我国在砒霜治疗急性早幼粒型白血病方面的开创性研究 砒霜是中国古代传统的“毒物”。明代《本草纲目》记载了利用砒霜以毒攻毒的一些应用：“砒石解毒治壅（yōng）、烂肉，蚀瘀腐、瘰疬（luǒ lì）”。 二十世纪70年代开始，哈尔滨医学院第一附属医院借鉴民间方子，制备了含有由砒霜、氯化亚汞的“癌灵1号”注射液 。在临床实践中, 哈医大一院的医生们逐步发现“癌灵1号”可单独治疗白血病，且对急性早幼粒型白血病（Acute Promyelocytic Leukemia，APL）效果最好 。在90年代初，又去除了有毒副作用的氯化亚汞，明确指出砒霜（即三氧化二砷）是“癌灵1号”的有效成分，单独使用三氧化二砷（以下简称ATO）注射液即可治疗急性早幼粒白血病 。 1994-1996年，上海瑞金医院与哈医大一院展开合作研究，应用ATO治疗对反式维甲酸和化疗不敏感的APL病人，取得良好治疗效果 。相关研究结果发表在1997年的《Blood》杂志，引发国际关注。 中国的知识产权保护情况 1995年8月23日，哈尔滨医学院第一附属医院以张亭栋为发明人申请了中国专利，1999年8月11日拿到授权，专利号为ZL95108768.1 。该专利只有一个独立权利要求： “1.一种抗白血病、肝癌、淋巴瘤注射液，其组成包括：注射用水，其特征是：所述的注射用水中溶有三氧化二砷1-10克，氧化钠8克，共计1000毫升。” 这是一个典型的注射液组分专利。由于“癌灵”的成分早已公开，1995年专利的新颖性主要在于去除了轻粉（氯化亚汞）。该专利存在以下几点严重的缺陷： 1. 发明点遗漏 该专利所称的“注射用水”其实指的治疗药品的起始配制液，而并不是注射入人体时的组分浓度或治疗病人每日所需的剂量。这样的权利要求完全没有保护到这一科技成果的核心价值点，严重的影响了技术的价值。 2. 权利要求范围太窄 注射用水液组分保护范围狭窄，ATO或氯化钠的含量稍多或稍少于权利要求所述的范围，就可以轻易绕过该专利。如溶解0.5g ATO于1L水中配制起始溶液，稀释成最终注射液时稀释比例减半，也可以达到相同的效果而不侵权。 3. 权利要求没有上位 在权利要求中提到的适应症包括白血病、肝癌、淋巴瘤。一般情况下，专利中一种药物能治疗三种以上的肿瘤，原则上能拿到这种药物治疗所有肿瘤的权利要求。但是此专利中并没有对ATO适应症进行上位。更为重要的是，虽然李元善与张亭栋早在1988年就已经用ATO对白血病外的癌症进行了研究 ，但是该专利的实施例中完全没有提及ATO治疗肝癌、淋巴瘤的内容。因此，即使是ATO治疗肝癌、淋巴瘤的这两种适应症，被无效的风险也很高。 值得注意的是，1996年，张亭栋也在美国申请了专利，申请号08702011，并要求了中国的优先权，但是在美国审查并不顺利 。直至2004年4月11日，该专利终于在美国拿到授权，即US6720011 。美国专利的授权权利要求范围相较于中国专利没有实质性的突破。其权利要求1的范围与中国授权专利的主要区别在于：1.将中国专利的“注射用水中溶有三氧化二砷1-10克，氧化钠8克，共计1000毫升”换算成了组分百分比。2.药物的适应症仅针对白血病，去除了无实施例支持的肝癌与淋巴瘤适应症，3.增加了10%葡萄糖的组分。独立权利要求3保护的范围稍大，要求了0.1%-1% ATO溶液治疗白血病的用途。美国专利的权利要求依然存在重大缺陷，作为一个注射液组分的专利，只要求了稀释使用前的ATO起始配制液的浓度，没有要求最终注入人体的ATO浓度，也没有要求ATO治疗病人的日剂量，致使发明无法得到有效保护。2012年6月5日，这一专利在美国因不交专利费而无权。 美国的跟进研究和知识产权运作 1997年，美国Memorial Sloan-Kettering Cancer Center（以下简称SK中心）的Raymond P. Warrell, Jr.博士在获知中国这一科研成果后，迅速开始了对这一药物的布局。首先，他在美国组织了用ATO治疗了12例APL的1期临床试验，效果良好；随后组织了包括40个病人的多中心参与的2期临床试验，获得巨大成功 。 在美国的临床实验中所用剂量参考了中国的临床实验数据，后来由于受试病人中的儿童对固定剂量的ATO有强烈副作用反应，Raymond等根据病人体重进行了剂量改进，最终确定0.15mg/kg的ATO每日治疗剂量。据此，1997年11月10日，SK中心申请了ATO治疗白血病的剂量方面的临时专利，申请号60064655 。 SK中心的工作受到了资本的青睐，1997年3月，派拉蒙投资公司（Paramount Capital）出资成立了PolaRx Biopharmaceuticals Inc.（以下简称PolaRx公司）。公司的核心成员包括Raymond P. Warrell, Jr.博士与Fred Mermelstein博士这样精通的早期药物研发与专利布局的资深人士 。PolaRx公司成立之后，为了使得ATO能顺利上市，开展了一系列的知识产权运作。 首先， 1998年2月9日，PolaRx公司许可了SK中心的60064,655专利 。PolaRx公司许可SK中心的专利后，利用美国专利申请规则，多次提出continuation，至今在全球已经申请了54个同族专利，其中进入FDA Orange Book列表的专利有六个。这一系列专利要求了ATO按照体重使用的剂量每人每天0.15 mg/kg治疗APL的方法，并对ATO所治疗APL的具体表征、使用剂量微调、首次治疗范围、治疗周期等方面进行了详细的定义 。 1998年3月3日，凭借Raymond组织的ATO治疗APL的临床二期试验，PolaRx公司获得了美国孤儿药指定权（Orphan drug designation），编号97-1096 。所谓孤儿病，是指每百万人口中的患者少于1000人的罕见病。因为病人数量少，市场小，医药公司缺乏开发相关药物的热情。为了激励孤儿病药物开发，美国规定“在治疗孤儿病的任何药物问世后的7年之内，如果再出现治疗同一种病的其他新药，卫生部不对其发放许可证 。”因此PolaRx公司得到了ATO治疗APL除专利外的另一层保护。 接着，PolaRx公司许可了中国的两个专利。1999年5月24日，PolaRx公司通过Samuel Waxman Cancer Research Foundation（以下简称Waxman基金）许可获得了哈医大一院张亭栋在美专利，也就是ATO起始配置液的组分专利 。1998年8月5日，PolaRx公司又从北京人民医院血液病研究所获得了雄黄治疗血癌的专利的全球独占许可 。值得一提的是，从北京人民医院血液病研究所2002年《Blood》杂志发表的临床实验结果来看，雄黄治疗APL也具有很好疗效，而且相较ATO具有可口服、毒性低等优势 。很显然，PolaRx公司许可雄黄专利的目的是防止竞争产品上市、为ATO上市并取得垄断创造条件。在雄黄的许可合同中，由于中方缺乏对PolaRx公司的关键性约束条款，如缺乏产品开发时间和专利回收的约定，导致该专利被束之高阁，雪藏至今。 美国三氧化二砷药物Trisenox®上市 2000年3月，美国Cell Therapeutics的全资子公司CTI Technologies, Inc. (CTIT)并购PolaRx公司，总价5百万股（市价约3400万美元）+1400万美元+2%销售提成，获得TRISENOX的全球权利 。2000年9月25日，美国FDA批准Trisenox® 上市，现在售价约为300美元支天。而ARSENIC TRIOXIDE的orange book编号为N021248 。PolaRx公司作为一家仅成立3年的小微型公司，通过小规模的临床2期试验与知识产权运营，挣得了 超过4千8百万美元的收益 ，并创造在美从临床试验到药品上市只用30个月的行业纪录！ 值得注意的是，Trisenox®在销售中使用小安瓿（ampule），10mL一瓿，ATO浓度为 1 mg/mL。仅从专利角度，这一浓度落入了张亭栋专利中起始ATO 浓度1-10 mg/mL的保护范围。但奇怪的是，据知情人士透露，哈尔滨医学院第一附属医院最终没能获得药物在美国市场销售的相关收益。推测原因可能有以下几点： 1. 美方对ATO最终使用浓度进行了改进。Trisenox® 在ATO注入人体浓度上采用0.038-0.091 mg/ml。而张亭栋专利中1-10 mg/mL的保护范围仅是限定在起始安瓿的浓度，而没有在权利要求中明确表述最终施用的浓度，根据专利说明书能算出ATO最终滴注浓度为0.020 mg/mL 。 2. 张亭栋的专利在2000年Trisenox®上市时还没有在美国授权，2004年授权后也没有进入FDA orange book的列表。 3. 张亭栋专利的国外开发权首先被Waxman基金以极低的价格取得，后又被PolaRx转手获得，其中的许可合同条款很可能存在隐藏的不平等条款，规避了PolaRx公司的支付责任。 ATO药物虽然在美国、欧洲、日本等地相继上市，但没能在国际上为中国挣得应有的利益；而雄黄（四硫化四砷）治疗白血病的药物更是被完全雪藏，至今没有药品上市，中方自然也无法获得收益。 PolaRx公司目光长远的专利布局 在PolaRx公司成立之初，该公司即开始在 砷化物治疗肿瘤整个领域 进行布局。除了上述介绍的通过专利运作促使Trisenox®成功上市用于治疗白血病，PolaRx公司还持续进行砷化物治疗实体瘤领域的专利布局。 1997年10月15日，在没有开展任何实质性研究的情况下，PolaRx公司提出了砷化物治疗实体瘤的美国临时专利申请（Provisional patent application），一举抢占了该领域的优先权。利用美国continuation-in-part（CIP）的申请规则，不断分案，补充数据，获得了砷化物治疗多种实体瘤的专利，如今已经在世界各国申请了70个同族专利 。 值得注意的是，仅是在美国FDA clinical trials官方备案进行的砷化物治疗肿瘤的临床研究就多达121个。 PolaRx公司的专利作为基础专利，dominate了该领域，为其后续收益奠定了基础。 启示 由于缺乏知识产权质量管理与交易管理， 中国的医生与科学家们辛勤研究了30多年的伟大科技成果最终转化为了美国公司的经济利益 ，这一教训值得深思。经过这些年的发展，中国已经初步逐步具有了产生世界级科研成果的潜力，然而 知识产权管理和运作能力 依然落后、专业化国际化 人才 严重缺失。这一短板将严重影响我国科技成果的有效转化和国家竞争力的进一步提升，如不改善，将有更多的技术流失。 本文意在抛砖引玉，如有错漏之处请多批评指教。 附注：中国的三氧化二砷药品 1998年，哈尔滨医大药业有限公司成立。1999年，公司拿到生产批文：国药准字H19990191，商品名伊泰达。这一成果因还为效果突出被破格提升为二类中药。2008年，北京双鹭药业拿到生产批文。如今伊泰达国内售价在一支130-200元之间。具体用法为亚砷酸注射液(10mg)加入250～500ml生理盐水或5%葡萄糖溶液（0.020-0.038 mg/ml）中每日一次静脉滴注3～4h滴完 。 参考文献 1.张亭栋, et al., “癌灵注射液”治疗6例白血病初步临床观察. 黑龙江医药, 1973. 3 p. 66-67. 2.哈医大一院中医科 and 哈医大一院检验科, 癌灵1号注射液与辨证论治对17例白血病的疗效观察. 哈医大学报, 1974. 2 p. 25-30. 3.张亭栋 and 荣福祥, 癌灵一号注射液与辩证论治治疗急性粒细胞型白血病. 黑龙江医药, 1979. 4 p. 7-11. 4.孙鸿德, et al., 癌灵1号结合中医辨证治疗急性早幼粒白血病32例. 中国中西医结合杂志, 1992. 12 p. 170-171. 5.Shen, Z.-X., et al., Use of Arsenic Trioxide (As2O3) in the Treatment of Acute Promyelocytic Leukemia (APL) II. Clinical Efficacy and Pharmacokinetics in Patients. Blood, 1997. 89(9) p. 3354-3360. 6.张亭栋, 癌灵注射液, 1995, 哈尔滨医科大学附属第一医院 CN. 7.李元善, et al., 癌灵1号注射液对人肝癌细胞杀伤动力学研究. 肿瘤防治研究, 1988. 15 p. 1-3. 8.张鹏, 发现三氧化二砷的历史, 2013 sciencenet. 9.Zhang, T.-D., Injectable composition for cancer treatment, 1995 US. 10.Soignet, S.L., et al., Complete Remission after Treatment of Acute Promyelocytic Leukemia with Arsenic Trioxide. The New England Journal of Medicine, 1998. 33(19). 11.WARRELL, R.P., P.P. PANDOLFI, and J.L. GABRILOVE, Process for producing arsenic trioxide formulations and methods for treating cancer using arsenic trioxide or melarsoprol, 2003 US. 12.Raymond P. Warrell, Jr., M.D. Chairman and Chief Executive Officer. 2012; Available from http://relburn.com/raymond-warrell/ . 13.CELL THERAPEUTICS INC - 8-K - 20000125 - EXHIBIT_2, 2000, Cell Therapeutics, Inc. . 14.关注“罕见病”立法让“孤儿病”不孤独. 2012; Available from http://news.enorth.com.cn/system/2012/02/28/008747688.shtml . 15.王进, 我所了解的三氧化二砷注射液开发过程, 2011 sciencenet. 16.Lu, D., Arsenic sulfide compounds and derivatives thereof for the treatment of malignancies, 1998 US. 17.Lu, D.-P., et al., Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia a pilot report. Blood, 2002. 99(9) p. 3136-43. 18.Orange Book Approved Drug Products with Therapeutic Equivalence Evaluations. 2000; Available from http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=021248TABLE1=OB_Rx . 19.Trisenox Arsenic Trioxide Injection. 2006; Available from http://www.pharmapal.com/pdf/trisenox_pi.pdf . 20.ELLISON, R.M. and F.H. 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中药的科学研究丰碑英文版 New Drugs from Ancient Chinese Remedies: Unsung heroes in Unusual Times Yi Rao 1, * , Runhong Li 2 and Daqing Zhang 2 1 School of Life Sciences and 2 Health Sciences Center Peking University Beijing 100871 China * To whom correspondence should be addressed: yrao@pku.edu.cn Summary In the early 1970s, while most Chinese scientists struggled to survive the Cultural Revolution with no chance for research, two junior researchers, Youyou Tu and Tingdong Zhang, played key roles in discovering artemisinin as a novel antimalaria drug and arsenic trioxide as a new drug for leukemia, respectively. There is no shortage of twists and ironies in the history of these discoveries. One began with China’s efforts to help the North Vietnamese defend against the Americans, and the other with observing, modifying and improving the recipe of a countryside practitioner. Although their drugs have now saved many lives across the globe, Tu is considered controversial and Zhang essentially unknown. Relevant literature has been buried in internal files and obscure journals. Based on original documents, articles and interviews, we outline here the history of these discoveries. It has not escaped our attention that ancient and current Chinese literature as well as Chinese medical practices may contain jewels that remain to be re-discovered to benefit the rest