Stockholm, Dec. 15(Greenpost)– Chinese Nobel Laureate in Medicine Tu Youyou gave a wonderful Nobel Lecture in the Aula at Karolinska Institute on Dec. 7, 2015 in Chinese. But with English text. The following is the whole text in English:
Tu Youyou’s Nobel Lecture.
Dear respected Chairman, General Secretary, esteemed Nobel Laureates, Ladies and Gentlemen:
It’s my great honor to give this lecture today at Karolinska Institutet. The title of my presentation is Artemisinin-A Gift from Traditional Chinese Medicine to the World.
Before I start, I would like to thank the Nobel Assembly and the Nobel Foundation for awarding me the 2015 Nobel Prize in Physiology or Medicine. This is not only the honor for myself, but also the recognition of and motivation for all scientists in China. I would also like to express my sincere appreciation to the great hospitality of the Swedish people which I have received during my short stay over last few days.
Thanks to Dr. William Campbell and Dr. Satoshi Ömura for the excellent and inspiring presenations. The story I will tell today is about the dilligence and dedicaiton of Chinese scientists during searching for antimalarial drugs from the traditional Chinese medicine forty years ago under considerably under-resourced research conditions.
Discovery of Artemisinin
Some of you may have read the history of artemisinin discovery in numerous publications. I will give a brief review here. This slide summerizes the antimalarial research program carried out by the team at the Institute of Chinese Malaria Medica(ICMM) of Academy of Traditional Chinese Medicine(ATCM) in which the programs highlighted in blue were accomplished by the team at ATCM while the program highlighted with blue and white were completed through joint efforts by the teams at ATCM and other institutes. The un-highlighted programs were completed collaboratively by the other research teams across the nation.
Discovery of Artemisinin at ICMM
The team at ICMM initiated research on the Chinese Medicines for malaria treatment in 1969. Following substantial screening, we started to focus on herb Qinghao in 1971, but received no promising results after multiple attempts. In September 1971, a modified procedure was designed to reduce the extraction temperature by immersing or distilling Qinghao using ethyl ether. The obtained extracts were then treated with an alkaline solution to remove acidic impurities and retain the natural portion.
In the experiments carried out on October 4th 1971, sample No. 191 i.e. the neutral portion of the Qinghao ether extract was found 100% effective on the malaria mice when administered orally at a dose of 1.0g/kg for consecutive three days. The same results were observed when tested in malaria monkeys between December 1971 and January 1972. This breakthrough finding became a critical step in the discovery of artenisinin.
We subsequently carried out a clinical trial between August and October 1972 in Hainan province in which the neutral Qinghao ether extract successfully cured thirty falciparum and plasmodium malaria patients. This was the first time the neutral Qinghao ether extract was tested in human. In November 1972, an effective antimalarial compound was isolated from the neutral Qinghao Ether extract. The compound was late named Qinghaosu(artemisinin in Chinese).
Artemisinin Chemistry Studies
We started to determine chemical structure of artemisinin in December 1972 through elemental analysis, spectrophotometry, mass spectrum, plarimetric analysis and other techniques. These experiements confirmed that the compound had a complete new sesquiterpene structure with a formula of C15H22O5, a molecular weight of 282 and contained no nitrogen.
Stereo Structure of Artemisinin
The formula of the molecule and other results were verified by the analytical chemistry department of China Academy of Medical Sciences on April 27th 1973. We started collaboration with Shanghai Institute of Organic Chemistry and the Institute of Biophysics of Chinese Academy of Sciences on artemisinin chemical structure analysis in 1974. The stereo-structure was finally determined using the X-ray diffraction technique which verified that artemisinin was a new sesquiterpene lactone containing a peroxy group. The structure was published in 1977 and cited by the Chemical Abstracts.
- Research group for Artemisinin. A new sesquiterpene lactone-Artemisinin. (Chinese Science Bulletin, 1977, 3:142)
Artemisinin and Artemisinin Derivatives
Derivatization of artemisinin was performed in 1973 in order to determine its functional group. A carboxyl group was verified in the artemisinin molecule through reduction by sodium borohydride. Dihydroartemisinin was found in this process. Further research on the structure-activity relationship of artemisinin was conducted. The peroxyl group in the artemisinin molecule was proven critical for its antimalarial function. Efficacy was improved for some compounds derivatized through the hydroxy group of dihydroartemisinin.
