Tag Archives: smallpox

Thomas Jefferson: Fighting Smallpox

Variolation was the world’s first practical measure to control smallpox. It was developed in China in the 11th century. The procedure involved inoculating uninfected individuals with material from the scabs of individuals who survived smallpox infection.

It was brought to England for the first time in 1721, by Lady Mary Wortley Montague—the wife of the British ambassador to Turkey—when she returned home after learning of the practice in Istanbul. It was brought to Colonial North America the same year by the prominent Puritan minister, Cotton Mather. New England was then experiencing a major smallpox epidemic.

Mather is perhaps best known for his role in the Salem witchcraft trials. He learned of variolation not from the British, but from his African slave, Onesimus, who had been inoculated as child in Africa. Onesimus was a “gift” to Mather in 1706, from his Boston congregation. Variolation was used in western Africa when Onesimus was a child.  The practice may have been brought there by caravans from Arabia. In any case, an enslaved African man played a key role in bringing variolation to North America.

In 1777, during the American War for Independence, General George Washington required the entire Continental Army to undergo variolation. Bearing in mind that more than two-thirds of the American casualties during the War resulted from disease, and that smallpox alone caused a total of about 100,00 deaths, some historians maintain that Washington’s policy of enforced variolation was his most important strategic decision of his entire military career.

Variolation nonetheless encompassed risks—a fatality rate of 1 to 2%—that would be unacceptable today. Not surprisingly then, the colonial and Revolutionary War periods were times when public fear and restrictive laws often prevented the use of variolation. Nonetheless, Thomas Jefferson was a lifelong advocate of smallpox-prevention measures. In 1766, Jefferson traveled to Philadelphia to undergo variolation, since the practice was banned in his native Virginia. As a lawyer in 1768, Jefferson defended a Norfolk doctor, whose house was burned down by a mob because he practiced variolation. In 1769, Jefferson placed a bill before the Virginia General Assembly to reduce the 1769 restrictions against variolation. In the 1770s and 1780s, he had his children and his enslaved servants (including Sally Hemings, his wife’s half-sister, and mother of several of his enslaved children) undergo the procedure.

In 1799, Boston physician and founder of Harvard Medical School, Benjamin Waterhouse, introduced Edward Jenner’s new cowpox-based smallpox vaccine to New England. Wanting to spread word of the vaccine to the rest of the new country, in 1781 Waterhouse sent a sample to his friend, Thomas Jefferson. At the President’s House in Washington, Jefferson selected an enslaved kitchen worker to be the first recipient of the vaccine. However, the vaccine did not take. So, Jefferson then had two of his slaves at Monticello undergo vaccination. When those vaccinations proved to be successful (as shown by exposure to actual smallpox), Jefferson serially transmitted the vaccine from the two original vaccines to almost fifty other slaves. By means of serial inoculations he then sent vaccine material to Washington (the city), and from there the vaccine traveled to Philadelphia and beyond. So, Thomas Jefferson, and his African slaves, played a seminal role in protecting many people in the new United States from smallpox.

Jefferson was an amateur, but serious scientist. He kept detailed notes of his observations, and corresponded with Jenner. Here is what he wrote to Waterhouse about the appearance of papules at the vaccination site:

As far as my observation went, the most premature cases presented a pellucid liquor the sixth day, which continued in that form the sixth, seventh, and eighth days, when it began to thicken, appear yellowish, and to be environed with inflammation. The most tardy cases offered matter on the eighth day, which continued thin and limpid the eighth, ninth, and tenth days. [http://www.smithsonianmag.com/smart-news/thomas-jefferson-conducted-early-smallpox-vaccine-trials-180954146/]






Thucydides and the Plague of Athens

The “Plague of Athens” was a severe epidemic, which struck the city between 430 and 427 B.C.E.; reemerging there in 425 B.C.E. It is believed to have originated in Ethiopia, and then to have spread throughout the Mediterranean. It hit Athens early during the Peloponnesian War (431-404 B.C.E), at a time when the city was under siege by Sparta. The Plague claimed the lives of about a third of Athens’ citizens. Yet the extent, to which it might have contributed to the ultimate Spartan victory in the war, or to the eventual decline of the Athenian empire, is not known.

The Athenian historian, Thucydides, in his History of the Peloponnesian War, provides the only known eye-witness account of the Plague. For that reason alone, Thucydides’ account is of great historical interest. Yet Thucydides also set down his own truly remarkable (considering the time) insights into the epidemiology of the Plague.

Thucydides (460-395 B.C.E.)
Thucydides (460-395 B.C.E.)

First, Thucydides noted that the most densely populated sections of Athens had the highest frequency of Plague victims. [The Athenian leader, Pericles, responded to the Spartan siege by moving people into Athens from the countryside. The resulting overcrowding unwittingly worsened the epidemic.] Second, Thucydides noted that physicians had highest likelihood of any group in the population of succumbing to the Plague. [Physicians were the ones most frequently exposed to affected individuals.] Moreover, Thucydides reported that the Plague could be transported from one place to another; an observation he made during the Athenian siege of Poteida (430/429 B.C.E.), when a reinforcing body of Athenian soldiers transmitted the Plague to Athenian soldiers already at Poteida. From this observation, Thucydides deduced that the Plague was not due to some “malign influence” confined to Athens and its immediate environs, as would have been consistent with Greek medical theory of the day (see below). [Incidentally, Plato tells us in his dialogues that Socrates was a veteran of the siege at Poteida.]

Taken together, these observations led Thucydides to put forward, perhaps for the first time, the notion that an affected individual might pass on a disease, directly, to another individual who is not yet affected. In contrast, medical theory of the day held that epidemics result from miasma: poisonous vapors, which inflicted anyone who might breathe them. Miasma could be caused by the weather, by the stars, or by the displeasure of the gods.

Miasma readily explained why large numbers of people could become ill at the same time. They simply breathed the same air. Yet Thucydides was in fact proposing something radically different; that is, contagions. And he did so twenty-three centuries before Pasteur, Lister, Koch and others in the 19th century established our modern germ theory of disease! Before then, western medicine continued to attribute epidemics to miasma.

Another of Thucydides’ key observations was that individuals who recovered from the Plague were resistant to future attacks. Moreover, he recognized that their resistance was specific. That is, survivors of the Plague were resistant to further attacks of the Plague, but not to other diseases. This insight too was remarkable since our modern concept of specific acquired immunity came even later than our concept of infectious disease. Thucydides’ deduction may have influenced his fellow Athenians, since those individuals who survived the plague comprised the few who were willing to care for those who fell ill.

Thucydides could not know the nature of the contagion he was proposing, although he thought it might be a fluid. And, while the epidemic in Athens is referred to today as a plague, it almost certainly was not bubonic or pneumonic plague.

Some modern references to the Plague of Athens presume that it was smallpox. Thucydides does mention the body “breaking out into small postules and ulcers,” and other aspects of his description of the disease are consistent with smallpox. Yet Thucydides also tells us that dogs too were susceptible to the Plague. However, humans are the only host for smallpox.

At any rate, the exact cause of the Plague of Athens is not known for certain. Modern experts have attributed it to a variety of pathogens, including Yesinia pestis, typhus, anthrax, measles, and even Ebola, in addition to smallpox. Yet none of the diseases associated with any contemporary pathogen exactly matches Thucydides’ description of the Plague of Athens. It is possible that the pathogen responsible for the Plague, and the Plague’s symptoms as well, might have changed over 24 centuries. Another possibility is that the pathogen responsible for the Plague has since become extinct.

Thucydides’ insights are not nearly as well known today as they ought to be. Perhaps that is because they had no lasting influence on his contemporaries or, for that matter, on those who came later. Consider how the history of medical science might have been different if Hippocrates, and others of Thucydides’ contemporaries, had been influenced by his observations.

How might we explain why Thucydides’ insights were largely ignored by his contemporaries and, indeed, lost to western medicine? One reason is that the ancient Greeks had precious little scientific knowledge that might have enabled them to understand the Plague. Moreover, Thucydides’ Athenian contemporaries made little distinction between medicine and religion. For instance, Sophocles (one of the great dramatists of classical Greece) believed that the plague had a supernatural cause, and that an oracle, rather than a physician, needed to be consulted for its resolution.

Hippocrates (about 460 to 370 B.C.E.) may have been the first physician to believe that diseases have natural causes, rather than being punishments inflicted by the gods. However, none of Hippocrates’ writings suggest the concept of a contagion. In any case, after Hippocrates’ death, the practice of Greek medicine actually regressed back to a more superstitious state.

What’s more, contrary to popular opinion; the Greeks did not actually invent the scientific method. Nor were their theories developed with the intent of experimental verification. Aristotle’s science held that nature did what pure logic suggested it should do. For example, he said that heavier objects fall faster than lighter objects, because it is their purpose to do so. Neither Aristotle nor his contemporaries actually looked to see if heavier objects indeed fall faster than lighter ones (they don’t). In fact, the first individual known to have actually tested this premise was Galileo (1564-1642). Only afterwards did observation become the basis for western science. And, this transition was not easy since, as we know well, the powerful churchmen of Galileo’s day rejected the concept that the universe might be governed by natural laws, since that notion might be at odds with the omnipotence of God.


Hays, J. N., Epidemics and Pandemics: Their Impacts on Human History, ABC-CLIO, Inc., Santa Barbara, California, 2005.

Holladay, A.J., and J.C.F. Poole. 1979. The Plague of Athens, The Classical Quarterly 29:282-300.

Related Postings:

Edward Jenner and the Smallpox Vaccine, posted on the blog September 16, 2014.

Smallpox in the New World: Vignettes featuring Hernan Cortes, Francisco Pizarro, and Lord Jeffry Amherst, posted on the blog February 24, 2014.




Edward Jenner and the Smallpox Vaccine

The Greek historian, Thucydides, discovered twenty four centuries ago that smallpox survivors were resistant to subsequent smallpox episodes. Thucydides’ remarkable perception, more than two thousand years before awareness of infectious agents, may have influenced his fellow Athenians, since those who survived the infection comprised the few who were willing to care for those who fell ill. Thucydides’ insight was lost to Western medicine. However, the independent perception in China, that that smallpox survivors are entirely safe from a second attack, led to the development there, about 1,000 years ago, of an empirically based smallpox control strategy, in which uninfected individuals were protected by inhaling powder prepared from dried smallpox scabs. The scabs were from individuals who survived a mild smallpox infection. They were dried to further diminish the likelihood of the recipient undergoing a severe infection.

By 1700, the process had spread to Africa, India, Arabia, and the Ottoman Empire. The Arabians streamlined this approach by transferring the dried postular material on the point of a needle. Lady Mary Wortley Montague, the wife of the British ambassador to Turkey, had her children undergo the process in the early 18th century, and then brought the practice to Europe, where British physicians dubbed it “variolation.” [See Cotton Mather, Onesimus, George Washington, and Variolation, posted on the blog November 20, 2013, for an account of the introduction of variolation to the New World.]

As might be expected, variolation carried risks that would not be acceptable today. However, those risks were tolerable in 18th century Europe, when as many as one person in ten died of smallpox. We now have the smallpox vaccine, which was the first, and arguably the most successful vaccine ever put into practice. Remarkably, the smallpox vaccine was developed in 1798 by an English country doctor, Edward Jenner, a half-century before the germ theory of disease, and 100 years before the actual discovery of viruses!

