December 6, 2019
Just like today, it was not uncommon for someone to get sick in the early twentieth century. The only difference between then and now is that something as simple as a cut that got infected could kill you. The things that made them sick are not very different from those found today; in fact, some are actually the same. So why are those same things that killed people in the past not killing people today? Well, in short, medicine and medical practices have improved and so has our understanding of the things that make us sick. We started to study viruses (virology), and equally as important, we studied the microorganisms (microbes) that we encounter everyday (microbiology). One of those microbes that makes us sick are bacteria, which have been around for millions of years and are found virtually everywhere on earth. Though not all of them can cause illness (in fact, some are beneficial and essential to living a healthy life), there are some that can cause horrible infections that, if untreated, can even cause death. It took an unclean lab bench and just enough luck for one scientist to find an answer to stopping fatal bacterial infections. He would change the world and save countless lives, but he even admitted that “When I woke up just after dawn on September 28, 1928, I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I guess that was exactly what I did.”1
Bacteria are single-celled organisms known as prokaryotic cells. This means they do not have discrete compartments within the cell, and are smaller than animal and plant cells. Bacteria are extremely old to say the least. They emerged around 1.5 billion years after the creation of the planet and they were probably the sole living inhabitants for the next 3 billion years. Some of them are very beneficial as well as vital in the development and health of humans. Humans do not possess all enzymes to digest all carbohydrates. It is estimated that if humans did not have some gut bacteria, we would have to ingest 30 percent more food to maintain our body weight. Some bacteria can also produce helpful vitamins (such as vitamins K and H), and some help the gastric immune system to be primed against invasion by more pathogenic (harmful) bacteria. Some even help in protecting us against food poisoning. It should be no surprise that because they are so small and abundant, they can be found all over our skin, but it is important to know that some are essential. Their numbers alone can actually discourage the growth of pathogenic bacteria and some even stimulate the skin’s immune responses to repel transient invasion. Though they provide so many benefits, bacteria are unfortunately known more for the harm that they cause than for the help that they provide. More often than not, people immediately think of viruses as the one and only culprit that causes disease or illness; however, it is important that we recognize that some species of bacteria can play a critical role in causing disease or illness. Though no direct correlation has been established, some researchers have suggested that the bacteria Chlamydia pneumoniae is probably associated with heart disease. Some bacteria that cause disease can be sudden. E. coli O157:H7 for example, probably resulted in a change in foodstuffs fed to cattle, and Aeromonas salmonicida emerged most likely because of the concentrating of farmed salmon, as it is rare in wild salmon.2 Though Aeromonas salmonicida infects mainly salmon, there has been a case report in India of a woman that felt ill. She had complaints of low grade fever associated with weakness and malaise for ten days before she was properly treated. After several tests, researchers were able to show an isolation of the Aeromonas salmonicida bacteria.3 E. coli O157:H7 is a specific strain of Escherichia coli (commonly referred to as E. coli), that produces a powerful toxin and can cause severe illness. It is usually caused by any of the following: eating under-cooked, contaminated ground beef, contaminated produce items that came in contact with cattle feces in the field, drinking raw milk, and even swimming in or drinking water contaminated by farm animals.4 In extremely rare cases (usually in children under five, and the elderly), Hemolytic Uremic Syndrome (HUS) can develop as a result of a E. coli O157:H7 infection. The toxins of E. coli O157:H7 destroy red blood cells and HUS can lead to kidney failure, neurologic damage, and even death (it is estimated that 5–10% of HUS cases are fatal).5 Though these are rare and extreme cases, the most common type of harm to human health that bacteria are usually associated with is bacterial infections. It is not widely known, but bacterium actually causes more deaths than those caused by viruses alone.6 This fact was not known by the scientific community until more recently. In the past, it was known that bacteria could cause infection and it often was fatal, but what was not known was how to stop it.