Artemisinin and Artemisinin Derivatives
This slide shows the chemical structures of artemisinin and its derivatives –dihydroartemisinin, artemether, artesunate, arteether. Up to now, no clinical application has been reported with other artemisinin derivatives except for the four presented here.
Artemisinin and Dihydroartemisinin New Drug Certificates
This slide shows the Artemisinin New Drug Certificate and the Dihydroartemisinin New Drug Certificate(right) granted by the China Ministry of Health in 1986 and 1992, respectively. Dihydroartemisinin is ten times more potent than artemisinin, again demonstrated ”high efficacy, rapid action and low toxicity” of the drugs in the artemisinin category.
Worldwide Attention to Artemisinin
The World Health Organization(WHO), the World Bank and United Nations Development Program(UNDP) held the 4th joint Malaria Chemotherapy Science Working Group meeting in Beijing in 1981. A series of presentations on artemisinin and its clinical application including my report”Studies on the Chemistry of Qinghaosu” received positive and enthusiastic responses. In the 1980s, several thousand of malaria patients were successfully treated with artemisinin and its derivatives in China.
After this brief review, you may comment that this is no more than an ordinary drug discovery process. However, it was not a simple and easy journey in discovery of the artemisinin from Qinghao, a Chinese herb medicine with over two thousand year clinical application.
Commitement to the Clearly Defined Goal Assures Success in Discovery
The Institute of Chinese Materia Medica of Academy of Traditional Chinese Medicine joined the national ”523” anti-malaria research project in 1969. I was appointed the head to build the ”523” research group in the institute by the academy’s leadership team, responsible for developing new antimalarial drugs from Chinese medicines. It was a confidential military program with a high priority. As a young scientist in her early career life, I felt overwhelmed by the trust and responsibility received for such a challenging and critically important task. I had no choice but fully devoted myself to accomplishing my duties.
Knowledge is Prologue in Discovery
This is a photo taken soon after I joined the Institute of Chinese Materia Medica. Professor Lou Zhiqin(left), a famous pharmacognosist, was mentoring on how to differentiate herbs. I attended a training course on theories and practices of traditional Chines medicine designed for professionals with a modern(western ) medicine training background. ”Fortune favors the prepared mind”1 and ”What’s past is prologue.”2 My prologue of integrated training in the modern and Chinese medicines prepared me for the challenges when the opportunities in searching for antimalarial Chinese medicine became available.
- Quote by Louis Pasteur
- Quote in ”The Tempest” by William Shakespeare.
Information Collating and Accurate Deciphering Are the Foundation for the Success in Research
After accepting the tasks, I collected over 2000 herbal, animal and mineral prescriptions for either internal or external uses through reviewing ancient traditional Chinese medical literatures and folk recipes, interviewing those well-known experienced Chinese medical doctors who provided me prescriptions and herbal recipes. I summarized 640 prescriptions in a brochure ”Antimalarial Collections of Recipes and Prescriptions.” It was the information collection and deciphering that laid sound foundation for the discovery of artemisinin. This also differntiates the approaches taken by Chiense Medicine and general phytochemistry in searching for novel drugs.
Thorough Literature Reviewing Inspires an idea leading to Success
I reviewed the traditional Chinese literatures again when our research stalled following numerous failures. In reading Ge Hong’s ”A Handbook of Prescriptions for Emergencies,” (East Jin Dynasty). 3rd-4th century). I further digested the sentence”A Handful of Qinghao Immersed in Two Liters of Water, wring out the Juice and Drink It All” when Qinghao was mentioned for alleviating the malaria symptoms. This reminded me that the heating might need to be avoided during extraction, therefore the method was modified by using the solvent with a low boiling point.
The earliest mentioning of Qinghao’s application as a herbal medicine was found on the silk manuscripts entitled ”Prescriptions for Fifty-two Kinds of Disease” unearthed from the third Han Tomb at Mawangduei. Its medical applicaiton was also recorded in ”Shen Nong’s Herbal Classic”, ”Bu Yi Lei Gong Bao Zhi” and ”Compendium of Materia Medica”, etc. However, no clear classification was given for the Qinghao(Artemisia) regardless of a lot of mentioning of its name Qinghao in those literatures. All species in Qinghao(Artemisia) family were mixed and by the time of 1970’s two of Qinghao(Artemisia) species were collected in Chinese Pharmacopoeis and four others were also being prescribed.
