usually rely on large numbers of small farmers for their supply. In the past, China and Vietnam have accounted for about 80% of the harvest volume of A. annua, while East Africa has accounted for about 20%. After extraction, artemisinin is sent to specialized manufacturers (sometimes the manufacturer of the finished product) to be converted into its derivatives, and then the finished drug product is produced. The entire process, from the planting of the seed to the finished product, takes about 14 months.52
The supply of artemisinin has been erratic over the years. During shortages, prices skyrocket, which causes more farmers to grow A. annua, and then the supply increases greatly, depressing prices and causing another shortage.53 Consequently, artemisinin prices have fluctuated drastically, but there has been an overall downward trend over time. Prices ranged from $800-$1,100 per kilogram ($363-$499 per pound) in 2005, and from $270-$350 per kilogram ($122-$159 per pound) in 2013.54
From 2013 to 2014, the total number of ACT treatment courses procured from manufacturers actually decreased from 392 million to 337 million.17,55 This is partially because of increased efforts to diagnose malaria before administering ACTs. In the past, patients with fevers were often treated with ACTs without being diagnosed with malaria. Many of them did not actually have the disease.53 In fact, in sub-Saharan Africa, the number of diagnostic tests provided is now greater than the number of ACTs distributed. This was not previously the case. Despite the decrease in demand for ACTs from 2013 to 2014, between 68 and 80 million (74-87%) of the 92 million children with malaria in sub-Saharan Africa did not receive an ACT in 2014, so there is a need to increase availability of the drugs.17
Artemisia annua is not the only viable source of artemisinin. In 2004, the Bill and Melinda Gates Foundation helped fund the development of a semisynthetic process of producing the compound. The Foundation’s goal was to stabilize the supply of artemisinin and lower the cost of each ACT treatment from $2.40 to “well under a dollar.”53 The method that was eventually developed involves genetically modified yeast, which first converts glucose into artemisinic acid, a precursor to artemisinin. Then, a process using light converts the acid into artemisinin. French pharmaceutical company Sanofi has the capacity to produce between 50 and 60 tons of semisynthetic artemisinin per year using this method. That’s enough to produce 125 million treatments.54 In addition, this method drastically reduces the lead time to just a few days.52
However, partially because of a plentiful supply and low prices of A. annua, Sanofi reportedly produced no artemisinin using this method in 2015, and plans to sell its manufacturing facility.53 Despite this, the potential to quickly produce high-quality artemisinin that is not subject to seasonal and other growing conditions and that is comparable in cost to naturally-occurring artemisinin does exist.54
The discovery of artemisinin by Tu Youyou and her team would seem to validate that the ethnobotanical approach to drug discovery can be successful. In this case, extensive study of the TCM literature helped produce the most effective drugs ever discovered for treating one of the most devastating diseases in history: malaria.
“The ethnobotanical and ethnomedical roots of the development of artemisinin demonstrate, beyond a doubt, both the profound history of traditional medicine and the interface of traditional medicine and contemporary Western scientific drug development,” said Steven King, PhD, senior vice president of ethnobotanical research and sustainable supply at Jaguar Animal Health and member of ABC’s Advisory Board (email, April 12, 2016).
King also said that artemisinin “indicates that careful attention to the ethnobotanical detail of how plant medicines are prepared can make all the difference in discovering bioactive molecules that can become important therapies for global public health. … If [Tu and her team] had not carefully studied the ethnobotanical information, they might have given up on this plant and preparation.”
Beginning in the 1990s, when King was at Shaman Pharmaceuticals Inc., he was part of a group that looked for new drugs based on an ethnobotanical approach. Those efforts eventually produced crofelemer, a natural compound isolated from the red latex of the South American tree sangre de grado (dragon’s blood; Croton lechleri, Euphorbiaceae).56 In 2012, crofelemer (trade name Fulyzaq) became the second botanical, and the first orally administered botanical, to receive drug approval from the US Food and Drug Administration (FDA). The drug is used to treat HIV-associated diarrhea, and it demonstrates that, even decades after the discovery of artemisinin, plants and other natural sources should still be considered viable leads for new and effective drugs.
“The global large- and small-scale pharmaceutical research approach has shifted away from natural products and ethnobotanical information over the past 30 years, focusing rather on high throughput screening, genomics, and related approaches,” King said. The most often mentioned reason for this shift, according to King, is that the chemical diversity found in plants has been explored and hasn’t produced any new therapeutics. “This is not, by any means, fully accurate, but microorganisms, marine compounds, and extremophiles (organisms that thrive in extreme environments, such as hydrothermal vents in ocean trenches) continue to be of interest in the search for new drugs. It would be a wise idea to integrate the wisdom of traditional medicine with the latest advances in drug discovery and development. There are so many examples of new applications for ethnobotanically-derived therapeutics,” he said.
