Wladimir J. Alonso
Steven Zhixiang Zhou
Cynthia Schuck-Paim
Sao Paulo, Brazil & London, UK

Nanjing, capital of China at the time of the experiments Photography by Ryuch

Although over a millennium ago some clinicians already appreciated that fair comparisons are needed to infer causality about the effects of medical treatments,¹ it has been widely accepted until now that the first proper clinical trial was performed in the 18^th century by the British naval surgeon James Lind.^2,3,4 In this trial, Dr. Lind examined the effectiveness of lemon juice in preventing and treating scurvy on sailors by using experimental concurrently treated groups.

Unknown to Western science, however, planned medical trials had already been implemented in China as early as the beginning of the 15^th century by imperial doctors of the third emperor of the Ming dynasty. The experiments are described in the book “Talk on Keeping Healthy by Imperial Doctor Liu,”⁵ co-authored by the 24^th and 25^th descendants of Doctor Liu and guardians of the original documents. The book is itself a fascinating account of medical experimentation and practices lost in the pages of history. However, the authors did not discuss (they might have been unaware of it) the importance of those documents to the history of medicine.

Those experiments took place in the prisons of Nanjing, then capital of China and the biggest city in the world.⁶ They were aimed at finding the causes of diseases – such as common cold, lung fever (lobar), Zhixia (dysentery), sudden disorders (cholera), Xiaohe (diabetes), venereal diseases, impotence, Lijiefeng (rheumatoid arthritis), muscle atrophy, excessive force de-Qi (hypnopathia), Yang exhausted water flood (edema), Shizu (hepatitis), Zhuxia (summer fever), grimace sores (Lupus erythematosus), etc. – and the effectiveness of possible therapeutic interventions. Though carefully designed, these trials were performed under ethical standards that would be unthinkable today: maladies were provoked on prisoners sentenced to death, followed by testing of several treatments with little consideration for well-being or survival (those were in fact results of interest). On some occasions, prisoners were allowed to volunteer for medical trials in exchange for lighter sentences (such as exile in a remote area). Also, the pressure on researchers for results would be considered extreme even in the competitive environment of renowned scientific institutions today: death sentence and torture could fall upon doctors who failed to come up with treatments and results that pleased the emperor.

One example was the set of trials conducted to investigate the effects of thermal and nutritional regimens on the incidence of respiratory infections. Official doctors in Nanjing designed in this case a multi-step procedure to induce influenza-like symptoms on prisoners during winter. Prisoners were randomly assigned to four test groups, each of fifty persons. The basic design was that of a Latin-square, where the experimenters initially manipulated two factors: nutritional status (low and high) and exposure to disease (exposed and not exposed). Two groups (A and B) were maintained under a low nutritional status, which was achieved by the oral administration of limewater, aimed at inducing lesions in the intestine and stomach walls, hence impairing digestive function, and the subsequent provision of only rice and vegetables. The other two groups (C and D) were fed an appetizing soup (raw North Hawthorn and the herb Muxiang) to improve digestive function, followed by a period when they were fed soup simmered with carp to improve nutritional status. Within each nutritional status category, one group of prisoners (A and C) was forced to remain in a prison cell with sick prisoners for potentially infectious contacts, whereas the other (B and D) was not exposed to disease. To further determine the effect of climate on disease incidence, prisoners of groups A, B and D were then asked to get in and out of their prison rooms repeatedly to experience sharp changes in air temperature and humidity. The authors report that all prisoners in Groups A and C developed influenza-like symptoms (fever, running nose, coughing) within three days, whereas only a few prisoners in Groups B and D had symptoms within the same period, pointing to the importance of nutritional status on the development of this condition.

Based on this description, these experiments fit the modern definition of a controlled clinical trial, as they represent “a planned experiment to assess the efficacy of a treatment by comparing outcomes in a group of patients treated with the test treatment with the outcomes observed in a comparison group receiving a control treatment.”³ In fact, not only they precede the experiments by James Lind in 1747 (which, as mentioned above, was considered the first clinical trial in history), but also the first controlled experiments in the history of the biological (hence also medical) field. This title is currently hold by the experiment that tested the theory of spontaneous generation conducted by Francesco Redi in 1668.^7,8

Finally, we cannot resist commenting on the particular experiment we used to illustrate the ground-breaking nature of the ancient Chinese trials. Not only was this trial the first to investigate respiratory infections, but it also provides valid information on questions regarding their potential environmental and nutritional drivers that are still open today,⁹ such as the observation that nutrition has a noticeable effect on respiratory disease incidence.

