1、Tu Youyou For the discovery of artemisinin, a drug therapy for malaria that has saved millions of lives across the globe, especially in the developing world. The 2011 LaskerDeBakey Clinical Medical Research Award honors a scientist who discovered artemisinin and its utility for treating malaria. Tu
2、Youyou (China Academy of Chinese Medical Sciences, Beijing) developed a therapy that has saved millions of lives across the globe, especially in the developing world. An artemisinin-based drug combination is now the standard regimen for malaria, and the World Health Organization (WHO) lists artemisi
3、nin and related agents in its catalog of Essential Medicines. Each year, several hundred million people contract malaria. Without treatment, many more of them would die than do now. Tu led a team that transformed an ancient Chinese healing method into the most powerful antimalarial medicine currentl
4、y available. Malaria has devastated humans for millennia, and it continues to ravage civilizations across the planet. In 2008, the mosquito-borne parasites that cause the illness, Plasmodia, infected 247 million people and caused almost one million deaths. The ailment strikes children particularly h
5、ard, especially those in sub-Saharan Africa. It affects more than 100 countriesincluding those in Asia, Latin America, the Middle East, parts of Europeand travelers from everywhere. Symptoms include fever, headache, and vomiting; malaria can quickly become life-threatening by disrupting the blood su
6、pply to vital organs. Early diagnosis and treatment reduces disease incidence, prevents deaths, and cuts transmission. In the late 1950s, the WHO embarked on an ambitious project to eradicate malaria. After limited success, the disease rebounded in many places, due in part to the emergence of parasi
7、tes that resisted drugs such as chloroquine that had previously held the malady at bay. At the beginning of the Chinese Cultural Revolution, the Chinese government launched a secret military project that aimed to devise a remedy for the deadly scourge. China was particularly motivated to prevail ove
8、r malaria not only because it was a significant problem at home, but also because the Vietnamese government had asked for help. It was at war and the affliction was devastating its civilian and military populations. The covert operation, named Project 523 for the day it was announcedMay 23, 1967set
9、out to battle chloroquine-resistant malaria. The clandestine nature of the enterprise and the political climate created a situation in which few scientific papers concerning the project were published for many years, the earliest ones were not accessible to the international community, and many deta
10、ils about the endeavor are still shrouded in mystery. In early 1969, Tu was appointed head of the Project 523 research group at her institute, where practitioners of traditional medicine worked side by side with modern chemists, pharmacologists, and other scientists. In keeping with Mao Zedongs urgi
11、ngs to explore and further improve the great treasure house of traditional Chinese medicine, Tu combed ancient texts and folk remedies for possible leads. She collected 2000 candidate recipes, which she then winnowed. By 1971, her team had made 380 extracts from 200 herbs. The researchers then asses
