Dallas, Texas, United States
|Artemisia absinthium. Found in Bērzi village near Bauska city, Latvia. Photo by AfroBrazilian, 2013, on Wikimedia. CC BY-SA 3.0.
“To a synthetic chemist, the complex molecules of nature are as beautiful as any of her other creations.”
– Elias James Corey (Nobel Lecture, 1990)1
As the Vietnam War raged through the 1960s, the Northern Vietnamese army faced its greatest foe to date: drug-resistant malaria. Malaria typically causes cyclical waves of fever and chills followed by intense sweating.2 For centuries, the disease has been treated with quinine and quinine-derived medicines. The ancient Peruvians had long used cinchona bark, one of the few natural sources of quinine, as an anti-malarial. In the 1600s, the medicine was introduced to the Spaniards, who also began to use it.3 They even named Cinchona bark after the Countess of Chinchón, the wife of the viceroy of Peru whose malarial fever was cured by taking the medicinal bark.4 In 1834, the French chemist Pierre Joseph Pelletier extracted quinine from Cinchona bark.3 As European powers sent their soldiers across the globe, malaria became an important military concern. Tonic water, or water infused with large amounts of quinine powder, was so widely used that the British government in India imported each year some 700 tons of Cinchona bark to keep its troops from contracting malaria. The popular gin and tonic drink traces its origins to that era, to the British adding copious amounts of sugar to tonic water to mask its bitter taste.5
By the 1960s, however, quinine’s efficacy was waning, and many resistant strains of malaria were emerging. Quinine-resistant malaria ran rampant and depleted Northern Vietnamese manpower. To combat this growing military burden, the Northern Vietnamese reached out to its Communist ally, the People’s Republic of China. The Chinese government agreed that malaria was an endemic issue for both countries, especially in war.6 One of the earliest mentions of malaria affecting armies in East Asia comes from the fourteenth century Chinese novel Romance of Three Kingdoms.7 When the famed strategist Zhuge Liang finds himself in a military campaign against tribal leaders in southern China, his army is unable to cross the Lu River because of a “miasma,” a mysterious disease that appears only in March and April, but then disappears. Zhuge Liang meets an old hermit who directs him to an herb which, when chewed, can prevent the “miasma.” Many scholars believe that this mysterious “miasma” was malaria.8
The Chinese government responded to the Northern Vietnamese by creating Project 523, a joint effort to harness traditional Chinese herbal medicine and Western medicine in order to discover new anti-malarial agents.6 Project 523 was divided into three groups: one focusing on Western medicine-based malaria treatments, one on malaria prevention, and one on Chinese herbal remedies, the last of which was drawn from the nation’s thousand-year-old traditions.9 The Chinese medicine group, including future Nobel laureate Dr. Tu Youyou, screened over two thousand herbal compounds. Of 640 promising hits, 380 were screened in a murine model of malaria.10 From these experiments, Tu’s team eventually focused on an extract from the Artemisia plant family.11 The Artemisia genus represents a type of sweet wormwood; the herb is thought to be named after the Greek goddess Artemis or perhaps after the Greek botanist Queen Artemisia II of Caria. The plant is a short weed with small yellow buds, native to Asia, but also found naturally in many other parts of the world. It is known as qinghao in traditional Chinese medicine and was traditionally used to treat malarial fever.12
Although the anti-malarial potential of the Artemisia plant extract was promising, the results were at first not reproducible. Artemisinin seemed to have lost the potency shown in the initial experiments. When Tu combed through ancient Chinese medical texts such as the seminal Handbook of Prescriptions for Emergencies by the ancient Chinese physician Ge Hong, he discovered the following instructions for preparing qinghao: “A handful of qinghao immersed in two liters of water, wring out the juice and drink it all.”10 Since the ancient text recommended extracting the medicine at room temperature, Tu posited that using heat to extract the compound might inactivate its anti-malarial properties. After lowering the temperature, he was able to extract an active anti-malarial compound.10 This led to the development of artemisinin as a new anti-malarial. In 2005, the WHO designated artemisinin combination therapy as the standard of care for malaria.
At a time of unprecedented scientific discovery and innovation, history remains a crucial source of new therapeutics; nature remains the most accomplished chemist. Much of modern synthetic chemistry research centers on attempting to synthetically replicate what nature has evolved over millennia. As the arms race between man and parasite persists, our next silver bullet may indeed lurk in some unsuspected herb long known to mankind.
- Corey, EJ. The logic of chemical synthesis: Multistep synthesis of complex carbogenic molecules. Lecture, Harvard University, Cambridge, Massachusetts; December 8, 1990.
- Malaria. World Health Organization. July 19, 2014. Accessed March 15, 2023. Archived at: https://web.archive.org/web/20140903002027/http://www.who.int/mediacentre/factsheets/fs094/en/.
- Achan J, Talisuna AO, Erhart A, et al. Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011;10. doi:10.1186/1475-2875-10-144.
- Cintas, P. How serendipity led to an early treatment. Nature 2002;419:431. https://doi.org/10.1038/419431b.
- Raustiala K. Why the gin and tonic was the British Empire’s secret weapon. Slate Magazine August 28, 2013. Accessed March 15, 2023. https://slate.com/technology/2013/08/gin-and-tonic-kept-the-british-empire-healthy-the-drinks-quinine-powder-was-vital-for-stopping-the-spread-of-malaria.html.
- Jianfang Z. A Detailed Chronological Record of Project 523 and the Discovery and Development of Qinghaosu (Artemisinin). Houston: Strategic Book Publishing and Rights Co; 2013.
- Luo G, Roberts M. Three Kingdoms: A Historical Novel. Berkeley: University of California Press; 1991.
- Yang, B. The “Zhang” on Chinese Southern Frontiers: Disease Constructions, Environmental Changes, and Imperial Colonization. Bulletin of the History of Medicine 2010;84(2):163-92. https://jstor.org/stable/44451873.
- Traditional Chinese medicine: What you need to know. National Center for Complementary and Integrative Health 2019. Accessed March 15, 2023. https://nccih.nih.gov/health/traditional-chinese-medicine-what-you-need-to-know.
- Tu, Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med. 2011;17:1217-20. https://doi.org/10.1038/nm.2471.
- The Conversation. The Secret Project That Conquered Malaria – and Led to a Nobel Prize. US News & World Report 2015. Accessed March 15, 2023. https://usnews.com/news/articles/2015/10/06/project-523-behind-tus-nobel-prize-win-for-malaria.
- Elisabeth Hsu. The history of qing hao in the Chinese materia medica. Transactions of The Royal Society of Tropical Medicine and Hygiene 2006;100(6):505-8. https://doi.org/10.1016/j.trstmh.2005.09.020.
- Liao F. Discovery of Artemisinin (Qinghaosu). Molecules 2009;14(12):5362-6. doi:10.3390/molecules14125362.
VICKY LI is currently a MD/PhD candidate at the University of Texas Southwestern Medical Center in Dallas, Texas. She plans to pursue her current interest in genetics and chemical biology by becoming a physician scientist and combine clinical practice with scientific innovation.
Submitted for the 2022–23 Medical Student Essay Contest