An Interview with Professor Manuel Varela: Youyou Tu–and anti-malarial medicines

Sep 9, 2019 by

Michael F. Shaughnessy –

1) Youyou Tu is a Chinese Nobel Prize winner- where and when was she born and what led her into science?

Dr. Youyou Tu was born on the 30th day of December, in the year 1930, in the city of Ningbo, China, located in the eastern province of Zhejiang. Incidentally, her first name is Youyou, and her family surname is Tu. In the Chinese tradition, however, the personal names are frequently written as in the opposite order, i.e., Tu Youyou.

Her early education was an excellent one, having had the opportunity to attend the best private educational institutions in the province. At the age of 6 years, she was enrolled in a private school called Ningbo Chongde Primary School, starting in 1936 until about 1941. At that time, she moved to a private middle school called Ningbo Qizheng, till about 1945, when she attended the private school called Ningbo Yougjiang Girl’s School, for about a year.

Her interest in pursuing the study of science was brought about by a terrible illness that she had suffered as a teenager. Tu had contracted the Great Consumption, known also as tuberculosis or TB, an infectious ailment caused by a bacterium called Mycobacterium tuberculosis. The cough-laden illness has been called “consumption” because it consumes the patient.

Although she was home-schooled because of her illness, the episode, nevertheless, resulted in Tu having missed a great deal of private school, about two years’ worth. After Tu’s convalescence from TB, she resumed attendance at high school, enrolling in the private institution called Ningbo Xiaoshi High School, from 1948 to 1950, when she moved to Ningbo High School, till about 1951.

Having survived the terrible ordeal for years, Tu had made a life-changing decision to pursue the study of biomedical research for her lifelong career. The illness had convinced Tu that if she were to acquire biomedical science skills then she could play an important positive role in the health of others, possibly by discovering new medicines.

2) Now what led her to study malaria- and what parts of the world has it impacted. Plasmodium falciparum– how is this related to malaria- and where exactly does the word malaria come from?

After her high school graduation and as a result of her decision to study biomedical research for her medical profession, Dr. Youyou Tu studied pharmaceutical sciences in the School of Pharmacy, at the Beijing (Peking) Medical University, taking her doctorate in 1955. In 1952, a year after she entered the Pharmacy Department at medical school, the institution had been known as Peking University; and in 1955 when she graduated, it had been changed to Beijing Medical College. She then moved to the so-called China Academy of Traditional Chinese Medicine, focusing her studies on Chinese herbal medicines.

Malaria is a serious infectious disease caused by certain species of the protozoan genus called Plasmodium; the term malaria arises from Italian mala aria, meaning bad air. Medically speaking, the Plasmodium falciparum and Plasmodium vivax appear to be two of the most important infectious agents of malaria, being prevalent in tropical, sub-tropical (P. falciparum), and temperate regions of the world, especially in South America and Southeast Asia (P. vivax). Other important species include Plasmodium ovale (tropical Africa, plus Asia and South America), Plasmodium malariae (sub-tropical and temperate regions), and Plasmodium knowlesi (Southeast Asia, especially in Malaysia).

These Plasmodium blood parasites are transmitted to humans by the bites of mosquitoes, such as those from the genus Anopheles. When the human host is bitten by the Anopheles it spits its saliva that’s laden with the Plasmodium protozoan in the patient. The Plasmodium then moves via the blood to the liver where it multiplies inside the red blood cells of the patient. As the Plasmodium develops, it forms a so-called ring stage, which can form the basis of diagnosis using a microscope and examining a blood sample from the patient.

During the 1960s, the conventional treatment of malaria, chloroquine, had been compromised by the development of the chloroquine-resistant variants of the Plasmodium falciparum, leading to treatment failures and the resurgence of the malaria cases. After the implementation of new research programs in the mid-1960s by the U.S. and China, the programs of which were aimed at finding new anti-malarial medicines, thousands of candidate drugs were systematically tested, and no effective drugs were found.

It was at this point in the history of biomedical science, in 1969, that 39-year-old Dr. Tu, then still considered a young scientist, was appointed by the director of the China Academy of Traditional Chinese Medicine to run the program titled Project 523, an endeavor devoted to a systematic search of traditional Chinese medicines for potential antimalarial drugs. The new biomedical research effort ultimately led to her discovering the Nobel Prize-worthy anti-malaria medicine from sample number 191, containing artemisinin (or Qinghaosu, in Chinese), from an herb of the Artemisia family (or Qinghao, in Chinese).

