The Long Struggle of Humanity Against the Smallpox Virus

Smallpox is a severe infectious disease with a very high case fatality rate; it was once one of humanity's leading causes of death. Ancient Chinese medical texts contain extensive records of smallpox; in traditional TCM it was called "dou chuang" (pox sores), "pao chuang" (blister sores), or "lu chuang" (barbarian sores).

Smallpox probably originated in ancient India and ancient Egypt, then spread across Eurasia through trade and war between states. According to tradition, it entered China during the Han dynasty, brought by war.

Ge Hong recorded in Zhouhou Beiji Fang (A Handbook of Prescriptions for Emergencies) that smallpox was "obtained in Nanyang (possibly a scribal error for 'the southern frontier') while campaigning against barbarians during the Jianwu era, and was therefore called barbarian sores." The "Jianwu" Ge Hong mentions was the reign title of Emperor Guangwu of Eastern Han (Liu Xiu). Han histories record that during the Jianwu era, Zheng Jue and Zheng Er of Jiaozhi in the south rebelled, taking "more than sixty cities" and shaking the entire southern frontier; they declared themselves kings and defied Emperor Guangwu. Enraged, Liu Xiu dispatched General Fubo, Ma Yuan, to put down the southern rebellion.

In the 18th year of Jianwu (AD 42), Ma Yuan led the Han army to the southern frontier and, fighting Zheng Jue and Zheng Er in the towering mountains, won a great victory and beheaded the two. But in the 20th year of Jianwu (AD 44), when Ma Yuan's army returned, nearly half the officers and men had died of "miasma" caught in the south. This "miasma" is what Ge Hong called "barbarian sores"; ancient Chinese sources mostly accept this account of the origin of smallpox in the Han heartland.

Ge Hong wrote: "In recent years an epidemic has circulated: sores break out on the head, face, and body, in a moment spreading everywhere, looking like fire burns, all bearing white fluid; they break and regenerate at once. If not treated promptly, severe cases often die. Those treated with some relief are left with purplish-black pox scars that take a year to fade; this is a vicious poisonous qi." These are exactly the typical symptoms of smallpox.

The English word "smallpox" vividly describes the disease: "small" means small, and "pox" denotes pox or vesicular diseases; smallpox means small pox or small sores. Ancient Chinese medical texts likewise named smallpox "dou chuang" (originally written "bean sores")—sores as small as beans. Small as the sores were, they spread over the whole body and were highly lethal, which is what made them terrifying.

In ancient times, smallpox swept through in wave after wave, killing vast numbers of children and adults, children especially. When pediatrics was established as a specialty in Song-dynasty TCM, "dou chuang" was classified under pediatric diseases; later, many monographs devoted specifically to treating pox appeared.

Smallpox epidemics kept ancient Chinese child survival low, which was an important reason ancient China valued many children as a blessing. The Ming pediatrician Wan Quan (Wan Mizhai, born in what is now Luotian, Huanggang, Hubei) recorded in his Douzhen Shiyi Xinfa that "in the spring of the Jiajia Jiawu year (1534), pox poison raged, and eight or nine in ten of the sick died." In the Qing dynasty, large numbers of imperial family members died of smallpox; Emperor Shunzhi is believed very likely to have died of it. The 18th-century smallpox pandemic in Europe killed 60 million Europeans. After Europeans discovered the Americas, they brought smallpox, killing vast numbers of indigenous peoples and rapidly destroying their capacity to resist—one of the main reasons the Americas fell to Europe so quickly.

Although Wan Mizhai was a famous pediatrician (the Wan school of pediatrics is even a major TCM pediatric tradition), he could not offer an effective solution for smallpox; he even wrongly believed it to be a congenital fetal poison.

However, in Taiping County, Ningguo Prefecture (present-day Taiping, Huangshan, Anhui, not far from Wan Mizhai's home in Luotian, Hubei), a folk method called "variolation" appeared—the first form of smallpox vaccination. The Qing text Douke Jinjing Fu Jijie records: "We hear that variolation began during the Ming dynasty Longqing reign (AD 1567–1572) in Taiping County, Ningguo Prefecture (present-day Taiping, Anhui), and from there spread across the land."

