The Plague Cycle

by Charles Kenny

  One of the first truly effective preventative treatments against infection had been developed to fight smallpox a century and a half or more before Mary died. Variolation had been practiced in China since at least 1549. The common approach was to blow month-old smallpox scabs up the nose of the patient. (If it wasn’t possible to wait a month, the scabs were suspended in steam scented with herbs.) Unbeknown to it’s practitioners, this had the effect of killing off or weakening much of the viral material, reducing the risk of a bad case of smallpox.

  The Kangxi Emperor, who ruled from 1661 to 1722—during the same time the Stuart line was being erased by smallpox—boasted that he’d inoculated his whole family along with the army, and all had passed through mild cases of the disease. By that time, variolation was also widely used in India. There, the approach was to dip a needle in a smallpox pustule and then stab it in the skin of the patient, which was the approach that ultimately spread west.12

  Smallpox inoculation as practiced in the Ottoman Empire was written up in the Philosophical Transactions of Britain’s Royal Society in 1714, which led to an active correspondence. Massachusetts minister Cotton Mather wrote to the society to say that his slave Onesimus, who’d been born in southern Libya, had undergone the procedure. The Turkish version of inoculation involved putting pus from smallpox lesions in the scratched skin of the patient. Usually, that led to a comparatively mild case of the disease because the microbe’s preferred transmission route is via the lungs.

  In 1715, British aristocrat Lady Mary Wortley Montagu was struck with the pox, but survived—if without eyelashes. In that same year, she traveled to Turkey with her husband, the new ambassador to the Empire of the Ottomans, where she witnessed an inoculation. In one of a stream of amused, charming, and utterly self-confident letters she wrote to friends while abroad, she described the procedure:

  “The small-pox, so fatal, and so general amongst us, is here made entirely harmless by the invention of ingrafting.… [An] old woman comes with a nutshell of the matter of the best form of small-pox, and asks which veins you please to have opened. She immediately rips open that you offer to her with a large needle… and puts into the vein as much venom as can lie upon the head of her needle.… There is no example of anyone who has died of it; and you may believe I am very well satisfied by the safety of the experiment, since I intend to try it on my dear little son. I am patriot enough to bring this useful invention into fashion in England.”13

  Montagu was over-optimistic about the success rate and the risks of the procedure, but she was good to her word regarding both her son and her efforts to popularize the treatment back home. Caroline, Princess of Wales, was daughter-in-law to King George I, who’d come to the throne on smallpox’s extinction of the Stuart royal line. In 1720, she was persuaded by her friend Lady Mary to explore inoculating her children. After watching successful experiments on six criminals followed by six orphaned children, she did so. That helped spur growing acceptance of the measure.

  Smallpox inoculation may be one reason why survival rates for the children of the British royal family dramatically improved between the seventeenth and eighteenth centuries. About four out of every ten royals born between 1600 and 1699 died before their first birthday. That dropped to one child out of thirty-five in the years between 1700 and 1799. But death rates for babies born to commoners remained broadly unchanged, with about one in four dying before their first birthday.14 A combination of medical mistrust, expense, and risk (some people caught full-blooded smallpox from inoculation, and perhaps as many as one in fifty died from it) meant both that the treatment’s spread was limited and that smallpox remained a major killer.

  * * *

  The invention of a truly safe, cheap, and more reliable vaccination procedure against smallpox was an early step in a series that helped break the world out of the infectious Malthusian trap. It’s ironic that the Black Death had a connection with the discovery of that vaccine, which in the wake of the Great Mortality could be found in the observation that women recruited to fill the ranks of animal tenders appeared to be favored when it came to the risk of smallpox infection.

