In the 18th century, smallpox was a terrifying reality. Caused by the variola virus, it began with fevers and fatigue, followed by spots and rashes all over the body. These rashes would erupt, releasing new virus particles. The virus would replicate throughout the body, attacking the immune system, lungs, eyes, bones, and heart. This could lead to blindness, arthritis, heart failure, sepsis, and pneumonia. The mortality rate was estimated to be around 30% for those with symptoms.

At the time, scientific understanding was limited. People didn't know about viruses or microbes, and couldn't study them in a lab. The prevailing theory for disease spread was miasma, the idea that "bad air" caused illness. The only real protection was staying away from others. However, there was folk knowledge that survivors of one smallpox epidemic were immune to subsequent ones. One early theory was that the first infection depleted the body of necessary nutrients, preventing a second infection.

This set the stage for early attempts at inoculation. Jacob mentions the story of Edward Jenner noticing that milkmaids exposed to cowpox seemed protected from smallpox. He also brings up Lady Mary Wortley Montague, a British aristocrat who traveled to the Ottoman Empire and witnessed variolation, the practice of intentionally giving children a small, controlled dose of the smallpox virus. She brought this practice back to England, inoculating her own children and publicizing the procedure.

However, variolation was not without significant risk. Saloni highlights the stark choice parents faced.

You intentionally infect your child, and there's a 1 in 50 chance that your child then immediately dies as a result of the procedure. And I mean, I think that's freakishly scary to us now. But if you think about the alternative, which is smallpox, which is going to kill, you know, one in three, then the risk is much lower, and it's very reasonable as a parent.

This grim calculation underscores the desperation of the era. As Jacob concludes, it's a powerful lesson in why one shouldn't want to travel back in time.

Lady Montague's public variolation of her daughter was a significant risk. If the two percent chance of death had occurred, it could have set back the acceptance of vaccines considerably. The procedures for variolation at the time were quite crude. One method involved taking pus from an infected person and inserting it into a healthy child's nostril with cotton or a thin silver tube. Another technique was to powder the pus and blow it into the nostril.

There were even variations in the pus itself, such as using it fresh or using what was called "cooked pox." The process was essentially putting the actual smallpox virus into a child. Doctors would try to select pus from a child who had a mild case, but they were just guessing. They couldn't know if the mild disease was due to a weaker virus or simply a healthier child. This lack of microscopy and culture techniques meant there was no way to distinguish between these factors, making the risk inconsistent across different children.

It is interesting that nasal delivery methods were used for inoculation back then, while modern medicine still finds it challenging to develop nasal vaccines for respiratory viruses. The system did have a rudimentary feedback loop. A doctor could harvest pus from one infected person, who had many pustules, and use it on many others. If a particular batch proved to be especially dangerous, the doctor could stop using it after observing negative outcomes, which in turn would affect their reputation.

Edward Jenner's development of the smallpox vaccine began with rumors that milkmaids were protected from the disease after contracting cowpox. While other doctors had previously tried inoculating people with cowpox, Jenner's crucial contribution was meticulously documenting and publicizing the method. This allowed others to replicate and scale the process, highlighting that simply having an idea is often not enough to drive scientific progress.

Jenner's famous experiment involved inoculating a gardener's son, seven-year-old James Phipps, with pus from a cowpox infection. To test its effectiveness, he then variolated the boy with smallpox. Variolation, an older method of inoculation with a milder form of smallpox, was considered the safer option at the time. This is similar to challenges in modern vaccine development, such as for tuberculosis, where researchers must create safe challenge models that don't expose participants to the deadly, full-strength bacterium.

Despite the experiment's success, the path to acceptance was not smooth. When Jenner submitted his findings to the Royal Society's academic journal in 1797, he was rejected for having insufficient evidence. Undeterred, he compiled his case reports and self-published a monograph. Jacob humorously notes the parallel to today: after being rejected, Jenner essentially "became a Substacker."

