7 Youyou Tu

Youyou Tu is a preeminent malariologist, famous for her discovery of artemisinin. Born in the city of Ningbo, a city on the east coast of China, Ningbo grew up with her father, mother, and four brothers. Tu’s family highly valued education, and she would attend several prestigious schools over the course of her schooling. At one point during her early education, Tu would contract tuberculosis, forcing her to take several years off from her studies. Inspired rather than dissuaded by this bout of illness, Tu became determined to pursue a career in medicine. Tu would eventually be accepted into the medical school at Peking University, and graduated with a pharmacology degree in 1955. She would then go on to attain a research position at the China Academy of Medical Sciences, an academy centered around the research and development of Chinese medicines.

Having completed a training program in Chinese medicine, complete with a Western-based medical background, Tu aimed to develop treatments that applied both styles of medicine. Tu’s model was not without its criticism – it drew the ire of people who saw Chinese and Western medicine as two separate and exclusive entities. Tu, however, believed that the two systems could complement each other. This unique fusion of medical tradition was revolutionary at the time. For older generations more skeptical of modern medical developments, the traditionalist approach provided the familiarity essential for a patient’s trust and amenability. Having developed her novel traditional Chinese–Western fusion model of medicine, Tu began to her medical research career. In particular, Tu’s research focused on phytochemistry (applied plant chemistry) and how the processing of various herbs could be used for treatment and to alter their function.

Just as Tu’s career began taking off, the Chinese Cultural Revolution began. Launched under the authoritarian rule of Mao Zedong, this Cultural Revolution sought to restore Communist and socialist ideologies as the hegemonic structure of the People’s Republic of China. This movement made a point of targeting groups that deviated from the Communist and Maoist beliefs, collectively referred to them as “Stinking Old Ninths”. These included anti-Marxists, right-winged ideologists, and intellectuals. Since capitalism hadn’t firmly rooted itself in China, the Cultural Revolution also targeted landlords and rich agrarians, attempting to steal back their lands and put them under state control.

The impact of China’s Cultural Revolution led to the widespread closure of schools and educational institutions. Tu was forced to hide her research, as its Western influence potentially made her a target of fervent Maoists. Although scientific research in China was halted, military research continue. In particular, work into infectious disease and warfare-based medical advancements were developing at an unprecedented rate. One particular health problem facing East Asia at the time was the rise of chloroquine-resistant malaria, which was sweeping across many populations during the Vietnam War.

To combat this, the Chinese government funded projects aimed at finding treatment and cures against these particular strains of malaria. In 1969, Tu was appointed head scientist for Project 523. The goal of this project was to create an antimalarial drug based in traditional Chinese medicines. Thousands of compounds had already been screened, but none had been identified as possible cures. Tu fully invested herself in this project. However, Tu’s participation had a huge impact on her personal life. She was forced to prioritize research over family. Despite her efforts to find a cure, Tu’s family was targeted by the government. While continuing to run Project 523, Tu would see her husband detained and sent to a labor camp for “re-education”.

Despite multiple adversities, Tu’s commitment to the project and her research was unwavering. She and her team scoured traditional Chinese medical treatments, collecting thousands of herbal, animal, and mineral prescriptions, in their search for viable candidates for an antimalarial drug. They tested the substances on the rodent malaria parasite Plasmodium berghei. This approach of in vivo rodent research was effective in modeling human malaria due to “genetic and physiological similarities between the species”8. After numerous trials and errors with extractions from different plants, Tu discovered how applying the general chemistry concepts of solubility and boiling points could allow one specific plant to achieve near 100% antimalarial inhibition.

Upon re-analyzing Chinese medical literature, Tu found that Qinghao or sweet wormwood (Artemisia annua), an herb in the Artemisia family, showed effective but inconsistent results in alleviating malaria symptoms (see Figure 3). Artemisia annua had been used as a remedy for some malaria symptoms for millennia, and had traditionally been used as a tea. Tu followed this by extracting the leaves of Artemisia annua in boiling water.  The extract showed efficacy towards inhibition of malaria, but the extract was not consistent, and the amount of inhibition varied between samples. Tu found a reference to the use of Artemisia annua from a philosopher named Ge Hong wherein the Artemisia annua was simply submerged in water without heating.  Because of this, Tu thought that the heat might be destroying any active compounds within the Artemisia annua, and after performing the solid-liquid extraction at a lower temperature, her hypothesis was confirmed. Tu performed the extraction at lower temperatures and also changed the solvent to a compound called diethyl ether.  This not only boils at a lower temperature, but also Artemisinin has higher solubility in diethyl ether than in water. This is because Arteminisin is only moderately polar.  It contains several hydrophilic (water-loving) areas, but also contains hydrophobic (water-fearing) areas. The extract in diethyl ether showed nearly 100% inhibition for the rodent malaria parasite that Tu had been using as a model.

When discussing inhibition, most often it is used to mean the inhibition of enzymes.  Enzymes convert substrate into products as shown in Figure 3.  An enzyme will bind to a substrate and through a chemical reaction will convert it to the product. Inhibitors can interrupt this process in three different ways.  The first is called competitive inhibition.  In competitive inhibition, the inhibitor and the substrate bind to the same location in the enzyme, and they directly compete to try and bind. This reduces the total amount of substrate that can bind and so it increases the amount of substrate required.  However, competitive inhibition is not favored for medicines as it is very reliant on the concentration of the inhibitor as well.  The second type of inhibition is called non-competitive inhibition. In this type of inhibition, the inhibitor binds to a different part of the enzyme and once the inhibitor is bound to the protein, the substrate cannot bind anymore. This reduces the speed at which the enzyme can convert substrate to product. The final type of inhibition is called uncompetitive inhibition. In uncompetitive inhibition the inhibitor only binds to the enzyme while the substrate is bound. This slows the speed of the conversion of substrate to product and also requires more substrate. In modern medicine, derivatives of Artemisinin are used to treat malaria, and they can comprise all three types of inhibition.

After creating a sample that showed near full inhibition of malaria samples, the next step was to evaluate the safety of Artemisinin before use in a clinical trial but there were debates about the results from the animal trials and whether the compound would be safe for humans or not.  With very little time before the end of the malaria season, Tu and two others from the lab volunteered to test the compound on themselves.  This vastly expedited the process, and the first full-scale clinical trials were able to be held that same year.

While Tu did find a cure for malaria in the 1970s, it was not until decades after that she was truly recognized for her work. Before being awarded the Nobel Prize in Physiology or Medicine in 2015 as the first Chinese woman, Tu was “completely forgotten by the people” before this point.1 She is said to be regarded as the professor of three no’s—no postgraduate degree, no study abroad experience, and no member status of Chinese national academies. It is astonishing to see that despite her evident contributions, her title remained “the professor of three no’s.”

Today, artemisinin and artemisinin-based combination therapies are the main treatment against chloroquine-resistant malaria, further affirming the significant and lasting contributions Youyou Tu has made to the fields of chemistry, biology, public health and the military. Tu was a visionary whose work not only contributed to the malaria crisis in the 1970s but also to global health crises around the world today.