  Dr. Edward Jenner made his living as a country doctor, but his scientific interests were broad and voracious. He spent a decade working on his natural history of the cuckoo, published in the Philosophical Transactions of the Royal Society, the same journal that had reported on variolation. Jenner’s research had involved extensive observations, numerous dissections, posting cuckoo stomachs to London for further analysis, and swapping eggs between nests. That was just one part of a scientific exploration that led to his workroom being filled with such specimens as rooks, swifts, dogs, pigs, a bottlenose dolphin, and numerous hedgehog heads alongside human hearts (Jenner was one of the first to analyze the causes of angina). He became an expert in sexing eels, and constructed an early hydrogen balloon, which he flew over Berkeley Castle.15

  But it was Jenner’s observations on the prevention of smallpox that were to bring him international renown. He noted that many milkmaids had from their wards caught cowpox, a minor annoyance in humans but one that appeared to confer immunity to smallpox. In 1796, Jenner used cowpox lesions from a milkmaid to draw material that he injected into his gardener’s eight-year-old son, James Phipps. He then used the technique of inoculation to expose the boy to smallpox more than twenty times. James never developed the mild case of smallpox that usually accompanied inoculation, suggesting he was already immune.

  The doctor wrote up his results as An Inquiry into the Causes and Effects of the Variolae Vaccinae (Latin for “pustule of cows,” from whence the word “vaccine”), published in 1798. While Jenner’s contemporary Malthus inevitably suggested the vaccine would make little difference to lives in Europe unless it was coupled with less sex, others were more excited. In 1802, the British Parliament awarded Jenner a prize of 10,000 pounds (followed by twenty thousand more in 1807). Denmark made vaccination compulsory by 1810, followed by Russia in 1812 and Sweden in 1816. Smallpox deaths in Sweden fell from twelve thousand in the year 1801 to eleven deaths in 1822.16

  Jenner’s invention even sparked the first ever globe-spanning public health campaign. In 1803, King Charles IV of Spain shipped twenty-two orphans across the Atlantic on the Maria Pita. Vicente Ferrer (aged seven) and Pascual Aniceto (three) were infected with cowpox as the ship sailed, and as the cowpox reached its peak, pus was withdrawn from their poxes and injected into two more children in turn.

  Children were used because they were less likely to have been exposed to smallpox already. And the serial process ensured there’d be a child ripe with the pox available to provide the vaccine to American populations after the crossing. At each stop, more children were drafted to support the effort. In Lanzarote “five children of the poor class were sent in order for them to return vaccinated,” notes the expedition record. The Maria Pita provided vaccines to Venezuela and Mexico. Having crossed to Acapulco, the vaccination campaign recruited a new set of children to continue the cowpox chain across the Pacific. From Manila the expedition spread vaccines to Macau and Canton before returning home.17

  Taking the Venezuela vaccine strain to South America, Spanish army surgeon Josep de Salvany led the expedition across the Andes to Ecuador. Despite suffering from diabetes, malaria, diphtheria, and tuberculosis, as well as losing both a hand and an eye, Salvany continued the vaccination campaign down through Buenos Aires to reach Bolivia in 1810. There he collapsed and died at age thirty-six. A few days before his death, Salvany wrote that

  the lack of roads, the precipices, the large rivers, the deserted places we have encountered have not stopped us for even a moment, much less the waters, snows, hungers and thirsts we have suffered. The rigors of that cruel contagion offered in our first steps served as stimulus to bring a brilliant purpose to noble and humanitarian tasks.

  His poetic self-promotion was surely deserved: overall, 1.5 million people were vaccinated by the campaign. It was a moral failing that the children who�
�d carried the cowpox across the Atlantic were abandoned in Mexico City’s hospice. That said, Jenner was still surely right to call the expedition “a glorious enterprise.”18

  News of Jenner’s discovery reached Japan in 1803, the same year that the Maria Pita left Spain. But there was no cowpox in the country, so that vaccination had to be imported as it had been to the Americas. The problem: foreign children were not permitted to enter Japan.