Even after he published his own version of the manuscript, people were still quite critical of it at the time. He still only had that one experiment. He sort of mixed up the drawings a little bit and people were like, this isn't enough evidence.

This story dismantles the myth of a single "Eureka" moment in science. Acceptance was a gradual process built over decades, requiring continuous experimentation and evidence. People were convinced not by one paper, but by seeing the inoculation work repeatedly. The scientific community's initial skepticism was a form of rigor; it was vital to ensure the method was truly effective before widespread adoption.

The early method of spreading the vaccine was starkly different from today. It relied on "arm-to-arm transfer," where pus was taken from one person's fresh inoculation site and scratched into another person's arm. This method was fragile, as the vaccine lineages would often die out. In China, poorer families were sometimes paid by merchants or officials to have their children vaccinated simply to keep the vaccine chain from going extinct.

This process of transferring the pus from arm to arm, as you might be able to imagine, could also risk spreading other microbes between people. You could have contamination. You could accidentally give someone syphilis or hepatitis B. And that happened often.

This early technique carried significant risks, starkly contrasting with today's sterile, lab-based vaccine production in large bioreactors.

The early smallpox vaccine, while a significant improvement over both the disease itself and the practice of variolation, was still quite risky. Because the process involved breaking the skin, it created a direct path for other infections to enter the bloodstream. These risks meant that while the vaccine was a step in the right direction, many improvements were still needed before it could be considered a safe solution for vaccinating entire populations.

When considering methods to combat smallpox, the varying levels of risk are significant. Contracting smallpox carried a 30% mortality rate. An early method, variolation, reduced this risk considerably, but still had about a 2% mortality rate, which is not ideal. The subsequent method, vaccination using cowpox, was considered much safer. While specific numbers on its safety are not available, confidence in its lower risk comes from the nature of cowpox itself, which is not fatal to humans. The primary dangers associated with this early form of vaccination were not from the cowpox virus but from potential contamination during the procedure, such as with syphilis.

The next step in scaling vaccination after arm-to-arm transfer involved using cows. Initially, Saloni shared a personal anecdote about chickenpox. She never went to a "chickenpox party" for intentional exposure. Instead, she got actual chickenpox as a seven-year-old in India because her parents hadn't gotten her the available vaccine. She vividly remembers being sick for a week and feeling angry when she learned her cousin's friend was protected by a vaccine she didn't know existed.

Returning to smallpox, the solution for mass production was to grow cowpox directly on cows. Doctors in Italy developed this procedure in the 1840s, which involved cultivating the vaccine on the skin of calves. This method was much safer than arm-to-arm transfers because it avoided contamination with other human pathogens like syphilis and hepatitis B. However, it took several decades for the technique to be widely adopted because the exact method wasn't well understood.

This new process led to the creation of businesses called "vaccine farms," which harvested the vaccine lymph or pus from inoculated calves. The emergence of these farms prompted the first medical regulations for biological materials in the US. These regulations were primarily focused on ensuring the general hygiene of the farms to prevent the vaccine from being contaminated, a significant challenge given that this was before the introduction of antiseptic techniques.

Medical progress is not always a straight line. In the 1970s, Egypt experienced a high rate of Hepatitis C due to a public health campaign. The campaign aimed to eradicate schistosomiasis, an infectious disease spread by snails in the Nile. Treatment required over ten injections, but the needles used were not properly sterilized. This led to the widespread transmission of Hepatitis C, a virus that was not even identified until 1989. Fortunately, effective cures were eventually developed, and Egypt's prevalence rate has since dropped from around 10% to below 1%.

This story highlights the "weird mistakes of the past" that seem obvious in retrospect. The development of the smallpox vaccine followed a similar path of slow, empirical progress after its initial discovery. Several innovations were needed to scale it up. Glycerin was added to prevent the vaccine from spoiling. Later, freeze-drying techniques allowed it to be transported over long distances without losing effectiveness. A major breakthrough in the 1960s was the bifurcated needle, a two-pronged needle that held a tiny drop of vaccine between its prongs. This invention meant only a quarter of the usual dose was needed, making global vaccination campaigns feasible.