At thirteen years of age, Jenner was apprenticed to an English surgeon; a mister Ludlow. While Jenner was in Ludlow’s service, he heard the doctor suggest to an ill milkmaid that she might be coming down with smallpox. The milkmaid replied that she could not get smallpox since she already had cowpox. The notion, that having had cowpox protects one against smallpox, may actually have been common among English country folk of the day, but it was just as commonly dismissed by physicians.

At 21 years of age, Jenner continued his training under the prominent British surgeon, John Hunter. When Jenner ran the milkmaid’s comment by Hunter, the great surgeon encouraged his young protégé to investigate the matter further.

Now, perhaps the most remarkable part of the story. History usually credits young James Phipps as the first person “vaccinated” by Jenner. And, while Phipps, in 1796, was the first individual Jenner inoculated with cowpox, and subsequently challenged with smallpox, he was, in fact, not the subject of Jenner’s first experiment. Instead, that person was Jenner’s first son, Edward, Jr., born in 1789. Jenner inoculated Edward Jr. with swinepox when the infant was only 10 months old!

Jenner could not have known about microbes, and he left no records revealing his purpose in inoculating Edward Jr. with swinepox. It may be relevant that cowpox was relatively rare at the time, while a similar pox disease was more common in pigs. Regardless, Jenner’s baby son became sick on the eighth day with a pox disease, from which he fortunately recovered. Then, his father proceeded to challenge him with genuine smallpox!

Fortunately, Edward Jr. also resisted his father’s experimental attempt to transmit smallpox to him. His father tried again in 1791, when the boy was two, and again when he was three. Edward Jr. resisted each of Edward Senior’s smallpox challenges, most likely because the swinepox virus immunized him against smallpox. We can only guess how Mrs. Jenner regarded these happenings.

Jenner also used several other young children in his experiments, including his 11-month-old second son, Robert. One of these children died from a fever, possibly from a contaminant (streptococcus?) in the vaccine. In those days one could hardly know what might be in a vaccine.

In Jenner’s famous and classic experiment involving James Phipps, he used a lance to pierce a cowpox postule on the wrist of a young milkmaid, Sarah Nelmes. He then scratched James twice on the arm with the lance. Six weeks afterwards, Jenner challenged James with smallpox from a postule on the body of a smallpox patient. The smallpox challenge caused only a slight inflammation on James’ arm, indicating what now would be recognized as an immune reaction. During the next 25 years or so, Jenner challenged James twenty more times with smallpox, with never any sign of the disease.

JENNER Edward Jenner administering the first smallpox vaccination in 1796.  Painting by Ernst Board.

Not much else is known about James Phipps, who was only 8 years old when he was first inoculated by Jenner. Additionally, nothing is known about James’ parents and whether they may have consented to Jenner’s use of James. However, Jenner referred to his young subject as “poor James,” and looked after him in later years, suggesting he may have felt some remorse. Moreover, he eventually built a cottage for James and even planted flowers in front of it himself. Little is known of Sarah Nelmes.

Thankfully, the sorts of experiments Jenner carried out cannot be done today. Yet because of his efforts, the once dreaded smallpox virus now exists only in the laboratory.

More than a century would have to pass before it could be appreciated that the protection against smallpox that was generated by inoculation with cowpox and swinepox depended on the facts that these two viruses are immunologically cross-reactive with smallpox virus and that they produce a relatively benign infection in humans. [When contemporary vaccinologists develop vaccines to protect against viral diseases, they are essentially tapping into biological mechanisms that have been perfected through eons of natural selection. Indeed, the principal fact exploited by vaccinologists is that natural infection, by many different viruses, results in lifelong immunity against the same virus.]

Some final points:

It is possible that Jenner was not the first to use cowpox to vaccinate against smallpox. However, he was the first to eliminate the cow from the procedure. That is, he transmitted immunity from person-to-person, without the need for an infected cow. Nevertheless, he hung in his house the hide of the cow, which had initially given Sarah Nelmes cowpox.

Although Jenner demonstrated that his vaccine could be passed indefinitely from person-to-person, neither he, nor anyone else at the time, had the insight that this indefinite passage meant that the active agent in the vaccine must be able to replicate.


Greer Williams: Virus Hunters, Alfred A. Knopf, 1960.

Cotton Mather, Onesimus, George Washington, and Variolation, posted on the blog November 20, 2013.

Related Postings:

Smallpox in the New World: Vignettes featuring Hernan Cortes, Francisco Pizarro, and Lord Jeffry Amherst, posted on the blog February 24, 2014.

Notable Individuals Who Survived Smallpox and One Who Didn’t: Featuring Abraham Lincoln, Elizabeth I, Josef Stalin, and Pocahontas, posted on the blog March 10, 2014.

Remembering Ciro de Quadros and the Eradication of Polio in Latin America

Ciro de Quadros, who passed away at his home in Washington, D.C. on May 28, 2014, was a present-day hero, who ought to be much better known. In brief, de Quadros, a Brazilian epidemiologist, single-handedly initiated and then led efforts in the 1980s to eradicate polio from the Latin America continent.

The incidence of polio in Latin America had already been significantly diminished by the early 1960s via the introduction of Sabin’s vaccine. However, de Quadros insisted that epidemics would remain possible on the continent until mass immunization of the population might be achieved. He was particularly concerned with reaching unimmunized children who lived in the remotest areas. So, starting in 1985, in his role as an executive of the Pan American Health Organization (PAHO; a subsidiary of the United Nation’s WHO), de Quadros sent teams of health workers to 15 countries; some of which contained the most isolated and war-torn regions of Latin America.

El Salvador and Guatemala were particularly unstable at the time. So, in order to administer vaccinations in those nations, de Quadros first negotiated 24-hour cease-fire agreements between rebel and government forces. These so called “tranquility days” enabled health care workers to enter combat zones and carry out immunizations in relative safety.

In Peru, de Quadros was unable to secure cooperation from the Shining Path guerillas that operated there. So, he had his teams work around the areas controlled by the guerillas, and come back to those areas when the battle lines shifted elsewhere.

In 1994, the success of de Quadros’ immunization program led the PAHO to declare that polio had been officially eradicated from Latin American. The last reported case of polio on the continent occurred in 1991, in Pichanaki, Peru.

Interestingly, de Quadros had to fight an uphill battle to obtain support for his immunization efforts; even with the WHO, which preferred to use its limited resources to sustain primary health care. But, de Quadros forcefully maintained that vaccination is the starting point for effective primary health care, especially for children. And, while he was mainly concerned with polio, his vaccination teams also were prepared to immunize against measles, diphtheria, pertussis, tetanus, and tuberculosis.

Earlier in his career, in the 1970s, de Quadros was recruited by Donald A. Hendreson, then director of the WHO’s global smallpox eradication program, to help organize smallpox eradication in Ethiopia. In a phone interview with a NY Times reporter after de Quadros’ passing, Henderson recalled de Quadros’s steadfastness during Ethiopia’s civil war, when a half-dozen of his teams were kidnapped by rebels and one of his United Nations helicopters was commandeered along with its pilot. De Quedros helped negotiate the release of the health teams and the pilot, all of whom returned to their vaccination duties. Henderson noted that the helicopter pilot, who had vaccine aboard when he was hijacked, actually vaccinated the rebels who held him captive.

On May 2, 2014, less than one month before his death, de Quadros was honored by the PAHO/WHO as a Public Health Hero of the Americas. The award was presented to de Quadros by PAHO/WHO director Carissa F. Etienne, during an international vaccine symposium celebrating the 20th anniversary of the Sabin Vaccine Institute, where De Quadros was serving as Executive Vice President and Director of Vaccine Advocacy and Education. Etienne stated, “We at PAHO believe that no single person has done more to extend the benefits of immunization to people throughout the Americas.”

Dr. Carissa F. Etienne, Dr. Donald A. Henderson, Dr. Ciro de Quadros, Dr. Anthony Fauci, and Dr. Jon K. Andrus
Dr. Carissa F. Etienne, Dr. Donald A. Henderson, Dr. Ciro de Quadros, Dr. Anthony Fauci, and Dr. Jon K. Andrus

Etienne went on to say, “His (de Quadros’) leadership and vision were essential to our region’s becoming the first in the world to eradicate polio, a success story that inspired the global polio eradication campaign.” Also, de Quadros is regarded as a leader in the development of the surveillance and containment strategies that facilitated the eradication of smallpox worldwide, and he also directed measles eradication efforts in the Americas.




Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science

Paralytic poliomyelitis was one of the world’s most feared diseases during the first half of the 20th century. However, the dread of poliovirus ended abruptly with the advent of the poliovirus vaccines in the 1950s. This posting tells the stories of the key players in the race to develop a polio vaccine. In particular, it features the rivalry between Jonas Salk and Albert Sabin, the two main contenders in the pursuit. While their vaccines together have led to the near disappearance of poliovirus worldwide, neither was recognized by the Nobel committee for his achievement. We begin with some background.

Poliovirus has long been especially interesting to me, both as a virologist and personally as well. The reason is that I was a child and young teenager during the annual polio epidemics of the 1940s and early 1950s, and can vividly remember the panic that set in early every summer of the pre-vaccine days, when the first neighbor or schoolmate was stricken. You were kept home from school and couldn’t even play outside. A visit to a hospital in those times was associated with the pitiful sight of young polio victims in the iron lungs that filled the wards, and even the hallways of hospitals back then.

iron lung

Not even the emergence of AIDS in the early 1980s evoked fear comparable to that brought on by poliomyelitis. Yet despite the dread of poliomyelitis, the disease actually struck many fewer victims than was commonly perceived by the public. The number of poliomyelitis cases in the United States was typically 20,000 to 30,000 per year in the 1940s and 1950s, while influenza still typically kills 40,000 to 50,000 Americans annually. Yet most individuals, then and now seem indifferent to influenza. What’s more, even the 1918 “Spanish Flu” epidemic, which was arguably the most devastating epidemic in human history, did not cause any panic, despite the fact that during the single month of October 1918, it killed 196,000 people in the United States alone! Estimates of the total number killed worldwide by the 1918 Spanish Flu range between 20 million and 50 million.

So, how can we explain the terror brought on by poliomyelitis? It wasn’t simply because poliovirus struck suddenly, without any warning. So did the “Spanish Flu.” Rather, paralytic poliomyelitis mainly struck children, adolescents and young adults. In contrast, influenza mainly threatens the elderly. And, in truth, most parents are far more emotionally invested in their children’s well-being than in that of their parents or themselves. Furthermore, the sight of a child in an iron lung or leg braces (affected legs became atrophied and deformed) was truly heart rending.

The fear evoked by poliomyelitis was permanently ended in the United States and in much of the developed world as well, by the emergence of Salk’s killed polio vaccine in 1955. Sabin’s live attenuated vaccine followed soon after. [Live vaccines generally contain attenuated (weakened) variants of the virulent virus, which can replicate and induce immunity, but which cannot cause disease.] The response of the public to Salk’s vaccine was so great that he was hailed as a “miracle worker.” Nevertheless, and despite the fact that the vaccines created by Salk and Sabin have nearly ridden the world of poliovirus, neither man would ever be recognized by the Nobel committee.

salk Salk’s public acclaim was resented by his colleagues.

Most virologists of the day strongly favored live vaccines over killed ones, based on the belief that only a live vaccine could induce a level of immunity sufficient to protect against a challenge with live virulent virus. Indeed, the effectiveness of live vaccines had been established much earlier by Jenner’s smallpox vaccine (1798) and Pasteur’s rabies vaccine (1885). Jenner’s smallpox vaccine actually contained live cowpox virus, which was similar enough immunologically to variola to protect against smallpox, while not being able to cause smallpox itself. Pasteur’s rabies vaccine contained live rabies virus that was attenuated by passages through rabbit spinal cords. [Adapting the virus to grow in rabbits attenuated its virulence in humans, while not impairing its ability to induce immunity.] So, bearing in mind the well-established precedence of attenuated vaccines, why did Salk seek to develop a killed vaccine?

