by Daniel Keays

 

Nothing Small About It

The scourge, pestilence.

Extinct, but not forgotten.

Ineffable horror.

 

            We humans like keeping score. Factoids such as the highest mountain, fiercest hurricane, longest river, oldest living human, fastest animal…  The list is very long. Despite being macabre, some seek to ascertain the infectious disease causing the most deaths in human history. We have cholera, bubonic plague, typhus, tuberculosis, malaria, and others. All are formidable, but the one most often mentioned as causing the most deaths and human misery is variola. 

            The name variola was probably coined in the 6^th century. It is formally attributed to Bishop Marius of Avenches, Switzerland, in the year 570. It comes from one of two Latin words, “varius,” meaning “stained,” or “varus,” meaning mark on the skin. Common folk came to call it pocke, meaning sack. It was also called the “speckled monster.”

            In 1492 Columbus sailed the ocean blue. The introduction of European and African diseases into the New World is well documented, but such occurrences can go both ways. Shortly after Columbus and his crew’s travels, a horrific disease appeared in Europe, beginning in Spain, and spreading eastward. It left its victims with huge red welts on their skin, which soon desquamated into foul-smelling, weeping sores. It became known as the “Great Pox.”  Most today would recognize it by its current name, syphilis.

               To contrast it with the “other pox,” variola became commonly known as the “small” pox. The name stuck.

            The devastation that smallpox has wrought upon humanity cannot be overstated.  Generations of people were killed and maimed, and their communities were ravaged. In some cases, entire civilizations were nearly wiped out. Those sickened but able to survive were often horribly disfigured by the pockmarks on their face and body, some left with life-altering medical conditions. Many went blind. Josef Stalin is said to have once remarked words to the effect that one person’s misfortune is a tragedy; millions affected is a statistic. So it is with the history of smallpox. In the 18^th century in Europe, over 400,000 people died each year from smallpox; but reading about the numbers afflicted and the areas of epidemics gives little insight into the horror of its victims. Smallpox has scarred the entire human race as indeed as it scarred its individual casualties.

            For centuries, smallpox, or a disease of the pox virus family strongly resembling it, cursed humanity. One of the great pharaohs, Ramses V, is said to have a mark on his preserved skin resembling a pockmark. Theories abound, but it is possible that smallpox originated some 3,000 to 4,000 years ago in northeast Africa and was spread eastward to India by Egyptian merchants. Ancient texts in both China and India mention a strongly suggestive disease. It is likely that the virus first infected an animal, then jumped to humans, whence it became communicable, human to human, by the respiratory route. One theory holds that a pox virus that infected rodents in East Africa jumped to infect camels upon their introduction to that area as pack animals some three or four thousand years ago. The transformed virus in camels made it more likely to infect humans, who were just beginning to engage in travel for trade and commerce. That’s the most likely scenario, but the scientific evidence to support it is deficient.  

            The disease probably entered Europe sometime between the fifth and seventh centuries AD. The only mobile people at the time were merchants and traders, and the virus likely traveled with them, either by land or by sea. The incubation period is around two weeks, so one could travel a considerable distance before becoming ill and transmitting the virus. Patients are infectious a couple of days before symptoms become severe, so there was no way to simply avoid an infected person. Outbreaks would come in waves, often with several years’ quiescence. When it hit, it was ferocious. Most inhabitants of a town or village were affected. But two facts were obvious: it was transmissible from person to person, and it was a “one and done.” Once you got the disease and recovered, you were immune for the rest of your life. Those known to have recovered from the illness were obliged to care for the sick.  

            Many remedies were attempted: application of cold cloths, herbal concoctions, not allowing fire in the room, leaving the windows opened, leaving the top of the patient’s body uncovered, and “administering twelve bottles of small beer every twenty-four hours.” Of course, nothing worked. For centuries humans were compelled to just suffer through the ailment and hope and pray for the best. Quarantine of sickened individuals helped but was not foolproof because of the possibility of transmission during the late prodromal stage, the few days before the time one becomes severely ill. Also, the virus is exceptionally hardy, able to survive for some time on environmental surfaces. It was a fairly common practice in Europe to steam open letters with a noxious agent in the hope of killing any virus that may have been applied during the sealing of the letter. Myths and folklore prevailed.