Throughout this entire period, until the 1940s, no one had actually seen the smallpox virus. Scientists knew that something in the cowpox material protected people, but they did not know what it was or why it worked. This lack of fundamental understanding made it difficult to replicate the success for other diseases. Smallpox was a rare case where a milder, related virus happened to provide cross-protection, a lucky break that was not easy to find for other illnesses.

Finding another case of cross-protection similar to cowpox and smallpox is difficult, even today. For a vaccine to be developed this way, a milder disease must protect against a more severe one. While mild flus might offer some protection against lethal ones, their seasonal nature makes this hard to track. Other potential pairings exist, like meningitis B and gonorrhea, which share an outer membrane vesicle. Someone could theoretically infect themselves with the non-deadly gonorrhea to gain some protection against meningitis. However, establishing this link would be challenging.

The success with cowpox and smallpox was partly due to circumstance. Smallpox was so common and visible that it motivated people to find a solution. The distinct pustules of both cowpox and smallpox made them easy to identify and study. In contrast, diseases like gonorrhea might go unreported due to social stigma, making it hard to replicate any findings.

Another potential example is tuberculosis (TB). The first vaccine for TB, BCG, is derived from the cow version of the disease. However, at the time, scientists didn't know that the human and cow versions were different strains. They would have thought they were simply infecting someone with TB, not providing a safer, cross-protective alternative.

A key reason smallpox was successfully eradicated is that it doesn't have any animal reservoirs; it only infects humans. This makes it a prime target for eradication efforts. The first step in eradicating a disease is often identifying which ones do not have an animal host. So far, two diseases have been eradicated: smallpox in humans and rinderpest in cows. Rinderpest had a very high mortality rate and was spread easily between farms by inspectors carrying it on their shoes.

We are also close to eradicating guinea worm disease. This illness is caused by a parasitic worm from stagnant water, which grows inside the body and eventually erupts from the skin. Cases have dropped from over a million in the 1970s to just a dozen in recent years. Elimination was relatively straightforward, involving cleaning water sources or using larvicides. In one instance in Pakistan, the disease was unintentionally eliminated from a region simply because a drought killed all the eggs.

The smallpox vaccine was improved and scaled, which allowed it to be stored longer and administered in smaller doses. This made it possible to vaccinate a large number of people. The disease was finally eradicated in 1980 using a strategy called ring vaccination.

With ring vaccination, if any cases of smallpox appeared, health officials would vaccinate all of the person's contacts and everyone in the surrounding area. This method effectively controlled outbreaks before they could spread. A key figure in this effort was Bill Foege at the CDC. Another important scientist, Victor Zdanov, persuaded a skeptical World Health Organization to start the eradication campaign in the first place. Zdanov is the mascot of Works in Progress magazine.

After the development of the smallpox vaccine, no new vaccines were created for 90 years. This long gap was due to several major challenges. The principle of cross-protection, which worked for smallpox, is not common. Even when it exists, finding a mild, easily visible version of a disease is difficult. More fundamentally, there was no understanding of germ theory, microbes, or the mechanics of immunity. Without this knowledge, there was no systematic way to produce new vaccines.

The next logical step was to figure out germ theory. This would establish that microbes spread diseases, allowing them to be studied in controlled lab conditions. Once understood, a dangerous pathogen could potentially be modified to turn it into a vaccine. The process of discovering germ theory itself was challenging. One approach involved epidemiology, like Jon Snow's work tracing cholera. Another potential path was through microscopy, which could make bacteria visible. However, since the next major human vaccine was for rabies, which is caused by a virus too small to see with early microscopes, it suggests that major progress could be made even before microbes could be directly observed.