3) Apparently, ancient Chinese texts provided some background. What do we know about this?

The field of traditional Chinese herbal medicine pertaining to malaria goes back thousands of years. Such ancient Chinese medicine involved carefully documented records, including published books and treatises.

The ancient literature on the topic of Chinese medicine is extensive.

One of the earliest known publications is the ancient classic book titled Zhou Li published sometime within the Zhou Dynasty of China, which lasted from 1046 to 256 B.C. Another set of classic works, such as the Prescription for Universal Relief, and the famous Malignant Malaria Guide go back to the Ming Dynasty, between 1368 and 1644 A.D., and the Qing Dynasty, between 1644 and 1911, respectively. Many of ancient Chinese works of literature included recipes for treatments, complete with testimonials by ancient Chinese physicians, personally attesting to the efficacies of their remedies.

In starting her research program in Project 523 on the systematic search for malaria treatments, Dr. Tu had evaluated the ancient Chinese texts and coalesced a list containing over 2,000 recipes for potential herbal-, animal-, and mineral-based remedies. The generation of the anti-malaria medicine list, consisting of candidates from the ancient Chinese medical literature, took three months.

Further concentrating the approximately 2,000 recipes into those primarily dealing with malaria, Dr. Tu then shortened the list to 640 anti-malaria candidates. As head of Project 523, she included the recipes for each of the candidates into a brochure titled Antimalarial Collections of Recipes and Prescriptions, sending copies, in mid-1969, of the brochure to the heads of scientific laboratories whose work focused on malaria research.

In one of the ancient texts called A Handbook of Prescriptions for Emergencies, written by Ge Hong, Dr. Tu had come across a passage praising the effectiveness of the so-called Qinghao, the sweet wormwood herbal plant, as a good fever reducer during bouts of malaria. The recipe called for placing a handful of the sweet wormwood, the Qinghao, within two liters of water, wringing out the resulting plant juice and consuming all of it.

4) Sweet wormwood – how does this fit into the big picture?

The term sweet wormwood is one of the common names given to the plant from which Dr. Tu’s Nobel Prize-winning anti-malarial medicine, artemisinin, is extracted. The scientific name for the herbal plant is Artemisia annua L. (the “L.” referring to the Carl Linnaeus system of classification). Other common names include sweet Annie, annual wormwood, and qing hao.

The sweet wormwood plant has been used by the Chinese, having brewed its leaves as a bitter tea for over 2 millennia. The plant has also been used since ancient times to reduce fevers, including those fevers brought about by malaria. Interestingly, the herbal sweet wormwood tea has been used historically for treating dizziness, chills, headaches, inflammation, nosebleeds, and gastrointestinal disorders. Externally, the sweet wormwood was used as an application on boils and abscesses. In recent times, the plant herb has been used as a flavor in European beverages.

The focus of the sweet wormwood plant changed to address its efficacy against malaria with the more modern biomedical studies of Dr. Tu, having published her findings in 1972.

5) While early research was conducted on animals- apparently she tested the drug on herself- what do we know about this?

During her studies, Dr. Tu had recalled how the recipe from Ge Hong’s ancient Chinese text had called for simply placing the plant leaves of Artemisia annua L. into two liters of water, squeezing out the resulting juice and then drinking all of it. The preparation was to be used precisely for the purpose of treating malarial fevers, a common symptom of the disease. Furthermore, Dr. Tu ingeniously noticed that the preparation did not call for tea brewing. Thus, she astutely deduced that the heat from the boiling process might destroy the active principle contained in the Artemisia annua L. herb. Furthermore, Dr. Tu’s genius lies in the fact that she noticed that the ancient text called for wringing the herbal leaves, predicting that the active anti-malarial principle must be contained with these leaves.

Therefore, Dr. Tu’s experimental design involved the avoidance of heat in order to preserve the bioactivity harbored within the leaves of the Artemisia annua L. plant. Her design further focused on separating the leaves (predicted to contain the bioactive agent) from the plant stems (predicted to lack the bioactive agent). Using this protocol, Dr. Tu carefully prepared the plant extracts from various herbs, including the Artemisia annua L.

Next, Dr. Tu and her research team test their various herbal plant extracts on rodents with malaria, measuring the inhibition of the Plasmodium protozoa in the rodents. In the historic experiment of October 4, in 1971, Dr. Tu found that their sample number 191 completely inhibited the malaria parasites in the rodents!