of the world. Introduction Chinese medicines have been used for a long time in China, but have not been a major source of drugs for general use in other countries. Are Chinese medicines still helpful today or in the future? There are two opposite views, one believing that Chinese medicines are of little, if any, use today ； the other believing that Chinese medicines are useful, but they have to be used only as complex combinations whose effects should be judged by special criteria for Chinese medicines, but no by conventional science. These questions and debates can be addressed by our studies of the history of two lines of research: one on artemisinin and the other on arsenic trioxide. We show here that both drugs were uncovered by modern scientific approaches and tested by generally acceptable scientific standards. Furthermore, these drugs, by standing the test of time and saving human lives, have proven the value of chemically defined drugs from traditional remedies. We conclude that the discoveries of artemisinin and arsenic trioxide have established that Chinese medicines are still beneficial today and an ancient tradition has largely untapped potential to improve human health. Artemisinin and arsenic trioxide can be viewed as the most important discoveries from Chinese medicines in the last century. Although the Chinese government is investing heavily today in drug discoveries and many Chinese pharmaceutical companies are profiting from selling Chinese medicines, artemisinin and arsenic trioxide remain unsurpassed by chemicals from other Chinese medicines in their benefits to human health. Uncovering the history of these discoveries and recognizing Youyou Tu and Tingdong Zhang will not only do justice to the scientists, but also stimulate international interests in using traditional medicines to find chemically novel drugs and new applications of known chemicals. At a time when many Chinese pharmaceutical companies profit from chemically undefined combinations with vague disease targets and have not actively taken the proven track of artemisinin and arsenic trioxide to reveal the truly effective components for specific diseases, it will be a wakening call for them to put real efforts in understanding the relationships between chemical components in Chinese medicines and specific diseases. National and international efforts may take Chinese medicines to a new era and save more lives. Leading Characters Artemisinin was discovered in a large project called “Task 523” to find anti-malaria strategies and its major representative is Youyou Tu from the Institute of Chinese Meteria Medica at the China Academy of Traditional Chinese Medicine (now known as China Academy of Chinese Medical Sciences) in Beijing. The anti-leukemia effect of arsenic trioxide was discovered during research by individual scientists in a small group, with the major contribution from Tingdong Zhang of the First Affiliated Hospital of Harbin Medical University. Youyou Tu was born in 1930 and studied from 1951 to 1955 at the School of Pharmacy of Beijing Medical University (known now as Peking University Health Sciences Center). According to the practice of that time she was assigned a job upon graduation, to the China Academy of Traditional Chinese Medicine. With only an undergraduate degree, she was drafted in 1969 into the “Task 523” with colleagues from her institute. Tingdong Zhang was born in 1932 and graduated in the 1950s from Harbin Medical University, after studying the regular (Western) medicine. He took classes of traditional Chinese medicine in the 1960s. Their most important research was carried out in the early 1970s, under conditions unimaginable by today’s graduate students. Cultural Milieu of China in the Early 1970s Knowledge of the cultural milieu and working conditions in the early 1970s is necessary before we can understand the peculiar significance of discoveries related to artemisinin and arsenic trioxide. Social background is required so that one can understand why Youyou Tu and Tingdong Zhang, rather than senior scientists with Western training, were the ones who made the discoveries. This article will use Chinese Medical Theories （ CMT ） to describe what is generally called Traditional Chinese Medicine (TCM) and use Chinese Medicines （ CM) to describe drugs from traditional Chinese sources. These are different from the conventional translation because we believe that TCM has combined CMT and CM. It is much clearer to discuss drugs from CM, whereas controversies about CMTs will remain unresolved for a while. The best known early studies of CMs were carried out by K. K. Chen. During the early 1920s while he worked at Peking Union Medical College (PUMC) funded by the Rockefeller foundation, Chen studied the pharmacology of chemical components from CMs, and his work on the function of ephedrine became well known. Before Chen worked at PUMC, he was trained in the US, where he would return after a few years at PUMC. He was internationally well recognized in academia (especially by pharmacologists) as well as in the pharmaceutical industry. From the 1950s, China was isolated from the West for more than two decades. It was not possible for Youyou Tu in Beijing and Tingdong Zhang in Harbin to obtain training comparable to that of Chen. In the mid- to late- 1960s, China went through the peak of “the Great Proletarian Cultural Revolution”, a strange period in Chinese history, pursuing leftist ideology and tramping knowledge and civilization. Some Chinese were involved in fierce infighting. Most scholars with Western education were affected, being suspected of being spies, viewed as “reactionary academic authorities” or “elements interested only in their research and not in the society”. Some died during attacks and some committed suicide after being humiliated. CS Jang (or Changshao Zhang) of Shanghai First Medical College, the father of the advisor of one of the authors (YR), was a pioneer of antimalaria drugs from Chinese sources with a 1946 Science paper and 1948 Nature paper on the anti-malaria effects of the herb Changshan and its active chemical. He committed suicide in 1967 after political criticism of him. More researchers were put into “cow pens” (either local rooms or far away farm fields where scholars were isolated from their families), and more were set aside. For example, the grandfather of one of the authors (YR), a Professor of Geometry without Western experience and insensitive to politics or ideologies, was isolated in a “cow pen”. The same author’s father was sent to the countryside to work on farm fields. Farmers and peasants, who wanted a doctor more than a farmhand, immediately reinstalled him as a doctor. In the early 1970s, many in Chinese universities and research institutes were still idle. The major daily activity for some was to read People’s Daily , a newspaper with a single sheet with four pages. During working hours, some male researchers played chess while some female researchers knitted sweaters. Many books and journals were sent to paper recycling stations. In most middle schools, there were no regular biology classes. “Basic Knowledge of Agriculture” was a close proximity, with the goal of teaching how to grow chickens, fish, pigs and cows, which was all biology taken by one of the authors (YR) in middle school. Funding for science was little until at least the 1980s. From the late 1950s to the mid-1960s, China has supported and successfully made Two Bombs and One Star (the atomic and the hydrogen bombs, and the artificial satellite; the satellite project continued in the 1970s and expanded to date as the missiles program and the space program of today). In the late 1960s and 1970s, there were few such projects and the support was much smaller. Among them was “Task 523” to deal with malaria, which led to the discovery of artemisinin. In the 1970s, projects supported nationally included Bronchitis, which collected recipes for treating bronchitis of Mao Zedong, although it was