To understand modern microbiology, it helps to go back to the theory it replaced: spontaneous generation. This was the idea that life, such as maggots on rotting meat, simply appeared out of thin air or from bad environments. One of the first attempts to disprove this theory came in 1668 from an Italian doctor, biologist, and poet named Francesco Redi.

Redi conducted a controlled experiment using flasks containing various dead creatures, which Jacob noted sounded like witchcraft. Two sets of flasks were prepared, one open to the air and the other sealed.

In each of the four flasks, one of them had a snake, one of them had a river fish, one of them had four little eels... And the fourth one had a cut of meat from a young calf that had been feeding on its mother's milk.

Redi observed that maggots only appeared in the open jars. He also saw flies leaving droppings on the sealed flasks, indicating they were trying to get to the meat. Finally, he watched the maggots and saw them eventually turn into flies. He concluded with the adage, "omne vivum ex vivum," meaning all life comes from life. While it might seem obvious that watching maggots turn into flies would be enough proof, the experiment was crucial to solve the "chicken and the egg" problem of where the very first maggots came from.

Despite this, the theory of spontaneous generation persisted. It took another 200 years for Louis Pasteur to finally disprove it with a different experiment. He used glass flasks with long, curvy swan-necks containing broth. The curved neck trapped dust and microbes, preventing them from contaminating the broth, which remained sterile indefinitely unless the neck was broken. While effective, Jacob found this experiment less exciting than Redi's menagerie of eels and snakes.

Louis Pasteur conducted elegant experiments to disprove spontaneous generation. Using a swan-neck flask, he showed that while air could get into a broth, dust and microbes could not. This demonstrated that life didn't just appear from nowhere. Pasteur then applied his understanding of microbes to industry, particularly the French wine and silkworm industries, to prevent contamination and spoilage.

He developed a process now known as pasteurization, which saved the French wine industry. It involves briefly heating wine to 50-60 degrees Celsius. This kills harmful microbes without ruining the product. Saloni jokes, "I thank him. I've actually drunk French wine myself, so thank you, Pasteur."

At the time, the distinction between bacteria and viruses was not understood. Viruses are not alive and require living cells to replicate, which is why they couldn't be cultured in a lab. It wasn't until the 1930s that microscopy and crystallography confirmed what viruses actually were. Before that, scientists knew something infectious could pass through bacterial filters, leading to a popular theory that viruses were some kind of fluid.

After his success with wine, Pasteur turned his attention to animal diseases like chicken cholera. However, the key breakthrough for the chicken cholera vaccine was made by his assistant, Emile Roux. While Pasteur was away, Roux conducted experiments and found that some cultures left out for a while went sour. When he injected chickens with these weakened cultures, they survived chicken cholera, while others died. Pasteur and Roux later worked together to figure out how to reliably replicate this, discovering that prolonged oxygen exposure and acidity weakened the bacteria, thus creating an effective vaccine.

Louis Pasteur, a chemist, worked alongside a younger doctor named Emile Roux. Roux was crucial for the practical side of the research, conducting many of the key experiments involving animals and humans due to his medical expertise.

Their work on the chicken cholera vaccine introduced a method called attenuation. This process involved weakening the pathogen by exposing the broth containing it to oxygen and acidity for an extended period. These environmental conditions caused the microbe to evolve into a different, weaker strain that could no longer cause severe disease but would still prompt an immune response, effectively acting as a vaccine.

Pasteur theorized this was a general principle for vaccine development. He then applied the same method to create a vaccine for anthrax, a deadly disease affecting farm animals. In a move that seems unusual today, Pasteur conducted a live, public demonstration to prove his anthrax vaccine worked, gathering a crowd to witness the experiment's results.