Next, in late 1971 and early 1972, they tested an acidic and a neutral extract of the Artemisia annua L. herb on malaria-infected monkeys. The Tu research team found that the neutral version of the sweet wormwood extract maintained its effectiveness against malaria in the laboratory animals. Dr. Tu presented the results from these historic experiments at a conference in Nanjing, China, in March of 1972. The profound findings were widely disseminated.

Back in the laboratory after the successful conference presentation, Dr. Tu and her team conducted an equally startling experiment!

The shocking new experiment came about due to conflicting data regarding toxicity studies in test animals. Theoretically, it would have taken at least another year to resolve the conflicting issue on whether the herbal remedy was too toxic for humans. With the new malaria season looming near, potentially hundreds of thousands of new cases, if not millions, countless millions were on the verge of acquiring the infection.

In order to resolve the toxicity question in an expedited manner, Dr. Tu asked for permission to take the plant extracts herself, and she was granted the permission! She was wholeheartedly given the go-ahead to take the extracts!

In the month of July, in 1972, Dr. Tu and two of her laboratory personnel from her research team were voluntarily hospitalized, and the trio of humans took the extracts, on purpose! After close monitoring of the human volunteers for a week by the hospital staff, no side effects were noticed. Thus, the herbal extracts were next provided to an additional five human volunteers, and this time the dosages were enhanced!

The testing of the Qinghao herbal extract by Dr. Tu and her colleagues was not entirely without precedent. In traditional Chinese medical history, an ancient physician by the name of Dr. Shen Nong had recorded how he took many of the Chinese herbal medicines himself! He had claimed to have tasted hundreds of Chinese herbs on his own. The dosages of the Qinghao in the ancient Chinese texts, used for thousands of years, were much lower than those amounts contained within Dr. Tu’s modern Qinghao preparations.

Such highly concentrated amounts of the bioactive principles inherent in her laboratory-based Qinghao extracts had not been tested before. One impetus in conducting the unprecedented experiment, however, was the fact that Dr. Shen Nong had tasted hundreds of herbs himself. Dr. Tu’s feeling on the safety issue was why couldn’t they take more-concentrated Qinghao herbs, just as well?

6) Artemisinin and dihydroartemisinin – how are these two related?  

In mid-1972, Dr. Tu and her research team began experiments that were devoted to the purification of the bioactive agent, the active ingredient of the Qinghao extract, which probably harbored many individual ingredients. First, the Tu team were successful in isolating crystals from a few of these ingredients, using a special biochemical tool called silica gel column chromatography. A single compound, called artemisinin, i.e., Qinghaosu, was isolated. See the figure.

Artemisinin

Clinical trials of the artemisinin in tablet form against the dreaded malaria were less than desirable. The tablets did not release the artemisinin in therapeutic amounts. New tablets were made, but the malaria season was already at an end, too late to make an effect dent against that year’s malaria numbers, in 1973.

At about this same time, a new compound, called dihydroartemisinin, had been chemically derived from the original artemisinin by the Tu laboratory. The new compound differs from the old version in that the dihydroartemisinin harbors a hydroxyl group (OH) where a carboxyl group (C═O) had been in the artemisinin. See the figure.

Dihydroartemisinin

The dihydroartemisinin was actually demonstrated in the Tu laboratory to be more effective against the rodent form of malaria and in lower doses. In fact, dihydroartemisinin was shown to be ten times better than the artemisinin. To make matters better, the dihydroartemisinin structure, with its dedicated hydroxyl group, was less prone to the development of malarial resistance during medical treatments. Thus, both artemisinin and dihydroartemisinin have been used and studied over the many years since their discoveries by Dr. Tu.

7) What have I neglected to ask about this Nobel Prize winner?

Dr. Tu’s published research findings had been given little attention in the Western world. In fact, for many years, up until the 2000s, traditional Chinese herbal medicine has been given a poor reputation by non-Chinese investigators. More recently, with many new modern studies of the Chinese remedies undergoing scientific scrutiny in peer-reviewed journals, their promise as medical treatments in Western biomedicine has been given scientific prominence. With the surprising bestowment of the Nobel to a key biomedical scientist who has been prominent in the Chinese herbal medicine field, perhaps this scientific and medical research area has officially been recognized as a bona fide field of modern biomedical science.

For future study:

Youyou Tu: Discovery of Artemisinin – A gift from Traditional Chinese Medicine to the World – YouTube www.youtube.com Youyou Tu delivered her Nobel Lecture on 7 December 2015 at Aula Medica, Karolinska Institutet in Stockholm. The lecture was presented in Mandarin.
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