unclear whether he knew the existence of offices across the country for bronchitis. The father of the same author left the countryside to work in a major city because he was called to the local Bronchitis Office, though he had little patience for sitting in offices and soon went to work directly with common patients in a hospital. It should be noted that publications of a significant fraction of scientific journals were halted for a few years during in the Cultural Revolution. Furthermore, in the leftist atmosphere, for quite a few years, with the exception of Mao Zedong and Marxism classics, publications (books, magazines, or journals) did not encourage authorship (so that no one should fight for or get credits). There was either no authorship, or group authorship, leading to collective authorships such as Qinghaosu Cooperative Research Group or China Cooperative Group on Insulin. This created debates about credits that remain unresolved today. It is ironic that the egalitarian idea of no credit increased the fighting for credits later. In what seems now the ridiculous leftist era, some measures were not futile. For example, a friend of the same author felt that he would never have had the same quality of education, if his teachers had not been those sent to his village from big cities. This person later went to the US and was the mentor of a current editor at Cell . In a separate order, Mao Zedong asked doctors in big cities to serve patients in the countryside. “Circulating Medical Teams” were thus formed to send doctors to the countryside on a regular basis. These teams indeed improved the quality of medical care for farmers. Incidentally, a Circulating Medical Team from Harbin Medical University actually contributed to the beginning of the second part of our article, because it led to the finding of the effect of arsenic oxide to treat leukemia. If these measures are applied more voluntarily today, they can still be beneficial. It is only a small exaggeration to call important discoveries made under such circumstances miracles. Artemisinin (aka Qinghaosu) and Youyou Tu By now, artemisinin is relatively well known. It is a fast acting anti-malaria drug, which can be used as a frontline drug or when resistance develops for other drugs such as chloroquinine. It has treated a large number of patients and has saved lives. Chemically, it is novel and efforts are still under way to find derivatives with higher efficacy and less resistance. Scientifically, its mechanisms are still under investigation. Much have been written about the discoveries of artemisinin, but debates, sometimes heated debates, still rage today. A major problem is whether Youyou Tu can be considered a representative. “Task 523”, the national program to design strategies to fight malaria, is believed to be initiated with the instructions of the then Chinese president Chairman Mao Zedong and Premier Chou Enlai, when they responded to requests from North Vietnamese leaders for help to fight malaria, taking into the consideration that malaria was also a problem for the southern China. It is now also an open secret that several hundred thousands of Chinese soldiers went to Vietnam to help them defend against Americans, though in supportive roles such as artilleries and engineering. Among the documents, files and publications, we found the responsible officials to be below the rank of ministers, with no direct evidence for Mao and Chou’s involvement. The national organization was formed after a week-long meeting beginning on May 23, 1967, in the height of the Cultural Revolution when the organizers had a hard time to find a location for meeting in the middle of social upheavals. The leaders were from the Chinese Military, the Ministry of Health and the National Commission on Science and Technology) with the coordinating office always located in the Military Academy of Medical Sciences. Participating institutions were spread across China, involving hundreds of individuals, from Beijing, Shanghai, Yunnan, Shangdong to Guangdong and Guangxi, which borders Vietnam. It was undoubtedly a large collaborative project, with contributions from administrators, scientists and soldiers who volunteered for tests of the early treatments. Was there a representative contributor? If so, who would that be? In 1969, Youyou Tu was called into the “Task 523”, at a time when most senior scientists could barely survived the “struggles” against them. “Task 523” had several parts, one for copying known Western drugs or making their derivatives, one for finding antimalaria drugs from Chinese medicines, and one for producing mosquito repellents. Among the CMs, different research groups had tried many different ones, including Changshan (from the herb Dichroa febrifuga ) . Changshan has been studied in the 1940s by Changshao Zhang (CS Jang) and coworkers, who reported antimalaria effect of a crude extract of Changshan on humans in 1943, the effect of Changshan and three alkaloids from Changshan on a chicken model of malaria in 1945, and the antimalaria effect of dichroine b in the chicken model in 1946, and the antimalaria effect of dichroine g , dichroine b , dichroidine and quinazolone isolated from Changshan in 1948, and determined the molecular formula of all the alkaloids in 1947 and 1948. Changshan was considered again by Task 523, but it run into the same problem: although it was powerful against malaria, it had strong side effects. Changshan was abandoned but the approach used for Changshan was basically the same as that for artemisinin. The plant Qinghao ( Artemisia annua ) was not only recorded in ancient Chinese books, but also was used in the 1950s and 1960s among Chinese farmers to treat malaria. In the early 1970s, Yagang Yu in Youyou Tu’s group went through the Chinese literature of anti-malaria recipes and came up with a list of 808 CMs. The Military Academy of Medical Sciences tested nearly a hundred of them on a rodent model of malaria, and found Qinghao to have an efficacy of 60% to 80%, but it was unstable. Youyou Tu gave her group a list of CMs including minerals (such as arsenic disulfate), animal products (such as snake skin) and herbs. Qinghao was among the last category on this list. Yagang Yu was asked by superiors to move onto the bronchitis project and left the Tu group in early 1971. Youyou Tu’s group observed the effect of Qinghao: on the rodent model, water extract of Qinghao was ineffective but 95% ethanol extract of Qinghao showed an efficacy of 30% to 40%. It should not be ignored that several ancient books recorded water boiling of Qinghao, which would not result in much artemisinin. Similar mistakes can hamper modern efforts to discover the effects of CMs. In late 1971, Youyou Tu played a key role by proposing the use of ether to extract Qinghao, which resulted in an efficacy of 95 to 100%. This was an important step in recognizing the efficacy of Qinghao. In March 1972, Tu reported her findings on a meeting organized by Task 523 in Nanjing. It attracted immediate attention, but did not make Qinghao the only or the top candidate. In the meeting summary, the organizers listed two other medicines (a chemical from a Chinese herb and the other with a candidate chemical) before Qinghao. The goal for Qinghao was listed as “to confirm its clinical efficacy and purify its effective chemical components”. The work of Tu group was then focused on Qinghao. Muyun Ni of the group tried to purify active components of Qinghao. Yurong Zhong of the group succeeded in purifying “Qinghao Su II” in crystal forms (later called Qinghaosu or artemisinin). In February 1974, Tu reported the molecular formula of artemisinin at a meeting at the China Academy of Traditional Chinese Medicine, which was attended by researchers from her own institute, as well as those from Shandong Institute of Chinese Materia Medica and Yunnan Institute of Materia Medica. Other groups collaborated with the Tu group to determine the structure of artemisinin. Major roles were