Our subsequent investigation proved that only Artemisia annua L contains artemisinin and is effective against malaria.
In addition to the confusion in the selection of right species and the difficulty caused by the low content of artemisinin in the herb, variouables such as the meicinal part of the plant, the growing regions, the harvest season, and extraction/purificaiton processes, etc, added extra difficulties in the discovery of artemisinin. Success in identifying effectiveness of Qinghao neutral ether extract is not a simple and easy win.
No doubt, traditional Chinese medicine provides a rich resource. Nevertheless, it requires our thoughtful consideration to explore and improve.
Persistency in front of Challenges
Research condition was relatively poor in China in the 1970s. In order to produce sufficient quantity of Qinghao extract for clinical trial, the team carried out extraction using several household water wats. Some members’ health was deteriorated due to exposure to a large quantity of organic solvent and insufficient ventilation equipment. In order to launch clinical trial sooner while not compromising patient safety, based on the limited safety data from the animal study, the team members and myself volunteered to take Qinhhao extract ourselves to assure its safety.
Unsatisfied results were observed in the clinical trial using artemisinin tablets, the team carried out a thorough investigation and verified poor disintegration of the tablets as the root course which allowed us to quickly resume the trials using capsules and confirm artemisinin’s clinical efficacy in time.
Collaborative Team Efforts Expedited Translation from Scientific Discovery to Effective Medicine
An antimalarial drug research symposium was held by the national project 523 office in Nanjing on 8th March 1972. In this meeting, on behalf of the Institute of Chinese Materia Medica. I reported the positive readouts of the Qinghao extract No. 191 observed in animal studies performed on malaria mice and monkeys. The presentation received significant interests. On 17th November 1972, I reported the results of successful treatment of thirty clinical cases in the national conference held in Beijing. This triggered a naitonwide conllaboration in research on Qinghao for malaria treatment.
Today, I would like to express my sincere appreciation again to my fellow project 523 colleagues in the Academy of Traditional Chinese Medicine for their devotion and exceptional contributions during discovery and subsequent applicaiton of artemisinin. I would like to, once again, thank and congratulate the colleagues from Shandong Provincial institute of Chinese Medicine, Yunnan Provincial Institute of Materia Medica, the Institute of Biophysics of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry of Chinese Medicine, Academy of Military Medical Sciences and many other institutes for their invaluable contribution in their respective responsible areas during collaboration and their helps to and care for the malaria patients. I would also like to express my sincere respect to the mational 523 office leadership team for their continuous efforts in organizing and coordinating the antimalarial research programs. Without collective efforts, we would not be able to present artemisinin-our gift to the world in such a short period of time.
Malaria Remain as a Severe Challenge to the Global Public Health
”The findings in this year’s World Malaria Report demonstrate that the world is continuing to make impressive progress in reducing malaria cases and deaths”. Dr. Margaret Chan, Director-General of World Health Organization commented in the recent World Malaria Report. Nevertheless, statisically, there are approximately 3.3 billions of population across 97 countries or regions still at a risk of malaria contraction and around 1.2billion people live in the high risk regions where the infection rate is as high as or over 1/1000. According to the latest statisitical estimation, approximately 198 million cases of malaria occurred globally in 2013 whih caused 580.000 deaths with 90% from severely affected African countries and 78% being children below age five. Only 70% of malaria patients receive artemisinin combinaiton therapies (ACTs) inAfrica an as high as 56 millions to 69 millions of child malaria patients do not have ACTs available for them.
- WHO World Malaria Report 2014
The Severe Warning of Parasites Resistant to Artemisinin
- falciparum resistance to artemisinin has been detected in five countries of the Greater Mekong sub-region: ambodia, the Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam. In many areas along the Cambodia-Thailand border. P. Falciparum has become resistant to most available antimalarial medicines.
This slide shows the areas where artemisinin resistant malaria appears according to this year’s report. Artemisinin resistant P. Falciparum has been detect in the areas highlighted in red and black. Clearly, this is a severe warning since the resistance to artemisinin is not only detected in the Greater Mekong sub-region but also appreas in some of African regions.
Global Plan for Artemisinin Resistance Containment
The goal of the Global Plan for Artemisinin Resistant Containment (GPARC) is to protect ACTs as an effective treatment for P. Falciparum malaria. Artemisinin resistance has been confirmed within the Greater Mekong sub-region, and potential epidemic risk is under a critical review. An unanimous agreement has been reached by over hundred experts involved in the program that the chance of containing and eradicating artemisinin resistant malaria is very limited and there is an urgent need to constrain artemisinin resistance.
