https://www.youtube.com/watch?
v=UPqFwaxLvqg
https://www.nobelprize.org/prizes/medicine/2015/tu/biographical/
Lasker DeBakey Clinical Medical Research Award 2011
2011 年拉斯克奖
Tu Youyou
屠呦呦
For the discovery of artemisinin, a drug therapy
for malaria that has saved millions of lives across
the globe, especially in the developing world.
http://www.laskerfoundation.org/awards/2011clinical.htm
Malaria
The incidence of malaria in Zambia since 1975.
Malaria
• 41% of world’s population live malaria-infected areas
• > 100 countries, > 2 billion people
• 300 million clinical cases each year
• > 90% in tropical Africa
• 0.7 – 2.7 million deaths a year
• 75% of them are African children under 5
• 4th cause of death in children (2002)
• After perinatal conditions, pneumonias, diarrhea
• Other high risk groups
• Pregnant women, non-immune travelers, refugees, displaced
persons, labor forces entering into endemic areas
http://www.cdc.gov/malaria/facts.htm
Malaria
• In Sub-Saharan Africa, 15% of all disability-
adjusted life-years (DALYs) lost to malaria
• Disproportionately affects the poor people
• Unlike AIDS which affected developed
countries, malaria receive far less funding for
drug development
Malaria is a vector borne disease
•4 human protozoan parasites
– Plasmodium falciparum
– P. vivax
– P. malariae
– P. ovale
•Transmitted by mosquito bites
– Female Anopheles mosquito
– Common in China/Hong Kong:
• 中華按蚊 (Anopheles sinensis)
• 微小按蚊 (Anopheles minimus)
Anopheles sinensis ( 中華按蚊 )
http://wrbu.si.edu/www/SpeciesPages/SpeciesPages_ANO/ANO_A-hab/ANsin_hab.html
Anopheles minimus ( 微小按蚊 )
http://wrbu.si.edu/www/SpeciesPages/SpeciesPages_ANO/ANO_A-det/ANmin_A_det.html
Causative agent: Plasmodium spp.
•4 human Plasmodium spp.
– P. falciparum
• Major cause of death
• Cerebral malaria
– P. vivax
– P. malariae
– P. ovale
Life cycle
Infects
Red blood cells
Bursting of RBC:
Undulating fever
http://www.dpd.cdc.gov/dpdx/HTML/ImageLibrary/Malaria_il.htm
Animated Life Cycle of Plasmodium
falciparum
(causative agent of malaria)
Animated life cycle of malaria
(Trends in Parasitology, 21 (12), p.573-580)
https://www.youtube.com/watch?v=A2-XTlHBf_4
Blood smear of P. falciparum
http://www.rph.wa.gov.au/malaria/diagnosis.html
http://www.dpd.cdc.gov/dpdx/HTML/ImageLibrary/Malaria_il.htm
Fever in malaria
Undulating fever in patients about every 24 hours;
this happens when parasites break from red blood cells and causing fever in patie
Plasmodium falciparum
“Malaria: Principles and Practice of Malariology” ed. W. H. Wernsdorfer and I. McGregor
(Churchill-Livingstone, Edinburgh, 1988) Volume 1, Ch. 25, pp. 709-734.
Artemisinin
• The only medicine (Coartem; artemether +
lumefantrine) derived from Chinese medicine that
has worldwide application
Not true anymore; artemisinin-
• Most potent and latest anti-malarial drug resistance found in SE Asia
• No artemisinin-resistance reported
• Originated from the leaves of a plant commonly
found in China
• Artemisia annua 青蒿
• Malaria used to be a problem in southwest China
• Vietnam war brought Chinese soldiers into more
contact with malaria.
Vietnam War (1954 – 1975)
Chemical synthesis
Screening of old medical books
Project 523
• 23-May 1967
• Led by both Chairman Mao & Premier Zhou
• A secret nation-wide program
• Goal of Project 523
• to produce antimalarial to be used in battlefield
• Search for new antimalarial drugs by searching recipes and practices of
Chinese medicine
• > 500 scientists in 60 groups involved.