12、sed whether these substances could clear Plasmodia from the bloodstream of mice infected with the parasite. One of the extracts looked particularly promising: Material from Qinghao (Artemisia annua L., or sweet wormwood) dramatically inhibited parasite growth in the animals. Such hopeful results, ho
13、wever, were not reproducible, so Tu dove back into the literature and scoured it for possible explanations. The first known medical description of Qinghao lies in a 2000-year-old document called 52 Prescriptions (168 BCE) that had been unearthed from a Mawangdui Han Dynasty tomb. It details the herb
14、s use for soothing hemorrhoids. Later texts also mention the plants curative powers. Tu discovered a passage in the Handbook of Prescriptions for Emergencies (340 CE) by Ge Hong that referenced Qinghaos malaria-healing capacity. It said Take a handful of Qinghao, soak in two liters of water, strain
15、the liquid, and drink. She realized that the standard procedure of boiling and high-temperature extraction could destroy the active ingredient. With this idea in mind, Tu redesigned the extraction process, performing it at low temperatures with ether as the solvent. She also removed a harmful acidic
16、 portion of the extract that did not contribute to antimalarial activity, tracked the material to the leaves rather than other parts of the plant, and figured out when to harvest the herb to maximize yields. These innovations boosted potency and slashed toxicity. At a March 1972 meeting of the Proje
17、ct 523 groups key participants, she reported that the neutral plant extract number 191obliterated Plasmodia in the blood of mice and monkeys. From branch to bedside Later that year, Tu and her team tested the substance on 21 people with malaria in the Hainan Province, an island off the southern coas
18、t of China. About half the patients were infected with Plasmodium falciparum, the deadliest of the microbial miscreants, and about half were infected with Plasmodium vivax, the most common cause of a disease variant that is characterized by recurring fevers. In both groups, fever disappeared rapidly
19、, as did blood-borne parasites. In the meantime, Tu started to home in on the active ingredient, using chromatography to separate the extracts components. On November 8, 1972, she and her colleagues obtained the pure substance. They named it Qinghaosu (literally, the principle of Qinghao) and it is
20、now commonly called artemisinin in the west. Tu and her colleagues subsequently determined that it had an unusual structure. It proved to be a sesquiterpene lactone with a peroxide group, a completely different kind of compound than any known antimalarial drug. Later studies would show that the pero
21、xide portion is essential for its lethal effects on the parasite. Subsequent clinical trials on 529 malaria cases confirmed that the crystal they had isolated delivers the antimalarial blow. Many scientists from other institutes then joined efforts to improve the extraction procedures and conduct cl
22、inical trials. The first English language report about artemisinin was in December 1979; as was customary at the time in China, the authors were anonymous. By that point, the China-wide Qinghaosu research group had given the substance to more than 2000 patients, some of whom had chloroquine-resistan