            Medieval medical records don’t document it, but somewhere in the history of the disease, a second, less virulent strain emerged. Known as variola minor (as opposed to the much more virulent variola major), this second strain had a much lower mortality rate. From an evolutionary perspective, this makes sense. A “good” parasite doesn’t kill its host; if it does, it dies with it. Strains of the virus that were far less likely to kill would be more likely to be spread, therefore having a better chance of surviving. For evidence of this, we need to look no further than the “great pox,” which invaded Europe around 1500. Syphilis is caused by a bacterial form known as a spirochete, an organism that is well-named because of its spiral shape. It slithers through our tissues like a corkscrew and can infect multiple organs after its transmission by sexual activity. The disease has three main stages: primary (a chancre on the genitalia), secondary (a rash), and tertiary (invasion of the deep tissues). It is the secondary stage of the disease that is of interest. When first introduced into Europe, the great pox was easy to spot. The infected patient in the secondary stage had many skin lesions, several of which became infected with other bacteria like Strep and Staph. The result was a patient who was very ill, had weeping sores, and obviously had a sexually transmitted disease. Such a person would be unlikely to engage in sexual activity any time soon, which is the chief means of transmission of the spirochete. Strains that mutated to give a much-reduced skin rash activity would be more likely to be transmitted, so they out-competed their more aggressive cousins.  

            Could that scenario have been playing out with the variola viruses? One catastrophically severe, the other more benign? Could be. Unfortunately, historical records are too limited, and direct molecular evidence is not available to know just when the variola minor strain emerged, so it remains only a theory. But the minor strain did exist, and, with the help of human intervention, variola’s days were numbered.

 

            Mary Pierrepont was ahead of her time. Way ahead. Born in London in 1689, the daughter of the English Duke of Kingston, she grew up in the very highest reaches of British society. She had the best of everything and grew up knowing firsthand the finest life had to offer. At 23, she married Lord Edward Wortley Montagu, and her life and future seemed fixed. But in 1715, the “speckled monster” attacked, and her life and the disease's future were inexorably altered.

            Lady Wortley Montagu was no ordinary aristocratic debutant. Incredibly brilliant and a gifted writer, she was limited only by her sex from becoming recognized as one of the best authors of her time. She also had a bulldog disposition.  Females of her time were not allowed to learn Latin. She taught herself. Her father wanted her to marry a well-positioned aristocratic man she didn’t like. She eloped with a man of her choosing. Feisty, fierce, and unwavering, she was not to be assailed.  

            But attacked and ravaged she was, by smallpox. Her beloved brother died of the disease, and she, while a survivor, was permanently disfigured. She was devastated.

            In 1717 her husband, Edward Wortley Montagu, was appointed ambassador to the Ottoman Court. Contrary to custom, she and her children accompanied him to Constantinople (now Istanbul) and remained with him there for two years. Lady Mary was not one to sit around the embassy all day and engage only in the finer dignities of British society. She took delight in seeking out local customs and practices and writing about them in her own inimitable and prolific style. Being a woman, she had access to areas where English men couldn’t go – to the places where the local women congregated. There she was keen to observe and write about local activities and culture. Her Letters From Turkey became a classic and an inspiration for travelers for years to come.

            During her preoccupation with local customs, one especially captivated her. Turkish folklore had it that if you took the scabs from smallpox patients, ground them up, and injected (or inoculated) them onto the upper arm of a healthy individual, it may make them ill for a while. But they invariably recovered and were immune to smallpox for the rest of their lives. She witnessed the procedure herself. In a dimly lit back room, a woman came in, ground up the pustules from a smallpox patient in a walnut shell, and used a knitting needle to scratch the material onto the arm of the person to be protected. The practice was said to have been handed down by word of mouth for centuries in several countries, like China, India, and some in Africa. Eventually, it made its way to the Middle East.