According to King, the Nobel Prize reinforces “that plant medicine has been, and continues to be, a critical part of the global management of human health. A plant-based medicine does not have to become, or lead to, a new drug to demonstrate its utility to human and animal health. … Plants as medicines are part of the foundation of human health care worldwide, and will become more so in the 21st century.”
He also said that the Nobel Assembly’s recognition of Tu Youyou and artemisinin, as well as its recognition of avermectin, is “timely and symptomatic of a scientific community that is hopefully becoming more holistic and integrated.”
SIDEBAR In-Depth: Malaria
Malaria, sometimes called the scourge of the tropics, has probably existed for hundreds of thousands of years, likely predating modern humans.2,14 It is thought that the first vertebrate hosts of the disease were reptiles.
In 400 BCE, long before the term “malaria” was coined, Hippocrates wrote about the disease in his treatise On Airs, Waters, and Places.15 And long before that, a Chinese medical text, The Canon of Medicine, from 2700 BCE, described several characteristic symptoms of malaria.16 It was not until 1880 that French army surgeon Charles Louis Alphonse Laveran discovered the parasites that cause the disease in the blood of a patient. For his discovery, Laveran was awarded the Nobel Prize in Physiology or Medicine in 1907.
The term “malaria” is derived from the Italian mal’aria, a contracted form of mala aria, meaning “bad air,” because the disease was once thought to be caused by the foul, vaporous air of marshy areas. The term is thought to have first been used by Italian historian Leonardo Bruni (circa 1370-1444).15
According to the WHO’s World Malaria Report 2015, there were 95 countries and territories with ongoing malaria transmission in 2015. This includes almost all of Africa, almost all of the Middle East, almost all of Central and South America, and most of Asia and Southeast Asia.17 Malaria was eliminated from the United States in the early 1950s.18
In 2015, there were about 214 million cases of malaria, an 18% decline from 2000 when there were about 262 million cases. About 88% of the cases in 2015 occurred in the WHO African region. In 2015, there were about 438,000 deaths from malaria (an average of 1,200 deaths per day), a 48% decline from 2000 when there were about 839,000 deaths. About 90% of the deaths in 2015 occurred in the WHO African region. In 2015 about 306,000 deaths (70% of the total) were in children under five years old. About 95% of these deaths occurred in the WHO African region.17
Malaria in humans is caused by five protozoan species in the genus Plasmodium: P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi (though it has been shown that P. knowlesi is not spread from human to human like the other four species, but occurs when a mosquito becomes infected after biting an infected monkey and then infects a human [zoonotic transmission]).17 These primitive, unicellular protozoa are eukaryotic, meaning that unlike bacteria, which are prokaryotic, they contain membrane-bound organelles (e.g., a nucleus). And unlike viruses, which consist of genetic material encapsulated in protein and are smaller than single cells, these ancient, animal-like protozoa are considered living.19,20
The life cycle of malaria parasites is fairly complex, and can be divided into two main phases: the asexual cycle in humans and the sexual cycle in female mosquitoes of the genus Anopheles. There are about 400 species in this genus, but only 30 are significant to the transmission of malaria.17, 21-24 When an infected female, acting as a “vector,” bites a human, it injects saliva to prevent the blood from clotting. From the mosquito’s saliva, the parasites (called sporozoites at this stage) move into the bloodstream, and, within about 30 or 40 minutes, make their way to the liver, part of the body’s blood filter system, where they invade liver cells (hepatocytes).
Over the next 6 to 15 days, the parasites undergo asexual multiplication, copying their DNA over and over again. A single parasite can multiply thousands of times in a single hepatocyte. The specific molecular mechanisms that facilitate sporozoite selection and infection of hepatocytes are not fully understood, but the parasites avoid being overcome by white blood cells (leukocytes) and mature into schizonts in this environment. The schizonts then rupture and release daughter cells called merozoites, which are modified to infect red blood cells (erythrocytes). In P. vivax and P. ovale, a dormant liver stage (hypnozoites) can remain in the liver and cause relapse weeks, or even years, later, when they enter the bloodstream.
After infecting the erythrocytes, the parasites become young trophozoites (this is called the ring stage because of the parasite’s morphology at this point). This is the stage during which the parasite is absorbing nutrients from the host. As the parasite gets larger, the ring shape disappears, and the parasite is then known as a trophozoite. The trophozoites then undergo another round of asexual multiplication and develop into schizonts. The infected erythrocytes then burst and release the merozoites, which can then infect new erythrocytes and restart the process, or, inexplicably, develop into gametocytes (a dormant sexual stage).