played by the Institute of Organic Chemistry and the Institute of Biophysics of the Chinese Academy of Sciences (CAS). Upon learning the results of Qinghao extracts reported by Tu in March 1972, Shangdong Institute of Parasitology in collaboration with Shangdong Institute of Chinese Medicine, and Yunnan Institute of Materia Medica, independently purified active chemicals from similar (though not identical) plants. They named their chemicals Huanghuahaosu and Huanghaosu, respectively. Qinghaosu (aka artemisinin) of Beijing, Huanghuahaosu of Shangdong and Huanghaosu of Yunnan were believed to be the same molecule in 1974. It is important that our analysis of the history of artemisinin research has led to the conclusion that, although there are debates about the discovery of artemisinin, there is no dispute that: 1) Youyou Tu proposed the idea of ether extraction of Qinghao, which immediately led to the discovery of its powerful effects and raised the priority of Qinghao among hundreds of recipes; 2) Yurong Zhong, who first succeeded in purifying the active molecule, was a member of the Tu group; 3) Other groups that also succeeded in purifying the active molecule did so after learning Tu’s March 1972 report and after the Tu group had purified the same molecule. There are numerous reports mentioning artemisinin discovery. The work of Tu group was based on previous. Other groups have played important roles. Tu and colleagues only tested on a rodent model of malaria, whereas the clinical efficacy on humans was carried out by others, some on soldiers and some on patients. When the crystals of the Tu group were not very effective and had toxic side effects, Zeyuan Luo of Yunnan provided their crystals which Guoqiao Li of Guangdong used effectively on humans. Since 1976, Powerful derivatives of artemisinin have been developed, including artemether by Ying Li of the CAS Institute of Materia Medica and artesunate by Xu Liu of Guilin Pharmaceutical Company in Guilin, Guangxi. The present article is focused on clarifying one question: that Youyou Tu has indeed played a key role. We can only hope that more detailed research will show the roles of others involved in “Task 523”, with contributions from its organizers, researchers and volunteers. Arsenic Trioxide and Tingdong Zhang Arsenic has been used for a long time, both in China and in the West. There are several traditional Chinese medical recipes that contain arsenic (trioxide or disulfide), with Chinese names of Pishuang, Pishi, Xionghuang and Cihuang. Treatment of leukemia by arsenic was reported in the 1930s in the West, but was not generally accepted. In a Circulating Medical Team, Taiyun Han, a pharmacist of the First Affiliated Hospital of Harbin Medical University, learned that a countryside practitioner of traditional Chinese medicine used a combination of arsenic, mercury and toad venom to treat lymphatic tuberculosis and cancers. In March 1971, Han dissolved the three components in a solution, which he called “713” or “Ailin (literally meaning cancer sensitive)”. This was injected intramuscularly into patients, showing effects in some cancer patients. It was hotly sought after locally for a while but abandoned because of its toxicity. Tingdong Zhang, a doctor in the same hospital, collaborated with Han and continued on this line of work. After 1972, Tingdong Zhang and colleagues focused on leukemia. They also separated the components of “Ailin” and discovered that arsenic was solely responsible for the therapeutic effect, whereas mercury had kidney toxicity and toad venom caused hypertension. Neither of the latter two was therapeutically useful for leukemia. Their first paper on this line was published in 1973, when Tingdong Zhang, Pengfei Zhang, Shouren Wang and Taiyun Han reported in a local journal that they had used “Ailin solution” (also known as “Ailin No.1”) to treat six cases of chronic granulocytic leukemia. They explicitly stated that the components of the solution were arsenic trioxide and a trace amount of mercury chloride. All six improved after the treatment. They also mentioned that they were working on acute leukemia patients. In 1974, using the authorship of The Departments of Traditional Chinese Medicine and Laboratory Medicine of their institution, they published a report in their university journal, summarizing their treatment of 17 cases of leukemia patients from January 1973 to April 1974. After going through different types of leukemia, they reported that Ailin No.1 was effective in treating multiple types of leukemia, leading to complete remission (CR) in acute leukemia patients. In 1976, they used institutional authorship to publish a report on five cases of acute leukemia in which they had achieved CR. In 1979, Fuxiang Rong and Tingdong Zhang published two acute granulocytic leukemia cases, one with CR for 4 and half and the other for 3 years. In a second paper in 1979, Tingdong Zhang and Fuxiang Rong published a summary of 55 cases of acute leukemia. Among those, 23 were treated with Ailin No.1 alone (from 1973 to 1974), 20 were treated with Ailin No.1 in combination with Western chemotherapy and other CMs from 1975 to 1976, and 12 cases treated with Ailin No.1 plus other CMs and chemotherapy from 1977 to 1978. For each patient, they presented the subtyping of leukemia and the clinical observations. All 55 cases improved to some extent, with a remission rate of 70% and with CR in 12 cases. The side effect was small with the doses they used. They then applied 10 times the equivalent of what they used for adult human patients into 12 rabbits. No toxicity was observed in the heart, the liver, the spleen or the kidney of the rabbits. While the 1973 paper reported their pioneering findings, the second 1979 paper represents their understanding of the therapeutic effect. There are three important questions: 1) Had Tingdong Zhang and colleagues shown that the therapeutic effect came from arsenic trioxide, but not from other Western chemicals or Chinese medicines? 2) Did they realize that the effect of Ailin No1 came from arsenic trioxide but not from mercury in the solution? 3 ） did they know the effect of arsenic trioxide on acute promyelocytic leukemia (APL)? Answers for all three questions can be found in Zhang and Rong (1979) which explicitly stated ： 1 ） Significant improvement was observed in three patients （ one adult and two children ） used only Ailin No.1, but no other Western or Chinese drugs. At the time of publication, the children had survived for more than 4 years and the adult more than 9 months. When using other Chinese medicines, Zhang and Rong pointed out that those were not used for treating leukemia, but for supporting the general health of the patients so that they could tolerate more treatment; 2 ） on page 11 of their paper, they pointed out that the effective component of Ailin No.1 was arsenic trioxide; 3 ） on pages 10 and 11, they reiterated that acute granulocytic leukemia (M3 type) was the most sensitive to the treatment. We can conclude that, by 1979, Tingdong Zhang and his collaborators had clearly achieved our current understanding: that arsenic trioxide could treat leukemia, especially acute promyelocytic leukemia ( APL, also known as M3 type of the French-American British FAB classification). In 1981, an institutional authorship with a footnote indicating Tingdong Zhang as the supervisor (with 8 other authors) reported 73 cases of acute granulocytic leukemia patients, with a CR of 24% and remission rate of 86% 。 