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As the world scrambles to develop an inoculation against Covid-19, it’s worth understanding the early, extraordinary history of the technique.
The english doctorThomas Dimsdale was nervous.
It was the evening of October 12, 1768, and Dimsdale was preparing the empress of Russia, Catherine the Great, for her procedure. From a technical perspective, what he planned was simple, medically sound, and minimally invasive. It required only two or three small slices into Catherine’s arm. Nevertheless, Dimsdale had good reason for his concern, because into those slices he would grind a few scabby pustules teeming with variola–the virus responsible for smallpox and the death of nearly a third of those who contracted it. Though he infected Catherine at her behest, Dimsdale was so concerned about the outcome that he secretly arranged for a stagecoach to rush him out of Saint Petersburg should his procedure go awry.
What Dimsdale planned is alternatively called a variolation or inoculation, and while it was dangerous it nevertheless represented the pinnacle of medical achievement at the time. In a variolation, a doctor transferred smallpox pustules from a sick patient into a healthy one because–for reasons no one at the time understood–a variolated patient typically developed only a mild case of smallpox while still gaining lifelong immunity.
Twenty-eight years later, Edward Jenner improved this proto-vaccination when he discovered he could use a safer, sister virus of variola called cowpox to inoculate his patients. But it’s the original variolation–not Jenner’s vaccine–that first established the efficacy of the crazy, and at the time ludicrously dangerous, idea upon which nearly all vaccines rely: the intentional infection of a healthy person with a weakened pathogen to bequeath immunity.
Modern immunologists have advanced this life-saving concept to such a degree that if they find a vaccine for Covid-19, it will pose no risk of widespread infection. Inoculums today induce the production of antibodies while being incapable of large-scale reproduction. But that wasn’t the case when they were first discovered. When Dimsdale variolated Catherine, his process merely gave her immune system the upper hand. He knew she would sicken.
By now we are so familiar with the lifesaving concept behind vaccines that it’s easy to forget how insane, genius, and unethical these first inoculations must have been. Even Dimsdale, who had performed the procedure thousands of times, was clearly skeptical that he could talk his way out of a noose should Catherine’s variolation end poorly.
And yet the idea to intentionally infect a patient with a lethal virus to help them did first occur to someone–and it was perhaps the greatest idea in the history of medicine.
It was not Jenner’s idea, nor was it Dimsdale’s. But it may have been a single person’s. Remarkably, variolation may not have been independently discovered. Instead, the earliest documentation suggests it began in China–probably in the southwestern provinces of either Anhui or Jiangxi–before spreading across the globe in a cascading series of introductions.
Chinese sea merchants introduced the procedure to Africa, brought knowledge of it overland to India, and carried it along the Silk Road to Turkey, which is where 18th-century European ambassadors finally learned of the technique and brought it home. The timing and paths of variolation’s introductions around the world suggests that the idea spread out of one place, at one time. Perhaps from one person.
According to one legend, recounted in Yü Thien-chhih’s Collected Commentaries on Smallpox, written in 1727, the first inoculator was “an eccentric and extraordinary man who had himself derived it from the alchemical adepts.”
Who was this “eccentric and extraordinary man” who invented immunology with one of the greatest ideas and boldest experiments in medical history?
HIS OR HER name is not only long lost, but it was probably never written. However, legends and ancient Chinese medical treatises make it possible to construct a plausible biography for someone who I’ll simply call the “extraordinary man,” after Thien-chhih’s legend, or “X” for short.
X may have been a healer, a traveler, and someone who believed in practices outside the contemporary Chinese medical mainstream, according to the biochemist and historian Joseph Needham. By the time “he” (if we take Thien-chhih’s legend literally) practiced, mainstream Chinese medicine was soundly based on pharmacies, physical therapy, and rational techniques. But X existed on the edge of it, mixing mainstream medical methods with magic.