In 1941, Thomas Francis, one of the great pioneers of medical virology, working at the University of Michigan, developed a killed influenza vaccine. Providentially, in the same year, Jonas Salk (recently graduated from NYU medical school) came to Francis’ laboratory for postgraduate studies. In Francis’ lab, Salk learned his mentor’s methods for producing his killed influenza vaccine and assisted in its field trials.

Salk’s experience in Francis’ laboratory led him to believe in the potential of a killed poliovirus vaccine. And, Salk learned practical procedures from Francis that would be valuable in his pursuit of that objective. These included the use of formaldehyde to kill the virus, the use of adjuvants to enhance the immunogenicity of the killed vaccine, and protocols for conducting field tests.

In contrast to Salk, Sabin firmly believed that a live attenuated vaccine would be vastly superior to a killed one. And, although Salk won the race to produce an actual vaccine, Sabin had been doing polio research well before the younger Salk emerged on the scene. Indeed, Sabin made several important contributions to the field; some of which are discussed below. For now, we mention that in 1936, Sabin and colleague Peter Olitsky demonstrated that poliovirus could be grown in cultured human embryonic nervous tissue. While this might appear to be a key step towards the development of a vaccine, Sabin and Olitsky feared that nervous tissue might cause encephalitis (inflammation of the brain and spinal cord) when injected into humans.

sabinAlbert Sabin, who developed the live polio vaccine.

John Enders, at the Children’s Hospital of Boston, is the next key player in our story. Enders believed that poliovirus should be able to grow in non-nervous tissue, particularly tissue from the alimentary canal, as suggested to him by the amount of the virus that was present in the feces of many patients. So, in 1948, Enders, and colleagues Thomas Weller and Frederick Robbins, succeeded in growing poliovirus in cultured non-nervous tissue, including skin, muscle, and kidney. As a result of Ender’s work, sufficient amounts of poliovirus could now be grown, free from the hazards of nervous tissue, thereby enabling the mass production of a vaccine.

[Aside: Enders, Weller, and Robbins maintained their tissue samples in culture using the roller culture procedure, in which a horizontally positioned bottle is laid on its side and continuously rotated around its cylindrical axis. In comparison to the older process of growing tissues in suspension, the roller culture method enabled the prolonged maintenance of the tissues in an active state and, consequently, the growth of large amounts of virus. For readers who read Renato Dulbecco and the Beginnings of Quantitative Animal Virology (on the blog), note that Dulbecco developed procedures for growing pure cell types as flat adherent monolayer cultures, thereby making possible quantitative plaque assays of animal viruses.]

In 1954, Enders, Weller, and Robbins shared the Nobel Prize in Physiology or Medicine for their contribution described above. What’s more, the Nobel award to Enders, Weller, and Robbins was the only Nobel award ever given in recognition of polio research! Ironically, Ender’s true interests actually lay elsewhere; with measles. He would later develop a measles vaccine. [Enders has been referred to as the “Father of modern vaccinology.”]

The next key player of note in our story is not a person but, rather, a foundation; the “National Foundation for Infantile Paralysis,” which led and financed the crusade against polio in the pre-NIH days of the 1950s. The National Foundation was actually an outgrowth of the Georgia Warm Springs Foundation, a charitable organization founded by Franklin D. Roosevelt, himself crippled by polio. However, after Roosevelt became president of the United States, he was too polarizing a figure (particularly after his “court-packing” scheme in 1937) to head up a philanthropic organization. Consequently, in 1938, Roosevelt announced the formation of the nonpartisan National Foundation for Infantile Paralysis.

roosevelt Photos of Franklin Roosevelt in a wheel chair are rare and were not shown to the public, which was generally unaware that he was paralyzed from the waist down.

[Aside: The National Foundation was initially funded by the contributions of wealthy celebrities who attended Roosevelt’s yearly birthday bashes. At one of these fundraisers, the vaudevillian, Eddie Cantor, jokingly urged the pubic to send dimes directly to the president. And, bearing in mind the fear evoked by polio, the public, perhaps not recognizing the joke, did exactly that, flooding the White House with nearly three million dimes. And so, the slogan “March of Dimes,” for the Foundation’s grass-roots fund-raising campaign, came to be. And, it was not coincidental that a dime (the Roosevelt dime) was issued in 1946 to memorialize the late president.

In 1950, a March of Dimes chapter in Phoenix, Arizona held a “Mother’s March on Polio,” in which volunteers went door-to-door raising money for polio research. People were urged to leave their porch lights on to show that the volunteers would be welcome. The Phoenix initiative soon spread to other locals, and the Mother’s March became a nationwide annual event.]

The role of the National Foundation went beyond merely raising money for research. It also attempted to provide direction to the research, which often placed it at odds with its grantees. This was the case because Harry Weaver, the director of research at the National Foundation, was focused on bringing a vaccine to the public. In contrast, most of the Foundation’s grantees were largely motivated by their desire to understand basic virological issues, such as poliovirus transmission, replication, and dissemination. What’s more, they believed that there was still too much to be known about poliovirus and poliomyelitis before a vaccine might be a realistic possibility.

[Aside: Apropos the sentiment of some poliovirus researchers that there was too much yet to be known before a polio vaccine might be possible, Jenner’s 1798 smallpox vaccine was developed a half century before the germ theory of disease was proposed, and 100 years before the actual discovery of viruses. It was based on the empirical observation that milkmaids seemed to be “resistant” to smallpox; apparently because they had been exposed earlier to cowpox. The initial smallpox vaccine simply contained matter from fresh cowpox lesions on  the hands and arms of a milkmaid. It was then serially passed from one individual to another; a practice eventually ended because of the transmission of other diseases. And, Pasteur’s 1885 rabies vaccine too was developed before viruses were recognized as discrete microbial entities.]

Sabin’s objection to the Foundation’s priority of having a vaccine available as quickly as possible was somewhat more personal. Since a killed vaccine should be more straightforward and, therefore, quicker to develop than an attenuated one (see below), Sabin believed that Weaver’s sense of the urgent need for a vaccine would lead him to favor supporting Salk’s killed vaccine over his attenuated one. Moreover, Sabin felt that he was being shunted aside. And, Since Sabin remained firm in his belief in the superiority of a live vaccine; he also felt that Weaver’s main concern of having a vaccine available as quickly as possible, would compromise the efficacy of the vaccine that would be implemented in the end.

[Aside: Back in the Enders laboratory, Thomas Weller and Frederick Robbins wanted to enter the polio vaccine race. But, Enders viewed the project as boring and routine; a view pertinent to the question of why Salk and Sabin were never recognized by the Nobel Committee. Furthermore, Enders didn’t believe that a killed vaccine could ever provide adequate protection against polio, or that a live vaccine would be possible without years more of research.]

Sabin’s worry that a killed vaccine would be faster to develop than an attenuated one was borne out when, in1953, Salk was preparing to carry out a field-test of his killed vaccine. Yet Sabin and other poliovirus researchers remained inclined to move slowly, placing them in opposition to Harry Weaver’s sense of urgency. Moreover, Sabin and the other polio investigators were also piqued at the National Foundation for promoting Salk’s vaccine to the public and, also, for promoting Salk himself as a miracle worker. The Foundation’s reason for publicizing Salk was to stir up public enthusiasm for its fund raising campaigns. And Salk indeed was becoming the symbol of the miracles of medical research to an admiring public.

In fairness to the polio researchers who dissented with the National Foundation’s single minded emphasis on bringing a vaccine to the public, there were valid reasons for believing that the Foundation might be moving too quickly. So, consider the following excerpts from a letter that Sabin wrote to his rival, Salk: “…this is the first time they (the Foundation) have made a public statement based on work which the investigator has not yet completed or had the opportunity to present…in a scientific journal…Please don’t let them push you to do anything prematurely or to make liters of stuff for Harry Weaver’s field tests until things have been carefully sorted out, assayed, etc., so that you know what the score is before anything is done on a public scale.”

While Sabin’s advice to Salk seems eminently sensible, Sabin had never before shown any inclination to look out for Salk’s interests. So, might Sabin be sending a non-too-subtle warning to Salk that he could either play by the traditions of the scientific community, or face the consequences of playing to the interests of the Foundation? For his part, Salk was well aware of what was happening and he was indeed embarrassed by the adulation of the press; correctly sensing that it was compromising his standing with his colleagues.

[Aside: The media, in the person of the legendary broadcaster, Edward R. Murrow, provided Salk with a notable and very satisfying moment in the public spotlight. During an April, 1955 interview on the CBS television show See it Now, Murrow asked Salk: “Who owns the patent on this vaccine?” To which, Salk replied: “Well, the people, I would say. There is no patent. Could you patent the sun?”

While Salk’s answer to Murrow endeared him even more to the public, some colleagues questioned whether it might have been disingenuous. Both the University of Pittsburgh, where Salk carried out his work, and the National Foundation, which financed it, indeed had been looking into the possibility of patenting Salk’s vaccine. But, when patent attorneys sought to determine if there was a basis for a patent, Salk readily acknowledged that his vaccine was, for the most part, based on tried and true procedures developed by others.

In point of fact, Salk’s critics held him in low esteem largely because there was little about his vaccine that was innovative. Indeed, Sabin once quipped: “You could go into the kitchen and do what he (Salk) did.” But in fairness to Salk, he never claimed that his vaccine was unique. Instead, in the face of much skepticism, his point had always been that a killed vaccine could protect against polio. He persevered and he was right.

Note that Sabin too gave his vaccine to the world gratis.]

By 1954, field tests of Salk’s vaccine went ahead on a massive scale, involving nearly 1.5 million schoolchildren nationwide. The tests were overseen by Thomas Rivers, an eminent virologist who, at the time, was Director of the Rockefeller Institute. Like most virologists, Rivers favored a live vaccine as the ultimate solution to polio. Nevertheless, he believed that the world couldn’t wait ten or more years for an ideal vaccine, when a satisfactory one might be available at present.

With 57,879 cases of poliomyelitis in the United States in 1952, the peak year of the epidemic, Harry Weaver’s sense of the urgent need for a vaccine was widely shared by the public. Unsurprisingly then, the public eagerly supported the 1954 field test of Salk’s vaccine, as indicated by the fact that 95% of the children in the test received all three required vaccinations. [Killed vaccines require multiple doses. That is so because the first dose only primes the immune system. The second or third dose then induces the primed immune system to produce protective antibodies against the virus. Inoculation with a live vaccine resembles a natural infection and, consequently, a single dose is sufficient to induce immunity.]

The field test of Salk’s vaccine was unprecedented in its size. What’s more, it was supported entirely by the National Foundation, which strenuously opposed outside interference from the federal government. In actuality, the Foundation considered federal funding for polio research to be a “Communistic, un-American…scheme.”

[Aside: President Dwight Eisenhower, a Republican and a fiscal conservative, also believed that the federal government had no proper a role in health care. Consequently, Eisenhower took little interest in his Department of Health, Education, and Welfare (HEW). What’s more, Eisenhower’s Secretary of HEW, Oveta Culp Hobby, was even more conservative in that regard than Eisenhower himself. In 1955, after the field trials showed the Salk vaccine to be a success, and with the public clamoring for it, there were insufficient amounts of the vaccine available to meet the public’s demands. Thus, even some Republicans were stunned to learn that the Eisenhower administration had taken no actions whatsoever to watch over production of the vaccine or its distribution, believing that this was in the province of the drug companies. When pressed on this, Mrs. Hobby responded: “I think no one could have foreseen the public demand.”