  Every year between 1821 and 1826, and then again in the 1830s and 1840s, Dutch ships carried bottled cowpox lymph and lancets on the long journey from the East Indies to the port of Nagasaki in Japan, but the vaccination was ineffective by the time it reached its destination. Japanese doctors who’d used variolation understood that smallpox scabs could be preserved, so they asked for the Dutch to send cowpox scabs in 1849. One child was inoculated with the cowpox scabs and developed pocks. Nagasaki city officials brought in children from neighboring communities to be vaccinated and then, arm to arm, they passed on the vaccine to others. By the end of the year, vaccination clinics had been opened across the country.19

  * * *

  Jenner’s discovery and its adoption saved many millions of lives. In the late eighteenth century in London smallpox accounted for 9 percent of all deaths. By the second half of the nineteenth century that had fallen to around 1 percent.20 But it wasn’t enough to reverse declining health during the early part of the Industrial Revolution. Jenner’s work remained a one-off. His breakthrough wasn’t based on a fully developed theory of infection or broader experimentation that would allow the benefits to spill over to the creation of other effective preventatives and cures for different diseases.

  As a sign of limited progress in broader medical approaches, leech farming became a growth industry in Europe in the early nineteenth century, with leeching the stylish way to partake of bloodletting. Demand reached into the tens of millions of leeches a year.21 Or look at the treatments given to George Washington as he lay in bed on December 14, 1799, fevered with a throat infection. His medical team drained him of two quarts of blood. They also encouraged him to inhale vinegar and water, gargle more vinegar mixed with sage tea, take doses of mercurous chloride—a laxative—and tartar emetic to encourage vomiting. He was burned to raise blisters and underwent an enema. Washington died on the same day that the doctors had been called.22

  Regarding the underlying causes of infection, while the germ theory had its adherents, the many different routes taken by microbes to reach a new host helped obscure their role, seemingly contradicting any universal causal theory. Smallpox seemed to demonstrate human-to-human contagion at work, but other diseases did not: yellow fever appeared to spread seasonally, not from person to person (had doctors known it was mosquito-borne, that would have made sense). Both plague (delivered by fleas and rats) and cholera (spread through tainted water) affected the poor more than the rich, suggesting the importance of environment over human contact.23 This will be one reason why the eighteenth and early nineteenth century saw a distinct recovery of “miasmist” over “contagionist” thinking, especially among the sanitarians who constructed sewer systems to remove smells.

  The strength of miasmist belief in the nineteenth century is underscored by the reaction to one medical professional who was partial to the germ theory of disease spread—John Snow. In London’s 1854 cholera epidemic, the anesthetist noticed the number of cholera victims who’d used a particular water pump in Broad Street, Soho. He managed to persuade local authorities to remove the pump handle, preventing people from collecting the lethal liquid that poured from it. In evidence to Parliament, Snow explained why the water was so toxic: water closets, filled with cholera germs from victims, flushed human waste into an aging sewer system that leaked into the water supply. Members of Parliament scoffed at the idea: “After careful enquiry we find no reason to adopt this belief.” Cholera, they concluded, “multiplies rather in air than in water.”24 (Doubtless many MPs also backed a common treatment for the condition: calomel, a powerful purgative. The supposed cure, which only sped the onset of catastrophic dehydration, was a form of unintentional manslaughter.) Snow died in 1858, his theory still on the fringes of respectability.

  German physician Robert Koch’s research on anthrax, tuberculosis, and cholera helped turn the tide in favor of the germ theory, as we’ve seen. His contemporary Louis Pasteur used that knowledge to create the tools for a broad and effective medical response to the threat of infection.

  Pasteur himself discovered a number of microorganisms and demonstrated that freshly boiled broth only spoiled if exposed to air, suggesting it was something airborne rather than innate to broth that caused putrefaction. He also showed the role of microorganisms in turning milk sour and wine into vinegar, and the ability to kill those organisms through heating (pasteurization). But Pasteur’s greatest contribution to human well-being was to understand the concept that lies behind most common vaccines. That allowed him to take Jenner’s one-off miracle and lay the basis for a wide range of cheap immunizations.

  Pasteur discovered by accident that old lab-grown chicken cholera didn’t kill chickens where fresh cholera samples did. So he tried injecting chickens with old cholera before injecting them with a fresh batch. The chickens stayed healthy. This reminded Pasteur of smallpox vaccination, suggesting that perhaps intentionally “attenuated” (weakened) bacteria could be used to vaccinate people and animals against the disease-causing variant. And he discovered a range of methods to attenuate the chicken cholera: heating, aging, and passing the bacteria through a succession of different animals.