23、t P. falciparum malaria infections. In addition, the drug cured 131 of 141 individuals with cerebral malaria, a particularly severe form of the disease. Comparative studies on a small number of cases suggested that the drug acted more quickly than chloroquine did. The investigators reported no harmf
24、ul side effects. The paper drew international attention. In October 1981, the scientific working group on the chemotherapy of malaria, sponsored by the WHO, the World Bank, and United Nations Development Business, invited Tu to present her findings at its fourth meeting. Her talk evoked an enthusias
25、tic response. She told the audience not only about artemisinin, but also about some of its chemical derivatives. In 1973, as part of her structural studies, Tu had modified artemisinin to generate a compound called dihydroartemisinin. She later found that it delivers ten times more punch than artemi
26、sinin and that it reduces risk of disease recurrence. This compound provided the basis for other artemisinin-derived drugs. Starting in the mid 1970s, Guoqiao Li (Guangzhou College of Traditional Chinese Medicine) performed clinical trials with artemisinin and these substances. They all delivered mo
27、re therapeutic clout than did standard drugs such as chloroquine and quinine. The derivatives tend to hold up better than the parent compound in the body, and they form the foundation of todays therapies. In 1980, Keith Arnold (Roche Far East Research Foundation, Hong Kong) joined Lis enterprise and
28、 two years later, they published the first high-profile clinical trial of artemisinin in a peer-reviewed, western journal. The same group then conducted the first randomized studies that compared artemisinin alone with the known anti-malarial agents, mefloquine and Fansidar (sulfadoxine-pyrimethamin
29、e). Artemisinin enhanced effectiveness without adding side effects. Li, Arnold, and others subsequently showed that suppository forms of artemisinin and its derivatives are effective. This mode of drug delivery is especially important for babies and unconscious patients. Almost every new antimalaria
30、l drug has initially slashed incidence of the disease, and then the parasites stop succumbing to it. At that point, sickness and death rates climb again. Small pockets of resistance to artemisinin-based compounds have already cropped up in Western Cambodia. To avoid resistance, patients typically ta
31、ke two drugs that attack the parasite in different ways, and since 2006, the WHO has discouraged use of artemisinin compounds as solo therapies. The organization now recommends several combination treatments, each of which contain an artemisinin-based compound plus an unrelated chemical. In 2001, th
32、e WHO signed an agreement with Novartis, the manufacturer of one of these drug combinations, Coartem; it consists of artemether and lumefantrine, another antimalarial agent, which was originally synthesized by the Academy of Military Medical Sciences in Beijing. The company is supplying the drug at
33、no profit to public health systems of countries where the disease is endemic. To date, Novartis has provided more than 400 million Coartem treatments. Tu pioneered a new approach to malaria treatment that has benefited hundreds of millions of people and promises to benefit many times more. By applyi