Not surprisingly, American drug companies lobbied intensely to keep vaccine production under their own control. A different scenario played out in Canada, where the government viewed polio as a national crisis, and took control of its vaccination program, with overwhelming public support.]

All did not go well for Salk and his vaccine after the successful 1954 field tests. In April 1955, more than 200,000 children were inoculated with a stock of improperly inactivated vaccine made by Cutter Laboratories; one of the five companies that produced the vaccine in 1955. [The others were Eli Lilly, Parke-Davis, Wyeth, and Pitman-Moore.] The Cutter vaccine caused 40,000 cases of abortive poliomyelitis (a form of the disease that does not involve the central nervous system), and 56 cases of paralytic poliomyelitis; 5 of which were fatal. What’s more, some of the children inoculated with the Cutter vaccine transmitted the vaccine virus to others, resulting in 113 more cases of paralytic poliomyelitis and 5 fatalities.

A congressional investigation blamed the “Cutter incident” on the NIH Laboratory of Biologics Control, for insufficiently scrutinizing the vaccine producers. In point of fact, the NIH did little testing on its own. Instead, it mainly relied on reports from the National Foundation, whose agenda was to proceed with the vaccinations. Yet the NIH did have an early, in-house warning of potential problems with the Cutter vaccine, which it failed to act on. Bernice Eddy, a staff microbiologist at the NIH, reported to her superiors that the Cutter vaccine caused paralysis when inoculated into monkeys. However, no action was taken in response to Eddy’s warning. [In 1959, Eddy discovered simian virus 40 (SV40) in monkey kidney tissue that was used for vaccine production. By that time, live SV40 had unknowingly been injected into hundreds of millions of people worldwide; perhaps the subject of a future blog posting.]

Salk was exonerated of any fault in the Cutter incident. Moreover, after that episode, not a single case of polio in the United States would be attributed to Salk’s vaccine. Nevertheless, while Salk’s killed vaccine was perfectly safe when properly prepared, the Cutter incident led to the perception that it was unsafe. Consequently, Salk’s killed vaccine was eventually replaced by Sabin’s live attenuated one. Ironically, as we will see, the perception that Salk’s vaccine was dangerous led to its replacement by a more dangerous one.

Sabin’s work on his live polio vaccine began in 1951 and, like Salk; he was supported by the National Foundation. Sabin’s task was more difficult than Salk’s because it is more straightforward to kill poliovirus, than it is to attenuate it. [The attenuated virus must be able to replicate in the digestive tract and induce immunity, yet be unable to damage the nervous system.] But Sabin persisted, sustained by his conviction that a live vaccine would invoke stronger, longer-lasting immunity than a killed vaccine. Sabin attenuated his vaccine by successive passages through monkey tissue, until the live virus could no longer cause paralysis when inoculated directly into chimpanzee spinal cords.

[Aside: At this early date, live-vaccine-proponents could not have known that only a live vaccine could activate T-cell mediated immunity, which is generally necessary to clear a virus infection. Instead, their preference for live vaccines was based on the simpler, but correct notion that inoculation with a live vaccine would more closely approximate a natural infection. Also, since the vaccine virus is alive, vaccinated individuals might transmit it to unvaccinated ones, thereby inducing immunity in the latter as well. On the other hand, the attenuated vaccine poses a deadly threat to individuals with impaired immune systems, such as AIDS patients and individuals on immunosuppressive regimens following organ transplants.]

In 1954, a successful small-scale test of Sabin’s vaccine was carried out, which involved thirty adult human prisoners at a federal detention facility. The promising outcome of this test warranted a larger field-trial of Sabin’s vaccine. But, several obstacles stood in the way. First, the National Foundation was not inclined to support another massive field trial, now that Salk’s vaccine was already in use. Second, the Foundation was still reeling from the Cutter incident, and had no inclination to be caught up in another such debacle. Third, it would be virtually impossible to conduct the trials in the United States, since millions of American children had already been inoculated with Salk’s vaccine. The ensuing course of events was rather remarkable.

By 1956, poliomyelitis had become a serious public health crisis in the former Soviet Union. Consequently, a delegation of Russian scientists came to the United States to meet with Salk and consult with him on how to produce his vaccine. However, the Russians were disposed to meet with other polio researchers as well. Thus, Sabin seized this opportunity to invite the Russians to visit his laboratory at the University of Cincinnati, where he was able to tout his live vaccine to them. Sabin’s pitch was apparently effective, as he secured an invitation from the Russians to visit the Soviet Union, where he spent a month, further hyping his vaccine.

[Aside: While Sabin was in Russia, the Russians requested from him a sample of his live vaccine. So, when Sabin returned to the United States, he sought permission from the State Department to send the Russians the samples they requested. The State Department approved the request; but it did so over objections from the Defense Department, which was concerned that the vaccine virus might have “biological warfare applicability.”]

With the incidence of poliomyelitis on the rise in the Soviet Union, the Soviet Health Ministry needed to quickly decide which vaccine to adopt; Salk’s or Sabin’s. The Russians were already producing the Salk vaccine, but were unable to consistently maintain its efficacy from one batch to another. So, the Soviets invited Salk to visit Russia, so that he might help them to solve the problems they were having producing his vaccine.

Salk then made a decision that he would long regret. Because of pressure from his wife to spend more time with his family, Salk turned down the Russian invitation. The upshot was that the Russians turned instead to Sabin. In 1959 they vaccinated 10 million children with vaccine strains sent to them by Sabin. Soviet results with the Sabin vaccine were so promising that the Soviet Health Ministry decided to then use it to vaccinate everyone under 20 years of age. A total of seventy-seven million Soviet citizens were vaccinated with Sabin’s vaccine, vastly exceeding the number vaccinated during field trials of the Salk vaccine in the United States.

The U.S. Public Health Service did not endorse the Sabin vaccine for use in the United States until 1961. By then, the Salk vaccine had virtually eliminated polio from the country. Nevertheless, Sabin’s vaccine supplanted Salk’s in the United States and in much of the rest of the world as well.

Yet all did not go well with Sabin’s vaccine either. As noted above, after the Cutter incident, there were no cases of poliomyelitis in the United States that could be attributed to Salk’s vaccine. In contrast, Sabin’s vaccine caused about a dozen polio cases per year, a frequency of about one case per million vaccinated individuals. At least some of these cases resulted from the ability of the attenuated virus to revert to a more virulent form. What’s more, reverting viruses posed a threat to non-vaccinated individuals in the population. For instance, in 2000/2001, there were 21 confirmed cases of poliomyelitis in the Dominican Republic and Haiti, which were traced to a single dose of the Sabin vaccine that was administered during the preceding year. [As noted in an above Aside, since the Sabin vaccine is alive, vaccinated individuals might transmit the vaccine virus to unvaccinated individuals.]

In actual fact, the few cases of poliomyelitis that now occur in the West are vaccine-related, resulting from the rare reversions of Sabin’s vaccine. Ironically, the Sabin vaccine, which played a crucial role in the near eradication of polio from the world, had become an obstacle to the complete eradication of the virus. In 2000, the U.S. Centers for Disease Control (CDC) recommended the complete return to the Salk vaccine in the United States. However, the Sabin vaccine would continue to be used in much of the developing world.

[Aside: Several polio hotspots remain in the world. Three major ones are Pakistan, Afghanistan, and Nigeria. Recent outbreaks have also occurred in Syria and Somalia. In each of these instances, social and political climates make it difficult to carry out eradication campaigns.

As recently as March 2014, militants attacked a polio vaccination team in northwest Pakistan, detonating a roadside bomb and then opening fire on their convoy, killing 12 of their security team, and wounding dozens more. Some Pakistani religious leaders denounced the vaccination campaign in Pakistan as a cover for spying or as a plot to sterilize Muslim children.

In the developed world there is a very different problem. Ironically, the great success with which the polio vaccines eradicated the virus in the West has created conditions there in which poliomyelitis might make a most unwelcome return. That has come about because too many parents in the developed world now view polio as ancient history, and have become complacent about having their children vaccinated. What’s more, some parents are heeding unsubstantiated warnings that the risks of vaccines are greater than the risks of the viruses. Consequently, the frequency of vaccinated individuals in the West is declining to the point where the West may be susceptible to outbreaks sparked by imported cases. These issues will be discussed at length in a subsequent posting.]

We turn now to an issue raised at the outset of this posting; neither Salk nor Sabin was recognized by the Nobel Committee for his contribution. That is so, despite the fact that their individual efforts, taken together, have virtually eliminated polio from the world.

Max Theiler, at the Rockefeller Institute, is relevant regarding the Nobel issue, and for several other reasons as well. First, Theiler took an early interest in Sabin’s career during Sabin’s years at the Rockefeller (1935 to 1939). Second, during those years Theiler was working on a live attenuated vaccine for yellow fever. Like most virologists of the day, Theiler believed that only a live vaccine could provoke significant long-lasting immunity. And, Theiler’s thinking on this matter likely influenced Sabin’s later approach to a polio vaccine. Thirdly, and important in the current context, in 1951 Theiler was awarded the Nobel Prize in Physiology or Medicine for his yellow fever vaccine. Fourth, Theiler’s Nobel Prize was the only one ever awarded for the development of a virus vaccine!

Why was Theiler’s Nobel award the only one ever given for the development of a virus vaccine? In addition, recall that John Enders, Thomas Weller, and Frederick Robbins shared the 1954 Nobel Prize for Physiology or Medicine, for demonstrating that poliovirus could be propagated in non-nervous tissue. Moreover, the Nobel Prize shared by Enders, Weller, and Robbins was the only one ever given in recognition of polio research! Why weren’t Salk and Sabin recognized as well? Didn’t they also contribute substantially “to the benefit of mankind;” a standard for the award, as specified by Alfred Nobel?

Apropos these questions, it may be relevant that Alfred Nobel also specified that the prize for physiology or medicine should recognize a “discovery” per se. With that criterion in mind, the Nobel committee may have viewed the contributions of Salk and Sabin as derivative, requiring no additional discovery. In contrast, the discovery of Enders, Weller, and Robbins, refuted the previously held belief that poliovirus could be grown only in nervous tissue; a breakthrough that paved the way to the vaccines.

But then, what was there about Theiler’s yellow fever vaccine that might be considered a discovery? Hadn’t Pasteur developed an attenuated Rabies vaccine in 1885? And, what of Jenner’s earlier 1798 smallpox vaccine, comprised of live cowpox virus?

To the above points, Sven Gard, at the Karolinska Institute, and a member of the Nobel committee for Physiology or Medicine, wrote the following in his evaluation of Theiler’s prior 1948 Nobel nomination: “Theiler can not be said to have been pioneering. He has not enriched the field of virus research with any new and epoch-making methods or presented principally new solutions to the problems, but he has shown an exceptional capacity to grasp the essentials of the observations, his own and others, and with safe intuition follow the path that led to the goal.”

Despite the seeming inconsistency between Gard’s comments and Nobel’s instruction that the prize be awarded for a discovery, Gard nonetheless concluded that Theiler’s contributions indeed merited the Nobel award. [Incidentally, Theiler’s 1948 Nobel nomination was a detailed six-page-long document, written and submitted on his behalf by Albert Sabin!]

