Appendix C

A Brief Anecdotal History of Disease, Civilization, and the Quest for Immunity

While we’ve only recently developed a reliable immune-based therapy against cancer, we have had immune system–based therapies against disease for centuries. The most familiar form of these immune system–based medicines is the vaccine. A vaccine is an agent intentionally introduced into a living body in order to stimulate a specific and direct protection against a specific disease. In its most basic form, this could be a crude introduction—say, a scratch—with the corpse of one of the dead pathogens. There’s a lot of information on a bacterial corpse. You can think of them as hints and insights about the enemy you may one day face. And the immune system is a quick learner.

We owe the word vaccine to cows (it comes from the Latin vacca, for “cow”), and the vaccine itself to observations of the work of milkmaids.

Edward Jenner observed that persons who milked cows often developed a bovine-borne disease called cowpox, and those who did were also far less likely to catch its deadly human cousin, smallpox. In 1796 Jenner re-created this incidental inoculation. He used pus scraped from the blisters of a milkmaid named Sarah Nelmes; Nelmes’s cowpox had been caught from a heifer named Blossom. Jenner then transferred the pus to the eight-year-old son of his gardener. His experiment inoculated the boy, and in turn granted the concept of intentionally engineered immunity scientific recognition and acceptance.

Jenner invented the modern vaccine—the ones you get at Walgreens to get immunity from this year’s flu are essentially the same—and his breakthrough saved millions of lives. He was the first to use the scientific principle of borrowing one person’s immune response (the pus) to a weaker cousin of a disease and weaponizing it for another person, making them immune to the disease itself. But even in the seventeenth century, the concept of immunity was nothing new. It had been familiar for so long that we took it as a sort of folk wisdom—common sense, even. People who had survived exposure to a disease usually weren’t susceptible to that disease the next time it came through. That sort of thing is almost impossible not to notice.

The words in Latin are immunitas and immunis. Both referred to a legal concept of exception. In ancient Rome immunity was a legal pass from a citizen’s usual responsibilities or duties, such as an obligatory period of military service, or taxes. With poetic license the first century AD Roman poet Lucan uses the word to describe the Psylli tribe of North Africa, whose members were famously said to be “immune” to snakebite. (See Arthur M. Silverstein, A History of Immunology.)

In fact, immunity from the terrible toll of poisons was a particularly well-subscribed field of study, being popular with those who had both the need to survive assassins as well as the gold to pay for such protection.

In her Milestones in Immunology: A Historical Exploration, Debra Jan Bibel cites the relatively more recent desire of kings, fearing death and succession by poisoning, to seek immunity from poison. In the first century we have a record, or perhaps a fable, of King Mithridates VI, whose kingdom of Pontus bordered the Black Sea. Mithridates attempted to give himself such immunity by taking a daily prescribed dose of the poison he assumed would be used to assassinate him. This assumes the state of fable because he reportedly succeeded, grew old, and wanted to end his life by poisoning himself—only to discover he was truly immune, and could not.

By the fourteenth century immunity had come to have implications of a special dominion of exemption from the toll of disease, bestowed by God. (This and the following come from Antoinette Stettler’s Gesnerus review of “History of Concepts of Infection and Defense,” as quoted by Silverstein in his History of Immunology.) “Equibus Dei gratia ego immunis evasi,” wrote Colle, referring to his escape from the plague epidemic.

Plagues and pestilence were a common feature of the ancient world. The plague that ravaged Athens in 430 BC killed an estimated 25 percent of the city’s population. The historian Thucydides recorded the incident and made the observation that it was those Athenians who had been sickened and recovered who were best able to care for the dying: “They knew what it was from experience, and had now no fear for themselves; for the same man was never attacked twice—never at least fatally,” he wrote. The phenomenon Thucydides is unwittingly describing is acquired immunity.

This was an early observation but one made repeatedly during pandemics; for example, one thousand years later, the historian Procopius described another plague, this one named for the emperor of Byzantium as the Plague of Justinian: “It left neither island nor cave nor mountain ridge which had human inhabitants; and if it had passed by any land, either not affecting the men there or touching them in indifferent fashion, still at a later time it came back; then those who dwelt round about this land, whom formerly it had afflicted most sorely, it did not touch at all” (Procopius, The Persian War, vol. 1, trans. H. B. Dewing [London: Heinemann, 1914]).

