Edward Jenner and the Dawn of Immunology

If medical historians were asked to name the individual who saved the largest number of human lives, it's quite likely that the majority would choose British physician Edward Jenner. Jenner was the doctor who famously inoculated a small boy with the cowpox virus and thereby made him immune to smallpox, one of the most significant events in the history of medicine and possibly of science in general. Smallpox, a highly contagious and deadly disease caused by the variola virus, was one of the greatest killers in human history, although fortunately it is now completely eradicated. Estimates as to its number of victims through human history range between 1 and 10 billion. Its main rival for the title of biggest killer, tuberculosis, or TB, is still around and therefore likely to eventually win the competition, but we will talk about TB a bit later when we discuss the birth of microbiology and another enormous scientific accomplishment, the invention of antibiotics. For the moment, let's focus on smallpox. In the 20th century alone, smallpox had 300 million victims. Yet, for young people, particularly those born in the 21st century, the name smallpox may not even be familiar. Your parents might have been vaccinated against it as children, but since the disease has been completely eradicated, children are no longer vaccinated against it, and the scourge has disappeared completely from public discussion, relegated now only to the history books. But the story of smallpox is a fascinating one and can be considered one of the greatest victories of man over nature. Let's start from the beginning. The smallpox virus belongs to the family Poxviridae, and it is a DNA virus, meaning that its genetic material is DNA rather than RNA, just 186,000 base pairs to be precise. The origin of the virus is disputed, but signs of the disease have been found on Egyptian mummies, and therefore the virus is clearly thousands of years old. At the very least, it is clearly recognized in history only after the work of the Persian physician Razis, who in the 9th century described the signs of the disease in minute detail, allowing doctors from then on to diagnose smallpox with a reasonable degree of certainty. The virus has been endemic for thousands of years, with sudden outbreaks which, due to increasing globalization, have rapidly spread to the whole world. The mortality rate of the virus was about 30%, although it was higher in infants, up to 90%. There are several grades of the disease, but for the sake of simplicity, we will just speak of the most common form, or the ordinary version. The virus was readily transmitted from human to human via aerosol droplets from coughing and sneezing, like most viruses. It had a long incubation period, after which high fever ensued. The virus had a predilection for skin cells, and one of its manifestations was the appearance of an early skin rash. The individual spots, called macules, rose over the skin to become papules, which slowly filled with pus and became pustules, or pox. The pus slowly leaked out of the pox, forming scabs all over the body, which left the survivors disfigured and sometimes blind. Death could occur by a variety of organ failures, most notably in the lungs. Among the most famous smallpox survivors, we can include George Washington, Abraham Lincoln, and Joseph Stalin. Among its victims, there was Sioux Chief Sitting Bull, and an enormous collection of European monarchs and princes that is too long to list. Smallpox was indeed widespread. It has been known to destroy entire armies and almost wipe out entire cities. As we mentioned, regarding infectious diseases, mankind was helpless against them for more than 99% of our existence. The situation was similar, at least at first, for smallpox. There are many deities or saints dedicated to smallpox. The Hindu goddess Shitala was believed to protect the faithful against the disease, whereas the Christians prayed to the patron saint of smallpox, Saint Nicaseus. Prayer efficacy was estimated at about 70%, which we now know was the natural survival rate. Fascinatingly, a rudimentary form of vaccination was developed, completely empirically, either in India or in China, probably around the 10th century, and was practiced regularly after the 16th century. The practice is called variolation. It involved the inoculation of healthy people with the pus drained from the pustules of smallpox patients. Another form consisted of desiccating the scabs of smallpox patients to a powder, and having healthy volunteers inhale this powder through their nose. Variolation is believed to have afforded substantial protection from the disease. Naturally, these procedures exposed the patient to active viral particles, and mortality was in the range of 0.5 to 3%, depending on the practitioner. The procedure migrated from China to the Middle East, and then reached Europe in the early 18th century, where it was slowly accepted and modified to be made increasingly safe. European explorers are even said to have conquered North America due to smallpox, which they brought with them from Europe, and for which civilizations indigenous to the Americas had no immunity. Some populations were reduced by as much as 90% upon first exposure to the virus. Aztec king Quitláhuac died of smallpox in 1520, as well as Inca king Huayna Capac in 1527, facilitating the collapse of their empires and the conquest of Central and South America by the Spanish. A similar strategy was used by the