To the same point, Hilding Bergstrand, also at the Karolinska Institutet, and chairman of the Nobel Committee for Physiology and Medicine, said the following during his otherwise laudatory speech honoring Theiler at the 1951 Nobel Prize ceremony: “The significance of Max Theiler’s discovery must be considered to be very great from the practical point of view, as effective protection against yellow fever is one condition for the development of the tropical regions—an important problem in an overpopulated world. Dr. Theiler’s discovery does not imply anything fundamentally new, for the idea of inoculation against a disease by the use of a variant of the etiological agent which, though harmless, produces immunity, is more than 150 years old.”

Even Theiler himself agreed that he had not done anything fundamentally new. But then, what might Bergstrand have had in mind when referring to Theiler’s discovery? Perhaps it was Theiler’s finding that passage of the Asibi strain of yellow fever virus in chick embryos, which were devoid of nervous systems, generated viable, non-neurotropic attenuated yellow fever virus. If so, then did that discovery fulfill the condition for the Nobel award, as specified by Alfred Nobel? And, if that is the case, then might this discovery have been what makes Theiler’s contribution more worthy than those of Salk and Sabin in the eyes of the Nobel committee? [A more detailed account of Max Theiler’s yellow fever vaccine, particularly with regard to the “discovery” noted here, can be found in The Struggle Against Yellow Fever: Featuring Walter Reed and Max Theiller, now on the blog.]

The seemingly trivial distinction between the worthiness of Theiler’s contribution from that of Salk and Sabin, suggests that we may need to look elsewhere for answers to why Salk and Sabin were bypassed by the Nobel committee. One reason suggested in the case of Salk is that in the elitist world of big-time science, he had never spent time at a prestigious Research institution like the Rockefeller. Yet he did carry out postgraduate studies in association with the eminent Thomas Francis. So perhaps he was passed over by the Nobel committee because it did not see anything innovative about his vaccine. Or, perhaps it was because he allowed himself to be promoted as a celebrity by the March of Dimes, thereby causing resentment among his colleagues.

But, how then might we explain the case of Sabin? Sabin had not been used by the National Foundation to promote its fund-raising. And, he had done research at the Rockefeller Institute. Moreover, Sabin made seminal contributions to the poliovirus field before and after beginning his vaccine work. As noted above, Sabin and Peter Olitsky demonstrated that poliovirus could be grown in cultured human embryonic nervous tissue. Moreover, Sabin provided experimental evidence that the poliovirus port of entry is the digestive tract, rather than the respiratory tract, as was previously thought. And, Sabin established that the incidence of poliomyelitis tended to be highest in urban populations which had the highest standards of sanitation.

[Aside: Sabin’s finding, that the poliovirus route of entry is via the alimentary tract, validated the premise that poliomyelitis might be prevented by a live oral vaccine. In contrast, Salk’s killed vaccine needed to be injected. An advantage of a vaccine being administered by the oral route, particularly in developing countries, is that trained medical personnel are not required for its administration. On the other hand, the killed vaccine is safer. The few cases of poliomyelitis that now occur in the West are vaccine-related, resulting from rare reversions to virulence of the attenuated virus.]

[Aside: Why was the incidence of poliomyelitis highest in urban populations that had the highest standards of hygiene? Polio infection tends to be milder in the very young, perhaps because they are partially protected by maternal antibodies. But, in areas with high standards of hygiene, infection tends to occur later in life, when maternal antibodies have waned, and the infection can then be more severe.

Before this was appreciated, poliomyelitis was thought to originate in the slums and tenements of cities, and then spread to the cleaner middle-class neighborhoods. Thus, during polio outbreaks in New York City, there were instances when slums and tenements were quarantined, and city dwellers fled to the suburbs, all to no avail.]

Were Sabin’s discoveries noted above, taken together with his vaccine, worthy of a Nobel Prize? In any case, Sabin indeed had been nominated for the Nobel award by numerous colleagues, including Enders. So, why was Sabin never awarded the Nobel Prize? Perhaps the Nobel committee could not recognize Sabin without also recognizing Salk, which it may have been reluctant to do for reasons noted above. Or, as has been suggested, the continual back-and-forth carping between supporters of Salk and Sabin may ultimately have diminished enthusiasm in Stockholm for both of them.

Salk (in 1956) and Sabin (in 1965) each received the prestigious Lasker Award for Clinical Research (often seen as a prelude to the Nobel) and, earlier, in 1951, Sabin was elected to the U.S. National Academy of Sciences. In contrast, Salk was the only prominent polio researcher not elected to the Academy. And regarding the Nobel Prize, Salk once joked that he didn’t need it, since most people thought he had already won it.

In 1963 Salk founded the prestigious Salk Institute for Biological Studies in La Jolla, California. Francis Crick (1), Renato Dulbecco (2), and Leo Szilard (3), each of whom is featured elsewhere on the blog, were among the eminent scientists recruited by Salk to the La Jolla campus. Bearing in mind Salk’s alienation from other medical researchers of the day, we might enjoy his remark “I couldn’t possibly have become a member of this institute if I hadn’t founded it myself.” Jonas Salk died of congestive heart failure in 1995 at the age of 80. He remains one of the most venerated medical scientists ever.

salk instSalk Institute for Biological Studies

[Aside: Salk married Dora Lindsay in 1939, right after he graduated from NYU medical school. But, the marriage eventually fell apart, and the couple divorced in 1968.

In 1970, Salk married the artist Francois Gilot, who had been the mistress of Pablo Picasso for nearly ten years and with whom she had two children. Salk and Gilot met in 1969, at the home of a mutual friend in Los Angeles. They remained married until Salk’s death in 1995.

The following is from an April 27, 2012 article in Vogue by Dodie Kazanjian, entitled Life after Picasso: Francois Gilot.

“On a trip to Los Angeles in 1969, a friend introduced her to Jonas Salk. She had no interest in meeting him—she thought scientists were boring. But soon afterward, he came to New York and invited her to have tea at Rumplemayer’s. ‘He didn’t have tea; he ordered pistachio and tangerine ice cream,’ she recalls. ‘I thought, Well, a scientist who orders pistachio and tangerine ice cream at five o’clock in the afternoon is not like everybody else!’ He pursued her to Paris and a few months later asked her to marry him. She balked. “I said, ‘I just don’t need to be married,’ and he said, ‘In my position, I cannot not be married.’ He gave me two pieces of paper and told me to write down the reasons why I didn’t want to get married.” She complied. Her list included: ‘I can’t live more than six months with one person’; ‘I have my own children’; ‘I have my career as a painter and have to go here and there’; ‘I’m not always in the mood to talk. Et cetera, et cetera, et cetera.’

Salk looked at the list and said he found it ‘quite congenial.’ They were married in 1970 and were together until he died in 1995. ‘It worked very well,’ she says, because after all we got along very well.’”]

Albert Sabin became president of the prestigious Weizmann Institute of Science in Israel, but stepped down in November 1972 for health reasons. He passed away in 1993 at the age of 86. Unlike in the case of Salk, and despite the fact that he never was awarded the Nobel Prize, Sabin’s standing among his colleagues always remained high.

Before concluding, we note two other important contenders in the quest for a polio vaccine. The first of these was Isabel Morgan, the daughter of the great geneticist, Thomas Hunt Morgan. Isabel Morgan nearly produced a killed polio vaccine before Salk succeeded in doing so. Working at Johns Hopkins, she generated formalin-inactivated poliovirus preparations that indeed protected monkeys against intracerebral injections of live poliovirus. However, Morgan gave up her research in 1949 to marry and raise a family. At that time, Salk had barely begun his work. But, if Morgan had remained in the race, Salk may yet have beaten her to the finish line, since she was reluctant to test her vaccine on human subjects.

Hilary Koprowski was the other noteworthy contender in the race to a polio vaccine. Koprowski was a Polish Jew who immigrated to Brazil in 1939, after Germany invaded Poland. He later came to the United States, where, in 1945, he was hired by Lederle Laboratories to work on a project to develop a live polio vaccine. Koprowski’s foray into polio had a few interesting happenings. Moreover, he went on to have a renowned career as a virologist. Thus, we discuss him in a bit more detail.

[Aside: Salk and Sabin also were Jewish. And Sabin too was born in Poland. In 1921 he immigrated with his family to the United States, at least partly to escape persecution of Jews in his birth-land.]

Koprowski began his work at Lederle before John Enders developed methods for growing poliovirus in monkey kidney cell cultures. Consequently, Koprowski attenuated his live vaccine by passaging it in mouse brains in vivo. In 1950, several years before Sabin’s vaccine was ready for testing, Koprowski found that his vaccine indeed protected chimpanzees from challenge with virulent poliovirus. Koprowski then tested his live vaccine in humans; first on himself, and then on 19 children at a New York State home for “feeble minded” children.

Koprowski was still an unknown figure in the scientific community when he made the first public presentation his test findings. This happened at a 1951 National Foundation roundtable that was attended by the major polio researchers of the day, including Salk and Sabin. The conferees were aghast upon hearing that Koprowski had actually tested his live vaccine, grown in animal nerve tissue, on children. Koprowski’s response was simply that someone had to take that step. Also, it didn’t help Koprowski’s standing with his academic colleagues that he was employed by Lederle. In those pre-biotech days, he was looked down on as a “commercial scientist.”

Human testing was of course a necessary step in the development of this or any human vaccine. What’s more, using cognitively disabled children as test subjects was a common practice back then. So, the actual concern of Koprowski’s colleagues was that he inoculated human subjects with a vaccine that was grown in animal brains. Koprowski also may have been treading on shaky legal ground, since it is not clear whether he ever obtained consent from the children’s parents.

[Aside: The only guidelines for such tests back then were the so-called Nuremburg Code of 1947, which was formulated in response to Nazi “medical” experiments. Informed consent was one of the Nuremburg guidelines, which, in the case of children, meant consent from a parent or guardian. Note that federal approval was not required to test vaccines or drugs in those days.]

Irrespective of whatever uproar Koprowski caused by testing his vaccine on helpless institutionalized children, he indeed had a live polio vaccine in 1949; several years before Salk and Sabin brought out their vaccines. However, Koprowski’s vaccine began its demise soon afterwards. A small field trial in Belfast showed that the attenuated virus could revert to a virulent form after inoculation into humans. But, bearing in mind that there was not yet any alternative to his vaccine, Koprowski firmly believed that the greater risks of natural poliovirus infections justified its use.

The fate of Koprowski’s vaccine was sealed in 1960, when the U.S. Surgeon General approved the Sabin vaccine for trial manufacture in the United States, while rejecting Koprowski’s vaccine on safety grounds. Tests showed that Sabin’s vaccine was the less neurovirulent of the two vaccines in monkeys. Sabin had carefully tested plaque-isolated clones of his attenuated viral populations for neurovirulence in monkeys, and he then assembled his vaccine from the least neurovirulent of these clones. Moreover, by this time millions of children in the Soviet Union had had been successfully immunized with the Sabin vaccine.

Koprowski left Lederle Laboratories in 1957 after clashing with its management. After that, he became Director of the Wister Institute in Philadelphia. He then transformed the then moribund Wistar into a first class research organization.

The relationship between Koprowski and Sabin was quite adversarial at the time their vaccines were in competition, but they later became friends. In 1976, Koprowski was elected to the U.S. National Academy of Sciences, an honor shared with Sabin, bit never afforded to Salk.