He may have been what was referred to at the time as a fangshi, writes Chia-Feng Chang in Aspects of Smallpox and Its Significance in Chinese History. But fangshi is a word that in some ways defies translation, because comparative English words like exorcist or diviner bring to mind more nefarious individuals than he probably was. Instead, he was a traveling healer who, while certainly a believer in magic, also preached practical medical ideals such as hygiene and a healthy diet.
X is unlikely to have received any formal medical training. Instead, he learned his secrets and practices from relatives or masters. He was probably illiterate, or nearly so, and thus learned and taught his techniques entirely through oral tradition. This partly explains why his name wasn’t lost so much as it was never recorded–but even if he could have documented his discoveries he is unlikely to have done so. Traditionally, fangshi like X kept their practices and methods secret to all but a few disciples. Variolation may have been what was called a chin fang–or “forbidden prescription,” writes Needham in Science and Civilization in China. Chin fang were “confidential remedies handed down from master to apprentice, sometimes sealed in blood.”
In a way, X was not unlike a modern Western magician. His secrets were his livelihood. Revealing them might ruin the magic, but it would certainly hurt future business.
The fangshi tradition of secrecy–along with the numerous legends surrounding inoculation–have sparked intensive scholarly debate about when exactly variolation began.
The earliest written evidence of inoculation originates from mid-16th-century writing. A medical treatise written in 1549 titled On Measles and Smallpox by the physician Wan Chhüan describes “transplanting the smallpox” into healthy patients. But inoculation probably began at least a few generations before Chhüan’s mention of it, because he notes the practice may bring about menstruation. The knowledge of this fairly specific side-effect suggests healers had been practicing this procedure for some time.
But exactly how much earlier is a matter of debate. If you take the legends surrounding variolation seriously, then the practice began as early as the 11th century. In one of the most popular accounts, documented in the Golden Mirror of Medical Orthodoxy, written in 1749, a hermit living on a sacred mountain in the Sichuan province of China invented variolation at the turn of the first millennium. According to this legend, the healer heeded the pleas of the prime minister Wang Tan and descended the mountain to save the minister’s family from smallpox.
Yet many scholars are suspicious of this and similar tales. Why do no contemporary accounts exist of such a remarkable event as the inoculation of this prime minister? And why is there no evidence for more than 500 years of such a revolutionary and effective practice when there are numerous, far older written documents concerning the treatment of smallpox itself?
The weight of the evidence, and sudden burst of documentation, suggest the practice first arose in the late 15th or early 16th century shortly before its appearance in medical texts. In all likelihood, X variolated his first patient around the same time Christopher Columbus landed in the New World.
But rather than obfuscating the origin of variolation, the existence of the legends may themselves be evidence. If the first practitioners existed outside the medical mainstream, their first patients would have been deeply suspicious of the radical technique. They would have been justifiably reluctant to intentionally infect themselves or their children with variola. So, like any good traveling healer, the first practitioners concocted stories to add to the procedure’s credibility. These were “legends to justify its origin and function,” writes Chang. As any good salesman would know, one doesn’t sell their elixir by saying that they came up with the recipe. “Variolation took lots of effort and time to gain trust and support to become popular,” Chang writes to me. Part of this effort to gain trust involved myths of its invention. If a patient believed the mysterious remedy originated from an eccentric healer who lived on a sacred mountain centuries ago, they were more likely to try it. It wasn’t necessarily fraud. It was just good business.
Yet even if the legends are true, and X lived thousands of years earlier than scholars believe, he still had to invent variolation. Unfortunately, just how exactly he did so is as lost as his name.
“What made them try a thing as weird as variolation? Unfortunately, we don’t have a neat origin story like the one about Jenner,” Hilary Smith, author of Forgotten Disease: Illnesses Transformed in Chinese Medicine, writes to me in an email.
But we do know many of the traditional Chinese medicines a healer like X would have practiced that, when combined with what he knew about smallpox, may have led him to his remarkable conclusion.