British in North America. The mortality rate among Native Americans was 80 to 90%, and the conquerors are even known to have distributed blankets infected with the smallpox virus to hasten the demise of the local tribes. In this way, the campaign against Native Americans was won with biological weapons. Quite remarkably, although there was no scientific knowledge about microorganisms, as the field of microbiology had not yet been born, mankind was able to utilize the immune system before the science of immunology was created. Edward Jenner was a physician from Berkeley, a town in Gloucestershire in the United Kingdom. In his dealings with smallpox, he noticed that milking girls at local farms often developed a benign form of the disease, called cowpox, which seemed to render them immune to smallpox. This was not a new observation, but Jenner believed there was a causal relationship. Of course, we now know that the cowpox virus belongs to the same family as smallpox, and as such, the two viruses offer cross-protection, although cowpox leads to only a very mild infection in humans. However, none of this was known at the time. What Jenner decided to try in 1796 was to inoculate a young boy with the pus from a milkmaid's lesions, and then, a few days later, challenge him with the live smallpox virus, only to find that he was now immune to it. Of course, this experiment would be unethical today, but Jenner's reputation soared after successfully demonstrating this strategy on 23 patients. Jenner called the treatment vaccination, from the Latin vacca, which means cow. Indeed, the scientific term for the cowpox virus is variolae vaccinae. The years that followed for Jenner were spent improving the vaccine and actively promoting its use. Slowly, more and more people were getting vaccinated. As the procedure was perfected, it became safer and safer, until in 1840 variolation was outlawed in favor of the Jenner protocol. Mortality, due to the new immunization procedure, dropped down to one to two cases out of a million. Napoleon, after vaccinating his entire army, called Jenner one of the greatest benefactors of mankind. Vaccination became so successful that the World Health Organization, in 1959, developed a plan to wipe out the disease from the face of the Earth. The plan involved mass vaccination all over the world, and smallpox cases declined steadily. Around 1970, vaccination was discontinued in the US and in much of Europe, when the risk of dying from catching the disease became lower than that associated with the vaccination. The last known outbreak occurred in Yugoslavia in 1972, when a Muslim clergyman returned from a pilgrimage in Iraq and fell ill, but recovered quickly. When a man he came into contact with became ill, he was treated with penicillin, and the ensuing rash and death were interpreted as a reaction to the antibiotic. It took quite a while to recognize the disease, and by that time, over 100 cases had arisen. The outbreak was quickly controlled by immunizing the entire population of 18 million, imposing curfews and martial law. A total of 175 cases were registered, with 35 deaths. And finally, the last verified smallpox case in history occurred in 1979. In 1980, the World Health Organization proudly announced that It was one of the greatest triumphs in the history of medicine. It had taken 20 years of systematic war to get rid of the disease. Of course, given the power of modern molecular biology, anything can be brought back from extinction. Given that we are attempting to recreate the woolly mammoth using modern cloning techniques, it goes without saying that it would not be too difficult to recreate the smallpox virus in a lab. But we can say that, as far as nature goes, we have won the battle. And if smallpox were ever to re-emerge in an act of bioterrorism, the United States maintains a strategic national stockpile of the vaccine, although the possibility of a worldwide outbreak appears extremely remote. Sadly, smallpox is the only major viral disease we have completely eliminated. Other programs have not been as successful as the smallpox program. For example, there has been an ongoing campaign to wipe out measles. Although we have a completely safe and effective vaccine, this has not come to pass, partially due to general resistance of the population to forced vaccination. To this day, about 70,000 people per year still die of measles, an easily preventable disease. Although medicine has solved this problem, political and social obstacles still remain on the way to total victory. Edward Jenner has been named one of the 100 most influential Britons of all time. His house in Berkeley is now a museum. The horns of the cow Blossom, from which the original cowpox virus came, are on display in the house. It is truly a shame that the person behind such a monumental triumph for mankind is not better known amongst the public, and is not even the most famous person with the last name Jenner by a long shot, a disheartening indicator of the priorities of modern society. Even more worrying is the growing public animosity towards vaccines, which is accompanied by a host of absurd conspiracy theories. Unfortunately, there is no time to dig into these phenomena with great depth, but if you are more interested in this topic, please visit my immunology playlist for a thorough treatment of the immune system and an in-depth analysis of vaccinations in all their forms. Otherwise, let's shift gears from pathogens and dive into the world of small molecules.