In 1906, Alexander Fleming was accepted into St. Mary’s Medical School, London University, and was fortunate enough accompany Sir Almroth Wright, a pioneer in vaccine therapy, in his research. During his time at St. Mary’s, he earned his M.B., B.S. and eventually became a lecturer at St. Mary’s until 1914. His time as a lecturer was briefly interrupted by the First World War, as he served as a captain in the Army Medical Corps.7 In the First World War, Fleming had noticed that most deaths came from infections in wounds rather than from direct battle casualties. He knew that to prevent some of these infections, some sort of medicine was required that could be given systemically to combat bacterial infection.8 After the war in 1918, he returned to St. Mary’s, and eventually, in 1928, he was elected as a professor of the school.9 Early in the 1920s, he was excited about the properties of a germ-killing compound that he had found in human tears, that he named lysozyme. Though it proved not much help in direct medical benefit, since it effected exclusively harmless organisms, he did develop a range of techniques for investigating the effect of specific chemicals on bacteria.10 He was working on colonies of a bacteria called Staphylococcus aureus on nutrient agar in a Petri dish before he left for a month-long holiday in 1928.8 When he returned from the holiday in September, he made the discovery of a lifetime. He had discovered a heap of neglected, dirty Petri dishes that were left over from the holiday on his dirty lab bench. He discarded them, but recovered a peculiar one that caught his eye. It had a small growth of dark green felty mold. The mold was surrounded by a sterile ring separating it from the ‘staph’ bacteria. Fleming wondered what caused this, and hypothesized that the mold might be exuding a substance similar to lysozyme.12
Life was horrific before the invention of antibiotics. In the summer of 1348 the infamous bacterial pandemic of Yersinia pestis, better known as the Black Death, had spread to the British Isles. Known as the second plague, it originated from Asia and was brought to Europe by black rats, and in just two years the plague killed about a third of the whole population of England and half the population of London. A combination of families living in close proximity with one another, poor hygiene, and rats coming into close contact with humans, all resulted in fleas from rats infecting humans. The scare of the Black Death had completely changed the way fourteenth-century life looked. As a result of such a loss of such a huge proportion of the population, society was undermined. Along with the plague, leprosy was considered one of the two major epidemics from the Middle Ages until the eighteenth century. Though not as prevalent today, with the proportion of cases in the world now only 10 percent, the causative bacterium for leprosy, Mycobacterium leprae, is still very notable. In 1854, during the Crimean War, deaths of soldiers from severe bacterial infections, including dysentery and cholera, exceeded deaths from the battlefield by ten times. Around the same time in the American Civil War, doctor George Tichernor was successful in the use of alcohol on wounds rather than amputation to stop infection. He performed the first use of chemicals to control infection and would later patent his alcohol ‘antiseptic.’ Shortly after this, in 1865, the practice of concerted antisepsis, the control of infections with chemicals, began. These chemicals were administered on the surface of the body rather than inside the body, though they helped at the end of the nineteenth century. Bacterial infections were the primary cause of premature death in the developed world.13 The treatment for infection was archaic and cruel at times to say the least. The practice of bloodletting had been typically used as a medical therapy for over 3,000 years. Bloodletting was based on an ancient medical theory that the four bodily fluids, or “humors” (blood, phlegm, black bile and yellow bile), must remain in balance in order to preserve health. The belief was that infections were thought to be caused by an excess of blood, and as a result, blood was removed from patients. From 1363 to 1910, mercury compounds were applied to skin, taken orally, or injected, in order to treat syphilis, with side effects that included extensive damage to skin and mucous membranes, kidney and brain damage, and even death.14 If it were not for antibiotics, it is a very realistic possibility that we would be living in a world with rampant, continuous, deadly bacterial epidemics.
Using the techniques he developed from earlier experiments with lysozyme, Fleming studied the effects of the filtered broth of nutrient on which the mold had grown.10 He was able to repeat his initial observations, only this time he substituted the ‘staph’ bacteria with other pathogenic bacteria. He then observed that it was able to kill almost all Gram-positive bacteria but did not have a significant effect on Gram-negative bacteria.16 The main difference between the two types of bacteria is the make-up of their cell walls, Gram-positive bacteria have a thick layer of peptidoglycan while Gram-negative bacteria have a thin layer of peptidoglycan.17 Though they are generally considered easier to kill, some Gram-positive bacteria are typically pathogenic in humans. He also discovered that it was unstable, and its antibacterial activity was short-lived. Most of the penicillin administered was rapidly cleared from the body by the kidneys.18 He failed to separate the mysterious chemical in the “mold juice” that killed the bacteria. However, he identified the fungus as Penicillium notatum and so he named the unknown compound or rather the mold juice as a whole that killed the bacteria after it, penicillin. Fleming soon published a report of his unique findings in the British Journal of Experimental Pathology in 1929, and then widely distributed samples across Europe and the United States. About a decade later, in 1937, biochemist Ernst Boris Chain at University of Oxford under professor of pathology Howard Florey, read Fleming’s paper. Chain was the first one to grasp the chemical challenge of separating penicillin, and Florey was in full support of Fleming. Florey quickly applied for and received a grant from the Rockerfeller Foundation of New York, the world’s richest funder of scientific research at the time. Though they were both very interested in penicillin as a substance, Florey actually misidentified it originally. He incorrectly assumed that the penicillin was a protein and they attempted to separate it through freeze drying. Though they produced pure penicillin, it was just 1 percent; it was originally described as making up of only one part in a million of the original “mold juice.” After testing the sample on mice and observing no immune response, swelling, or illness, Chain determined that it was not a protein. He had proven that penicillin could be isolated, with no impurities and most importantly, it could be non-toxic. The night before Chain experimented with mice, Norman