Smallpox first entered China after general Ma Yüan’s campaigns to conquer what is now Vietnam in 42 CE, according to the third-century philosopher Ko Hung. In 340 CE, Hung wrote that Yüan’s army caught the disease while attacking the “marauders” and brought it home–which is why the Chinese called smallpox “the marauders pox.” (In nearly every language, the original term for smallpox is often some form of “the foreigner’s disease.”)
The ensuing epidemic wracked China. Smallpox so comprehensively killed or immunized the population that as the centuries passed the average age of the infected person began to drop. By the year 1000, smallpox had so thoroughly ravished the country that children possessed the only naïve immune systems left to attack. Everyone else was either dead or immunized.
The disease became so endemic that Chinese doctors viewed its contraction as an inevitability. They believed the disease was a passage all children would have to eventually cross, and called smallpox “the gate of humans or ghosts.” With a death rate of at least 30 percent, outbreaks produced tragic results. Over a single Beijing summer in 1763, variola killed more than 17,000 children.
Smallpox’s inevitability, combined with its predilection for children, caused many to believe the disease was a kind of original sin. By the turn of the first millennium, doctors were convinced smallpox was caused by a kind of “fetal toxin” that, like puberty, would break out at some undefinable point in a child’s early years. In an attempt to remove this toxin, doctors performed extensive “filth and mouth cleanings” on newborns.
At the same time, healers like X would have understood that the disease could be passed from human to human and couldn’t be caught twice. Those who hadn’t caught the disease (“raw bodies,” as the Manchus called them) fled when outbreaks occurred, and those who had survived (“cooked bodies”) cared for the sick. As early as 320 CE Hung wrote of smallpox, “He who knows it can pass safely through the worst epidemics, and even share a bed with a sick person, without himself being infected.”
Understanding these two concepts are foundational to the principles of inoculation, but they were not unique to China. So perhaps X was aided by beliefs specific to traditional Chinese medicine.
One ancient Chinese medical technique X may have practiced was called “yi tu kung tu” or “fighting poison with poison.” For centuries, medical healers in China had mixed teas of known poisons such as camptothecin and periwinkle to fight cancers, so the idea of using a lethal substance as a cure may not have been as foreign to X as it would have been in other cultures.
Of course, there is a significant difference between poisonous teas prescribed to sick patients and administering a lethal pathogen to an entirely healthy person. And yet this, too, fell in line with Chinese traditional medicine, which focused heavily on preventative care as opposed to Western doctors’ emphasis at the time on reactive treatment.
We may never know exactly what motivated or inspired the first inoculators, but if X was aware of person-to-person transmission, knew a person could only be infected once, knew a child would almost inevitably contract the disease naturally, believed in the efficacy of poisonous medications, and had a strong preference for preventative care–the stage was then set for a keen observation.
Perhaps X watched siblings pass around a particularly mild case of smallpox and suggested to a pair of desperately concerned parents that rather than running from the inevitable, they fight poison with poison and guide their child through the gates of humans and ghosts with this apparently milder form.
Or at least, that could be how X conceived of it. But like any good traveling diviner, this healer punched up his story to convince what must have been a pair of incredibly skeptical parents. The earliest variolation technique was to simply wear the used clothing of a smallpox infected patient, according to Needham. But X wouldn’t have simply handed his patient old clothes. Instead, early healers performed dramatic inoculations on auspicious dates. They lit incense, burned money, recited charms, and invited the gods and goddesses responsible for smallpox to protect the child. Then they handed them the clothes–and waited.
If X’s first patient experienced a typical inoculation, then by the fifth day the child would have developed a fever and sprouted bulbous pocks of pus. But rather than the sheets of black pustules that develop in a lethal case, X’s patient would grow only a smattering of smaller and lighter-colored pox. As soon as X noted these smaller pox, they would have known the child would progress into only a mild case of the disease. They would have known that remarkably–stunningly–this reckless experiment had worked.
The obvious question, of course, is why? Why did the child experience a mild case instead of a lethal one? Why is variolation a safer means of contracting smallpox? X certainly would have had an explanation, but it’s unlikely to have been correct.