            Rather than being frightened to death by such a strange procedure, Mary Montagu was enthralled. With her strong personality, writing skills, and nearly maniacal hatred of smallpox, she went on a mission to have the procedure introduced in her native England. To say she ran into some obstacles and roadblocks understates it immensely. One can almost hear an English physician say something to the effect, “You want to prevent someone from getting smallpox by giving them smallpox”? The very thought of it was preposterous, bordering on lunacy. To make it even worse, it was proposed by a woman in the early 18^th century: an aggrieved woman, no less. To have the procedure used routinely, as it must, required winning over not just a handful of physicians but some of the most ardent critics. Her chances of pulling something like this off were slim and none, with a strong bias toward the “none” side. But she did.  

            She used all her tools and advantages. Her intelligence, daring, guile, passion, and tenacity played a role. So did her first-hand knowledge and insight into the procedure. But she had something else going for her: the acquaintance and friendship with Caroline, Princess of Wales.

            Caroline was special. Born in Ansbach, Germany, she has been described by one historian as “the cleverest Queen consort ever to sit on the throne of England.” King George I had, to say the least, a very troubled marriage. So he allowed his son George II to marry a woman of his choosing rather than an arranged marriage. Young George chose wisely. Caroline was intelligent, well acquainted with the arts, and, by all accounts, a good and loving wife. She and George II had eight children, seven of whom survived to adulthood. She was to become the Princess of Wales and Queen of England. Popular with the people and looked upon with respect by the ruling class, Caroline carried much influence.

            Like Lady Mary Montagu, Caroline had contracted smallpox. It was shortly after her marriage in 1705. Her husband, George II, devoted to her and unwilling to leave her sick bed, also nearly died of it. But they both survived and, given their royal position, were very concerned about the disease affecting their family, not just for personal reasons but for royal succession. Caroline and Lady Mary were soul mates.  

            Lady Mary had done, at the time, the unthinkable. She had her son and daughter inoculated with the variola virus. One was done in Turkey, the other in England. Both children survived and weren’t all that sick, just a few days of fever and muscle aches.  

            Having Caroline’s ear was Lady Mary’s strong suit. She was very persuasive, and Caroline listened intently. It was authorized to have six criminals under sentence of death inoculated. All survived with a limited illness and no severe side effects. Next, it was tried on several children at an orphanage. All survived and thrived. Seeing this, Caroline agreed to have her children inoculated. It went well. Here was the first successful attempt at vaccination in Western culture. The children of two prominent women, one a famous aristocratic writer and adventurer, the other the heir to the throne of England, had their precious children deliberately inoculated with the pus from a scab of a person with smallpox, and they became ill for only a couple of days. It was the birth of what was to become known as vaccination.

            Indeed, though, there was heated controversy. The term genocide wasn’t used back then, but depopulation was. Experimenting on criminals and orphans left the government open to widespread criticism. In some circles, that assessment continues to this day. Some maintain that the use of vaccines is an attempt by influential individuals to curtail or even eliminate the “undesirables” of society. Science is often neglected.

            As crude and dangerous as it was, inoculation with the smallpox virus, or variolation as it came to be known, was the first formal attempt by humans to intervene in the natural course of an infectious disease. Using a less robust strain (we presume, but don’t know for sure, they used variola minor) and an inoculation site different than the natural entry point, the disease was not eliminated but curtailed. It was the first documented effort in what has become one of the great marvels of human invention, vaccination.

            

            As dramatic and lurid as the variolation work was in England, it was no less duplicated in the American colonies.  

            The infamous Salem witch trials occurred in 1692-93. Over 200 people were imprisoned. Twenty died; one was stoned to death, and 19 were hung by the neck until they were dead. The ugly event and its psychology are still topics of conversation today. (A reasonable explanation of the precipitating event, the delirium and seizures experienced by two teenage girls, may have been due to a fungus, Claviceps purpurea, which infects grains such as rye, leaving a residue of mind-altering toxins, one of which is known today as lysergic acid diethylamide, or LSD). One notable clergyman of the day who had a tangential part in the proceedings was a fascinating gentleman named Cotton Mather.  

            Mather wrote a letter to the court designed to alleviate the tension and paranoia of the time. He implored the court not to consider spectral evidence, that is, testimony about dreams and visions. The court ignored his advice, and the travesty continued. Some felt that his admonitions didn’t go far enough; he should have been more forceful in denunciating the events. His reputation became tarnished. He needed to redeem it.