In 1982, Tingdong Zhang and Yuanshang Li presented a report to a national meeting on 22 cases of CR by Ailin No.1 and on 98 cases of non-lymphatic leukemia. In 1984, Tingdong Zhang and Yuanshang Li published a summary of 81 cases whom they had treated since 1971. Among the 22 cases of CR, they pointed out that 7 were of the M2 type and 15 were of the M3 type. They again stated that the effect on M3 type were particularly obvious. In 1985, Tingdong Zhang and colleagues published another paper on the effect of Ailin No.1 on non-lymphatic acute leukemia. In 1991, Hongde Sun, Lin Ma, Xiaocheng Hu, Tingdong Zhang, Fuxiang Rong, Qinghua Wang, Jinmei Li and Xiuqing Hong reported 16 cases of APL, which should be a continuation of Zhang and Li (1984). They reported that Ailin No1 had been used to treat 32 APL cases from 1974 to 1985, with CR in 19 cases and that 16 cases had survived for more than 5 years. In 1992, Hongde Sun, Ling Ma, Xiaocheng Hu and Tingdong Zhang published a short “Sharing Experience”, reviewing materials identical to the 1991 paper. Strangely, most English papers cite this 1992 paper for the discovery of arsenic trioxide treatment of APL. Both the 1991 and the 1992 papers were in Chinese. But as we documented, the key findings were published in 1973 and the effect on APL was clear by Zhang and Rong (1979). The often cited 1992 paper of Sun et al was not substantially different from that of 1979, in either what chemicals were applied or the subtype of leukemia treated. Questions Related to the Research of Tingdong Zhang There were no simultaneous controls for Zhang’s clinical research. Was it because he did not know? In 1982, Zhang published a commentary, which showed that he was aware of the standards in medical research, but he followed by stating “ it is not permissible to set up ‘blank controls’ for patients with severe diseases, and one can only compare new therapies to existing therapies that are conventionally considered good. For some ‘absolute’ therapies, one can also choose not to use controls, such as with acute leukemia or other malignant cancers”. Clearly not everyone will accept his argument, but his reasoning was clear. Zhang’s research should be compared to similar work in the West in the same period. When Bernard et al (1973) in France established the effect of daunorubicin on APL , the comparison was made between patients before the availability of daunorubicin treatment and those after it. From 1983 to 1986, case studies in the West on APL were all published without controls: Flynn et al (1982) in the US, Nilsson ( 1984 ) in Sweden, Daenen et al ( 1986 ) in the Netherland and Fontana et al ( 1986 ) in the US. The 1988 report from the group of Zhen-Yi Wang, which is widely known, also did not have simultaneous controls. Thus, work of Tingdong Zhang from 1973 to 1979 was not below the international standards of the time. Are CMTs helpful for using arsenic trioxide to treat leukemia? We can not find evidence that CMTs have helped defining or refining the treatment. For example, when they discussed five types of leukemia based on CMT classification, there was no difference of arsenic trioxide on different CMT types. It was Western classification of leukemia which was helpful. When they completely gave up the CMT classification, the effect was more obvious. Interestingly, their first paper in 1973 did not mention CMTs, while their latter papers did. It is odd that they never dropped the trace amount of mercury until 1996, although they already stated that only arsenic trioxide was therapeutically effective on leukemia. Was it due to their considerations of CMTs or their unwillingness to change a therapeutically proven recipe? Lack of evidence for the utility of CMTs does not disprove CMTs, but it is so far unclear whether CMTs are important or essential for scientific studies of CMs. Chinese Contributions to APL Treatment APL was one of the most aggressive and fatal type of leukemia. In 1973, Bernard et al. of Paris reported their use of daunorubin in treating APL since 1967. It has since become the mainstream treatment for APL to use anthracyclines (including daunorubin) and cytosine arabinoside (Ara-C). In 1973, Tingdong Zhang and colleagues of China reported the therapeutic effect of arsenic trioxide （ As 2 O 3 ） on leukemia, and Zhang and Rong (1979) reported that APL was particularly sensitive to As 2 O 3 . In 1983, Koeffler summarized the effect of multiple chemicals including retinoic acid (RA) on differentiating human leukemic cells cultured in vitro. A single case of APL treatment by 13-cis RA was reported in 1983 by Flynn et al of Minnesota, USA, in 1984 by Nilsson of Lund, Sweden, in 1986 by Daenen of the Netherland and in 1986 by Fontana et al of West Virginia USA. In 1985, Zhen-Yi Wang of Shanghai Second Medical College used all trans-RA (ATRA) to treat a five year old girl. In 1987, his group published a paper in the English edition of the Chinese Medical Journal , reporting the use of ATRA (alone or in combination) to treat six APL patients. In 1988, Wang’s group published in Blood their use of ATRA in treating 24 APL patients, with CR. This English paper published in the US certainly drew the attention of the world. The findings were soon replicated and the application became the convention. This paper, but not the 1987 one (also in English), was widely cited. In 1995, Huang and coworkers from Dalian China reported that a tablet with multiple components derived from CMs (herbs and minerals) led to 98% CR in 60 APL patients. One of the components contained arsenic disulfide. In February 1996, Peng Zhang et al from the same hospital as Tingdong Zhang published their use of As 2 O 3 in treating 72 APL cases. This summarized their experience of using As 2 O 3 alone (without the trace amount of mercury) in 130 APL cases from 1992 to 1995, among which 72 went through one ore more course of treatment. A CR of 73% was reported for patients undergoing initial treatments and 52% in recurrent patients. No cross-resistance was observed between As 2 O 3 and ASTRA. In August, 1996, Guoqiang Chen and 18 other authors (including Tingdong Zhang in the middle and Saijuan Chen, Zhen-Yi Wang and Zhu Chen as the last authors) reported work in Shanghai Hematology Institute that used in vitro culture leukemic cells to pioneer mechanistic studies of the therapeutic effect of As 2 O 3 on leukemia at the molecular level. In 1997, Jingshu Xu, Jingxiu Duan, Ying Xu, Xiaomin Xin, Xiaohong Song and Tingdong Zhang reported in the Chinese Journal of Hematology a case of who had recurrent APL three times. The patient was treated with Ailin No1 every time and had survived for 20 years. In 1997, Shen et al from Shanghai reported in Blood that they used pure As 2 O 3 to treat 15 APL patients, among which 10 cases with only As 2 O 3 . CR was achieved in 90%. In 1998, Soignet et al from the Memorial Sloan-Kettering Cancer Hospital and Cornell Medical College reported in the New England Journal of Medicine ( NEJM ) that they had treated 12 recurrent APL cases with As 2 O 3 and observed CR in 11 cases. The mechanisms were thought to be partial cellular differentiation and apoptosis. This NEJM paper led to general international acceptance of As 2 O 3 as a treatment of APL, achieving what could not be achieved by many papers published in China by Chinese doctors over the previous 2 decades. Belated, or Lack of, Recognitions The findings of Tu and Zhang have been well accepted (and generally used) nationally and internationally, saving lives in China and other countries. However, neither scientist has been duly recognized nationally or internationally, for different reasons. While artemisinin is well known, the contribution of Youyou Tu has been controversial. The reasons remain to be investigated by other historians. A major cultural problem is that, while facing such an important discovery, Chinese authorities did not try to find out where credits are due when they saw controversies and conflicts. The authorities opted to stay out of the controversies, leading to scarcity of recognition for all of those involved in the discovery. The international community have difficulties in understanding or even reading internal circulations and meeting reports in Chinese and inaccessible to the outside. During our research of the history of artemisinin, we have examined materials that no Chinese authorities had spent time on. Unlike the best known large projects such as the Two Bombs