In 1881, Louis Pasteur conducted a famous public experiment to demonstrate his anthrax vaccine. He gathered 58 sheep and 10 bovines. Half of the animals received his attenuated vaccine. Weeks later, all the animals were injected with a highly virulent, live culture of anthrax. The experiment was a resounding success. All the vaccinated animals remained healthy, while nearly all the unvaccinated animals died. Pasteur invited people from all over the country to witness the results, proving the efficacy of his vaccine.

This dramatic success, however, concealed a significant secret. Pasteur's lab notebooks, which were kept private until after his death, revealed a different story. The vaccine used in the demonstration was not prepared through attenuation, the method he publicly championed. Instead, his assistants, Emil Roux and Charles Chamberlain, had used a different method, chemically inactivating the bacterium with potassium bichromate.

Why would he hide this? The deception was driven by scientific rivalry. Another scientist, Henri Toussaint, had already published similar results using a chemical method. Pasteur wanted to prove that his principle of attenuation was the superior way to develop vaccines, so he hid the true nature of his preparation. His own institute was the primary producer of the vaccine in France, so others couldn't easily discover that his claimed method didn't work. Saloni commented on the situation:

That is so sketchy. Also, what did he think was gonna happen to his reputation after he died? If all these secrets are coming out and then fast forward to 2025. Two people are roasting him on a podcast.

Today, such a secret would be much harder to keep. Patents require public disclosure of methods. Even without a patent, regulatory bodies like the FDA would know the composition. Furthermore, competitors could simply buy the product and analyze its contents. The story raises questions about the value of live scientific demonstrations. The high stakes and fear of public humiliation might incentivize cheating, which undermines the core purpose of an experiment. A good experiment must have a real chance of failure; otherwise, nothing is truly learned.

Louis Pasteur turned his attention to rabies, a terrifying disease that was almost always fatal once neurological symptoms appeared. Since rabies is caused by a virus too small to be seen under a microscope at the time, Pasteur couldn't identify the specific microorganism. However, he knew that brain tissue from a rabid animal was infectious.

His approach was highly empirical, involving hundreds of detailed experiments. The process to develop a vaccine was lengthy and gruesome. It started by extracting brain tissue from a rabid dog and injecting it into the brains of rabbits, which required drilling a small hole into their skulls. This was repeated from rabbit to rabbit in a series that eventually reached 90 rabbits. The brain tissue from the final rabbit was then placed in a flask and allowed to dry to weaken, or attenuate, the pathogen. This method was risky; in some animals, it could accidentally make the pathogen more severe rather than weaker.

The weakened material was then injected into dogs, gradually exposing them to more virulent strains to build up their immunity. After this proved successful, Pasteur moved on to treating humans who had been bitten by rabid animals. This was a scary step, as the procedure hadn't been tested on humans. It involved administering a series of injections with increasing potency after the person was already infected.

This Frankenstein-like process helps explain why 19th-century society might have been wary of scientists. You can sort of get why people had a view of scientists that was kind of like, what the hell are they up to? I just want to drill a hole in this rabbit's brain so I can inject its brain into a dog.

In 1885, Pasteur and Emile Roux successfully treated two young boys bitten by rabid dogs, proving the procedure worked. This was a massive breakthrough. However, it didn't contribute significantly to germ theory at the time because Pasteur couldn't isolate the virus. His focus remained on the experimental results. As Jacob noted, it's amazing that Pasteur had the persistence to continue such a complex process without a full theoretical understanding of the underlying mechanism.

This era's medical procedures were often brutal. Saloni compared it to early surgery, which was a low-status profession before the development of antisepsis and anesthetics. Surgeons were essentially just people ready to chop off a leg, performing amputations in under a minute due to the intense pain without anesthetics.

Robert Koch advanced germ theory by developing his postulates, a method for establishing causation between a microbe and a disease. Interestingly, it was not Koch but his student, Friedrich Schloffler, who compiled them into the four distinct rules that became famous.