• Screening
• 380 extracts from 200 different herb preparations
• Preliminary success from extracts of qinghao (Artemisia) in 1971
• Boiling, ethanol extractions gave successful but inconsistent results
Qīng Hāo - - and Traditional Chinese Medicine
Discourse on Prescriptions for
Treatments
Wǔ Shí Èr Bìng Fāng Lùn for 52 Sicknesses; Mawangdui Han
Dynasty; 168 BC.
Collection of Prescriptions for
Emergency
Zhŏu Hòu Bèi Jí Fāng Treatments; Ge Hong (281-340 AD); East
Jin (Chin) Dynasty; 340 AD.
Thousand Pieces of Gold Medical
Prescriptions; Tang dynasty; 7-9
Qiān Jīn Yào Fāng
Centuries.
Compendium of Foundations of
Materia
Běn Căo Gāng Mù
Medica; Li Shi-Zhen; 1596
Book of Seasonal Fevers; Qing
Wēn Bìng Tiáo Biàn Dynasty; 1798.
Artemisia annua 青蒿
•( 英 )Sweet Wormwood Herb
•【 别名 】
– 香蒿、苦蒿、黄蒿。
•【 采制】 1. 蒿芩清膽湯《通俗傷寒論》：青蒿
– 秋季花盛开进割取地上部分，除去老茎， 、黃芩、半夏、陳皮、枳殼、竹茹、茯
苓、碧玉散。治外感濕熱之邪，留戀不
阴干 解、微惡寒而發熱、有汗不解、頭重肢
•【性味与归经】 倦、胸悶痞滿等症。
– 苦，辛，寒。归肝、胆经。
2. 青蒿鱉甲湯《溫病條辨》：青蒿、
•【功能与主治】 鱉甲、知母、生地、丹皮。治瘧疾及溫
– 清热解暑，除蒸，截疟。用于暑邪发热， 病之暮熱早涼汗解渴飲者。
阴虚发热，夜热早凉，骨蒸劳热，疟疾寒 3. 清骨散《證治準繩》：青蒿、地骨
热，湿热黄疸。 皮、銀柴胡、胡黃連、秦艽、鱉甲、知
母、甘草。治骨蒸勞熱。
Artemisia annua 青蒿
http://digilander.libero.it/felrig/photos/artemisia_annua.htm
Qinghao & Chinese science in 1960s – 70s
•Institute of Chinese Meteria Medica, China Academy of Chinese Medical Sciences
(CACAMS) 中国科学院上海药物研究所
•Shanghai Institute of Organic Chemistry 有机所、
•北京生物物理所
•1967
– Screening programs for antimalarials
•1971
– Found ether extract, but not water extract, of Qinghao to be effective
•1972
– Active compound purified and named Qinghaosu (artemisinin)
•1975 Sept – Oct
– Clinical trial by 中国中医研究院 in 海南昌江
– Parasitemia turns negative faster than CQ by 12 hours
– Fever subsides faster than CQ by 15 hours
•1982
– First publication in China Cooperative
•Many original Chinese studies were not acceptable to Western governments because
of lack of standard practices
Qinghao (Artemisia annua 青蒿 ; 黄花蒿 )
•1971
•extraction of aerial parts of
– A. annua with diethylether
– Antimalarial properties on
animals
•1972
– main active principle:
artemisinin (qinghaosu)
– a sesquiterpene lactone with an
endoperoxide bridge.