and One Star, the collaborative atmosphere of Task 523 has not been the same, with fighting for credits between different groups, as well as among members of the same group. Group leaders were relatively junior and were not always highly respected by group members. Publication of articles did not follow the usual convention. Here the shadow of the Cultural Revolution is obvious. In conventional science, instead of presenting unpublished work on the March 1972 meeting, Tu could have hold onto her data about ether extraction before publication. Her group could also have published the purification of artemisinin when Yurong Zhong in her group obtained the crystals. These two papers would have established their priorities. In real life, they only presented reports in closed door meetings, before the first paper was published in Chinese in 1977 under the collective authorship of Qinghaosu Coordinating Research Group. English articles were in 1982, under the collective authorship of China Cooperative Research Group on Qinghaosu and Its Derivatives as Antimalarials. These left ample room for controversies. Now, while sharing of information without publication did not help assuring credits for scientists, it was faster than normal to apply the seemingly successful drug on many patients than the normal convention would require. If all patients had to wait for the clarification of authorship and publication of papers, some of them would not have lived through that period. From more than one source, it appears that Tu’s unwillingness to credit her own group members and other groups is a non-negligible factor in the controversies. There were complaints that, in her later publications, her citations sometimes skipped others to move her own name forward. It was sometimes difficult for us as a third party to communicate with Tu. It is not helpful that she keeps at her home original notebooks which belonged to her institute, making them inaccessible to others interested in the original record. The obscurity of Tingdong Zhang is even more striking. He remains largely unknown in academic and medical communities nationally or internationally, although there was a story about him in the New York Times in 2001. The reason is not controversies. There was a contention for patent by a member of his group (Hongde Sun), but it was quite late and the judge ruled in Zhang’s favor. It was clear, if one reads publications from 1973, that Tingdong Zhang played an undisputed key role. The lack of recognition for Zhang may be more due to where he worked, the scarcity of English papers by him, lack of international perspective and communications. It can not be ruled out completely that he did not quite realize the significance of his own work. It certainly did not help that most of Zhang’s papers were published in journals that were obscure even in China. In 1998, Guoqiang Chen, Saijuan Chen, Zhen-Yi Wang and Zhu Chen published in a Chinese journal that “from the early 1970s, Harbin Medical University (HMU) discovered through clinical practices that arsenic trioxide could effectively treat APL. In the past two years, we have collaborated with HMU and used arsenic trioxide solution to treat APL patients resistant to ATRA and conventional chemotherapy”, affirming the work and priority of HMU. In English literature, the key role of Tingdong Zhang was not mentioned and cited papers did not mention his name. Almost no English paper realized that Tingdong Zhang had published his findings from 1973 to 1979. Most English papers, including those by Chinese scholars as well as non-Chinese scholars, cited Sun et al (1992) and sometimes Peng Zhang et al (1996) as the first paper for arsenic trioxide treatment of leukemia. For example, the NEJM paper of Soignet (1998), which replicated the findings of Tingdong Zhang in the 1970s and played a major role in the international acceptance of As 2 O 3 treatment for APL, mentioned recent Chinese reports of CR in APL by As 2 O 3 in its introduction, and cited only the Sun et al (1992), Peng Zhang et al (1996), and Shen et al (1997). It is impossible to know from the NEJM paper that the original findings were made in the 1970s by Tingdong Zhang. A 1996 news report in Science did mention Tingdong Zhang, but stated that he published his paper in 1992. Tingdong Zhang has published few English papers. In 2001, Tingdong Zhang and Guoqiang Chen were co-first authors (with Zhugang Wang, Zhen-Yi Wang, Saijuan Chen in the middle and Zhu Chen as the corresponding author) published a review about As 2 O 3 in an international journal Oncogene . In the introduction, they also stated recent studies of As 2 O 3 treatment of APL, citing Guoqiang Chen et al (1996). On the second page, they stated that the research on As 2 O 3 started in 1971, without citing any publications, and claimed to have treated more than a thousand patients of different types of cancers including “chronic granulocytic leukemia, lymphoma, esophageal cancer, and particularly APL” , but again without citing any literature. Thus, Tingdong Zhang, as a first author himself, neglected to cite his own early papers, effectively burying his own pioneering findings in 1973, 1974, and his clear understanding in 1979 that APL was the most sensitive. In 2002, Jun Zhu, Zhu Chen, Lallemand-Breitenbach and de The published a review in Nature Reviews Cancer . In the figure illustrating milestones in APL treatments, Tingdong Zhang in the 1970s were placed, but the citation in the text was Sun et al (1992) and the explanation in the reference credited Sun et al (1992) as “first report of As 2 O 3 therapy in APL” . Furthermore, both Sun et al (1992) and Peng Zhang et al (1996) were published in Chinese, and neither cited papers of the 1970s. Thus, even if any international scholars attempted to obtain English translations of the 1992 and 1996 papers, they would still not know the original 1970 papers. In 2008, Zhen-Yi Wang and Zhu Chen reviewed progresses in APL treatment in Blood , the initial citation for As 2 O 3 was the Zhu et al (2002) review. The citations for As 2 O 3 treatment of APL were Sun et al (1992), Zhang et al (1996), Chen et al (1996), Shen et al (1997) and Niu et al (1999). Therefore, the contributions of Tingdong Zhang, and the year of his discoveries, are virtually unknown in the international literature. Significance of Recognizing Youyou Tu and Tingdong Zhang National and international recognitions of Tu and Zhang are not only fair to the scientists, but also important to stimulate China and the rest of the world to realize that treasures of traditional Chinese medicines remain largely untapped. One would need to be able to read Chinese literature, and distill layers of confusions, before targeting a drug against a disease, as Tu and Zhang have done in the 1970s. A direct suggestion is that one can test other therapeutic effects claimed by early reports. Zhang and other Chinese researchers have reported As 2 O 3 treatment of multiple cancers, from liver, stomach and colon cancers to lymphomas. For example, Fang et al (1981) reported the effect on 42 cases of late liver cancer. Surgery alone led to 8% of 3 year survival and no 5 year survival whereas surgery plus Ailin No.1 led to 42% of 3 year survival, among which 5 patients lived for over 5 years. In 1988, Yuanshang Li, Tingdong Zhang, Xingrong Wang and Xu Liu published effect of Ailin No1 on cultured liver cancer cells. An indirect inference is that rigorous studies of components of CM may lead to more discoveries. For example, drugs used vaguely by Chinese hospitals or marketed aggressively by Chinese companies (without prior stringent tests), may prove to be more powerful and specific after rigorous studies, and become more internationally acceptable and will eventually help more patients and save more lives. Research on the history of artemisinin and Task 523 will help to understand the management of big science projects, pros and cons of large collaborative projects. Two Bombs and