            Cotton Mather was among the more interesting figures of the American colony days. He entered Harvard when he was only 12; he received his master’s degree at 19. Early in life, he thought about pursuing a career in science but ended up in the ministry instead. But his interest in science and nature never waned. He was a frequent reader of the publications of the Royal Society of London and other scientific literature.

 

            In 1721, His Majesty’s Ship, the Seahorse, sailed into Boston Harbor. It had been chasing pirates in the Caribbean and had spent time in Barbados, a center of a smallpox outbreak. Thomas Durrell, an experienced seaman, commanded her. At the time, it was the duty of ships sailing into Boston harbor that were known to have frequented epidemic areas to make for a place called Spectacle Island, where it should remain in quarantine. (Such a place was known as a pest house). For some reason, Captain Durrell made for Castle Island, a military base. While docked there for repairs, several of the ship’s crew were given shore leave. What in the world Captain Durrell was thinking is anyone’s guess. They almost certainly were the source of the Boston smallpox outbreak which soon followed. 

            Cotton Mather had read of the occurrences in London using variolation. He also was familiar with the procedure from another account written in Turkey. Still another source was a family slave named Onesimus. Onesimus had informed Mather that while in Africa, he had “been given an operation, which had given him something of ye small-pox, and would forever preserve him from it.” He showed Mather the scar. It made a believer out of him.

            Just as Lady Mary Montagu and Princess Caroline met stern resistance to variolation in England, so did Cotton Mather in New England. He was convinced the procedure could prevent or mitigate a calamity, but proposing such a preposterous idea invited ridicule and contempt. He was not a medical doctor, and his contributions to the scientific community had been minimal. But Mather was convinced of his opinion, and he made a great pest of himself in seeking to convince the medical establishment of the worthiness of the procedure. He finally found a doctor intrigued by his idea just as the disease was beginning to progress out of control. His name was Zabdiel Boylston.

            Physicians in New England in the early 1700s rarely had a formal college education. They learned their craft much like tradesmen through an apprenticeship. They lacked formal foundational education; the day-to-day application of medical practice was learned from a “master” physician. Given the level of medical technology of the time, they did all right.  Boylston first learned from his father, a military physician who also practiced in rural Boston. After his father’s death, he apprenticed to a leading surgeon in the Boston area. After beginning his practice, Boylston became one of the top physicians in Boston.

            Boylston had two circumstances in his past that left him open to the idea of inoculation against smallpox. One was that his medical experience frequently exposed him to Native Americans and their remedies, which he found to be sometimes beneficial. The other was that he, like Lady Mary Montagu, had a horrific personal encounter with smallpox. He nearly died from it. Most people who were as sick from variola as he had been developed long-term sequelae, like organ failure or blindness. He miraculously had none. But the disease left mental scars, and he was open to anything that could prevent its ravages. His wife, Jerusha, had also been badly affected by the disease. At age nine, she lost both of her parents and three of her four brothers to the malady. After living with an uncle, two of her foster brothers also died of it. She also had come down with smallpox. 

             Boylston’s description of the disease is one of the most poignant ever:

            Purple spots, the bloody and parchment Pox, Hemorahages of Blood at the Mouth, Nose, Fundament, and Privities; Ravings and Deliriums; Convulsions and other Fits; violent inflammations and Swellings in the Eyes and Throat; so that they cannot see, or scarcely breathe, or swallow any thing, to keep them from starving.  Some looking as black as the Stock, others as white as a Sheet; in some the Pock runs into Blisters, and the Skin stripping off, leaves the flesh raw….Some have a burning, others a smarting Pain, as if in the Fire, or scalded with boiling Water….Some have fill’d with loathsome Ulcers; others have had deep, and fistulous Ulcers in their Bodies, or in their Limbs or Joints, with Rottenness of the Ligaments and Bones:  Some who live are Cripples, others Idiots, and many blind all their Days.”