The four postulates are: 1) The microbe must be found in every case of the disease. 2) It must be isolated and grown in pure culture. 3) It must cause the same disease when introduced into a healthy host. 4) It must then be recovered from that new host.

These rules brought a new level of scientific rigor to the field. They provided a systematic way to test if a microbe was causing a disease. As a result, many of the microorganisms identified in the late 1800s for diseases like tuberculosis, cholera, and tetanus are still recognized as the correct causes today. However, the postulates had significant problems. Their strictness made them difficult to apply universally. For example, they effectively ruled out viruses, which couldn't be seen at the time. Some diseases, like meningitis, have multiple microbial causes. Furthermore, isolating certain microbes in a pure culture can be incredibly difficult. The bacteria that causes syphilis, for instance, could not be cultured in vitro until around 2017; researchers previously had to culture it in rabbits.

Koch himself struggled to satisfy his own postulates. When investigating cholera, he quickly isolated the bacterium but failed to reproduce the disease in animals. He even took 50 mice from Berlin to Egypt for his experiments, but none got sick. He eventually had to concede this point in a report.

No one ever observes animals with cholera. Therefore, I believe that all the animals available for experimentation and those that often come into contact with people are totally immune. True cholera processes cannot be artificially created in them. Therefore, we must dispense with this part of the proof.

This failure to meet his own standards gave ammunition to his rivals, like Max Joseph Pettenkofer. Pettenkofer argued that cholera was spread by miasma, or dirty soil and air, not by germs. He pointed to the fact that cholera was more common in places with poor sanitation as evidence. This highlights how early pioneers in the field were simultaneously working across what are now distinct disciplines like microbiology, epidemiology, and vaccine development.

To prove cholera was caused by a microbe, an epidemiological analysis was conducted. The study focused on two adjacent cities, Altona and Hamburg. Surprisingly, the Hamburg side constantly faced cholera outbreaks, while the Altona side was free of the disease. A comparison of the areas showed that the soil and sewers were the same on both sides of the boundary. The only difference was their water supply.

Upon studying the water, the same bacterium causing cholera was found in the Hamburg supply but not in the Altona supply. This discovery effectively resolved the debate.

This debate also had a political dimension, pitting germ theorists against sanitationists. In Germany at the time, sanitationists wanted to improve living standards and reduce poverty. Germ theorists argued that tackling poverty was unnecessary; diseases could be eliminated simply by vaccinating against them.

Of course, these two ideas are not mutually exclusive. Improving sanitation and hygiene reduces the chance of microbial growth and infection. Sanitationists had many victories in the 19th century, as their reforms to water supply and waste management reduced many infectious diseases. However, their approach had limits. If sanitationists had remained dominant, we might not have developed the smallpox vaccine, as some diseases are very difficult to eradicate using only sanitation and hygiene.

This history illustrates the evolution of disease prevention. Early methods included Jenner's cowpox vaccine. Later came attenuation, where a microbe is weakened by growing it in a different environment. Another method is inactivation, where the pathogen is killed with chemicals or oxygen. However, a major breakthrough came with better methods for culturing bacteria in a lab.

Until the late 19th century, there were no great ways to grow bacteria in a lab. Early methods were quite basic, including using slices of boiled potato or various broths. Robert Koch, for example, worked with anthrax bacteria on boiled potato slices. These techniques were not very effective, didn't work for many types of bacteria, and were difficult to standardize.

An ingenious idea was to solidify the existing liquid broths to create a solid substrate for bacterial growth. Koch first tried this using gelatin, but it had a significant flaw: it melted during the summer months, ruining experiments. The solution came from Fanny Hesse, the wife of Koch's assistant. She suggested using agar, a gelatinous material from seaweed, which remains stable at higher temperatures.

Another key innovation came from Koch's assistant, Julius Petrie. At the time, cultures were grown on a plate covered by a cumbersome bell jar. Petrie's simple but brilliant idea was to replace the bell jar with a second, slightly larger dish that acted as a lid. This invention, the petri dish, kept cultures sterile from airborne microbes while still allowing for easy observation.