In conclusion, exactly six centuries ago (the experiments are dated 1415-1416), at a time when Western medicine was still trapped in the dogmas of Hippocratic-Galenic teachings, researchers in Asia were advancing medical knowledge by probing nature through sophisticated experimentation, which the Western world would still take centuries to set in motion. We can commemorate this anniversary by granting those pioneering researchers their right place in the history of medicine.

References

1. Chalmers, Iain, Estela Dukan, Scott Podolsky, and George Davey Smith. 2012. “The Advent of Fair Treatment Allocation Schedules in Clinical Trials during the 19th and Early 20th Centuries.” Journal of the Royal Society of Medicine 105 (5): 221–27. doi:10.1258/jrsm.2012.12k029.
2. Bull, J.P. 1959. “The Historical Development of Clinical Therapeutic Trials.” Journal of Chronic Diseases 10 (3): 218–48. doi:10.1016/0021-9681(59)90004-9.
3. Greenfield, Mary Lou. 2004. “Of Plagues, Blights, and Bloodletting: Historical Highlights of the Randomized Controlled Trial.” Department of Anesthesiology, University of Michigan. http://odin.mdacc.tmc.edu/~jjlee/clinical_trials2008/Greenfield,%20historical%20highlights%20of%20randomized%20controlled%20trial.pdf.
4. Bown, Stephen R. 2005. Scurvy: How a Surgeon, a Mariner, and a Gentleman Solved the Greatest Medical Mystery of the Age of Sail. New York: Thomas Dunne Books/St. Martin’s Griffin.
5. Liu, Hong Zhang, and Bo Liu. 2006. Talk on Keeping Healthy by Imperial Doctor Liu. Beijing, China: Friendship Publishing Company of China. 2. http://www.360doc.com/content/11/0319/23/6085925_102738542.shtml.
6. Chandler, Tertius. 1987. Four Thousand Years of Urban Growth: An Historical Census. Revised edition. Lewiston, N.Y., U.S.A: Edwin Mellen Pr.
7. Roncalli Amici R. The history of Italian parasitology. Vet Parasitol. 2001 Jul 12;98(1-3):3–30.
8. Wikipedia, the free encyclopedia. 2015 Francesco Redi [Internet]. [accessed 2015 May 16]. Available from: http://en.wikipedia.org/w/index.php?title=Francesco_Redi&oldid=661108247
9. Tamerius, J., M. Nelson, S. Zhou, C. Viboud, M. Miller, and W.J. Alonso. 2010. “Global Influenza Seasonality: Reconciling Patterns Across Temperate and Tropical Regions.” Environ Health Perspect 119: doi:10.1289/ehp.1002383.

WLADIMIR J. ALONSO obtained his PhD at Oxford University on mathematical modeling of the spatial distribution of diseases. He conducts consulting work in Brazil and works as a Research Fellow of Fogarty International Center (US National Institutes of Health). He published papers on subjects from evolution of biological altruism, vaccination policies, pandemics, and the importance of preservation of historical death certificates. He developed Epipoi, a free software for epidemiological time-series analyses and has taught workshops on data visualization and time-series in twelve countries.

STEVEN ZHIXIANG ZHOU obtained his BSc degree in meteorology at the Nanjing University of Information Science and Technology (China) and MSc in occupational and environmental health at the University of British Columbia, Canada (2001). He received his postgraduate diploma in epidemiology (2012) and is conducting advanced studies at the London School of Hygiene and Tropical Medicine (UK). He currently works as a Certified Industrial Hygienist (CIH) internationally and has co-authored several epidemiological studies.

CYNTHIA SCHUCK-PAIM received her PhD degree at Oxford University (2003), and has authored several articles on subjects ranging from evolutionary biology and infectious disease to the modeling of spatial distributions based on climate. She participated as invited speaker in conferences in various countries and has taught data analysis and experimental design for students in the medical and biological sciences for several years.

Highlighted in Frontispiece Winter 2016 – Volume 8, Issue 1
Winter 2016   |  Sections  |  Science