The actual answer is thanks to something epidemiologists call the dose-response curve.
The dose-response curve is the relationship between the severity of one’s disease and the quantity of the initial dose. This is different from the “minimum infectious dose,” which measures the fewest virus particles you can receive before you’re likely to become infected. In variola the minimum infectious dose is somewhere around 50 viral particles–also called virions–which sounds like a lot, but 3 million could sit on the head of a pin. According to Rachael Jones, a professor of health and sciences at the University of Utah, a single virion could theoretically infect you, but it’s unlikely. According to her, an infectious dose of variola is a little like playing Russian roulette: More virions equal more bullets.
But all things being equal, more virions also equal greater severity. And this is the relationship the dose-response curve attempts to chart.
Unfortunately, dose-response is incredibly difficult to establish outside clinical settings. It’s nearly impossible to re-create the dose a person naturally received, so quantifying dose-response requires intentionally infecting a group of patients with a measured amount of a given pathogen. That’s problematic, particularly with dangerous infectious diseases like variola.
Obviously, you cannot infect humans with increasing amounts of variola and measure their response, but a study on mice found there is likely a correlation between the virus’s infectious dose and severity. Small quantities of variola injected into mice left them mildly sick or asymptomatic, while the largest doses were universally fatal.
It’s difficult to definitively establish dose-response curves, but the evidence suggests that the larger the infectious dose of variola, the worse a patient’s prognosis. Mark Nicas, a professor emeritus at UC Berkeley who researches pathogen exposure and risk assessment, tells me that a relationship between the size of the initial dose and the severity of your outcome is probably true for all pathogens.
The dose-response curve of variola likely explains why X’s patient experienced a mild case, and why variolation worked. By choosing the clothes of a patient who came down with a mild case, X unknowingly took advantage of two basic principles of variola: First, patients with milder cases shed fewer virions in their pustules; second, as the clothes sat, many of those virions would have died. As a result, X’s patient would have been initially infected with a smaller dose than they would have been likely to contract naturally. The dose would have been sufficient to spark an infection and induce the production of antibodies but low enough to significantly reduce the risk of death.
Variolation was a balancing act: Too potent a dose and the patient would contract a dangerous case; too little and they wouldn’t produce antibodies. As inoculators gained experience they refined the procedure to produce milder infections, but even the earliest inoculators report death rates of 2 to 3 percent, compared to the natural rate of 30 percent. The oldest instructions for variolation suggest selecting pustules from only the mildest smallpox cases and prescribe the proper method for storing and aging the scabs. Using these simple processes, inoculators unknowingly performed the earliest viral attenuations. By the time of Dimsdale’s procedure, fewer than 1 in 600 patients died from variolated smallpox.
In the end, Dimsdale need not have been concerned. Catherine developed only a mild illness, and his getaway vehicle sat unused in her driveway. The variolation was so successful, Dimsdale later said he had to use a microscope to see the pustules that formed around her cut. In a letter to Voltaire, Catherine wrote “the mountain had given birth to a mouse” and that her era’s brand of anti-vaxxers were “truly blockheads, ignorant or just wicked.”
Three decades after Catherine’s inoculation, Jenner discovered and popularized cowpox pustules as a replacement to smallpox’s. His procedure resulted in even safer inoculations, and Jenner named his method vaccination. When Louis Pasteur discovered he could attenuate and inoculate other pathogens such as anthrax and rabies–Jenner’s name stuck.
Even as immunologists have evolved their techniques, the principle behind vaccines has largely remained the same since the magic-believing X first discovered it.
It seems surprising that one of medicine’s most ingenious inspirations arose in someone who so loosely tied their beliefs to scientific-based medicine. As Needham writes, “It remains paradoxical that inoculation arose among the exorcists.”
But perhaps the idea to intentionally infect someone with one of humanity’s deadliest infectious diseases was so outrageously dangerous that variolation could only have been conceived and popularized by someone outside the medical mainstream. Maybe it could only have been tried by an observant believer who could tell a great story.
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