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  What this story fails to convey is that Cotton Mather was actually one of the most progressive and iconoclastic thinkers of his time. Evidence for this arose from a conversation regarding variolation that Mather had with his slave, Onesimus, who was gifted to Mather by his congregation.50 The reality that Mather owned a slave doesn’t seem progressive to modern readers (in his diary, he records he did not seek out this gift but later refers to his good fortune to be given a slave as a “mighty Smile of Heaven”). Mather, despite being a slaveholder, at least had some regard for Onesimus, which distinguished him as relatively progressive for this time and place. As it happened with many of the unfortunate victims of slavery, it is difficult to trace the lineage of Onesimus, who was named so by Mathers based on a slave mentioned in the Bible.51 A common attribution cited by some academic sources suggests that the man was a “Guaramante,” which has been referenced by some to indicate a person from the Akan or Twi people of the Gold Coast (now Ghana) in West Africa.52 Such an origin for Onesimus would be consistent with the fact that most slaves sent to North America were native to a swath of coastal lands ranging from west Africa or west central Africa. However, the practice of variolation at the time was largely restricted to the extreme eastern and southern regions of the African continent, as well as the lands north of the Sahara that were occupied by the Ottoman Turks (who, as we have seen, were relatively early adopters of variolation).53 Other sources suggest that the Guaramante people represent a tribe in what is now southern Libya.54 This alternative origin would be geographically closer to Ottoman lands but raises the question of how Onesimus had had the misfortune to become enslaved and shipped from the Gold Coast.

  Regardless of these geographical considerations, it is clear that Onesimus conveyed the advantages afforded by variolation. In 1714, Mather wrote a letter to the Philosophical Transactions of the Royal Society (of London), to which he was the first American colonist to be elected:

  I had from a servant of my own an account of its being practised in Africa. Enquiring of my Negro man, Onesimus, who is a pretty intelligent fellow, whether he had ever had the smallpox, he answered, both yes and no; and then told me that he had undergone an operation, which had given him something of the smallpox and would forever preserve him from it; adding that it was often used among the Guramantese and whoever had the courage to use it was forever free of the fear of contagion. He described the operation to me, and showed me in his arm the scar which it had left upon him.55

  Mather further maintained that Onesimus instructed him as to the best means of conducting the procedure, which again demonstrates the exceptional intellect of the slave. Mather sought out and spoke with other African slaves, who similarly advocated the advantages of inoculation. In the early spring of 1721, Mather inspired a period of experimentation with variolation that was triggered by an obnoxious outbreak of smallpox in Boston. Mather invited the town’s physicians to attempt the new technique, but, despite his renown in old and New England, Mather was soundly rebuffed. He continued advocating for variolation to Boston’s leading families and haranguing local physicians as a group and individually. Eventually one Bostonian doctor, Zabdiel Boylston, relented and inoculated his six-year-old son and two slaves.56 By that time, Boylston had already gained a reputation as a bit of a maverick. In 1710, he was the first American-trained physician to perform surgery (removing a gallbllader stone). In 1718, Boylston became the first surgeon to successfully remove a breast tumor. Word spread of the audacious experiment with inoculation and became the talk and consternation of Bostonian society. Within a few days, Boylston felt pressured enough to announce the success of the procedure in a June 1721 edition of the Boston Gazette.57

  Almost immediately, letters and cries of denunciation were directed at both Boylston and Mather. The primary accusation was that the procedure would propagate smallpox. Quite different arguments questioned the morality of intervening in the providence of God.58 Unbeknownst to Boylston, Mather had already obtained reports from his Royal Society colleagues about the successes being achieved in London with variolation (recall the efforts by Lady Montagu). In an attempt to assuage nerves, Boylston also announced the English findings in a later edition of the Boston Gazette. By then, the local furor over variolation grew to the point where a grenade was thrown though Mather’s bedroom window. The bomb failed to explode but contained a note with the words:59

  COTTON MATHER, you Dog, Dam You: I’ll inoculate you with this, with a Pox to you.

  In an act of defiance, Mather and Boylston conducted a large study of at least 280 persons (presumably volunteers) in which only six ended up dying from smallpox. This survival rate was a considerable improvement upon the non-variolated population. A preponderance of objective data eventually quieted the riotous Boston medical community and society.60 Because of the increasingly obvious advantages conveyed by variolation, the practice was adopted, again among the most learned members of the community, and spread thereafter throughout New England and the remaining colonies. Likewise, variolation gained acceptance throughout the rest of the 18th century in much of Europe. However, this practice was doomed to obsolescence, as the closing years of the century would witness a breakthrough with unprecedented abilities to eradicate not just smallpox but many of the deadliest plagues that had ever afflicted mankind.