Klayman, D. L. Science 1985 228 1049-51
Major breakthrough in extraction method for artemisinin
1970 Late 1971
60 – 80%% anti-malarial 100% anti-malarial
青蒿一握，以水二升渍，绞取汁，尽服之
A handful of qinghao immersed in two liters of water,
wring out the juice and drink it all
Ether extraction
Ether: low boiling point
Extract artemisinin from qinghao
Did not destroy artemisinin structure
Mild temperature to remove ether;
Obtain pure artemisinin
Chemical analysis
<< 治寒热诸疟方 >>
Zhŏu Hòu Bèi Jí Fāng http://news.now.com/home/international/player?newsId=153324
东晋 葛洪
Qinghaosu (Artimisinin, 青蒿素 )
• Total synthesis achieved
• Analogs: artemether
• ↑ potency, solubility
• Rapid acting in ↓ parasitemia
• Short half-life
• Used with other longer-acting
antimalarials
• Artemether + primaquine
• Anti-malarial mechanism
• Disturb redox system of parasite
黄花蒿素 , 艾斯宁（ artemisinin ） • The only antimalarial effective
against drug-resistant malaria
Endoperoxide
•Active functional group: endoperoxide
•Different synthetic analogs
H H
OO H OO H
O H O
O OO O
H
O O
O
O
Artemisinin O Artemether
O H
O
O
Artesunate
The Antimalarial Drug Artemisinin
(Qinghaosu)Since the discovery of artemisinin
from Artemisia annua L., a plant used in
青蒿素 traditional Chinese medicine, by Youyou Tu and
colleagues, many derivatives have been
synthesized, including dihydroartemisinin, which
is more active than artemisinin. To protect this
important antimalarial drug, combination
therapy with another antimalarial drug is the
only treatment used today. The future synthesis
of new antimalarial drugs may be possible,
青蒿
originating from the endoperoxide bridge that is
required for artemisinin's antimalarial activity
(Charman et al., 2011).
Louis H. Miller , Xinzhuan Su
Artemisinin: Discovery from the Chinese Herbal Garden
Cell Volume 146, Issue 6 2011 855 - 858
http://dx.doi.org/10.1016/j.cell.2011.08.024
Current status
• Fast acting in reducing parasitemia
• Neurotoxic problem
• High recrudescence rates
• Need prolonged treatment to 5-7 days
• Artemether combined with other antimalarials like lumefantrine
(Coartem) or piperaquine
• Recommended for chloroquine-resistant cases
• Growth of Artemisia annua plants almost monopolized by Chinese &
Vietnam (70%) and E. Africa 20%
• Leaves from 8-month old plant extracted with hexane
• Artemisinin analogs
• Reducing neurotoxicity
• Increase bioavailability
• 100 million treatments of Coartem distributed to 39 malaria-endemic
countries worldwide
Race to grow Artemisia annua in China
•2004: WHO approved artemisinin to be used to treat malaria
– Major achievement for Chinese medicine
•Burst of Artemisia planting business in China
•2006:
– 100,000 acre plantation => 800,000 acre
– 4 Chinese companies => >100
– Price: RMB 8,000/ Kg
•2007:
– Dropped to 50,000 acre Artemisia plantation
– Price dropped to 1,500 – 2,000 RMB / Kg
•Long term solution
– Total synthesis of artemisinin by synthetic chemistry
– Genetic engineering of yeast to make artemisinin precursor (artemisinic acid) +
conversion of artemisinic acid to artemisinin
High-level semi-synthetic production of the potent antimalarial artemisinin
http://www.cs.com.cn/ssgs/gsyj/201207/t20120728_3429332.html
Growing artemisia annua in Congo
• Drugs made at where the disease occurs: Boosting
local economy
https://www.youtube.com/watch?time_continue=68&v=ehNZ3H9hb_c
Production of plant-derived artemisinin compared to semisynthetic artemisinin. Production of
plant-derived artemisinin takes from 14 to 18 months from planting to production. Plant-derived
artemisinin requires cultivation of A. annua, followed by extraction of artemisinin from the leaves
and conversion to artemisinin derivatives for incorporation into antimalarial ACT medication.
Semisynthetic artemisinin, by contrast, uses engineered yeast to produce amorphadiene in
fermentations. The amorphadiene extracted from the fermentor is chemically converted to
dihydroartemisinic acid and then to artemisinin derivatives for incorporation into ACT drugs. The
entire process could be accomplished in weeks.