As a folk medical practice, inoculation had a long history but no scientific explanation. The Moors and the Pouls of the largely Muslim West African region that lies between Senegal and Gambia would stab a knife through the lungs of a cow that had died due to pleuropneumonia, then use it to make incisions in the hides of their healthy cattle. It was a de facto inoculation, introducing a bovine pneumonia to the immune system of healthy cows. Whether success was considered dependent on the specific knife or the specific person making the incision, or words incanted during the ritual or the design of the cuts is not known; the practice, reported in Western scientific journals in 1885 (e.g., Compus Rendus de l’Académie des Sciences), was already said to have an origin “lost in the obscurity of history.”

As Silverstein wrote, the keen observer “could not help but notice that often those who by good fortune had survived the disease once might be ‘exempt’ from further involvement upon its return.” This was the same phenomenon later to be described more scientifically by Jenner, who’s credited with the great experiment that brought about the smallpox vaccine, and “intentionally” acquired immunity.

In 1714, two Greek-Italian physicians reported on some of these inoculation rituals as they applied to humans for the Royal Society of London, which was a sort of clearing house of officialdom for Western medicine. The disease in question was smallpox.

The first recorded epidemic of this disease farther west occurred in Arabia during the sixth century:

In 570, an Abyssinian (Ethiopian) army provided with war elephants, under the command of the Christian zealot Abraha Ashram, set forth from Yemen (then occupied by the Abyssinians) and attacked Mecca (now in Saudi Arabia) to destroy the Kaaba in that city. Kaaba was the sacred shrine of the Arabs, who were then heathen and kept their idols in it. According to Muslim tradition, this shrine was built by Abraham, the father of Isaac and Ishmael, whose descendants are the Jews and the Arabs, respectively. As stated in the Koran, the holy book of the Muslims, God sent flocks of birds which showered the attacking army with stones producing sores and pustules that spread like a pestilence among the troops. Consequently, the Abyssinian army was decimated, and Abraha died from the disease; thus, the Kaaba was saved from destruction. The year AD 570, which is also the birth year of Mohammad, the prophet of Islam, was designated by the Meccans as the year of the elephant. Medical historians have interpreted the above pestilence as an outbreak of smallpox which introduced this disease to Arabia from Africa (A. M. Behbehani, “The Smallpox Story: Life and Death of an Old Disease,” Microbiological Reviews, 1983, 47:455–509).

Descriptions of smallpox appear in the most ancient Indian, Egyptian, and Chinese medical writing. Pharoah Ramses V appears to have died of the disease in 1157 BC. Behbehani cites the translation of Arabic medical books into Latin by Constantinus Africanus (1020 to 1087) as the origin of the name “variola” for the disease described in 910 by the eminent Islamic physician Rhazes. For centuries it was considered an innocuous disease, but somewhere in the tenth century it transformed into a more virulent strain, which returned from the holy land with the crusaders in the following centuries. By the sixteenth century it had traveled on slave slips to the West Indies, and from there to Central America and Mexico, where it decimated populations and was at least partially responsible for Hernán Cortés’s ability to conquer the mighty Aztec empire with only five hundred men and twenty-three cannons. In his wake the disease continued its ravages, killing more than three million persons, while Cortés himself traveled to Cuba, the disease in tow. Five years later it would travel across the isthmus to Peru, where it decimated the Inca and wiped out entire Amazonian tribes across South America.

By this time it had also hopped the channel to Britain, and by 1562 it had infected Queen Elizabeth 1. The monarch survived the disease, but it left her bald and facially disfigured. By the seventeenth century, outbreaks were deadly and regular occurrences. It is estimated that at this time, the disease was responsible for four hundred thousand deaths in Europe each year, and caused one-third of the cases of blindness. Urban centers were hit especially hard by contagious diseases, and the teeming streets of rapidly populating London suffered disproportionately.