Heatly, another biochemist, suggested to Florey that through a different process they could make a more concentrated solution.19 After Florey combined both techniques of isolating the substance, the process was greatly improved and eventually they took the bold step to move on from mice experimentation to human experimentation. The results that they received varied. They were able to concentrate it, stabilize it, successfully further purify it, and most importantly, they were able to eventually produce a product one million times more active than Fleming’s original “mold juice.”20 The Rockefeller Foundation visited the team in Spring of 1941, and Florey expressed just how disappointed he was that he could not persuade British companies to make penicillin. The Rockefeller Foundation invited Heatly and Florey to come to the United States to find and instruct some American companies that were able to raise the mold, to undertake a large-scale production of penicillin. The Foundation’s New York-based head of science, Warren Weaver (who had recommended their grant originally) was confident that it was possible that this new agent would “outrank the sulfa drugs in combating a long series of infectious diseases.”21
After the incredible success of Chain and Florey, labs in the United States were enlisted in mass production of the miracle cure for the last year of the war.20 They chose to grow penicillin at the Peoria laboratory in Illinois. They had technology that was far superior and significantly more efficient, and as a result, the yield improved drastically. In just two days they could produce more than four-fifths of the theoretical limit.23 Though the penicillin produced was only effective against the less common type of infection (Gram-positive bacterial infections as opposed to Gram-negative), it was still a very important contribution to the war effort. It ended up saving countless allied soldiers’ lives.24 In 1942, Ethel Florey (Howard Florey’s wife) conducted systematic experiments of the drug on airmen recovering from horrific burns in a few hospitals in Britain. Later, more experiments were done in the Glasgow Royal Infirmary and in the General Military Hospital near Oxford. Ethel eventually conducted more studies on different infections, and with her work in conjunction with the Flemings’ work, as well as the American work, the drug’s amazing general utility was now being proven. It would then be sent to the front lines of North Africa in July of 1942, but its full potential to totally prevent infection was not realized until the next year, when Florey demonstrated the drug on wounded soldiers from Sicily. His demonstration convinced the British army, and he soon worked with the War Office to train 200 pathologists and 500 clinicians on the use of penicillin. Though this was certainly an amazing scientific discovery that would benefit all the allied forces, the United States lagged behind in understanding the drug’s potential. But when they confirmed the power of the drug, those soldiers who would have otherwise died, could now be saved. Towards the end of the North African campaign in 1943, British and American forces both received the drug in significant quantities and later in the invasion of Italy and fighting in Italy, there was enough for all the wounded. Though it is still being debated, the full effect that penicillin had on the health of allied soldiers should not be overlooked. It still made a huge impact on soldiers who suffered from arterial wounds. About half suffered infective complications if they did not get penicillin, but the infection rate was halved for those with penicillin. In those that had chest wounds, the death from infection fell around two-thirds if penicillin treatment was used. By the end of the war it was estimated that one in every thirteen British soldiers that was wounded died from his wounds if he could reach medical assistance.25
In a time when the world was grim and people yearned for good news, after the Second World War, penicillin became more available. Penicillin became a beacon of hope that gave to those who had survived the inhumanity of world war, something to look forward to, a new, more luxurious life after their great suffering. It was eventually introduced to the public and the media reported numerous stories of patients on the verge of death receiving a life-giving injection. It had a reputation of being “the wonder drug of 1943” as Time Magazine put it, and many were impressed by the stories of how it could be used and its potential benefits. In 1944, within the United States, there was enough penicillin for both civilians and military patients, and it ultimately became an icon of medicine. By the end of the war, in July of 1946, less than a year after the war ended, any doctor throughout the United States could prescribe penicillin. During the next ten years after the Second World War, people all over the globe had enormous trouble in getting access to penicillin. It was needed, as right after the war there were many societies that had epidemics. It was seen as a necessity all over the world to control certain epidemics, as a way to raise the hopes of the individual as well as a way to benefit entire nations. Originally manufacturing was only found in the United States and Britain, but soon after the war, across Europe and China, Japan, and India, governments installed their own manufacturing plants for the drug. Relatively speaking, penicillin’s travel across the world was very fast. It started in a few centers of Western Allies to countries completely across the world.26 Though penicillin was very remarkable and seemed to be the answer to almost anything and everything, it was not the final nor most effective answer. After enough exposure to antibacterial drugs, some bacteria have mutated enough to become drug-resistant. As a result, in some cases, penicillin became obsolete, and was no longer as powerful. Soon after enough research by the scientific community, it was determined that there was more than one type of penicillin. There were different compounds that had slightly different compositions. To take advantage of this, a number of semisynthetic penicillin derivatives were produced. Their goal was to improve on the original properties of penicillin, which had barely changed since penicillin was first commercialized. The simple mistake of leaving Petri dishes out led to the saving of countless lives all over the world. The effort to help stop harmful bacteria is still continued today, as there are still efforts to find new antibiotics that are effective against the countless other drug-resistant bacteria.27
Ernst Boris Chain
Wow, an accident result in saving the lives of so many people. I feel like the discovery of Penicillin would have come about sooner or later, but there’s no knowing by how many years that discovery would’ve been delayed. With the horrible hygiene practices that the world had back then, I’m glad it was discovered when it was. I can’t wait for the next ‘accident’ to happen until we find the cure for the next big problem in medicine.