Other medical books suggest China may have had variolation as early as the Kaiyuan era of the Tang dynasty; for example, Dong Yushan wrote in Niudou Xinshu: "Examining the world, before the Tang Kaiyuan era there was no variolation; in the Jiangnan region, a family named Zhao first transmitted the method of nasal-seed variolation..." But this account has no other historical corroboration and is generally not accepted by scholars.

Variolation must have originated among the people. Smallpox raged and infected countless people; among them some survivors were inevitable. The Qing Kangxi Emperor, for instance, is recorded as a lucky survivor of smallpox; his face was pockmarked with scars left by the infection.

The idea behind variolation is the same as vaccination in modern immunology; only then had no method as safe as modern vaccination been developed. In ancient times, our ancestors deliberately inoculated people with smallpox once. Early variolation used scabs from naturally occurring smallpox lesions on infected people, called "fresh seeds" (shi miao). These were highly toxic and not 100% safe; about 10% of those inoculated died from the method itself. It was far from the ideal vaccine.

In long practice, ancient Chinese variolators (once a well-paid specialty) kept trying to improve "fresh-seed" inoculation and lower mortality. The Qing Yizong Jinjian contains dedicated records of selecting and breeding pox seed, with "gray-waxy luster, plump and thick" as the standard for a good seed.

Chinese variolators gradually worked out two rules to reduce mortality: first, never use natural pox as seed (i.e., do not use fresh seeds); second, use pox scabs rather than pox pus, because they had found fresh seeds and pox pus to be highly virulent.

They found that variolation required a "cultivated seed," which had to go through "nurturing" and "selective refinement" to become a "ripe seed" before use. A ripe seed was one whose toxicity had been reduced through serial passage and selective refinement. The pox seeds later used were therefore attenuated products passed through many generations of human infection. Many variolator families kept highly safe "ripe seeds," which were expensive and affordable only by wealthy households.

The Qing Zhongdou Xinfa says: "The longer the seed is passed on, the more refined its medicinal power becomes, and the more skillful the manual selection and refinement, the more the fiery poison is washed out and the pure essence alone remains; thus it is perfectly safe and harmless." This method of breeding pox seed conforms exactly to the modern scientific principle of directed attenuation in vaccine preparation.

From these attempts by ancient Chinese physicians, we can see that the Chinese people were very wise and that traditional Chinese medicine has always been progressing. Records show that this Chinese variolation lowered the death rate among those inoculated by 80% to 90%. Had the Englishman Edward Jenner not later invented the safer "cowpox vaccination," Chinese variolation might have remained the world's most advanced smallpox-prevention method.

Chinese variolation spread widely to Korea, Japan, Russia, and Europe. In 1688, Russia sent people to China to learn variolation. In 1744, the Chinese physician Li Renshan arrived in Nagasaki, Japan, bringing Chinese variolation to Japan for the first time. In 1790, Korea sent envoys Pak Jaega and Pak Yang-dok to Beijing; on their return, Pak Jaega inoculated variola vaccine according to the method recorded in Yizong Jinjian, with success. In 1721, Lady Mary Wortley Montagu, wife of the British ambassador to Turkey, learned in Constantinople of variolation, which had spread from China to the Middle East, and brought it back to Europe; in 1772, the British royal family allowed British children to receive variolation.

The French philosopher Voltaire, upon encountering Chinese variolation, praised it highly, calling it "a great example set by the wisest and most courteous nation on earth."

But there was a flaw: after variolation reached England, it at one point caused many inoculated children to die of smallpox, at a horrifying rate, so that the British eventually dared not use it. This may have depended on the operator's skill, or on low population immunity to smallpox in England at the time.

Against this historical background, the English country doctor and naturalist Edward Jenner made an epoch-making contribution: inspired both by variolation and by careful observation of daily life, he pioneered "cowpox vaccination."