            As in many dramas, Mather and Boylston had a formidable antagonist. William Douglass was a young, recently arrived physician from England. Born in Scotland, he was educated at some of Europe’s top universities, and he let everyone know. Arrogant and outspoken, he disdained an equally arrogant and outspoken Cotton Mather and the minimally educated physicians of the area. Politically connected, he was a daunting foe.

            The main character list of the time reads like something out of a dime novel: Cotton Mather, a fire and brimstone Puritan preacher best known for his involvement in the Salem witch trials; Zabdiel Boylston, a prominent local physician familiar with folk medicine who had a near-death experience with smallpox, and William Douglass, a brash, young, but knowledgeable physician. The drama that ensued did not disappoint.

            In late June of 1721, Dr. Boylston took pus from several smallpox lesions of one of his patients and placed it into a vial. He then scratched the material onto the upper arms of three individuals: his slave Jack, Jack’s two-year-old son Jackey, and his own son Thomas. We don’t know if the strain was of the variola minor variety. Still, Boylston wrote that he used material from a discreet lesion, not malodorous (that is, not secondarily infected by bacteria). After about eight days, the two boys came down with a fever and several scars. The disease lasted two or three days, after which the boys resumed their everyday activities. Jack, the slave, had only a blister or two, indicating that he had probably had the disease previously.

            The uproar was virulent. Boylston and Mather were accused of misconduct of a criminal nature. Dr. Douglass was most emphatic in seeing the procedure halted, suggesting that the act of giving smallpox in such a way was threatening patients’ lives and spreading the disease. He enlisted the town’s politicians, physicians, and newspapers to fight against Boylston and Mather. (One of the journalists at the time was a 16-year-old apprentice, Benjamin Franklin). 

            The melodrama continued as Boylston continued to inoculate, and townsfolk presented themselves to receive the procedure, especially for their children. People were dying from naturally acquired smallpox much more than from the variolation procedure, and word of mouth was much in the procedure’s favor. In the end, the conclusions were clear: variolation, while a crude, dangerous, and sometimes fatal technique, did, in fact, usually prevent most people from getting a much more virulent form of the disease. Even William Douglass, by 1730, had endorsed the method.

            Zabdiel Boylston eventually was admitted to the Royal Society of London and traveled there to share his experience and statistics with variolation.  His results, combined with those seen in England, allowed for the general acceptance of variolation, especially when an outbreak was not well contained and threatened mass devastation. It was humans' first bona fide attempt to alter the natural course of an infectious disease by using a strain of reduced virulence and altered route of administration. The characters, a British Lady of high breeding and strong personality, a Princess, a fire-breathing cleric, and a self-taught British colony physician, were certainly an odd lot. But they were on to something. For the next eighty years, variolation was used widely but selectively, primarily for protecting the military, the affluent, or the children of royal families.

 

            Edward Jenner was born in England in May 1749, the son of a vicar. Orphaned at age five, he went to live with an older brother. At age eight, he was inoculated with smallpox in the county of his birth, Gloucestershire. He was one of the thousands of children variolated that year, as the procedure was considered the lesser of two evils.  

            Jenner was a very bright student, and at a young age, he developed an interest in science and nature. At thirteen, he began to serve as an apprentice to a country surgeon; then, at age 15, he apprenticed to a renowned physician named George Harwicke. At age 21, he went to London and studied under one of the eminent surgeons and biologists of the time, John Hunter. Jenner developed a strong bond with Hunter and was closely tied to him for the next two decades. He was well-connected.

            Jenner’s professional reputation came not so much from the practice of medicine but from his interest in nature. He came very close to accompanying Captain Cook on an exploratory mission. He worked in many areas, including comparative anatomy, species classification, geology, and ornithology. He even built a hot air balloon and sailed it some 13 miles. He also researched medical treatments and natural science, including studying human blood. He played the violin and wrote poetry. Edward Jenner was a true Renaissance man.

            In 1773 Jenner returned to the area of his birth, Berkeley, to establish a medical practice. He was very professional, skillful, and quite popular with his patients, many of whom worked in agriculture. Berkeley was a leading dairy farming district of the time because of the favorable weather and verdant pastures, so many of his patients and acquaintances were involved with milk production. Of course, the cows had to be milked by hand, and many hands were required, both the farmers’ families and professional milkmaids.  