Here is one last bit on Koprowski. Recall that early lots of the Salk and the Sabin vaccines unknowingly contained live SV40, which had been injected into hundreds millions of people worldwide. While the unknown presence of a live tumor virus in a vaccine must be one of a vaccinologist’s worst nightmares, this finding did not attract the attention of the public. In contrast, a 1992 article in Rolling Stone, which attributed the emergence of HIV to Koprowski’s polio vaccine, created a sensation. The premise of the article was that Koprowski’s vaccine was produced in chimpanzee cells that were contaminated with simian immunodeficiency virus (SIV), which then mutated into HIV when inoculated into humans. As might be expected, there was no evidence to support that premise. Indeed, PCR analysis could not detect SIV or HIV in the supposedly contaminated vaccine lots, and records from Koprowski’s laboratory showed that his vaccine was never grown in chimpanzee cells. So, faced with the possibility of a lawsuit, Rolling Stone issued a retraction.

Readers, who enjoyed the above account of the rivalry between Jonas Salk and Albert Sabin, may also enjoy the account of the rivalry between Robert Gallo and Luc Montagnier in Who Discovered HIV? More on the same topic can be found in How the Human Immunodeficiency Virus (HIV) Got its Name. For a very different kind of rivalry, that between Howard Temin and David Baltimore, see Howard Temin: In From the Cold.

1. Howard Temin: “In from the Cold” On the blog.

2. Renato Dulbecco and the Beginnings of Quantitative Animal Virology On the blog.

3. Max Delbruck, Lisa Meitner, Niels Bohr, and the Nazis On the blog.







Notable Individuals Who Survived Smallpox and One Who Didn’t: Featuring Abraham Lincoln, Elizabeth I, Josef Stalin, and Pocahontas

In the fall of 1863, Washington, D.C. was in the midst of a smallpox outbreak. Accordingly, on November 18 of that year, the day before Abraham Lincoln was to deliver his Gettysburg Address, during his train ride from Washington, D.C. to Gettysburg he told his private secretary and assistant, John Hay, that he felt weak. The next day, the day of the Gettysburg Address, Lincoln developed a high fever and severe headache, and within a week, his skin erupted with scarlet blisters.

Lincoln’s doctors officially diagnosed the President’s illness as a mild form of smallpox. However, contemporary researchers suggest that Lincoln’s physicians knew that his case was much more serious (as based on the length and severity of his illness), but wanted to reassure the public that their president was not gravely ill. Fortunately, by the tenth day of Lincoln’s infirmity, his fever began to abate and his rash began to peel.

Had Lincoln succumbed to smallpox in November of 1863, the American Civil War, and the subsequent history of the United States, would certainly have played out very differently. But, we also might wonder whether Lincoln’s bout with smallpox affected the Gettysburg Address per se. Lincoln did edit the speech during his November 18 train-ride to Gettysburg, when he was already experiencing the onset of his smallpox. The next day, despite his progressing illness, Lincoln rode by horseback to the Gettysburg cemetery, and then waited two hours for famous orator Edward Everett to finish his protracted speech. Lincoln then delivered his much shorter and more noted and remembered speech. Some have suggested that the succinctness of the Gettysburg Address may have been due in part to how badly Lincoln was feeling as he edited and delivered it. At any rate, Lincoln is said to have spoken eloquently on the occasion. But, if the Gettysburg Address had been scheduled one or two days later than November 19, Lincoln almost certainly would have been too ill to deliver it, and one of the greatest speeches in American history might never have come to pass.


Lincoln’s famous sense of humor remained in evidence during his potentially fatal session with smallpox. In one account, Lincoln’s physician is said to have informed Lincoln of his smallpox diagnosis while the President was interviewing an office-seeker. After the office-seeker heard the physician tell Lincoln that the disease is highly contagious, the office-seeker made excuses and left immediately. Lincoln then remarked, “There is one good thing about this. Now I have something I can give everybody.”

Elizabeth I of England (1533-1603), traditionally viewed as one of England’s greatest monarchs, was another notable individual who survived smallpox. Elizabeth was the daughter of Henry VIII and Ann Boleyn (executed by Henry two years after Elizabeth’s Birth) and the last monarch of the Tudor dynasty. In 1562 she contracted what she at first believed to be a bad cold, but which eventually was revealed to be a severe case of smallpox, leaving her mildly, but permanently scarred.

If Elizabeth had died from smallpox in 1562, there likely would have been a civil war between Protestants and the Catholic supporters of her cousin, Mary, Queen of Scots. Elizabeth’s half sister and predecessor on the English throne, Mary I, restored Roman Catholicism after the short-lived Protestant reign of her half-brother Edward VI. Mary’s re-establishment of Roman Catholicism was reversed after her death in 1558 by her younger half-sister and successor, Elizabeth I. The so-called Elizabethan Religious Settlement later evolved into today’s Church of England. And, Elizabeth did not persecute Catholics, thereby avoiding civil war.

During Elizabeth’s recovery, she made Robert Dudley (with whom she was romantically linked) protector of the kingdom. Dudley may be better known as the Earl of Leicester; who was raised to the peerage by Elizabeth in 1564.

Josef Stalin was yet another famous smallpox survivor, acquiring the disease at the age of seven. His face was badly scarred by the disease, and he had his later photographs retouched to make his pockmarks less apparent. What’s more, some accounts suggest that his disfigurement from smallpox was a cause of his later ruthlessness.

Earlier on the blog,we noted that the Inca emperor, Huayna Capac, and his son and heir, Ninan Cuyuchi, succumbed to smallpox, thereby indirectly enabling Francisco Pizarro to conquer the Inca Empire. 1 Pocahontas (about 1595-1617) was another, and more notable Native American, believed to have succumbed to smallpox. She was the daughter of the chief of the Powhatan Indian confederacy, and is probably best known for saving the life of English adventurer John Smith in 1607, and of the Virginia colony as well. In 1614 she married English tobacco farmer John Rolfe in Jamestown Virginia. The marriage of the couple, who were said to be in love, ensured peace between the Jamestown settlers and the Powhatan Indians for several years. In 1616 she accompanied Rolfe to England, where she was received as a princess, visited with Queen Anne, and was formally presented to King James I. Then, in 1617, Pocahontas and Rolfe prepared to sail back to Virginia. However, before the ship had progressed very far down the Thames, she became gravely ill, probably from smallpox, and was taken ashore, where she died in Rolf’s arms. Rolfe eventually returned to Virginia and was killed in an Indian massacre in 1622, perhaps brought on by the deteriorating relations between the colonists and the Indians, following-on the death of Pocahontas.

The couple had one child, Thomas, who was born in Virginia in 1815, before the family left for England. Thomas was raised in England and returned to Virginia in 1635, where he lived as an Englishman and became a tobacco planter. His descendents include Edith Wilson, the wife of Woodrow Wilson.

Before concluding, it would probably be good to offer up a disclaimer of sorts. First, there are several different accounts of the circumstances under which Lincoln said “There is one good thing about this. Now I have something I can give everybody.” Second, there are different accounts of the events surrounding the deaths of Pocahontas and John Rolfe. What’s more, it is not entirely certain that Pocahontas actually died from smallpox.

1. Smallpox in the New World: Vignettes featuring Hernan Cortes, Francisco Pizarro, and Lord Jeffrey Amherst

Smallpox in the New World: Vignettes featuring Hernan Cortes, Francisco Pizarro, and Lord Jeffrey Amherst

Smallpox was one of the greatest scourges in human history. Before it was pronounced to be officially eradicated in 1977, smallpox was estimated to have killed, crippled, or maimed nearly 1/10 of all individuals who ever lived. During the 18th century in Europe, smallpox killed, on average, about 400,000 persons per year. In fact, even during the 20th century, before worldwide vaccination led its eradication, smallpox is believed to have killed more than 300 million people! [The last documented smallpox case worldwide occurred in Somalia in 1977. The last case in the United States was reported in 1949.]

 Notwithstanding the decimation smallpox wrought in European populations, which had several thousand years to adapt to it, smallpox was even more devastating to Native Americans, who were exposed to it only after European explorers, conquerors, and colonizers brought it to the New World. The Europeans also brought other diseases to the New World; most significantly, measles, influenza, typhus, and bubonic plague. Yet smallpox was the most devastating of the European infectious diseases to the indigenous people of the New World. Importantly, smallpox readily spread throughout the Americas, decimating Native American populations, before most had ever actually made contact with the Europeans themselves.

Estimates of how many Native Americans were living in the Americas when Columbus arrived, and how many may have succumbed to smallpox and other Old World diseases, vary considerably. Some estimates claim that 95 percent of the pre-Columbian Native American population succumbed to these Old World diseases. At any rate, the ruin caused by these diseases among the Native American populations was unquestionably enormous. Moreover, this devastation continued into the 20th Century, particularly among the Alaskan Inuit peoples, as well as the native populations of Australia, New Guinea, and Africa.

Bearing the above in mind, we now consider that Hernan Cortes and Francisco Pizarro each came to the New World, in the early 16th century, with an entourage numbering a mere several hundred or less. Yet each conquered a fierce warrior empire numbering in the millions. Cortes conquered the Aztecs and Pizarro, the Incas. How were the Spanish conquistadores able to vanquish these empires, in the face of such overwhelming numerical odds?

Some historians attribute the Spanish conquests of the Aztecs and Incas to their steel weapons and armor and, even more so, to their horses. Others attribute the Spanish victories to the devastating effect of smallpox on those Native American civilizations. Thus, a key purpose of this posting is to sort through these differing points of view, to give each standpoint its proper due. Then, noting that smallpox was an inadvertent factor in the conquests of the Aztecs and Inca empires by the Spanish conquistadores, we recount how British forces in colonial North America, led by Lord Jeffrey Amherst, deliberately used smallpox as a bio-weapon against rebelling Native Americans, in the first documented instance of biological warfare in the New World. [To place these events in time, recall that Columbus first landed in the New World in 1492. Cortes’ encounter with the Aztecs happened a mere 27 years later, in 1519. Pizarro’s encounter with the Incas happened only 13 years after that, in 1532. Amherst’s episode happened in what is now western Pennsylvania, more than 200 years later, in 1763.]

John Keegan, a well known writer on military history, believes that the Spaniards’ horses were the foremost factor in their conquests of the Aztecs and Incas. These Native Americans had never seen horses before they confronted the horses ridden into battle by the conquistadores. Thus, we might very well appreciate how shocking it must have been to Aztec and Inca foot soldiers, when facing a charging horse for the first time. Moreover, horses gave the Spaniards tremendous advantages of speed and maneuverability on the battlefield. Hence, Keegan states, “…in a contest of hundreds against thousands, it was their horses that gave the invaders the decisive (my emphasis) advantage.”

Yet Cortez started out with only 17 horses and Pizarro with only 27. Thus, could so few horses have actually been the factor that enabled several hundred Spanish conquistadors to defeat warrior empires of several millions? In support of this premise, there were numerous battles, in which a mere few dozen or less Spanish horsemen routed thousands of Aztec and Inca warriors, while slaughtering many of them in the process.

Keegan also credits another factor with regard to the defeat of the Aztecs; the extraordinary limitations the Aztecs imposed on their own war-making ability; at least by European standards. Although Aztec armies were very well trained, organized, and supplied, the objective of Aztec warfare was the taking of large numbers (many thousands in some instances) of live prisoners for their ritual sacrifices. Consequently, Aztec weapons and tactics were designed to wound and immobilize, rather than to kill. Thus, while the Aztecs had bows and arrows, their favored weapon was a wooden sword, studded along its sides with flakes of flint, which was designed just to wound. The warrior’s objective was to close with an opponent and strike a disabling blow to his legs, thereby crippling him and enabling his capture. And, since Aztec battles were fought for the purpose of taking prisoners, they were characterized by a high degree of ceremony and rituals. Moreover, the fighting effectiveness of their enemies was similarly limited by the same ceremony and rituals. Battles were prearranged, and the fate of the captives was known in advance. Remarkably, it was all part of a culture in which prisoners were expected to be voluntary participants in their own ritual murders. What’s more, the Aztecs could engage in such ritualized warfare because they were not challenged at their borders by any existential threat. Thus, Aztec weapons, strategy, and tactics were hardly suited for battle against the invading Europeans, whose sole purpose was to win a decisive crushing victory.