The combination of agar and the petri dish revolutionized microbiology. It made it possible to grow pure colonies of bacteria, experiment with them, identify them visually, and ultimately develop vaccines. However, this method only worked for bacteria that could feed on the broth's nutrients. It was not effective for viruses, which require living cells to replicate, and the technology to grow cells in a lab did not yet exist.

In the late 19th and early 20th centuries, lab conditions for culturing dangerous bacteria were quite scary. Scientists had not yet developed antibiotics, and antiseptic techniques were not integrated into culture methods. Practices like mouth pipetting were still common, and some researchers would even deliberately infect themselves to prove a specific bacterium caused a disease. For instance, scientists trying to support Robert Koch's work on cholera would ingest the bacteria to test its effects.

At the same time, the fundamental concept that organisms are composed of cells was still a developing idea. It took improvements in microscopes to see individual cells and establish this as a universal principle for living things. Joseph Lister's father, a wine merchant and amateur lens maker, significantly improved microscope lenses around the 1830s by correcting distortions. This allowed for clearer visualization of bacteria.

This technological advance was crucial for Robert Koch's work on tuberculosis. Identifying the tuberculosis bacterium was difficult because it repels most water-based dyes. Koch's key innovation was adding ammonia to the standard dyes when staining lung tissue from an autopsy. The ammonia made the solution more alkaline, allowing the dye to attach to the bacteria's acidic cell walls. This breakthrough in 1882 made the previously invisible Mycobacterium tuberculosis visible.

Koch was reportedly not skilled at drawing his microscopic observations, which was the standard way to document findings. To create better and more reproducible evidence, he collaborated with developers to attach a camera to a microscope, creating a photomicroscope. These photographs provided powerful visual proof that specific microbes caused diseases, sparking a revolution in medicine.

Microscopy proved crucial for vaccine development by allowing scientists to see if their preparations were contaminated with other microbes. This led to safer, more reproducible vaccines because researchers could ensure they were working with the correct microbes. While several bacterial vaccines for cholera, bubonic plague, and typhoid were created, virus vaccines remained a major challenge. Viruses needed living cells to grow, and keeping those cells alive long enough for study was difficult.

A key breakthrough was the 'hanging drop technique', developed by Ross Harrison at Yale. This simple method involved placing cells from a frog embryo in frog plasma on a microscope slide and then turning the slide upside down. This created a larger drop of fluid, allowing the cells, such as neurons, to grow for weeks or even months while still being observable under a microscope.

Over the next few decades, other cell culture techniques advanced. Vaccines were grown in various animal tissues: the smallpox vaccine in calves, rabies in rabbit brain tissue, influenza in embryonated eggs, and polio in monkey kidney cells. Alongside these developments, sterilization methods improved with the advent of antibiotics and autoclaves, which use high-pressure steam to sterilize equipment. To grow larger quantities of cells, scientists developed the roller bottle system, where bottles filled with cell cultures are gently rolled to keep them bathed in nutrients. Jacob noted a maternal quality to this process, like rocking a baby in a cot. Another technique, microcarriers, uses large tanks filled with small spheres where cells can grow on the surface.

But we still don't have better microscopes to see viruses until the 1930s. This is so crazy that people are sometimes developing virus vaccines basically through a lot of experimentation, but they still don't actually know what is causing those diseases.

The major limitation was visibility. Scientists knew an infectious agent existed that wasn't a bacterium, but they couldn't see it. This changed in the 1930s when Ernst Ruska and Max Null developed the electron microscope. Light microscopes are limited by the wavelength of light; if two objects are closer than half a wavelength, they blur into one. Viruses are too small to be distinguished. Electron microscopes solve this problem by using electrons, which have a much shorter wavelength, allowing for much higher resolution to see smaller details. In these devices, magnetic coils act as lenses to focus a beam of electrons onto a sample in a vacuum, creating an image and finally making the world of viruses visible.