In a series of letters by Emanuele Timoni, a doctor affiliated with the Royal Embassy in Constantinople, he and his colleague Jacob Pylarini informed the esteemed scientific body of a folk practice known as “buying the smallpox,” which involved inoculating against smallpox, by collecting the hard, scab-like crusts that formed on the weeping pustules of someone who had been sickened, but not killed, by the disease—what the authors referred to as “favorable” cases of smallpox. These crusts would then be inserted directly into cuts in the skin of a smallpox innocent. Apparently the practice was unfamiliar to London society, but as Timoni and Pylarini witnessed, it was common practice and protection in the far eastern capital of Constantinople.

A British surgeon in Turkey described the practice as being performed by old women, who “scarred the wrists, legs and forehead of the patient, placed a fresh and kindly pock in each incision and bound it there for 8 to 10 days, after this time the patient was credibly informed. The patient would develop a mild case, recover, and thereafter be immune.”

In fact, the practice was long known to rural communities in Western Europe, the Middle East, North and West Africa, and Asia, where writers have speculated that the practice may have begun. In China, it is described by Chinese author Wan Quan in his 1549 medical volume Dou zhen xin fa. Here, rough custom had been refined with some elegant touches; the smallpox scabs were ground into a powder and blown into the nose of the person to be inoculated, using a special silver straw (boys were inoculated through the left nostril, girls through the right). The inoculation was far from perfect, and sometimes served as an intentional infection. Using live smallpox was reported to kill as many as 2 percent of the participants and turned the rest into temporary contagious carriers of the disease. Still, that was considered a favorable trade-off for the 20–30 percent mortality rate of the disease itself.

Initial resistance to using such foreign techniques in London was worn down by the addition of courtly charm and title in the person of Lady Mary Wortley Montagu, a poet and travel writer known for a beauty marked by a fierceness of the eyes, and whose husband, Lord Edward Wortley Montagu, had been appointed ambassador to Constantinople in 1716. Lady Mary traveled with him and observed the Turkish custom of variolation.

She had already survived the disease herself, which had scarred her face and caused her to lose her eyelashes—one potential source of their noted intensity. Her brother had been less fortunate. She was impressed with the local custom, enough to insist that the embassy surgeon inoculate their five-year-old son, Edward Jr., while her husband was away on official business at the Grand Vizier’s camp in Sophia. The embassy chaplain protested that the procedure was “unchristian” and could work only on “infidels,” but Lady Mary was persistent. Dr. Charles Maitland inoculated one of the boy’s arms with a lancet, an “old Greek woman” inoculated the other “with an old rusty needle,” and both presumably used the method Lady Mary described in her letters, with the pus of an eleven-year-old that had been extracted into a small glass bottle and kept at a proper temperature in the armpit of the physician. That boy’s apparent immunity made Lady Mary an enthusiastic booster for the “Turkish method,” which she called “ingrafting.” When she returned to London in 1721 she had the same embassy surgeon, Charles Maitland, repeat the procedure on her then four-year-old daughter. The technique was already customary in the countryside for nobody knows how long, but this was the first time it was performed by a medical professional, and certainly the first time it was done in view of royal court physicians. The little girl’s pale, thin arm was exposed, slight incisions were made, and as the blood ran and the brave girl allowed a stranger’s scabs to be stuffed against the wound, Sir Hans Sloane watched and considered.

Sir Sloane was an eminent physician, both president of the Royal Society and personal physician to the king. Lady Mary had been a vocal advocate for the method ever since her first letter back from Constantinople. She was a lady of social status, articulate and worldly and beloved by London society—but she was neither a physician nor a man. Sir Sloane, of course, carried both of these contemporary qualifications. His opinion, and that of the community of physicians at large, was that variolation was a dangerous procedure. But soon, news of the little girl’s successful recovery and immunity triangulated with Sloane’s eyewitness bona fides and Lady Mary’s example.

In the summer of 1721, London was in the midst of a smallpox epidemic. Among those hoping to escape its ravages were the royal family. Five reigning European monarchs (Joseph I of Germany, Peter II of Russia, Louis XV of France, William II of Orange, and the last elector of Bavaria) would succumb to this disease during the eighteenth century. The princess of Wales, Caroline of Ansbach, very much hoped to spare her own children this fate. She was familiar with Lady Mary through social circles, and was known as a bright and scientifically minded royal, interested in the advances of her day. (The court flatterer Voltaire referred to the princess as “a philosopher on the throne.”) Further convinced by the royal court physician, she and her husband (the future George II) agreed to sponsor a sort of clinical trial, of the sort that would pass exactly zero twentieth-century ethics boards.