To protect efficacy of ACT, I strongly urge a global compliance to the GPARC. This is our responsibility as a scientist and medical doctor in the field.
WHO Global Plan for Arteminsinin Resistant Containment, 2011.
Chinese Medicine, A Great Treasure
Before I conclude today’s lecture, I would like to discuss brieflly about Chinese medicine.”Chinese medicine and pharmacology are a great treasure-house. We should explore them and raise them to a higher level”. Artemisinin was explored from this resource. From research experience in artemisinin discovery, we learnt strengths from both Chinese and Western medicines. There are a great potential and future advance if these strengths can be fully integrated. We have a substantial amount of natural resource from which our fellow medical researchers can develop novel medicines. ” Since ”tasting hundred herbs by Shen Nong”, we have accumulated substantial experience in clinical practice, integrated and summarised medical application of most nature resource over last thousands of years through Chinese medicine. Adopting, exploring, developing and advancing these practices would allow us to discover more novel medicines beneficial to the world healthcare.
On the Stork Tower
To end my talk, I would like to share with you the well-known poem, ”On the stork tower”. Of Tang Dynasty
On the stork tower1
The sun along the mountain bows;
The Yellow River seawards flows;
You will enjoy a grander sight,
By climbing to a greater height.
Let’s reach to a greater height to appreciate Chinese culture and find the beauty and treasure in the territory of traditional Chinese medicine!
- By Wang Zhihuan(688-742 AD), The stork Tower is located in Yongji County, Shanxi Province.
Finally, I would like to acknowledge all colleagues in China and overseas for their contributions in the discovery, research and clinical application of artemisinin!
I am deeply grateful for all my family members for their continuous understanding and support!
I sincerely appreciate your kind attention!
Thank you all!
(Source, www.nobelprize.org, Nobel Media)
Editor: Xuefei Chen Axelssson
Chinese version: 中文版如下：屠呦呦诺奖演讲：青蒿素－中医药给世界的一份礼物。
谢谢William C. Campbell（威廉姆.坎贝尔）和Satoshi Ōmura（大村智）二位刚刚所做的精彩报告。我现在要说的是四十年前，在艰苦的环境下，中国科学家努力奋斗从中医药中寻找抗疟新药的故事。
关于青蒿入药，最早见于马王堆三号汉墓的帛书《五十二病方》，其后的《神农本草经》、《补遗雷公炮制便览》、《本草纲目》等典籍都有青蒿治病的记载。然而，古籍虽多，确都没有明确青蒿的植物分类品种。当年青蒿资源品种混乱，药典收载了2个品种，还有4个其他的混淆品种也在使用。后续深入研究发现：仅Artemisia annua L.一种含有青蒿素，抗疟有效。这样客观上就增加了发现青蒿素的难度。再加上青蒿素在原植物中含量并不高，还有药用部位、产地、采收季节、纯化工艺的影响，青蒿乙醚中性提取物的成功确实来之不易。中国传统中医药是一个丰富的宝藏，值得我们多加思考，发掘提高。
疟疾对于世界公共卫生依然是个严重挑战。WHO总干事陈冯富珍在谈到控制疟疾时有过这样的评价，在减少疟疾病例与死亡方面，全球范围内正在取得的成绩给我们留下了深刻印象。虽然如此，据统计，全球97个国家与地区的33亿人口仍在遭遇疟疾的威胁，其中12亿人生活在高危区域，这些区域的患病率有可能高于1/1000。统计数据表明，2013年全球疟疾患者约为1亿9千8百万，疟疾导致的死亡人数约为58万，其中78%是5岁以下的儿童。90%的疟疾死亡病例发生在重灾区非洲。70% 的非洲疟疾患者应用青蒿素复方药物治疗（Artemisinin-based Combination Therapies, ACTs）。但是，得不到ACTs 治疗的疟疾患儿仍达5千6百万到6千9百万之多。
最后，我想与各位分享一首我国唐代有名的诗篇，王之涣所写的《登鹳雀楼》：白日依山尽，黄河入海流，欲穷千里目，更上一层楼。 请各位有机会时更上一层楼， 去领略中国文化的魅力，发现蕴涵于传统中医药中的宝藏！