The development of the electron microscope in 1931 was a theoretical breakthrough, allowing scientists to achieve resolutions thousands of times higher than light microscopy and finally see viruses. However, this invention was not the key to unlocking viral vaccines. The real challenge was that electron microscopes often destroyed the biological tissue they were observing. The actual breakthrough for viral vaccines came from advancements in cell culture techniques.

The polio vaccine, developed in the 1950s, exemplifies this. The crucial work was done in the 1940s by John Enders and his colleagues. They discovered how to grow poliovirus in non-nervous human tissue, a discovery made somewhat by chance when they inoculated spare tissue samples from other experiments. This allowed them to study the virus, identify its different serotypes, and ultimately create vaccines. Enders himself had an unusual path into science, switching from a PhD in English to immunology after being inspired by his medical student roommate.

Building on Enders' techniques, Jonas Salk and Albert Sabin developed the two main polio vaccines. Salk created an inactivated (killed) virus vaccine, while Sabin developed a live attenuated (weakened) oral vaccine. The two men were famously rivals who intensely disliked each other and publicly disparaged one another's work.

Jonas Salk said of his rival, "Albert Sabin was out for me from the very beginning. He said to me, just like that, that he was out to kill the killed vaccine." Albert Sabin, in turn, dismissed Salk's vaccine as "pure kitchen chemistry," adding, "Salk didn't discover anything."

Their open animosity occurred while the public desperately needed protection from the terrifying disease.

In the mid-20th century, hundreds of thousands of people were paralyzed by polio each year. The development of the polio vaccine was amazing because it essentially eliminated the disease in many countries. It has been so successful that two of the three serotypes of polio have been eradicated worldwide, with only one remaining. This vaccine brought about a crazy change, ending the era where many children had their breathing muscles paralyzed and were put into iron lungs just to stay alive. The hope is that soon, the last remaining polio cases will be gone for good.

The measles virus is particularly dangerous because it infects the body's immune cells. Specifically, it targets memory T and B cells, which are responsible for recognizing past infections. The virus uses these cells to travel through the bloodstream and spread to organs like the spleen, bone marrow, and kidneys, leading to complications like pneumonia, blindness, and brain swelling.

Crucially, by infecting these memory cells, the virus depletes them. This means a person can lose their immunity to other diseases they were previously vaccinated against or had recovered from. Children who contract measles often have a higher risk of other infectious diseases for the next two to three years.

The vaccine was developed by John Enders, who had previously developed crucial cell culture techniques. During a measles outbreak at a school, his team took samples from students. They successfully grew a virus strain from a 13-year-old boy named David Edmondson, and the strain was named the "Edmondson strain" in his honor. To weaken the virus, Enders grew it in human kidney cells and fertilized chicken eggs, forcing it to adapt and lose its ability to cause disease.

While early trials in 1960 were effective, they often caused fevers and rashes. Eventually, Maurice Hilleman, who developed 40 vaccines in his lifetime, created a better measles vaccine and combined it with vaccines for mumps and rubella, creating the MMR vaccine in 1971.

This achievement marked the culmination of a long journey in vaccine development. The process evolved from a chance discovery with cowpox, where the underlying cause of the disease was unknown, to a systematic approach. This involved understanding germ theory, isolating specific pathogens, growing them in labs, and finding ways to make vaccines safer and more effective. This progression led to vaccines for numerous diseases.

Smallpox, rabies, cholera, typhoid plague, pertussis, tuberculosis, diphtheria, tetanus, yellow fever, tick borne encephalitis, anthrax, influenza, Japanese encephalitis, polio, measles, mumps, rubella, boom.

In the last 50 years alone, it's estimated that vaccines have saved more than 150 million lives. This progress was built on the work of many different people over a long period, transforming humanity's ability to fight infectious diseases.