One Star are successful examples. Artemisinin is different from them. Projects on bronchitis and others were also costly in the 1970s and had not led to drugs in use today. Was it because they were failures or because we have not examined them in sufficient details to find the jewels? If Youyou Tu and Tingdong Zhang are widely recognized nationally or internationally some day, we hope that the Chinese populace will not neglect the contributions of others. Task 523 was a national collaboration, involving hundreds of people including administrative organizers as well as researchers such as Luo Zeyuan of Yunnan, Zhenxin Wei of Shangdong, Guoqiao Li of Guangdong, Pengfei Li and Li Liang of Beijing, Zhaohua Wu, Weishan Zhou and Yuling Wu of Shanghai. Yurong Zhong, Yagang Yu and Muyun Ni of the Tu group also made important contributions. Soldiers and farmers were the early volunteers at a time when informed consent was not what it is now. Most importantly, these drugs have saved lives. The work of Tu and Zhang should be respected. Their achievements should be applauded. In science, with objective criteria, debates can take us closer to truth. Acknowledgements While one of the authors (YR) has been interested in the topic for more than a decade and had carried on inquiries on and off, it is in recent years that we have obtained sufficient materials to provide this outline. We thank researchers and others who granted us interviews for information, Fuchu He for access to files of the Task 523 office, Xin-Yuan Fu, Siyuan Gong, Kunliang Guan, Xin Hao, Hong Ma, Bai Lu, Hua Lu, Lin Mei, Eric Oermann, Hai Rao, Xiaodong Wang, Yue Xiong, Gang Zhi, Qiuding Zhou for comments. Relevant Literature (listed chronologically, some are files and some journals have no volume numbers and the citations are thus irregular) Artemisinin Jang, C.S., Fu, F.Y., Wang, C.Y., Huang, K.C., Lu, G. and Chou, T.C. (1946) Ch’ang shan, a Chinese antimalarial herb. Science 103:59. Jang, C.S., Fu, F.Y., Huang, K.C. and Wang, C.Y. (1948) Pharmacology of ch’ang shan (Dichroa febrifuga), a Chinese antimalarial herb. 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饶毅 1 黎润红 2 张大庆 2 中国 北京 100871北京大学 1 生命科学学院 2 医学部 摘要 1970年代早期，多数中国科学家，在文化大革命中努力生存而无机会开展研究。两位年轻的研究者屠呦呦和张亭栋，分别在发现抗疟新药青蒿素和揭示砒霜化学成分三氧化二砷对白血病的治疗作用的过程中起了关键作用。回顾四十年前开始的历程，不乏曲折和反讽。青蒿素工作源于中国帮助越南抵抗美国，三氧化二砷源于观察、验证和改进乡村中医的实践。虽然他们的药物挽救了世界上很多生命，两位研究者迄今未获国内外充分肯定，屠呦呦有争议、张亭栋基本默默无闻。相关的文献埋没于冷僻的杂志和一般不易看到的内部会议资料。基于原始中文论文、文件和采访，我们在此呈现这些发现的历史概貌。没有逃脱我们的注意，在古代和近现代中文文献及医疗实践中，可能还有尚待重新发现的珍宝。 引言 在中国使用了上千年的传统药物，能否改善现代人类的健康？在中国，有些人不认为这是问题，而在中国以外的世界，中药并非现代人类普遍使用药物的主要来源。 对中药有两种截然相反的看法：在现代医学进展到今天后中药意义很小，甚至毫无作用；或者，中药很有用，但中药必需使用复方，且不能按照现代科学标准来评判，必须用它自己特殊的标准。 我们试图通过研究青蒿素和三氧化二砷的历史，探寻这些问题的答案。我们研究显示，青蒿素和三氧化二砷都是以现代科学的方法所获得，遵循科学的标准所确立其效果。这些药物经受了时间的考验，并挽救了大量患者的生命，从而证明了从传统药物获得确定化学成分药物的价值。我们的结论是，青蒿素和三氧化二砷的发现清晰地肯定了古老的中药在今天仍然有益，传统中还沉睡着尚未开发的、可能进一步改善人类健康的潜力。 青蒿素和三氧化二砷，堪称中国过去一个世纪最重要的两项来自中药的药物发现。虽然现在中国政府大量投入支持药物开发，也有很多中国药厂从中药大量牟利，但其他中药来源药物迄今并未超越青蒿素和三氧化二砷所创造的对人类健康的价值。 研究青蒿素和三氧化二砷的发现历史、肯定屠呦呦和张亭栋为代表人物的工作，不仅对于他们个人有意义，而且能刺激国际医药界用传统药物寻找全新化学结构的药物、发现已有化合物的新用途。当很多中国药厂或者因为不知道、或者急功近利而不循青蒿素和三氧化二砷已经证明成功的道路，而继续用化学不确定、适应症不明确的中药获得大量收益的时候，这也是警醒它们认真努力试图确定中药特定化学成分和特定疾病的关系。中国国内和国际对中药的努力可能将中药带到一个新的时代，挽救更多人的生命。 主角 青蒿素发现于大型研究抗疟疾药物的“523任务”中，发现青蒿素的代表性人物是中医研究院中药研究所的屠呦呦。砒霜中三氧化二砷治疗白血病的作用发现于以个体科研小组模式自由探索性研究中药抗癌作用过程中，最主要贡献者是哈尔滨医科大学第一附属医院的张亭栋。 屠呦呦出生于1930年，1951年至1955年就读于北京医学院（现北京大学医学部）药学系生药学专业，其后分配到中医研究院工作。她仅有大学本科学位，于1969年与其他几位中医研究院的研究人员一道被召集加入“523任务”。 张亭栋出生于1932年，1950年代毕业于哈尔滨医科大学，1960年代曾参加过西医学中医的培训班。 文化和工作背景 需简要了解当时的文化背景和工作环境，有助于理解这两项工作的特色和重要性、为什么是屠呦呦和张亭栋等人作出发现，而不是年资更高的人，或受过较好的西方科学训练的人。 本文区分中医理论（Chinese Medical Theories，CMT）和中药（Chinese Medicines， CM)，而避免使用常见的中医一词（Traditional Chinese Medicine，TCM）。因为我们认为用后者不能明确药物与理论的区别，而目前虽然可以清晰地讨论药物，但对CMT的争论还会存在。 中药研究的早期著名工作，是陈克恢（K. K. Chen）进行的。他曾于1920年代初期在北京协和医学院工作过一段时间，研究中药成分、特别是麻黄素的功能。陈克恢到协和以前，曾留学美国获得很好的科学训练。在协和后他又回到美国，在学术界和药物工业界，特别是药理学界，陈克恢蜚声国际。 1950年代后，中国和西方隔离二十多年。在北京工作的屠呦呦和哈尔滨工作的张亭栋都不可能有类似陈克恢的科研背景。他们在从事关键发现的工作条件也远非理想。 1960年代中后期，中国经历了所谓“伟大的无产阶级文化大革命”的高潮，是中国历史上一个奇特的阶段，狂热追求极左意识形态的同时践踏知识和文明。有些中国人把人斗人的劣根性发挥到淋漓尽致。绝大多数有西方经历和西方科学训练的人受到不同程度的冲击，分别被认为是“特务嫌疑”、“反动学术权威”、或“白专道路”。有些甚至被批斗致死，有些因不堪羞辱而自杀。例如，上海第一医学院药理学教授张昌绍，是从中药研究抗疟药的先驱，1946年和1948年分别在《科学》和《自然》报道中药常山及其活性成分的抗疟作用。不幸的是，他于1967年自杀。文革中，相当一部分科学工作者被关牛棚，更多的被“靠边站”。 到1970年代初期，中国的大学、科研机构很多人还无所事事，甚至每天工作时间主要活动是看只有一张（4版）的《人民日报》等报刊，上班下棋、打扑克、织毛衣都非罕见。许多科技书籍进了废品收购站。全国的中学多年无“生物学”课程，而改装成《农业基础知识》，目的是教学生种田、养鸡、养猪、养牛、养鱼。 中国直至1980年代以前，科研经费和科研课题一直极少。1950到1960年代，中国由于国防的需要曾强力支持和成功地研制“两弹一星”（星的计划以导弹和太空计划持续至今）。十年文革期间科研经费更少，也不可能得到“两弹一星”同等的国力支持。抗疟研究的“523任务”是一个，它导致了青蒿素的发现。此外，因毛泽东的疾病（虽然不清楚他本人是否知道），在1970年代曾设置几个全国性研究课题，如各地都有的“气管炎办公室”，也大量收集过中草药方剂。 应该指出，文革中有几年相当大量的科学刊物完全停刊。在极左思潮主导下，中国的所有文章（无论是论文还是报刊上的文章），除了毛泽东的出版物和马列经典外，有段时间几乎都不标明作者，特别是个人作者，要么不标作者、要么用集体作者（如“青蒿素协作组”、“胰岛素合作组”）。不标明作者对以后确定科研工作的功劳带来较大困难，这也是青蒿素成就归属有争论的原因之一。为了平等而取消标明作者，带来其后更多争论，颇具讽刺意味。 在现在看来荒谬的极左时代，有些出于意识形态的社会措施，并非完全无效果。比如，受教育的人被迫到农村，被农民邀请做老师（虽然这不是决策者的本意），从而提高对农村的教育水平有所贡献。毛泽东曾明确要求城市的医生到农村为农民看病。“巡回医疗队”因此而组成，有助于提高农村的医疗水平。和本文有关的是，巡回医疗队导致了发现三氧化二砷治疗白血病的作用。即使今天，如果更加尊重人们的自愿，这类措施仍能起较好的作用。 在这样的时代背景下，出现重要的发现，说是奇迹不算很夸大。 青蒿素和屠呦呦 现在不少人知道青蒿素（artemisinin）的作用。它起效快，可以在一线使用，也是在其他常用药物如氯喹出现抗药性情况下，可以改用的药物。当然，青蒿素并非无缺点，也不是可以替代其他所有抗疟药的唯一药物。但是，它治疗了很多病人。在结构上，青蒿素完全不同于其他抗疟药，是全新的一类药物，迄今国内外仍然试图寻找更好的衍生物，以便改进疗效、减少抗药性。在科学上，青蒿素作用的机理，尚未完全阐明，仍是有待深入研究的科学问题。 不少人知道青蒿素的发现过程，但有较大争论。主要的一个问题是，屠呦呦是否可以作为其代表人物？ 全国性抗疟研究计划“523任务”，据说（但笔者未见资料证明）起始于毛泽东主席和周恩来总理应越南的要求、也考虑中国南方存在的疟疾问题。当然，今天的公开秘密是中国曾有几十万军人援助越南抵抗美国，虽然以高射炮兵和工程兵等形式。我们所见的正式文件，参与的主要是一些司局级官员，基本未见部级及其以上负责人出现。其正式组织成立于国家科技委员会与解放军总后勤部于1967年5月23日开始的一周联合会议“疟疾防治药物研究工作协作会议”，那是文革中开会都怕找不到安稳地方的时期。组织有统一的领导（解放军总后勤部、卫生部、国家科技委员会等），其协调办公室一直设在军事医学科学院。参与的单位遍布全国，北京、上海、云南、山东…，人员至少几百。毫无疑问，这是一个全国性的大规模合作项目，其中有很多人起了作用。 但是，青蒿素的发现是否有代表人物？谁是代表人物？ 1969年，高年资科学家绝大多数“靠边站”了，不可能参加科学研究。中医研究院中药研究所的实习研究员屠呦呦等应召加入“523任务”。 “523任务”分为几部分：仿造西药或制造衍生物、从中药中寻找抗疟药、制造驱蚊剂等。中药部分，不同研究小组试了很多中药，包括药效较强、但副作用较大的常山(Dichroa febrifuga)。张昌绍等于1940年代曾对常山有开创性的研究。他和同事于1943年报道用常山的粗提物治疗疟疾病人，1945年报道常山所含三种生物碱在鸡的疟疾模型上有作用，1946报道常山碱B（dichroine b，后称dichroine b）在鸡虐模型的抗疟作用，1948年报道常山提取的常山碱g （dichroine g）, 常山碱b（dichroine b）,常山次碱（dichroidine）和喹唑啉（quinazolone）具有抗疟作用, 1947年和1948年确定所有这些生物碱的分子式。“523任务”再次考虑和研究了常山，但遇到同样问题：虽然抗疟作用强，呕吐的副作用也很强，未能克服而不能推广应用。但是，研究常山的路径和方法，基本也是研究青蒿和青蒿素的方法。 而青蒿(Artemisia annua)不仅记载于古代中药书中，而且在1950年代和1960年代，中国民间也有使用的记录。屠呦呦研究小组的余亚纲梳理过可能的抗疟中药，开列了有808个中药的单子，其中有乌头、乌梅、鳖甲、青蒿等。军事医学科学院用鼠疟模型筛选了近百个药方，青蒿提取物有60%到80%的抑制率，但不稳定。屠呦呦给自己研究小组提供的清单含多个中药，包括矿物药：黄丹、雄黄、硫黄、皂矾、朱砂等；动物药：鼠妇、地龙、蛇蜕、穿山甲、凤凰衣等；植物药：地骨皮、甘逐、黄花、菱花、鸦胆子、青蒿、马鞭草等。1971年初，余亚纲从抗疟科研小组调出去研究支气管炎。屠呦呦研究小组后来也观察到青蒿的效果，但水煎剂无效、95%乙醇提取物药效仅30%到40%。应该附带指出，有些古书曾记载热水煮青蒿用于治疗疟疾，这种不可靠的记载妨碍了发现中药的真正作用。 1971年下半年，屠呦呦本人提出用乙醚提取青蒿，其提取物抗疟作用达95%到100%，这一方法是当时发现青蒿粗提物有效性的关键。1972年3月，屠呦呦在南京“523任务”的会议上报告这一结果，获得大家注意，但并未成为唯一的重点，会议总结时组织者建议“鹰爪要尽快测定出化学结构，并继续进行合成的研究；仙鹤草再进一步肯定有效单体临床效果的基础上，搞清化学结构；青蒿、臭椿等重点药物，在肯定临床效果的同时，加快开展有效化学成分或单体的分离提取工作”。 其后，屠呦呦研究小组的工作集中于青蒿。倪慕云先试图获得青蒿中的活性化合物，以后钟裕容成功地获得结晶“青蒿素II”（后称青蒿素），屠呦呦于1974年2月份在中医研究院召开的青蒿座谈会（中医研究院中药研究所、山东中医药研究所、云南省药物研究所共同参加）上提到了青蒿素II的分子式。从明确青蒿乙醚中性提取物（黑色胶状物，抗疟有效组分）的抗疟效果到获得青蒿素（白色针状结晶，抗疟有效单体），从而确定了抗疟分子。 屠呦呦研究小组成员还与其他研究组合作，其中起重要作用的有中国科学院上海有机所、中国科学院生物物理研究所等，分析青蒿素分子、解析其结构。这些研究小组发现青蒿素是一种新型的倍半萜内酯。在1972年获知屠呦呦小组青蒿粗提物有效的信息后，山东寄生虫病研究所与山东省中医药研究所合作，云南省药物研究所独立分别进行青蒿的提取工作。山东省中医药研究所和云南省药物研究所分别获得抗疟有效单体，并命名为“黄花蒿素”（山东）和 “黄蒿素”（云南）。1974年初，北京的青蒿素、山东的黄花蒿素和云南的黄蒿素初步被认为相同的药物。 很重要的是，根据我们对青蒿素发现历史的分析，虽然有很多争论，但无异议的是：1）屠呦呦提出用乙醚提取，对于发现青蒿的抗疟作用和进一步研究青蒿都很关键；2）具体分离纯化青蒿素的钟裕容，是屠呦呦研究小组的成员；3）其他提取到青蒿素的小组是在会议上得知屠呦呦小组发现青蒿粗提物高效抗疟作用以后进行的，获得纯化分子也晚于钟裕容。 有关青蒿素的历史回顾很多。一个药物的发现，除了确定粗提物有效以外还有提纯、药理、结构、临床等部分。屠呦呦的工作有前人的基础，她的研究小组其他成员有重要贡献。也不能忽略其他研究小组和科学家的重要作用。例如，中医研究院曾学习云南和山东的青蒿素提取工艺。在中医研究院用自己提取的结晶做临床实验结果不够理想并发现毒副作用时，云南药物所罗泽渊等人提供的结晶通过广州中医药大学的李国桥等人明确其对恶性疟尤其是脑型疟有效。而现在使用较为广泛的蒿甲醚、青蒿琥酯等青蒿素的衍生物则是由中国科学院上海药物所李英等和广西桂林制药厂刘旭等于1976年后多年研究的结果。 本文集中于一点：屠呦呦在青蒿素的发现过程中起了关键作用。 我们希望其他历史学工作者进行更深入和全面的研究，让人们知道“523任务”组织者和其他主要贡献者的工作。 三氧化二砷和张亭栋 砒霜的化学成分为三氧化二砷。 用砒霜治病，中药有传统，西方也曾用过。含砷的中药有砒霜、砒石、雄黄、雌黄等。北宋的《开宝详定本草》、明朝李时珍的《本草纲目》都记载了砒霜的药性。西方在十九世纪和二十世纪三十年代也曾用三氧化二砷治疗白血病，但未获普遍接受。 在巡回医疗过程中，哈尔滨医科大学第一附属医院的药师韩太云从民间中医得知用砒霜、轻粉（氯化亚汞）和蟾酥等治疗淋巴结核和癌症。1971年3月，韩太云将它们改制水针剂，称"713"或"癌灵"注射液，通过肌肉注射，对某些肿瘤病例见效，曾在当地风行一时，但因毒性太大而放弃。 哈尔滨医科大学附属第一医院中医科的张亭栋与韩太云合作继续此工作。