When a female Anopheles mosquito takes a blood meal from an infected person, it becomes infected. Ingested parasites other than the gametocytes are digested in the stomach of the mosquito, but the gametocytes mature into male and female gametes. Male gametes fertilize female gametes, forming zygotes, which develop into actively moving ookinetes that migrate to the outer lining of the mosquito’s stomach, where they form cysts. Each cyst produces thousands of sporozoites that then infest the mosquito’s salivary glands, thus starting the life cycle over again.
Plasmodium falciparum is the species responsible for the majority of malaria deaths.17 It typically has a shorter incubation period (the time before the first symptoms present), can multiply rapidly in the blood, and causes severe malaria at least partially by a property not shared by the other four species that cause the disease in humans: sequestration, in which infected erythrocytes stick to the endothelial cells of blood vessels, causing obstruction of the microcirculation and the dysfunction of organs, typically the brain in cerebral malaria.25-27Plasmodium vivax, however, is more widespread geographically than P. falciparum because it can develop in the mosquito host at lower temperatures and higher altitudes.17
It is important to note that blood stage parasites are responsible for the symptoms of malaria.23 Symptoms of uncomplicated malaria include fever, chills, general malaise, sweats, headaches, nausea and vomiting, body aches, increased respiratory rate, weakness, enlarged spleen, enlarged liver, and mild jaundice. Symptoms of severe malaria include cerebral malaria (which can cause impaired consciousness, seizures, coma, etc.), severe anemia, hemoglobinuria (hemoglobin in the urine), acute respiratory distress syndrome (ARDS), low blood pressure, acute kidney failure, excessive acidity in the blood and tissue fluids, and hypoglycemia (low blood glucose).28
Artemisinin: Mechanisms of Action
It is believed that artemisinin’s effectiveness is due largely to its unique endoperoxide bridge (i.e., two bonded oxygen atoms between two carbon atoms; C-O-O-C), which is contained within a six-membered ring. “The oxygen-oxygen bond in the endoperoxide bridge is somewhat stable, but not as strong as a carbon-carbon bond. Nonetheless, the endoperoxide bridge in artemisinin is very active when broken,” said Rodriguez. It is worth noting that artemisinin derivatives that lack this feature show no antimalarial activity.44
It is also believed that heme* is responsible for catalyzing the cleavage (breakage) of the endoperoxide bridge.44 During the trophozoite stage (the feeding stage) of the parasite’s life cycle (see previous sidebar), according to one estimate, P. falciparum ingests and digests about 70% of the hemoglobin (a protein that carries oxygen from the lungs to the body’s tissues) in an infected red blood cell (erythrocyte) in just a few hours. Hemoglobin is an important nutrient source for the parasite and enables its growth and maturation. As the parasite breaks down the hemoglobin, heme is released.57,58
When the endoperoxide bridge is cleaved in the presence of ferrous iron from heme, each of the previously bonded oxygen atoms retains one of the two previously shared electrons (i.e., homolytic fission) and becomes a free radical (a highly reactive, short-lived atom, or group of atoms, with one or more unpaired electrons).44,59 The unstable compound then damages the microorganelles and membranes of the parasite, as well as the infected erythrocyte, causing the host’s immune system to eliminate the infected erythrocyte. The theory that free radicals mediate the death of the parasites is supported by the fact that the presence of antioxidants (free radical scavengers) blocks the antimalarial effects of artemisinin.44
“You can imagine it like a dart sticking to a dartboard,” Rodriguez said. “In other words, the dartboard, in this case, could be a protein, an enzyme, and the dart is the small molecule that just jams that board, or that protein, and then it doesn’t function. … It’s always been a battle of small molecules against macromolecules.”
He proposed another explanation for artemisinin’s effectiveness. “We’ve done some preliminary, but unpublished, research in which we show that artemisinin is capable of cleaving DNA,” he said. “In other words, artemisinin can remove a proton or a hydrogen from DNA that can lead to the eventual breakdown of DNA. … If you have all these radicals just bombarding the DNA, it really messes it up.”
*Heme is a non-protein constituent of hemoglobin that contains, at its center, a ferrous iron atom (i.e., an iron atom with two more protons than electrons; Fe2+).
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- McNeil DG Jr. For Intrigue, Malaria Drug Gets the Prize. New York Times. January 16, 2012. Available at: www.nytimes.com/2012/01/17/health/for-intrigue-malaria-drug-artemisinin-gets-the-prize.html. Accessed February 25, 2016.
- The 2015 Nobel Prize in Physiology or Medicine. Nobel Prize website. October 5, 2015. Available at: www.nobelprize.org/nobel_prizes/medicine/laureates/2015/press.html. Accessed February 25, 2016.
- Johnson I. Nobel Renews Debate on Chinese Medicine. New York Times. October 10, 2015. Available at: www.nytimes.com/2015/10/11/world/asia/nobel-renews-debate-on-chinese-medicine.html?_r=0. Accessed February 25, 2016.
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