  2

  Vaccination & Eradication

  Just over a century after Columbus initiated his voyages to the New World and unwittingly triggered genocidal waves of disease, an emerging playwright by the name of William Shakespeare penned a tragedy about young love in the far-off land of Verona, Italy. In the first act of scene three, Mercutio utters his dying words as a curse upon the families of Romeo and Juliet, whom he correctly blames for his death. “A plague o’ both houses!” Since its composition in 1596 and for reasons not entirely clear, this line has been rendered by many into “A pox on both your houses.” These inaccurate reproductions may reflect the stigma associated with smallpox. A POX UPON BOTH PARTIES was the headline for an editorial lamenting the Republican and Democratic Parties for nominating unworthy candidates in the 2016 election.1

  Exactly two centuries after Shakespeare composed these lines, and fifty miles as the crow flies from his beloved Stratford-upon-Avon birthplace, an Englishman by the name of Edward Jenner was unknowingly writing the first lines in a drama that would ultimately end a real pox and for all houses. Perhaps because our society prefers simple solutions and triumphant heroes (and because a founding myth often needs to be neat and tidy), much acclaim has been placed upon the individual of Edward Jenner and his work to discover a vaccine for smallpox. The heavily propagated story goes something like this:

  Edward Jenner was a bird lover, whose first major contribution to science was Observations on the Natural History of the Cuckoo, a letter he composed while practicing as a physician in the quaint parish community of Berkeley in Gloucestershire, England, midway between Bristol and Gloucester on the Little Avon River.2 As a fourteen-year-old student, Jenner started his training in medicine in 1763 under the mentorship of Dr. Daniel Ludlow. Among his other studies, Jenner was instructed in the art of smallpox variolation.3 Seven years later, Jenner apprenticed in surgery and anatomy at St. George’s Hospital in London and then returned to Gloucestershire. The key moment in our tale arises during a conversation between Jenner and a local milkmaid, who informed the physician that ladies of that profession were rarely, if ever, afflicted with smallpox. This revelation provided an epiphany moment for Jenner, who deduced that the milkmaids were prone to cowpox, a skin infection that caused minor lesions somewhat akin to smallpox. Jenner then connected the dots (or the spots, if you will) and presumed that cowpox would protect the general public from smallpox.

  As a practitioner of conventional variolation, Jenner postulated that the transfer of material from a cow’s or milkmaid’s cowpox lesions might confer protection against smallpox. This idea was successfully tested on May 14, 1796 when Edward Jenner inoculated (a word
chosen to distinguish the transfer procedure of cowpox rather than variolation with smallpox) eight-year-old James Phipps, the son of a poor laborer who tended Jenner’s garden.4 The source of the infection was a pustule on the hand of a milkmaid by the name of Sarah Nelms, who in turn had been infected by a cow named Blossom. James Phipps developed a low-grade fever but was otherwise healthy. A few days later, Jenner intentionally infected James Phipps with smallpox, one presumes via variolation rather than by a means that could have conveyed a more lethal outcome. The normal inflammatory signs of variolation (swelling and fever) were absent, and the boy remained healthy without any signs of localized inflammation or infection—a sign that the original inoculation had protected the child from smallpox.

  Jenner then performed similar inoculations and infection schema with a total of two dozen people and published his research in an 1801 report to the Royal Society of London.5 The Royal Society remained cautious at first, likely based on their remembrance of the opposition targeted at Lady Montagu and Cotton Mather. Soon, however, they embraced Jenner’s approach. To honor his landmark achievement, the medical community adopted the term vaccine, which is based upon the Latin term for cow, to honor Jenner (and Blossom) for their contributions to the discovery of immunity in general and the smallpox vaccine in particular. Sadly, the end of the story for Blossom was not as favorable, as evidenced by the fact that her hide is prominently displayed at St. George’s Hospital in London. (A pelt was donated by Jenner’s family more than fifty years after the seminal event, but much speculation suggests the hide is not Blossom but faux fur.)

  As tends to be the norm in science, Jenner certainly deserves credit for advancing and widening the impact of a pivotal discovery. Nonetheless, serious doubts surround the question of whether Jenner truly was subject to an Archimedes-like epiphany moment in 1796 or if he ever had the oft-described conversation with the milkmaid. As we will see, it seems more plausible that Edward Jenner’s work built upon millennia of experience with prior observation and was highly influenced, if not entirely motivated, by a chance meeting he had at the beginning of his medical training. At the extreme, Jenner might not have innovated the smallpox vaccine at all but simply took credit for the work of others. Before returning to Jenner, we will need to take a minor detour to gain some understanding of why the over-attribution to Jenner is so common.