34、ng modern techniques and rigor to a heritage provided by 5000 years of Chinese traditional practitioners, she has delivered its riches into the 21st century. By Evelyn Strauss 屠呦呦获Lasker临床研究奖2011年的LaskerDebakey临床成就奖颁给了一名中国女科学家，为了表彰其对青蒿素的发现和在治疗疟疾方面的杰出贡献，这名女科学家就是中国中医科学研究院的科学家屠呦呦。她所发现的疟疾治疗方法在全球，特别是发展中国
35、家，取得了巨大成功，挽救了数亿人的生命。现在基于青蒿素的药物制剂已经成为治疗疟疾的公认疗法，而且世界卫生组织已把青蒿素及其相关制剂列为“基本药品”。每年数千万人会感染疟疾，如果缺乏有效的治疗手段，其死亡率将远远超过现在的水平。而正是屠呦呦领导的团队成功地将中国传统的治疗方法转变成了治疗疟疾的最有效的药物。疟疾已经困扰了人类长达上千年，至今仍在整个地球上吞噬着生命。2008年，一种靠蚊虫传播的疟原虫感染了2.47亿人，最终造成近一百万人死亡。这种病对儿童的伤害更为严重，尤其是那些生长在撒哈拉以南非洲的孩子。疾病影响了一百多个国家，比如亚洲、南美洲、中东、欧洲部分地区、以及来自全球各地的旅行者。症
36、状包括发烧、头疼和呕吐；一旦疾病破坏了重要器官的血供，疟疾就能威胁到人们的生命了。所以早期的诊断和治疗能显著减少疾病的发生、降低死亡率、切断传染途径。在五十年代末，世界卫生组织决定着手根除疟疾的计划。虽然取得了一定的成效，但疟疾在很多地方又卷土重来，部分原因就是出现了具有抗药性的疟原虫，比如抵抗传统疟疾治疗药物氯喹的疟原虫。中国文化大革命初期，中国政府启动了一项秘密军事计划，目标就是解决这种致死性的疾病。中国政府之所以有如此大的决心不仅因为这是国内的一个重要问题，更因为越南政府也为此求助。处于战争时期，疾病不只会给平民也会给军队带来毁灭性打击。正因为如此，以日期命名的秘密行动“523计划”于1
37、967年5月23日正式启动，志在征服抗氯喹性疟疾。该计划的绝密性和特殊的政治环境造成多年内没有相关文献的报道，国际社会无法搜索到最早期的数据，甚至至今很多细节依然是迷。1969年年初，屠呦呦被指派为她所在研究所的“523计划”组的项目组长，该研究所有着传统药物研究者与现代化学家、药剂学家及其他学科科学家通力合作的学术环境。为了响应毛主席“全力探索和进一步开发传统中医宝贵财富”的指示，屠呦呦仔细整理了古老文献和民间偏方，从中整理出2000个备选方案。截至1971年，她的团队已经从200种植物中制备出380种提取物，然后由研究人员评估这些物质能否清除感染疟疾的小鼠血清中的疟原虫。其中一种提取物看起
38、来很有潜力：青蒿提取物被证明可以有效抑制寄生虫在动物体内的生长。但这充满希望的结果却没有很好的重复性，所以屠呦呦又重新查找文献，寻找可能的原因。目前已知的对于青蒿的首次医学记载出现在从马王堆汉代墓葬群出土的“52处方”，距今已有2000年的历史，其中记载了用青蒿治疗痔疮的具体用法。晚些年代的记载中也提到了这种植物的药用作用。屠呦呦从葛洪的应急处方中发现青蒿有治愈疟疾的能力，其中记载道“取少量青蒿，浸于2升水中，然后滤出液体，饮用”。她这才意识到之前用标准程序处理青蒿时的煮沸和高温提取工艺可能已经导致有效成分失活了。有了这个想法，屠呦呦改进了提取工艺，使之可以在低温和乙醚溶剂中进行。同时她还发现
39、提取物中的有害酸性物质主要来源于植物的叶子，所以她还设法找到了采摘植物的最佳时机以最大限度地减少副产物的产生。这些创新显著提高了药效，同时降低了毒性。1972年3月，在“523计划”核心成员的会议上，她正式汇报了这种中性植物提取物191号可以清除老鼠和猴子血液中的疟原虫。之后，屠呦呦和她的团队在海南省21名病人身上进行了这种提取物的临床试验。受试患者中，一半感染了最致命的变异微生物镰状疟原虫，另一半感染了间日疟原虫一种会导致反复发热的常见致死疾病。这两组患者经这种提取物治疗后，发烧症状迅速消失，血液中的疟原虫数量也大大减少。同时，屠呦呦尝试着利用色谱分离提取物中的各种组分，以确定这种活性物质的
40、具体结构。1972年11月8日，她和同事们终于得到了纯净物，并命名为青蒿素，西文名“arteminsinin”。他们发现青蒿素具有其特殊的结构含有过氧基团的倍半萜内酯，这与已知的抗疟疾药物的结构都有很大的区别。研究表明过氧基团正是杀灭寄生虫的关键成分。后续的529个疟疾临床试验证明，屠呦呦团队分离得到的晶体确实可以发挥抗疟疾的功效。于是，来自其他研究所的多名科学家也参与进来，继续改进提取工艺，并进行更多的临床试验。关于青蒿素的首次英文报道发表于1979年12月，不过正如当时中国的惯例，作者都是匿名的。文章发表时，青蒿素研究组已经给全国范围内的2000多个病人服用了该制剂，其中也包括感染了抗氯喹
41、性疟疾的病人。此外，该药物还治疗好了131名患有更严重的脑型疟疾患者，治愈率高达93%。小规模病例表明青蒿素的作用速度要明显快于氯喹。而且研究人员没有发现青蒿素有任何有害的副作用。这篇报道引起了国际社会的关注。1981年10月，一支由世界卫生组织、世界银行和联合国商业发展部门出资筹建的研究队伍拜访了屠呦呦，希望了解她研究的成果。屠呦呦不仅讲解了青蒿素，也提起到青蒿素其他的化学衍生物，她的讲述显然引起了研究团的浓厚兴趣。1973年，屠呦呦对青蒿素进行了化学修饰，得到了一种名为二氢青蒿素的化合物。她发现这种衍生物对疟疾的治疗效果要强10倍，而且降低了疾病复发的几率。这个化合物的发现为其他抗疟药物的
42、研制提供了坚实的基础。从七十年代中期开始，广州中医学院的李国桥教授开始了该化合物的临床试验，结果表明它比传统的抗疟药物氯喹和奎宁都有着更强的疗效。这种衍生物明显比其原药在体内的效果更显著，为今天的治疗手段奠定了基础。1980年，罗氏远东公司的Keith Arnold加入了此项研究。两年后，他们在世界知名杂志上发表了第一篇倍数瞩目的疟疾临床试验结果。同一个研究组随后又发表了青蒿素与其他两种抗疟药物甲氯喹和治疟宁的随机比较试验。研究均表明青蒿素在提高药效的同时降低了副作用。除了学术界，多个制药公司也证明了青蒿素及其衍生物的栓剂是有效的，这种药物递送方式对于婴儿和无自主能力的病人更是尤为重要。几乎每
43、种新型的抗疟药物都是在初期能够有效减少疾病发生率，然而随后疟原虫就产生了抗药性，于是患病率和致死率又迅速爬升。例如在柬埔寨，已经出现了少数对青蒿素药物具有抗性的疟原虫了。为了防止抗药性的产生，病人一般需要服用两种药物，分别通过不同的途径治疗疟疾。从2006起，世界卫生组织已经不建议青蒿素化合物作为单独的处方，而建议采用复合疗法，每一种复合疗法都由青蒿素化合物和另一种化学药物组成。2001年，世界卫生组织与诺华公司签订协议，同意生产其中一种处方药Coartem，包含青蒿素和苯芴醇，其中苯芴醇是另一种抗疟成分，由北京军医学院最先合成。在疟疾肆虐的国家，诺华公司零利润地向公共卫生体系提供青蒿素药物，至今为止，已经提供了多于4亿份Coartem处方药。到今天为止，屠呦呦发现的抗疟疗法已经挽救了数亿人的生命，而且还将造福更多的人。受益于当今社会的先进技术和中国五千年传承下来的经验，屠呦呦将这项宝贵的财富带到了二十一世纪，成为举世瞩目的伟大成就。6