Nonetheless, while the Spanish had the advantages of horses, and superior weapons and tactics, could these factors alone have prevented the Aztecs from simply overwhelming them by weight of their sheer numbers alone. Indeed, the Aztecs nearly did just that in their first encounter with the conquistadores, in the Aztec capital, Tenochtitlan; at the time bigger and richer than any city in Spain. The conflict began when Cortes, famously and suddenly took the Aztec emperor, Montezuma, prisoner in his own palace. Despite the fact that the Aztecs were stunned by Cortes’ audacity, his assault on the now leaderless Aztecs nearly ended in disaster for him. Cortes lost two-thirds of his force, and was barely able to escape from Tenochtitlan, and then retreat back to the coast.

Cortes’ stroke of good fortune came after his failed attempt to capture Tenochtitlan. It was the chance introduction of variola (the smallpox virus), which spread rapidly through the densely populated Aztec empire, killing a third or more of its population in a mere few months. The smallpox victims included Cuitlahuac, the Aztec emperor who succeeded Montezuma. After that, in 1521, Cortes attempted to subdue Tenochtitlan a second time. In this instance, Cortes’ was reinforced with a large number of Indian auxiliaries (perhaps as many as 200,000). But, the defending Aztecs were no longer naïve regarding Spanish weapons and intentions, and they fought back tenaciously. Nevertheless, smallpox had been taking its inevitable toll, by then having killed nearly half of the Aztecs, and Cortes was able to capture the city.

Exactly how smallpox came to Mexico is not entirely clear. Some sources state that an infected slave, who arrived in Mexico in 1520 from Spanish Cuba, transmitted the infection to the Aztecs. Other accounts suggest that smallpox was carried by Cuban Indians, who the Spaniards brought along as auxiliaries. Regardless, since the Aztecs had no prior exposure to variola, most of them and their leaders were killed by the Old World germ, leaving the survivors bewildered and demoralized. It is estimated that 3.5 million Aztecs succumbed to smallpox in a mere two years, vastly exceeding the number that possibly could have been killed by Spanish guns and swords!

Shortly after Cortes’ conquest of the Aztecs in Mexico, Francisco Pizarro, in 1532, with a mere 168 Spanish soldiers, and only 12 guns, which were the slow-to- load, inaccurate harquebuses of the day, conquered the Inca Empire of millions. The first encounter between Pizarro and the Incas was at Cajamarca, a town in what is now the Peruvian highlands. At Cajamarca, Pizarro’s force of 168 men faced, and soundly routed an Inca army of 80,000, without losing a single man! As in the case of Cortes at Tenochtitlan, Pizarro, at Cajamarca, enjoyed the advantage of his horses (27 in this instance) and superior weaponry. What’s more, following the example set by Cortes’ capture of Montezuma, Pizarro captured the Inca emperor, Atahualpa, moments after he unleashed his surprise attack on the shocked Inca warriors.

To wholly grasp the audacity of Pizarro’s achievement at Cajamarca, reconsider that Atahualpa was surrounded by his army of 80,000 soldiers, in the middle of his own empire of millions, while Pizarro’s force was comprised of a mere 168 men. What’s more, Pizarro was isolated from any other Spaniards, the nearest of whom were 1,000 miles to the north, in Panama.

Jared Diamond, in his marvelous book, Guns, Germs, and Steel, provides gripping first-hand Spanish accounts of the confrontation at Cajamarca. One of the conquistadores relates that many of the Spanish soldiers, when first seeing the enormous numerical advantage of the Incas, were terrified to the point of incontinence. He continues: “All of us were full of fear, because we were so few in number and we had penetrated into a land where we could not hope to receive reinforcements…The Governor’s brother Hernando Pizarro estimated the number of Indian soldiers there at 40,000, but he was telling us a lie just to encourage us, for there were more than 80,000 Indians…At noon Atahualpa began to draw up his men and approach. Soon we saw the entire plain full of Indians, halting periodically to wait for more Indians who kept filing out of the camp behind them. They kept filing out in separate detachments into the afternoon. The front detachments were now close to our camp, and still more troops kept issuing from the camp of Indians. In front of Atahualpa went 2,000 Indians who swept the road ahead of him, and these were followed by the warriors, half of whom were marching in the fields on one side of him and half on the other side.”

Another eyewitness describes Pizarro’s actual attack on the Inca force: “We had placed rattles on the horses to terrify the Indians. The booming of the guns, the blowing of the trumpets, and the rattles on the horses threw the Indians into panicked confusion…The Governor (Pizarro) himself took his sword and dagger, entered the thick of the Indians with the Spaniards who were with him, and with great bravery reached Atahualpa’s litter. He fearlessly grabbed Atahualpa’s left arm…The Indians carrying the litter, and those escorting Atahualpa never abandoned him: all died around him…Atahualpa himself admitted that we had killed 7,000 of his men in that battle…It was extraordinary to see so powerful a ruler captured in so short a time, when he had come with such a mighty army.”

Our eyewitness continues: “The panic-stricken Indians remaining in the square, terrified at the firing of the guns and at the horses-something they had never seen-tried to flee from the square by knocking down a stretch of wall and running out onto the plain outside. Our cavalry jumped the broken wall and charged into the plain… It was an astonishing sight, for the whole valley for 15 or 20 miles was completely filled with Indians. Night had fallen, and our cavalry were continuing to spear Indians in the field, when we heard a trumpet calling for us to reassemble at camp.”

From the above eyewitness accounts, and others as well, we know that horses indeed played an important role in the Spanish conquests of the Aztecs and Incas. Apropos that, David Diamond notes that the only instances where Native Americans were able to stave off being subdued by European invaders and settlers for any length of time were when they were able to acquire horses of their own and guns as well, and master their use (e.g., the Sioux warriors who annihilated Custer’s forces at the Little Big Horn in 1876).  The Aztecs and Incas, like all other foot soldiers, were never able to defeat cavalry in the open.

Actually, we’ve said only little regarding guns in the conquest of the Aztecs and Incas. That is so because the guns of that day were difficult to load and fire, and were inaccurate as well, as noted above. Thus, aside from their ability to induce panic, guns played only a minor role in those conflicts. Instead, Spanish steel swords, lances, body armor, and helmets, were more important than their guns, when pitted against the Indian’s blunt wooden clubs and thin quilted armor. [The Sioux warriors at the Little Big Horn had accurate, easy to load, repeating rifles that, in point of fact, were superior to the single-shot rifles carried by Custer’s cavalry.]

We’ve said nothing thus far regarding smallpox in the downfall of the Incas. To redress that point, note that while some of the details of the encounter between Atahualpa and Pizarro at Cajamarca, as recounted above, may be familiar to many readers, less well known is the reason Atahualpa was at Cajamarca, rather than at Cuzco, the capital of the Inca Empire. The reason is a follows. In 1526, a smallpox epidemic, which was brought to the New World by Spanish settlers in Panama and Columbia, spread overland to the Inca Empire, killing the then emperor Huayna Capac and his son and heir, Ninan Cuyuchi. Many other Incas were killed as well. But, for the moment, the gap in Inca leadership, caused by the deaths of Huayna Capac and Ninan Cuyuchi, gave rise to a contest for power between Huayna Capac’s two other sons, Atahualpa and Huascar. Atahualpa, and his army, was at Cajamarca because he had just won a decisive battle against Huascar’s forces.

From the time of the battle at Cajamarca, when Pizarro captured Atahualpa, at until eight months later when the Spaniards executed him, the Incas would not take any offensive action against the Spaniards; for fear that doing so might place their revered sun-god emperor in jeopardy. Pizarro used this respite to arrange for reinforcements from Panama. Then, when hostilities resumed after Atahualpa’s execution, the Spaniards were in a much stronger position militarily against the Incas, who were by then decimated by smallpox, as well as by their civil war. What’s more, because Inca society was very much connected to its emperor, Atahualpa’s death further hastened its disintegration and, thus, the ultimate defeat of the empire by the conquistadores.

Before moving on, note that smallpox was a non- premeditated, chance factor in the conquests of the Aztec and Inca Empires by the Spanish conquistadores. In contrast, smallpox was used deliberately against Native Americans by the British military in colonial North America, in what was the first known example of biological warfare in the New World. But, before we begin that story per se, note that biological warfare was not a new concept. Indeed, there is evidence that it was practiced as early as the 6th Century B.C., when the Assyrians were said to have poisoned enemy wells with a fungus that was supposed to make the enemy delusional. Irrespective of whether this particular tactic might actually have worked, the concept was nevertheless in existence. Later, in medieval Europe, bubonic plague victims and their excrement were catapulted over castle walls. The last known use of plague corpses being used as a bio-weapon occurred in 1710, when Russian forces flung plague-infected corpses over the city walls of Reval, the capital city of Estonia. Incidentally, despite the devastation wreaked by natural smallpox infections over the course of several millennia, the earliest example that I found of smallpox actually being used as a bio-weapon is that which follows.

Our current tale features Lord Jeffrey Amherst, for whom my home-town in Massachusetts is named. Amherst was the commanding general of British forces in North America during the final battles of the so-called French and Indian war (1754-1763). The French and Indian War was the American theater of a much larger conflict playing out in Europe, known as the Seven Years War. In the New World, the British and French vied for domination over North America. The British were victorious, but at great cost to them. Their heavy taxes on the colonies, to recover the costs of the war, ultimately led to the American war of independence only 13 years later.

Amherst led military victories over the French forces that were critical to the British winning control over all of North America. Nevertheless, Amherst’s reputation is tarnished by the belief that he deliberately gave smallpox-infected blankets to North American Indians, thereby starting a deadly epidemic among them.

These events happened just after the French and Indian war, when relations between the British and Native Americans in the Ohio and Great Lakes region began to deteriorate, leading to the 1763 Indian uprising known as Pontiac’s Rebellion. The conflict is named for the Ottawa chief, Pontiac, who led a coalition of tribes in an attempt to drive British forces from the region. The Ohio and Great Lakes region was previously occupied by the French, who had been courting the Native Americans’ favor. However, when British forces took control, they treated the Native Americans as a conquered people.

Amherst believed that the Native Americans should have to unconditionally accept British rule. But, as Pontiac’s forces seized the military initiative in the Ohio and Great Lakes region, Pennsylvanian colonists sought refuge at Fort Pitt (located at what is now Pittsburgh). Next, after warriors of the Delaware tribe laid siege to the fort, Amherst wrote the following to the British colonel who was about to lead an expedition to relieve it: “Could it not be contrived to send the small pox among the disaffected tribes of Indians? We must on this occasion use every stratagem in our power to reduce them.” The colonel wrote back to Amherst in agreement, suggesting blankets as the vector by which to transmit the contagion. Amherst replied: “You will do well to inoculate the Indians by means of blankets, as well as every other method that can serve to extirpate this execrable race.”