By late July 1721 arrangements were made with the officials of London’s notorious Newgate Prison; six prisoners were to be selected with the help of the royal physician and the apothecary from the ranks of those condemned to hang for their crimes. These would be the human guinea pigs. In exchange, they would be granted their freedom—immunity for immunity. It wasn’t clear, however, whether they’d be alive to enjoy it.

On August 9, Dr. Maitland repeated the procedure on the prisoners, three men and three women, aged nineteen to thirty-six years of age. They were variolated on their arms and right legs as a group of twenty-five physicians, surgeons, and apothecaries watched. Five of the six developed smallpox symptoms by August 13; the sixth turned out to have already had the disease, and was already immune. All made a complete recovery and were granted their freedom, as promised.

But to test their immunity, the nineteen-year-old female prisoner was hired as a temporary nurse by the royal physician and transported to the town of Herford, which was suffering under the ravages of a particularly intense smallpox outbreak.

The girl worked as a nurse to a smallpox patient during the day, and at night was boarded in the same bed with another smallpox patient—a ten-year-old boy. After six weeks of this work, the young woman still showed no sign of the disease.

Newspapers covered the story of the experiments sponsored by the royal couple. They were generally favorable. (At this time a physician also variolated another female prisoner, this time through the Chinese method of powdered crusts blown into the nasal cavity. The newspapers at the time were highly critical of this experiment, because apparently the woman has been asleep when it was done.)

Soon volunteers began asking for the same treatment. Thus proven, the royal daughters—eleven-year-old Amelia and nine-year-old Caroline—were variolated on April 17, 1722.

The procedure received the sort of attention that attends all affairs of royal children great and small, but it was hardly a cure for the disease, only a better roll of the dice. Maitland, while concluding the experiments in Hertford, had privately variolated a number of children from private households; one had become ill and spread the smallpox to six household servants, one of whom died.

This pattern was repeated in other households, where servants were exposed to inoculated children and succumbed to the disease. Others who lined up to receive the fruits of what would become known as “the Royal Experiment,” such as the child of the Earl of Sunderland, did not recover from the illness and died days later.

Priests railed against the unnatural regimen from the pulpit, telling their flocks that “the dangerous and sinful practice of inoculation” was diabolical, promoted vice, and “usurp[ed] an authority founded neither in the laws of nature or religion.” The London surgeon Legard Sparham published a pamphlet against inoculating, and articulated his reasons against inserting diseases into healing wounds, calling it “bartering health for diseases.” (As we have seen, this “deal” had echoes in late-nineteenth-century New York City and in the foundational observations of cancer immunotherapy.)

But the variolation treatment received a more broad endorsement from the London Royal Academy, more so after its secretary and mathematician examined the results statistically. He found that death from variolation between 1723 and 1727 occurred in between 1 out of 48 to 1 out of 60 cases, while death from natural smallpox occurred in 1 out of 6. Royal opinion had been vindicated.

Inoculation would be the law in Britain. That sensibility didn’t necessarily translate to the rustics in the colonies, however—a fact that almost decided the War of Independence and ended America’s revolution.

We don’t know if Onesimus was his given name, that record is lost. It’s believed that he came from the Fezzan region of southwestern Libya, a land of rocks and high dunes surrounding the oasis capital of Murzuq, though it’s impossible to be sure. (At the time Murzuq was a thriving hub for both pilgrims and the slave trade that fed captives from Chad and the Central African Republic.)

What is certain is that as a young man, Onesimus was inoculated against smallpox in the Ottoman fashion, and the variolation left him with a telltale scar, and that at some point around 1718, Onesimus was kidnapped by slavers and shipped in chains to the American colonies to be sold at auction.

Since the seventeenth century, the center of the American slave trade was the port of Boston. Here Onesimus was purchased at auction by a man of God and science named Cotton Mather. Cotton Mather seems an especially curious figure—a widely read champion of learning best remembered for his involvement in the Salem witchcraft trials, a man of strict religious character who owned other human beings. None of that marked him as extraordinary in eighteenth-century Boston. What did make Mather unusual was that he was literate, well read, and both observant and curious about the world around him. Now he was curious about the variolation marks on Onesimus’s arm.