            Being native to the area, Jenner had heard for some time that dairymaids who had contracted vesicular lesions on their hands after milking infected cows were rendered immune to smallpox. The locals were adamant in their belief in it. The naturally curious Jenner set about proving or disproving the theory. For years, he interviewed dozens of farmers and dairymaids to hear their tales of infection with cowpox and their experience when a smallpox epidemic came through the area. Jenner wrote about many of these case histories and submitted them to the Royal Society of London for consideration. 

            Dairy cows are susceptible to several diseases on their udders, including pyogenic organisms such as Staph and Strep. Dairy workers often referred to these diseases as “the pox,” so care had to be taken to be sure the correct diagnosis was made. In what was referred to as “cowpox,” a characteristic bluish-purple nodule appeared on the udder surrounded by a red, inflamed area. Cowpox today is a sporadic disease. It is not found on cows but instead on mice and voles. That may have been one way the disease spread from farm to farm. 

            Cowpox in a human is not a benign disease. The infected person has numerous painful pustules on their hands and forearms, which may spread to other body parts by touching. The infected person is quite ill for several days, with body aches, chills, and fever. But it’s not nearly as bad as variola. Recovery is rapid, and the patient returns to good health in a few days.

            When a smallpox outbreak occurred in May of 1796, Jenner decided to test the hypothesis that cowpox exposure prevents smallpox. A young dairymaid, Sarah Nelms, had draining cowpox lesions on her hands and forearms. He expressed some of the fluid from her lesions and collected it in a vial. Taking a needle, he scratched the material onto the skin of his gardener’s eight-year-old son, James Phipps. He carefully observed the boy for two weeks, noting he became “indisposed” around the eighth day, with some pain in his armpit and a mild fever. In just a day or two, he was back to normal health.

            Jenner was experienced with the variolation procedure, having administered it multiple times (he had been variolated at age eight). With an outbreak of smallpox in the community, he had no trouble finding a suitable variola lesion. About six weeks after the boy’s cowpox inoculation, he applied the variola material to little James Phipps the same way the cowpox was administered. He was gratified that the boy did not react to the smallpox. He was completely immune. A new era of fighting disease had begun. (Because the infectious material came from a cow, Jenner called the procedure “vaccination,” after the Latin word vacca, or “cow,” and vaccinus, “from cows”).

            Using a pox virus from a cow to establish an immune state against smallpox was not unique to Edward Jenner. There is good evidence that a local Berkeley farmer, Benjamin Jesty, had performed the procedure on three of his family members some twenty years before Jenner. Seeing as they lived in the same area, it is reasonable to assume that Jenner had heard of it. Indeed, the act of contracting cowpox naturally and its rendering one immune to smallpox was common knowledge in the dairy community. But Jenner gets, and deserves, the credit. He wrote and published detailed descriptions of the cowpox lesions, the case histories of infected persons, and distinguished the pox lesions on cows from other cutaneous diseases. He also showed that the material from the cowpox vesicle on the arm could be used to inoculate other humans and that going back to a sick cow was unnecessary. He was doing good reproducible scientific research, writing about it, professionally sharing the knowledge, and giving an accurate description of obtaining the infectious material. This allowed for the wide dissemination of the procedure.

            Of course, people don’t get smallpox by having it scratched onto their skin; they breathe in the virus after being exposed to an ill individual. Jenner, and those who followed, had to wait and see that vaccinated people were immune to the natural disease. Their reckoning proved correct, and, though it took some time, variola was beginning its journey to extinction.

            No medical procedure, including vaccination, is free of risks and side effects, particularly in early attempts. Vaccination is never 100% effective. Some vaccinated people will still get the disease, and a few individuals will react badly. But to those who knew smallpox firsthand, and the horror and devastation it brought, the risks were worth it.

 Despite an utter lack of knowledge of microbes or the immune system, Edward Jenner developed and reported on the successful inoculation of a mild virus to prevent the infection by a much more serious one, a procedure he called vaccination. (LOC). Smallpox lesion (PHIL)

Prev Next