  Conceptions

  On September 16, 2011, President Barack Obama signed into law the America Invents Act (AIA), which represented the largest overhaul of the American patent system since the middle of the previous century.6 The major change of this legislation was a pivot from a system known as first-to-invent to one known as first-to-file. Up to this time, the claim for exclusivity for an invention was granted to an inventor so long as they could convince the patent examiner they were the first to conceive of the idea. This restriction led to many interesting examples, such as the notorious “bar napkin,” which did not refer to the legal bar but rather to a case in which the inventors came up with an idea while sipping cocktails. Despite having quaffed a few rounds, the inventors in this case retained the presence of mind to draw up their invention on the back of a bar napkin, and each then signed and dated the napkin. The thin sheets of paper provided incontrovertible evidence in a later trial to demonstrate the inventors had come up with their idea before their adversaries, whose ideas were documented with a date that was later than the napkin. In a single swoop, the bill signed by President Obama overrode such events and eliminated an entire field of patent law known as opposition. The first-to-file provision meant that the first entity to file a patent, regardless of who first conceived the idea, would thereafter be considered the inventor (even if another conceived the idea first).

  How does this relate to Jenner and the discovery of the smallpox vaccine? The attribution of the smallpox vaccine to Edward Jenner is consistent with the implementation of the AIA. Although he might not have been the first, even in southwest England, to conceive of the smallpox vaccine, Jenner was the first to put his invention into widespread use. Almost at the same moment that President Obama was signing AIA into American law, an article penned by Robert Jesty of Hampshire, England, and Gareth Williams of the University of Bristol, appeared in the scientific literature.7 This report amplified an argument that Edward Jenner was not the inventor of vaccines. Going back to our patent analogy, their argument was that the bar napkin had been written and signed by others. Jenner, by analogy, was the first to file and has mostly retained credit for discovering the smallpox vaccine. This article continued a centuries-long debate within the scientific community as to the paternity of vaccines. We will thus attempt to piece together the parts in an objective chronological overview.

  The earliest mention of what we now know to be smallpox immunity was deduced and recorded not by Jenner but at least as far back as ancient Greece (two hundred years before Archimedes), by the father of scientific history himself.8 Thucydides was a military commander, philosopher, and historian, who recounted his experiences during the Plague of Athens in the 5th century B.C.E. In his descriptions of the plague (which might indeed have been or included smallpox), Thucydides conveys the first recorded notation that individuals who had survived one round of infection could care for others without danger of becoming re-infected. The physiological basis for this protection was not known, and little was done to either gain understanding of the phenomenon or utilize the idea to protect the population.

  A few short years after Lady Montagu successfully advocated for the widespread use of variolation among the gentry of England, an entrepreneurial family of Suffolk physicians capitalized upon the opportunities in conveying the technology to the wealthy. The family patriarch, Robert Sutton, optimized the technique for variolation, whose quality and reproducibility had in the past been rather spotty.9 The Suttonian technique entailed a process involving specialized pre-treatment and post-treatment activities, which included rigid control over diet, exercise, and, to be polite, purgatory events.10 As part of the process, it was essential to verify that the treatment had taken hold by assessing the degree of overall fever and inflammation (redness, swelling, and pus) at the site of local infection (including large pox near the site of variolation). This refinement became a family business overseen by Robert and his six sons.

  Not only were these improvements fundamental to increasing the volume of patients that could be variolated, but they also gave rise to an enterprising business opportunity. You may recall that a newly variolated person, harboring an infectious form of smallpox, necessarily must be quarantined from the rest of the community to avoid spreading the disease. Thus, the Sutton family opened a series of “variolation houses,” which provided not only the medical service of variolation and subsequent care but also a location for quarantine and all the medical care, food, and libations needed for a month-long stay. Soon these package deals were popularized as a sort of spa and vacation opportunity. Indeed, the practice grew so lucrative that they began to franchise both the “Suttonian technique” and “variolation houses” to other physicians throughout the country. One entrepreneurial franchisee was John Fewster, who was based in Thornbury, a village in Gloucestershire.11 Fewster apparently oversaw a lucrative business utilizing a Suttonian variolation house located midway between the towns of Thornbury and Berkeley.

  The year 1763 was a landmark for smallpox. In addition to a natural outbreak in the mother country, English soldiers in the far-off North American colonies commenced a horrific new era of biological warfare by attempting the eradication of local Shawnee and Delaware Indians. These tribes were engaged in Pontiac’s war against Britain and had barricaded an English force within Fort Pitt (modern-day Pittsburgh). The British captain, Simeon Ecuyer, had received orders from his superiors, Colonel Henry Bouquet and General Jeffrey Amherst (the latter memorialized by a city and college in Massachusetts), to break the impasse by spreading disease to the besiegers. In a 1763 letter, Amherst wrote to Bouquet, “Could it not be contrived
to send smallpox among these disaffected tribes of Indians? We must on this occasion use every strategem in our power to reduce them.”12 During a lull contrived to facilitate negotiations, Delaware tribe emissaries were given a gift of blankets and a handkerchief as a sign of English intent. This was indeed a quite accurate sign of British motive, as the cloths had been purposefully infected with smallpox and were intended to exterminate the surrounding tribes. These actions did ultimately break the siege. Amherst was recalled to London to be rebuked, not for the barbarous use of initiating biological warfare but rather because his lax oversight had allowed the tribes to rise against the British forces in the first place.