Onesimus had unwillingly carried the technology of inoculation from Muslim northern Africa to the primitive American colonies. Mather was sharp enough to be curious about the practice, and did not understand why it wasn’t in the colonies as well.

In June 1721, the disease that raged in London the summer before arrived at the American colony via the HMS Seahorse, recently of the West Indies. Soon the disease showed all the hallmarks of an epidemic. It would be devastating to the small capital—a city in name only, laid along the paths worn by cattle and sheep. In matters of contagion, Cotton Mather was one of the few people in Massachusetts qualified to give advice.

This was a small, rough world, and Mather’s learned religiosity was leavened by an equally giant intellect that towered over most of his largely illiterate colonial peers. The few men who did read knew each other, and borrowed one another’s books. (Mather lent and borrowed volumes with Benjamin Franklin, then a precocious young apprentice at a printer’s shop near Mather’s home; he also had his own pamphlets printed at Franklin’s shop. Mather’s business helped Franklin establish himself in his own print shop; the lending and borrowing practice among the small community of readers led Franklin to initiate the colony’s first lending library.)

Mather was not a physician, but he read their journals when he could and was up-to-date on the most recent advances. (More so than most physicians, though this is not surprising; in all the colonies at that time there was only one working physician who held a medical degree—his book-lending acquaintance, Dr. William Douglass, formerly of Edinburgh University.)

Douglass subscribed to the latest medical journals from abroad. Mather borrowed them and found Timoni’s published letter to the Royal Academy in London regarding the practices of smallpox variolation as witnessed in Constantinople. The method Onesimus described was now mirrored in a medical journal, and validated by the Royal Academy of mother England, a holy trinity of conviction for a man like Mather.

Mather’s was a radical view, intellectually, not just for 1724 Boston but for the larger scientific community, and even more radical when Mather attempted to act on it. The colony’s only properly degreed physician violently opposed Mather’s inoculation attempts. During the year 1721 Mather spent a small part of his energies trying to press variolation technique onto the medical men of Boston. He convinced only one, a medically inclined stone cutter named Zabdeil Boylston. Boylston preformed the procedure on his son, his slave, and his slave’s son. All three survived and were safely inoculated, but the intellectual backlash was pronounced.

Boylston was attacked in the papers, and then physically by mobs in the street. Mather, undeterred by Boylston’s beating, then inoculated his own son in the same way. The procedure sickened the boy and almost killed him, which only made his fellow colonists more fearful and angry. Mather was seen as spreading disease and risking pandemic. Every smallpox victim was a potential grenade of illness in the small rural community, and as retort, at three o’clock that night an angry antivaxxer lobbed a real grenade through Mather’s window and into the house where Mather’s son and another minister, recovering from his own smallpox variolation, were then recuperating. The grenade survived—the lit fuse apparently became detached as it crashed through the window—and was found with an anti-inoculation note attached.

Boylston would report that by 1722 he had inoculated 242 people in the Boston area, of whom six died—a 2.5 percent mortality rate. That could be compared to a reported 15 percent mortality rate of cases of natural smallpox in the Boston area, 849 deaths among 5,889 cases of naturally occurring disease. Variolation involved treating healthy people with a deadly disease; it worked sometimes, it was true, but it did so through a mechanism that was beyond the best scientific minds of the time. Where man interfered in the natural order, whatever magic resulted might be of demonic design. The truth was wonder beyond the imagining of any contemporary watchmaker or apothecary.

Variolation would eventually gain greater appreciation in America, but it still lagged behind Britain. Several American states passed laws against it; some colonial cities declared themselves to be antivariolation zones and became sanctuary cities for antivaxxers.

George Washington believed in the effectiveness of the technique, however, and had his troops inoculated before the siege of Boston. But these inoculations were risky—during the infectious stage, the treatment could trigger an epidemic—and grudgingly, Washington stopped the program. Historians now believe that as a result, smallpox ravaged the colonial army in a way that it had not affected the variolated British forces, beneficiaries as they were of the monarch’s royal experiment.

It’s been suggested by some historians that it was smallpox and the antivariolation cities of the north that saved Canada for Britain.