Discovery = $$$ ? Not necessarily
•No patents awarded to original artemisinin discovery
– Secret project 523; no record; few publications
– Publications only with group’s name; no individuals
• Controversy over other’s contributions other than Ms Tu Youyou
•Western patents only awarded to Novartis
– Mixture of artemether (an artemisinin derivative) +
lumefantrine
– 2001, Novartis and Sanofi-Aventis provide ACT drugs
(Coartem) on a non-profit basis
http://www.malaria.novartis.com/malaria-initiative/the-malaria-initiative/
Artemisinin Mefloquine
Well tolerated; Neuropsychiatric side effects
fastest acting antimalarial
Unique structure & mechanism: Similar mechanism as other antimalarials
Disturb redox homeostasis of malaria like chloroquine: haem metabolism of
parasites parasites
Very limited drug resistant cases; Drug resistant cases
Used together with other drugs
(Artemisinin Combination Therapy; ACT)
Plant-derived; classic TCM story Improvement by synthesis of analogs of
existing antimalarial (quinine)
Is artemisinin a Chinese medicine?
• Chinese medical practice (Yin Yang) vs. Chinese medicine
(mixture of herbs with individual roles)
• Original formulation was a mixture
• Coartem is artemether + lumefantrine
• Original indication was not for malaria
• 168 B.C.
• 【功能与主治】
清热解暑，除蒸，截疟。用于暑邪发热，阴虚发热，夜热早凉，骨蒸劳热
疟疾寒热，湿热黄疸。
• Cause of malaria (by parasite Plasmodium) was discovered in 1897 by
Sir Ronald Ross (a British doctor) in India
• But 1st description of malaria-like symptoms by ancient Egyptians
(around 1550 B.C.) and the ancient Greeks (around 413 B.C.).
Is artemisinin a Chinese medicine?
• Artemisinin was discovered by drug screening
• Single compounds was isolated, characterized
in parasites and animals
• Discovered by traditional western drug
approach; but recorded in Chinese medical
books and used for treating similar symptoms
as malaria (fever)
• Future of Chinese medicine has similar fate?
• Not necessarily.
有人曾用一个形象的比喻来形容青蒿素与中医的关联：
" 一大群科学家，走进一间老祖宗留下的房子，翻箱倒柜试图寻
找到他们想要的东西，最后在屋后的垃圾堆里发现了宝贝，后
来还有证据表明，这个宝贝不是屋主的，是一个房客偶然留下
的，并被屋主丢弃了的。
" 在寻找青蒿素的过程中，与其说中医参与了，不如说中医实际
上只是一个研究对象而已。
http://discover.news.163.com/special/artemisinin/
Other contributors besides Tu
• Controversies exist over who else should also be honored for
the discovery of artemisinin; partly because of lack of official
records although understandable during Cultural Revolution
and being a secret project.
• 周维善 , 黄鸣龙
– Determined the chemical structure of artemisinin
• 李国桥
– Clinical trials
• 李英
– Synthesis of artemether (from artemisinin); improved potency
• 周义清
– Combining artemether with lumefantrine (to become Coartem)
http://www.who.int/bulletin/volumes/87/10/09-051009/zh/
沁园春 · 青蒿
青蒿群落，蔚然浩荡，凛然扩张。居荒郊野岭，亦占墙头；
春风化雨，催生萩菖，叶绿端午，花香中秋，结廋果万千生机旺。借
冬风，撒子向大地，无处不长。
原虫为疟难挡，值越战急需不相让。筛柴胡草果，稍验传闻；
常山鸦旦，略显征象。外来良方，金鸡纳霜，虽有效毒副亦亢。寻千
遍，中的青蒿素，寰宇同彰。
http://www.laskerfoundation.org/media/v_youyou.htm
Further readings
• Interview of Ms Tu Youyou
• Artemisinin: Discovery from the Chinese Herbal Garden
• For Intrigue, Malaria Drug Gets the Prize
• Lasker DeBakey Clinical Medical Research Award
• 《青蒿及青蒿素类药物》
• 青蒿素：源自中草药园的发现
• 科学网—屠呦呦获2011年拉斯克奖
• 科学网—中药的科学研究丰碑（修改版） - 饶毅的博文
• 科学网—周维善院士讲述青蒿素结构测定经过