  In March 1881, Pasteur demonstrated the same technique with an anthrax vaccine.25 Four years after Robert Koch first grew anthrax in the lab, Pasteur took anthrax samples and weakened the bacteria through aging and oxidation.

  The doctor was nothing if not a showman. Twenty-four sheep, six cows, and a goat were vaccinated against anthrax using the attenuated bacteria he’d developed. A while later, they were intentionally infected with full-strength anthrax alongside a group of unvaccinated animals. Two days after that, Pasteur presented both sets of animals to members of the Agricultural Society of Melun and members of the press.

  His vaccinated wards were all still alive. Of the unvaccinated animals, some were already dead, two dropped dead as the crowd watched, and the rest were obviously very sick. Koch wasn’t impressed, writing that his French colleague’s work was based on luck, and there was nothing new in what Pasteur had done. Those who celebrated him as “a second Jenner” forgot that “Jenner’s beneficial discovery was not in sheep but in humans.”26

  But Pasteur’s experiment was the start of a revolution: he followed up with a rabies vaccine in 1885, made using the spinal cords of infected rabbits that had been dried for ten days. This he administered to the young Joseph Meister, who’d been repeatedly bitten by a rabid dog and was brought to the lab by his distraught mother. He carried out the experiment with considerably more doubt and trepidation than Jenner reported with regard to his young subject, James Phipps, but Meister recovered—saved an agonizing death by Pasteur’s discovery.

  Whether driven by jealousy, nationalism, or the perception of legitimate flaws in Pasteur’s work, Koch wouldn’t relent: he said the Frenchman’s results “lack microscopic examinations” and “use unsuitable experimental animals.” But thousands of people were saved from rabies within years of the vaccine’s creation.27

  In the 1920s, French researchers used toxins derived from diphtheria and tetanus to create vaccines against those conditions. In 1940, an American researcher used flu virus grown in eggs and then killed with formaldehyde to create a flu vaccine. In the 1950s, Jonas Salk changed the world with his polio vaccine, cultured in monkey kidneys. In the years that followed, Maurice Hilleman, a research scientist at the pharmaceutical company Merck, took a lead part in research and development efforts that produced vaccines against measles, mumps, rubella, chickenpox, hepatitis A and B, pneumococcus, meningococcus, and Haemophilus influenz
ae type B (HiB).28

  Paul Offit, a noted vaccine inventor himself, described the approach taken by Dr. Michiaki Takahashi to attenuate the chickenpox virus that Hilleman would turn into a workable vaccine. Takahashi passed a viral sample taken from a three-year-old through fetal cells of both humans and guinea pigs at cold temperatures. The virus that emerged from the process, many generations evolved from the original, was weaker than wild chickenpox, and could be defeated by the human immune system. But it was close enough to the original virus that fighting it generated subsequent immunity to full-bore chickenpox. Prior to the vaccine, 4 million children in the US alone contracted chickenpox each year, and a few unlucky ones among them developed hepatitis, brain swelling, and fatal pneumonia as a result. Since the vaccine, chickenpox mortality in the US has fallen 90 percent.29

  A second health technology of immense consequence to the fight against infection was the antibiotic—a drug that could kill harmful bacteria. Penicillin was first discovered by Sir Alexander Fleming in the UK in 1929—he found that the penecillium mold produced a substance that killed the bacteria staphylococcus (a cause of pneumonia, skin infections, and food and blood poisoning among other maladies). Subsequently Fleming showed that penecillium was harmless to humans. But the antibiotic wasn’t manufactured at scale until the waning years of the Second World War. In 1941, total production worldwide was enough to treat only two hundred patients. By 1949, the US was producing 76,000 pounds of penicillin, and fifteen years later that number had climbed to 1.7 million pounds. The price per pound dropped from $1,114 to $49 over those same fifteen years.30