1972年后，张亭栋等一方面主要集中做白血病，而不是无选择地应用于很多疾病，另一方面他们分别检测“癌灵”的组分，发现只要有砒霜就有效，而轻粉带来肾脏毒性、蟾酥带来升高血压的副作用，后两者无治疗作用。 他们的第一篇论文发表于1973年。张亭栋、张鹏飞、王守仁、韩太云在《黑龙江医药》报道他们用“癌灵注射液”（以后也称“癌灵1号”）治疗6例慢性粒细胞白血病病人。他们明确知道主要用了砒霜的化学成分“亚砷酸（三氧化二砷）”和微量“轻粉（氯化低汞）”。经过治疗，6例病人症状都有改善，其中一例为慢性白血病发生急性变的患者也有效。该文还提到还在研究对急性白血病的治疗效果。 1974年，他们以哈医大一院中医科和哈医大一院检验科署名在《哈尔滨医科大学学报》发表“癌灵1号注射液与辨证论治对17例白血病的疗效观察”，总结从1973年1月至1974年4月对不同类型白血病的治疗效果，发现“癌灵1号”对多种白血病有效、对急性白血病可以达到完全缓解。1976年哈医大一院中医科曾撰文“中西医结合治疗急性白血病完全缓解五例临床纪实”，介绍5例经治疗后完全缓解的患者的诊治过程及各种临床表。 1979年，荣福祥和张亭栋在《新医药杂志》报道“癌灵1号”治疗后存活4年半和3年的两例病人，皆为急性粒细胞性白血病。 1979年张亭栋和荣福祥发表他们当年的第二篇论文，在《黑龙江医药》，题为“癌灵一号注射液与辩证论治治疗急性粒细胞型白血病”，总结他们从1973年至1978年治疗急性粒细胞型白血病共55例。其中1973年至1974年单用“癌灵一号”治疗23例，1975年至1976年用“癌灵一号”加其他中药和少量化疗药物治疗20例，1977年至1978年用“癌灵一号”加其他中药和加少量化疗治12例。对每一个病例，他们都根据血象分型，有明确的疗效观察。全部55例都有不同程度的好转，缓解率70%，12例完全缓解，对病人的毒副作用小。他们还用十倍于成人的剂量，给12只家兔注射“癌灵一号”，未见心、肝、脾、肾毒性作用。如果说，1973年的论文是他们发现“癌灵一号”的开创性论文，1979年这篇就是张亭栋等有关 “癌灵一号”的代表性论文。 有三个重要问题值得讨论：1）张亭栋等是否确切知道治疗癌症的作用来源于“癌灵一号”，而不是同时使用的其他中药和化疗西药；2）他们是否意识到“癌灵一号”的作用来源于三氧化二砷，而无需汞；3）他们是否知道三氧化二砷对急性早幼粒细胞白血病的作用。 这三个问题，在1979年《黑龙江医药》杂志中可以看到张亭栋和荣福祥有明确答案：1）有三例病人（一位成人、两位儿童），单纯使用“癌灵一号”，不用其他中药、不用化疗西药，也显示疗效，其中当时儿童存活已经4年，成人已存活9个月。在使用其他中药时，他们也指出其他中药并非治疗白血病、而用来支撑病人身体状况；2）在第11页，他们指出“癌灵一号”之有效成分为三氧化二砷；3）在第10页和第11页，他们两次明确指出对早幼粒型白血病效果最好。 可以说，到1979年，张亭栋和不同的同事合作发表的论文，清晰地奠定了我们今天的认识：三氧化二砷可以治疗白血病，特别是急性早幼粒白血病（法国-美国-英国FAB分型的M3型白血病，也即acute promyelocytic leukemia，APL）。 1981年哈尔滨医科大学附属第一医院中医科 （文章最后注脚标明 指导：张亭栋；执笔：李元善，胡晓晨；参加人：李明祥，张鹏飞，荣福祥，孙洪德，李会荣，吴云霞，检验科血研究室）在《黑龙江中医药》发表“癌灵1号结合辨证施治治疗急性粒细胞白血病73例临床小结”，报道“癌灵一号”对急性粒细胞白血病完全缓解率达24%、总缓解率达86%。1982年的全国中西医结合治疗白血病座谈会上，张亭栋、李元善交流了“癌灵1号治疗急性粒细胞白血病临床实验研究—附22例完全缓解分析”和“98例非淋巴细胞白血病分型与临床疗效探讨”。 1984年，张亭栋和李元善在《中西医结合杂志》发表“癌灵1号治疗急性粒细胞白血病临床分析及实验研究”，总结他们1972年以来治疗的81例急性粒细胞白血病，分析其中完全缓解的22例。他们指出，完全缓解的22例中，7例为M2型，15例为M3型白血病。他们也再次指出“以M3型效果尤为显著”。1985年张亭栋等撰写“癌灵1号（713）注射液治疗急性非淋巴细胞白血病临床观察及实验研究”。 1991年在《中医药信息》杂志，孙鸿德、马玲、胡晓晨、张亭栋、荣福祥、王钦华、李金梅、冯秀芹发表“癌灵1号结合中医辨证施治急性早幼粒白血病长期存活16例报告”，应该是延伸1984年张亭栋和李元善的文章。他们报道从1974年到1985年以“癌灵一号”治疗急性早幼粒白血病32例，19例完全缓解，16例存活超过五年。 1992年，孙鸿德、马玲、胡晓晨、张亭栋在《中国中西医结合杂志》发表“癌灵1号结合中医辨证治疗急性早幼粒白血病32例”，作为“经验交流”，实质相同于1991年论文。比较奇怪的是，英文文献基本都引用这篇文章。该文同1991年论文一样都是中文，内容不过是1991年论文的简介，而实际发现最早发表于1973年，到1979年已明确了对APL的作用最好。而1992的论文在本质上与1979年的文章无差别，既没有改变所用的药物成分、也没有改变适应症。可见国际同行对于此一重要发现的年代毫不知情。 张亭栋研究的几个问题 张亭栋等当时的研究没有设置同时对照。这是因为他们不知道对照的规范，还是觉得不能用不治疗作为对照？1982年，张亭栋在《中西医结合杂志》发表的评论，显示他知道医学研究的规范，但他指出“对于较严重疾病的患者建立对照组，即使是建立无害的‘空白对照’，也是不允许的，只能用平素认为较好的疗法与新疗法来对照观察。而对于某些‘绝对’的治疗也可以不必选用对照组，如对急性白血病或其他恶性肿瘤等”。张亭栋这种说法有些人会接受，有些人不会接受，但其道理很清晰。 张亭栋的临床实验设计与同期的国内外研究相比如何？1973年法国Bernard等用柔红霉素的新疗法是与过去疗法比较。1983年到1986年国外的几个病例，也都无对照而发表，它们是：美国Flynn等（1983）、瑞典的Nilsson（1984）、荷兰的Daenen等（1986）、美国的Fontana等（1986）。人们熟知的1988年王振义课题组对24位病人的报道，也未设对照。所以，张亭栋等在1973年到1979年的工作，并不低于同期国内外临床研究的标准。 中医理论（CMT）是否对于三氧化二砷治疗白血病有指导作用？如果我们今天复习这些文献，看不到中医辨证分型对三氧化二砷治疗白血病的意义。比如，他们谈到对急性白血病的中医分为五型，而治疗时使用三氧化二砷并无差别，对其他辅助的中药，也许这些分型起作用，虽然也待证明。而西医对白血病的分型才对他们找到适应症起了作用。他们完全放弃中医辨证分型以后，适应症和效果更确切。有趣的是，张亭栋、张鹏飞、王守仁、韩太云在1973年的第一篇论文完全没谈中医理论，而其后发表的多篇论文含中医辨证分型。奇怪的是，虽然他们说治疗作用来源于三氧化二砷，但他们直到1996年才完全放弃轻粉（氯化亚汞）。是他们考虑了中医理论、还是不愿改已经证明有效的药方？ 诚然，未能证明中医理论并非否认中医理论，但是，从这两个药的例子中我们尚不清楚中医理论对中药的科学研究是否必需。 中国对于急性早幼粒白血病治疗的贡献 急性早幼粒白血病（APL），曾被认为是白血病中比较凶猛且易致死的一种。1973年，法国巴黎第十大学的Bernard等报道他们自1967年以来用西药（daunorubin，柔红霉素）治疗APL的结果。此后蒽环类抗生素(anthracycline，包括柔红霉素)和阿糖胞苷（cytosine arabinoside）的化疗方案成为世界上治疗APL的主流方法。1973年张亭栋等发现三氧化二砷（As2O3）对白血病的治疗作用，至1979年完全清楚其最佳适应症为APL。 1983年，Koeffler 总结了多种化合物（包括维甲酸）在体外细胞培养对人白血病细胞的分化作用。1983年，美国明尼苏达大学的Flynn等报道用13-顺式维甲酸治疗一例APL病人，缓解了白血病、但病人后因其他缘故去世。1984年，瑞典Lund大学医院内科的Nilsson报道用13-顺式维甲酸治疗一例APL。1986年荷兰的Daenen等报道用顺式维甲酸治疗一例APL。1986年美国西弗吉尼亚大学的Fontana等报道用13-顺式维甲酸治疗一例APL。 1985年，上海第二医科大学王振义用全反式维甲酸治愈一例5岁白血病儿童。1987年王振义课题组在英文版《中华医学杂志》报道用全反式维甲酸（合并其他化疗药物或单独）治疗六例APL病人。1988年，王振义课题组在美国《血液》杂志发表论文，总结他们用全反式维甲酸治疗24例APL病人，获得完全缓解。这篇论文使全反式维甲酸在国内外较快得到重复和推广，为APL病人带来福音。 1995年，大连解放军中医血液病专科中心黄世林、郭爱霞、向阳、王晓波和大连医科大学附属第一医院的林慧娴、富丽等在《中华血液学杂志》发表“复方青黛片为主治疗急性早幼粒白血病的临床研究”，以复方青黛片治疗60例APL，完全缓解率达98%。所用中药复方含青黛、太子参、丹参、雄黄，其中雄黄含硫化砷(arsenic disulfide)。 1996年2月，哈尔滨医科大学第一临床医院的张鹏、王树叶、胡龙虎、施福东、邱凤琴、洪珞珈、韩雪英、杨惠芬、宋颖昭、刘艳平、周晋、金镇敬在《中华血液学杂志》发表“三氧化二砷注射液治疗72例急性早幼粒细胞白血病”，总结他们自1992年至1995年用三氧化二砷（不含汞）治疗130例APL病人中完成一个及以上疗程的72例。初治患者完全缓解率为73%，复发患者完全缓解率为52%，与全反式维甲酸无交叉耐药。 1996年8月1日美国《血液》杂志发表陈国强、朱军、石学耕、倪建华、仲豪杰、Si GY、金小龙、唐玮、李秀松、熊树民、沈志祥、孙GL、马军、张鹏、张亭栋、G Claude、陈赛娟、王振义、陈竺的合作论文，报道陈竺、王振义、陈赛娟等带领上海血液研究所，用体外培养白血病细胞，研究三氧化二砷治疗白血病作用的分子机理。 1997年，徐敬肃、段秀锦、徐莹、辛晓敏、宋晓红、张庭栋（原文笔误“张亭栋”的名字）在《中国血液学杂志》报道对于一例反复发作三次的APL病人，每次用“癌灵一号”，获得20年存活。 1997年《血液》杂志发表上海的沈志祥、陈国强、倪建华、李秀松、熊树民等论文，他们用纯三氧化二砷治疗15例APL，其中10例只用三氧化二砷，取得90%的完全缓解率。 1998年，世界最权威的医学杂志《新英格兰医学杂志》(NEJM)发表美国纽约的Sloan-Kettering癌症纪念医院和康奈尔医学院的Soignet等的论文。他们给常规化疗后复发的12例APL病人使用三氧化二砷，观察到11例完全缓解，其机理可能和细胞部分分化和细胞凋亡有关。 NEJM文章导致国际医学界广泛接受三氧化二砷对APL的治疗作用，起到了此前20多年中国医生在中文杂志上未能起到的作用。 迟迟未至的认同 以屠呦呦和张亭栋为代表的研究人员做出的成果都得到了普遍应用，直接产生了治病救人的效果。 但是，由于不同的原因，两位科学家个人没有获得中国充分的认可，也缺乏国际肯定。 青蒿素的发现和应用，广为人知。而屠呦呦的贡献，却一直有争议。其原因还待更多史家细究。一个重要的文化问题是，面对重要的发现，出现矛盾时，中国的有关部门不是确切地搞清楚各人的功劳而是回避矛盾、袖手旁观，导致缺乏认可。而国外的科学家和医药界不可能搞清楚中国内部刊物和会议的记录。 我们在研究青蒿素历史过程中读了中国有关部门没有费时研读的材料。矛盾和不清有多个来源。与齐心协力的“两弹一星”大计划不同，青蒿素的研究矛盾不断，有不同研究小组之间矛盾，也有研究小组内部不同成员之间的矛盾。当时的研究人员，因为文革的原因，一般年资都比较低，屠呦呦作为研究小组负责人仅为“实习研究员”，文革后才晋升为副研究员。 论文写作不及时、发表不规范。在此，文革的阴影很明显。常规科学实践中（无论是彼时的西方还是现在的中国），屠呦呦在1972年3月不一定要在发表论文以前在会上共享结果，而可以先发表乙醚提取的文章以后在共享。她的研究小组也应该会先发表钟裕容纯化获得青蒿素晶体的文章。这两篇文章应该建立屠呦呦小组的发现优先权。而实际上，起初她们在关门会议上报告，等到1977年才发表第一篇中文论文，而且还是以“青蒿素协助组”的集体笔名。英文论文更滞后到1982年，用“青蒿素及其衍生抗疟药合作组”的集体笔名。这样埋下了进一步争议的伏笔。 当然，如果按现在作者先发表论文再与他人分享的常规，争论会少很多，容易为作者评功。不过，这样对有些病人并不一定是最好：如果都要等一家发了论文，其他课题组才能用药，有些病人那时就不可能及时用药而无治疗机会、甚至可能因此丧生。 从多个来源的信息提示，屠呦呦突出自己作用时未充分肯定其他研究小组和自己研究小组其他成员的作用，包括她后来的出版物引用文献时，将他人的名字省略、自己的名字前移，也为 “523任务”其他参与者所诟病。我们作为无争议方试图和屠呦呦交流也有一定困难，不理解她把中医研究院的原始材料至少有段时间收藏在自己家，不愿给我们看。 张亭栋虽然被《纽约时报》报道过，但未受中国的肯定，在国际学术和医学界也基本继续默默无闻，其原因不在于矛盾。他的研究小组，有人（孙鸿德）提出过专利争议，但时间比较晚、且未获法庭赞同。从1973年开始发表的论文可以看到，张亭栋的关键作用很清晰。他未被很好地认可，可能与他工作地点有关，也和他英文论文较少、缺乏国际视野和国际交流有关。不能完全排除他本人未充分意识到其工作重要程度的可能性。 1998年，在《中西医结合杂志》，陈国强、陈赛娟、王振义、陈竺在专题笔谈中介绍“自70年代初期，哈尔滨医科大学（以下简称哈医大）在临床实践中发现三氧化二砷（简称氧化砷）治疗急性早幼粒白血病（APL）有效。近两年来，我们与哈医大合作，应用氧化砷注射液治疗对全反式维甲酸（ATRA）和常规化疗药物耐用的APL复发病人”，肯定了哈医大的工作。 但几乎所有英文文献作者似乎都不知道张亭栋的关键作用，引用的文献不提他的名字。而且，几乎所有英文文献并不知道张亭栋早在1973年到1979年就已经发表论文，报道他们发现三氧化二砷治疗白血病的作用。很多英文文献，包括国内学者在国外发表的文献以及国外学者的文献，都将三氧化二砷治疗白血病的发现引用成1992、甚至1996年。例如，重复中国结果、也非常有助于将中国发现推到世界的1998年Soignet等的论文，在摘要中说中国有两篇报道三氧化二砷治疗APL的文章，在引言中称中国最近有报道三氧化二砷可以引起APL完全缓解，然后引用了孙鸿德等1992年《中西医结合杂志》的短篇“经验交流”、张鹏等1996年《中国血液学杂志》、沈志祥等1997年《血液》等论文，而未引用张亭栋发表于1973和1979的文章。 1996年《科学》记者对三氧化二砷的介绍，虽然介绍了张亭栋，但说他的文章发表于1992年。 张亭栋本人很少发表英文论文。2001年，张亭栋和陈国强为共同第一作者（其他作者为王铸钢、王振义、陈赛娟，通讯作者为陈竺）在国际期刊《癌基因》发表论文，介绍三氧化二砷。在引言中，他们称最近发现三氧化二砷对APL的作用，引用陈国强等1996年《血液》论文。在正文第二页内，说三氧化二砷的研究始于1971年，但未引用文献。号称治疗了一千多不同癌症的病人，观察到对几种癌症的作用，包括“慢性粒细胞白血病、淋巴瘤、食管癌、和特别是APL”，但也未引用文献。然后，文章说对APL作用的初步报道于1992年，也是引用孙鸿德的“经验交流”。这样，张亭栋本人作为第一作者的英文文章就未引用自己1970年代的几篇文献，全部淹没了自己在1973年和1974年公开发表的三氧化二砷对白血病的疗效、和1979年明确提出对APL疗效最好的发现。 2002年朱军、陈竺、Lallemand-Breitenbach、de The等在《自然综述癌症》介绍砒霜治疗作用时，在插图中显示了1970年代张亭栋的里程碑工作，但引文是孙鸿德等（1992）和张鹏等（1996）的论文，在参考文献中孙鸿德文章下注明它“证明三氧化二砷治疗APL作用的第一篇论文”）。 因为1992和1996这两篇文章是中文文章，而且它们未引用1970年代的文献，所以，国外学者即使请人翻译这两篇的全文、也不能从中知道原始文献。 王振义和陈竺2008年在《血液》杂志综述APL研究进展，对于三氧化二砷对多种癌症的治疗，引文为朱军等（2002）的文章。对三氧化二砷治疗APL引文为孙鸿德等（1992）、以及张鹏等(1996)、陈国强等(1996)、沈志祥等(1997)、牛等(1999)。 因此，张亭栋的作用和发现年代，在国际上几乎不为人知。 肯定张亭栋和屠呦呦的意义 中国和世界肯定张亭栋和屠呦呦等，不仅是对他们迟到的感谢，也有利于中国和世界认识中药是尚未充分开发的宝库。人们必须研读中文文献，可能还需透过几层迷惑，才能发现哪一个药是针对哪一个疾病，正如屠呦呦和张亭栋在1970年代所做。 直接提示我们的是：可以通过研究确定三氧化二砷是否确实还有其他治疗作用。因为张亭栋和其他中国研究者曾报道三氧化二砷可以治疗多种癌症，包括肝癌、食管癌、胃癌、结肠癌、淋巴肉瘤等。比如，方锦声等1981年在《江苏省医学科学情报所》总结其对42例晚期原发性肝癌的治疗作用，“癌灵一号”加外科手术的三年存活率为42%，其中5例生存超过5年，而单纯手术的三年存活率为8%，无超过5年者。1988年李元善、张亭栋、王兴榕、刘旭在《肿瘤防治研究》报道他们在体外细胞培养观察到“癌灵一号”对肝癌细胞系的作用。 间接提示：严格地研究其他中药成分的作用，可能还会有更多发现。比如中国一些医院模模糊糊用的一些药、和很多企业马马虎虎地制造和推销的一些药，如果经过严格检验和研究，可能会更明确适应症、有更好疗效，世界才能接受，真正适合的病人才能得到帮助。 研究 “523任务”的历史，有助于了解中国大科学计划、大协作的优点和缺点。“两弹一星”是成功的例子，青蒿素的经验并不同于两弹一星。而彼时还有遍布全国的“气管炎办公室”、“慢性老年性肺心病”等课题，耗费的人力、物力不少，是取得了我们大家不熟知的成果，还是结局不乐观？汲取这些先例的经验和教训，对目前的多个大项目，也许有所裨益。 如果屠呦呦和张亭栋获得了中国的广泛认可、甚至世界的肯定，我们希望，中国大众不能简单地英雄崇拜，更不应该否认其他人的工作。在青蒿素发现过程中，很多人参与并作出重要贡献，包括“523任务”组织者，也包括云南的罗泽渊，山东的魏振兴，广东的李国桥，北京的李鹏飞、梁丽，上海的吴照华、周维善和吴毓林等。屠呦呦研究小组的钟裕蓉、余亚纲、倪慕云也有重要贡献。解放军战士、农民是早期临床疗效的志愿者，而那时志愿的程序不同于现在。 最重要的是，这些药物救了成千上万人的生命，我们应该推崇他们的工作、肯定他们的成就。科学，有着客观的标准，通过争论可以将我们带近真理。 相关文献 青蒿素部分 Jang, C.S.（张昌绍）, Fu, F.Y., Wang, C.Y., Huang, K.C., Lu, G. and Chou, T.C. 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标签: 张亭栋