While Amherst is generally regarded as the villain of this episode, there is evidence that the British commander at Fort Pitt (the Swiss-born captain, Simeon Ecuyer) had already, and independently of Amherst, attempted this very tactic, by giving representatives of the besieging Indians blankets and a handkerchief that were deliberately exposed to smallpox at the fort’s hospital. This is not meant to exonerate Amherst, whose intentions and hatred of Native Americans are clear from his own correspondences. Nevertheless, in fairness to Amherst, we need to view his attitudes and actions in the context of his own times.  While eighteenth century European rules of warfare indeed had strictures against the use of “poison” weapons and the “poisoning” of streams, springs, and wells, they nevertheless allowed for excessive brutality when putting down rebellions or against populations or groups regarded as heathens or savages. That was the code of warfare of the day, to which Amherst adhered. Apropos that, Amherst never showed any obsessive desire to “extirpate” his other enemy, the French. Yet irrespective of who may have initiated the attempt to spread smallpox among the Native Americans besieging Fort Pitt, this was the first documented example of deliberate germ warfare in North America.

We might ask whether this tactic on the part of the British at Fort Pitt actually worked. But, historians writing on this issue have not come to a consensus for several reasons; most importantly because smallpox was already present among the Native Americans in the region, before the start of their rebellion. At any rate, in the spring and summer of 1763, the Indians around Fort Pitt were stricken with smallpox.

Some final points on bio-weapons:

First, whereas bio-weapons have been used throughout the past three millennia, many contemporary military experts believe that infectious agents would be of little use on a modern battlefield. One reason is that unlike nuclear, chemical, and conventional weapons, they would not immediately stop an advancing army. Another reason is that once released, the spread of a bio-agent would be virtually impossible to control. Finally, use of bio-weapons would invite retaliation in kind. Thus, in the contemporary world, bio-weapons are feared mainly for their potential use by terrorist groups. In this regard, when used as a terror agent, an infectious bio-weapon does not need to cause an epidemic to cause widespread panic and disruption. This was shown by the 2001 episode in the United States, in which B. Anthracis was sent through the postal system.

Second, of the many pathogenic microorganisms that might be used by terrorists, most biological warfare experts believe that smallpox and Bacillus anthracis pose the major threats. Bacillus anthracis offers the advantage of being highly stable in the environment. The advantages of smallpox are that it can spread very rapidly from person-to-person, it is difficult to diagnose until the variola infection is well underway in an individual, it is highly virulent (killing about 30% of infected humans), and there is no effective treatment.

Third, until recently, any incentive to use smallpox as a bio-weapon was greatly diminished by the success of worldwide vaccination. However, this state of affairs began to change in 1980, three years after smallpox was declared to be eradicated. At that time,the World Health Assembly recommended an end to routine vaccination, and most countries complied. Thus, most individuals living today have never been vaccinated against smallpox, and it is not known for certain whether those who received vaccinations 25 or more years ago are still protected.

Fourth, and finally; because of the success of the 20th century’s smallpox eradication program, all reference stocks of variola virus in laboratories worldwide were destroyed, with the exceptions of those at the U.S. Centers for Disease Control and Prevention (CDC), and at Russia’ State Research Center of Virology and Biotechnology (VECTOR). What’s more, the former Soviet Union weaponized variola virus, in contradiction of the 1972 Biological and Toxin Weapons Convention. Because of concern that any of this remaining virus might somehow fall into the hands of terrorists, or inadvertently escape from these laboratories, and since rogue nations or terrorist groups may also be able to develop it as a bio-weapon, many have argued that these last remaining variola stocks should be destroyed. Yet a case can also be made for maintaining them (e.g., for continuing research on the virus). Perhaps this issue might be the topic of a future posting.



Guns, Germs, and Steel, by Jared Diamond, (W. W. Norton & Company, 1999)

1493, by Charles C. Mann, (Alfred A. Knopf, 2011)

 A History of Warfare, by John Keegan, (Alfred A. Knopf, 1993).

                The first two of these books were my principal sources for matters concerning the conquests of the Aztecs and Incas. Diamond’s book offers fascinating insights into human history in general and, apropos this posting, eyewitness accounts of the battle at Cajamarca. Mann’s book tells of human life in the Americas before the arrival of Columbus. It contains a detailed, spine-tingling description of Cortes’ capture of Tenochtitlan. Each of these books is very strongly recommended. Keegan’s book, which is a general history of warfare, gives an intriguing depiction of warfare in Aztec culture.

 Fenn, E.A., (2000) Biological Warfare in Eighteenth Century North America: Beyond Jeffrey Amherst, American Journal of History 86:1552-1581.

 This paper contains a detailed account of the events at Fort Pitt in 1763. It also notes other possible, but not as well documented examples of biological warfare in colonial North America.

Cotton Mather, Onesimus, George Washington, and Variolation, on the blog.

See this posting for more on smallpox in colonial North America.







Cotton Mather, Onesimus, George Washington, and Variolation

Here are a couple of vignettes that may be particularly interesting to American history buffs. They concern the introduction of variolation to New England during the Colonial Period in North America. A major smallpox outbreak occurred in Boston in 1620, and again in 1702 and 1721. These happened before the advent of Jenner’s smallpox vaccine, in the late 1790’s. Note that Native Americans suffered especially severely from smallpox.

The colonialists initially dealt with smallpox by quarantining individuals who might transmit the disease. However, bear in mind that variolation had been used successfully in China and India since the 11th century to block the spread of smallpox. Variolation is the practice whereby uninfected individuals are inoculated with material from the dried out scabs of individuals who survived a smallpox infection. [Variolation worked because the dried-out scabs on the skin of a smallpox survivor contained virus that had been partially inactivated by that individual’s immune response, as well as by the drying itself. And, the inactivated virus might yet induce immunity in the inoculated recipient.] The practice was inspired by the yet earlier recognition by the Chinese, well before the advent of the germ theory of disease in the West, that individuals experience some illnesses only once in a lifetime. [Remarkably, Thucydides came to the same realization 24 centuries ago in Greece. The reason Thucydides’ observation had no lasting effect on Western medicine is the subject of another tale.]

A transmission electron micrograph of smallpox viruses.  Source: CDC/ Fred Murphy
A transmission electron micrograph of smallpox viruses. Source: CDC/ Fred Murphy

By 1700, variolation had spread from China to India, the Ottoman Empire, and Africa. Lady Mary Wortly Montague, the wife of the British ambassador to Turkey, learned of the practice while in Constantinople, and brought it home to England in 1721. Before that, while still in Turkey, she had her 5-year-old son, Edward, undergo the procedure. Subsequently, in 1721, in England, she also had her 4-year old daughter variolated. Physicians of the royal court were present on that occasion to witness the procedure. English doctors then insisted that the relatively simple process of variolation be preceded by severe bloodletting to “purify” the blood, thereby excluding non-physicians from carrying out, and profiting from the practice.

The story of Lady Montague’s role in introducing variolation to England is rather well known. In contrast, the story of the introduction of variolation into North America is less well known, even though it has several intriguing aspects. So, the earliest known use of variolation in North America occurred during the 1721 smallpox outbreak in Boston. Its use resulted from the efforts of the prominent Puritan minister Cotton Mather, who persuaded a Dr. Zabdiel Boylston to try variolation in order to control the outbreak.

Most interestingly, Mather learned of variolation from his African slave, Onesimus, who had been inoculated as child in Africa, and who was a “gift” to Mather in 1706, from his Boston congregation. Variolation was then being practiced in western Africa, perhaps brought there by caravans from Arabia. So, an enslaved African man played a key role in bringing variolation to North America.

Mather tried to convert Onesimus to Christianity, but, finding him increasingly rebellious, Mather gave Onesimus the opportunity to purchase his freedom in 1721. Onesimus did so by helping Mather purchase another African slave to take his place. However, once freed, Onesimus continued to do chores for Mather and his family. Little else is known of Onesimus’ life.

The most bizarre aspect of this story may be that Mather is best known for his role in promoting the Salem Witchcraft trials. In 1688, he argued that the peculiar behavior of four Boston sisters was the result of witchcraft practiced on them by a washerwoman named Mary Glover. What is more, he argued that the behavior of these sisters should be taken as evidence against the accused during the trials. Yet Mather was also a prolific writer and, incongruously, he wrote extensively on science, as well as religion. Moreover, he acknowledged that his scientific writing was strongly influenced by Robert Boyle’s The Usefulness of Experimental Natural Philosophy. Furthermore, in 1716, following up his observation of differences among various strains of corn, he carried out one of the first recorded experiments with plant hybridization. And, for his scientific accomplishments, in 1713 he was elected as an honorary member of London’s Royal Society. Thus, this man who supported and witnessed the execution of “witches,” was in at least some ways a man of the Enlightenment. And, while Mather had no reservations regarding the morality of slavery, he believed that blacks had souls; actually a liberal view that was contrary to the prevailing views of the day. But, while he was enthusiastically committed to converting black slaves to Christianity, he also strongly held that conversion of slaves to Christianity was not incompatible with their remaining in bondage.

At any rate, Mather urged Boston’s doctors to try variolation, finally succeeding with Boylston. Boylston first tried the procedure on his only son and two slaves; one a child and the other grown. [Interestingly, although history credits young James Phipps as the first subject of Edward Jenner’s smallpox vaccination experiments in the 1790’s, the first vaccine recipient was actually Jenner’s 10-month-old son Edward Jr. Jenner also inoculated several other young children, including his second son Robert, when he was 11-months-old. More on this in another tale.]

Considering the risks associated with variolation (2 to 3% of variolated individuals died from variolation-transmitted smallpox), this practice generated considerable controversy among physicians of the day, with some asserting that it helped to spread, rather than contain the epidemic. In the end, critics of variolation, after observing its overall positive results, came to accept its use. [During the 1721 Boston epidemic, some 6,000 of Boston’s slightly more than 10,000 residents contracted smallpox, and some 14% of the infected individuals succumbed to the disease. In contrast, less than 3% of the variolated individuals died.]

Oddly enough, Mather went against his own Puritan ethic in promoting variolation. The Puritans viewed all afflictions, including smallpox, as part and parcel of God’s plan. What’s more, the debate over variolation between medical professionals and the clergy caused the latter to lose influence over secular matters in eighteenth-century New England.

A related vignette concerns George Washington, whose experiences during the French and Indian War (1754-1763) made him aware of how seriously smallpox might impair the fighting effectiveness of his soldiers. Later, in 1777, during the American War for Independence, and after the loss two major battles against British soldiers, who all had been variolated, Washington required the entire Continental Army to undergo variolation. Moreover, all new recruits had to be variolated immediately upon joining. [These were the days before informed consent.] Also, a political cartoon of the day implies that before Washington ordered the entire Continental Army to be variolated, he first tested the safety of the procedure on his Hessian mercenaries. One in 500 variolated soldiers died as a result of the procedure, but the odds still strongly favored variolation over taking one’s chances with an actual smallpox infection. There is speculation that at least some of Canada (Quebec) would have ended up as part of the United States if Washington had variolated his troops earlier in the Revolutionary War.

And, when did Jenner’s cowpox-based smallpox vaccine first come to be used in the New World? It first came to the attention of New England, and the rest of America, in 1799, thanks to Benjamin Waterhouse, a European educated Boston physician. Waterhouse wrote letters to newspapers throughout New England chronicling the new smallpox control method. Waterhouse not only wrote letters, but also introduced the Jenner vaccine in Boston, using cowpox that Jenner shipped to him by request (on threads dipped in cowpox exudates, sandwiched between glass plates that were sealed in lead). The vaccine could then be transferred from one individual to another by means of a lancet; a practice acceptable at the time because of the much greater danger of smallpox and the limited scientific knowledge of the day. Incidentally, Waterhouse also co-founded Harvard Medical School.