Jenner was a country doctor unusually gifted at observation, and also a naturalist. In his day, naturalists were the most respected intellectuals in England; Charles Darwin, who proposed evolution, and his cousin Francis Galton (founder of eugenics), were both famous English naturalists.

Born in 1749 in the town of Berkeley, Gloucestershire, Jenner was apprenticed to a physician at age 12 and later worked and studied anatomy in a hospital. In 1770, at 21, he left Berkeley for London to study medicine under the renowned scholar John Hunter. Hunter was both a prominent physician and a famous naturalist.

Studying under Hunter, Jenner's observational gifts flourished. In 1771, the naturalist Joseph Banks returned from a three-year global voyage aboard the Endeavour, bringing back a huge number of novel specimens that needed organizing. Hunter recommended his student Jenner for the job, which Jenner completed excellently and from which he gained valuable training.

At 24, Jenner returned home, continuing both his naturalist work and medical practice. He supplied his teacher with large numbers of plant and animal specimens, and Hunter greatly appreciated what he did. Jenner even observed the cuckoo's brood-parasitism behavior and wrote it up as a paper; Banks read it to the Royal Society, and Jenner was elected a Fellow of the Royal Society.

Such observational ability is essential for a scientist. The keen Jenner noticed that milkmaids who had caught cowpox (a mild cattle disease) never got smallpox. In May 1796, Jenner inoculated material from a cowpox pustule into 8-year-old James Phipps, and later confirmed the boy was immune to smallpox. He then recruited more than twenty volunteers and vaccinated them all with cowpox, with success.

This convinced Jenner that cowpox vaccination was a safe and effective way to prevent smallpox. He wrote up his findings in "An Inquiry into the Causes and Effects of the Variolae Vaccinae," in which he outlined the principle, freely released the technical details of cowpox vaccination worldwide, and even provided samples free of charge.

His great discovery and selfless approach allowed cowpox vaccination to spread and be adopted rapidly. In the early 19th century, the British Army and Navy made it mandatory, and the technique quickly spread to Europe, the Americas, and China. China—the birthplace of variolation—welcomed this safer new method and became one of the first countries to adopt cowpox vaccination, showing that the Chinese people have always been open rather than conservative.

More than 180 years after cowpox vaccination was born, humanity finally eradicated the smallpox virus. In 1980, the World Health Organization declared smallpox eradicated worldwide. Today, the virus that once ravaged humankind exists only in laboratories and no longer circulates among people.

Writing this, I cannot help reflecting: without the precious experience our ancestors accumulated, and without Jenner's selfless and great devotion, we might still live today under the threat of smallpox, still enduring the nightmare of this highly lethal plague.

Today Jenner is honored as the father of modern immunology; the word "vaccine" derives from the Latin "vacca" (cow), a tribute of the scientific community to Jenner's cowpox vaccination, and all honors he deserves. But I believe what drove Jenner himself was not these honors but his love for medicine and his curiosity.

Besides Jenner, the nameless people of ancient China who contributed to the invention of the smallpox vaccine deserve our respect. The first person to invent variolation may have been an utterly ordinary commoner, but that genius-like innovation left invaluable experience to later generations.

Today's textbooks habitually divide medical history into an era of empirical medicine and an era of scientific medicine, but I think there is really no sharp dividing line. In any age, humanity's curiosity about natural phenomena and its tireless exploratory drive under the pressure of survival are the most fundamental forces moving medicine forward—the essence and core of science itself.

From this arduous history of humanity's struggle against smallpox, there are many lessons to draw.

We see that in every age and every land, many people have boldly advanced in the life sciences, and they are all worthy of respect. We also see, as Mao Zedong said, that Chinese medicine is a great treasury with many precious things for us to mine. At the same time, we should see that these precious experiences have shortcomings; as we draw inspiration from them, we must also keep pace with the times and improve ancient medical experience to make it safer and more effective, rather than resting on our laurels.