When we look back on human history, we see that many cities were devastated one after another during Europe’s Middle Ages by acute bacterial infections that rarely occur these days, such as Bubonic plague, cholera, and diphtheria. We know anecdotally that the population of a European city was drastically reduced to one-third due to a plague pandemic. It is a known historical event, and has even been novelized. The hygiene conditions in European cities at that time were dire compared to Edo city in Japan during the Edo period, which was the period in Japan corresponding to the Middle Ages.

In Europe, the significance of keeping the city clean, the idea of “hygiene” became prevalent during the 19th century. German medical science was far advanced compared to other countries in the world in the 19^th century, and Rudolf Virchow, who applied optical microscopy in medical science, is respected as “the father of modern medical science.” The scientist Robert Koch contributed to advances in bacteriology.

An important clue for research that elucidated the mechanism of antibody production against bacterial antigens and the complexity of the immune system was discovered at that time. These findings led to advances in medical science. Dr. Ehrlich, who was mentioned in the latter part of the previous essay, was also one of these researchers. He discovered Salvarsan, a therapeutic agent for syphilis. Bering developed and clinically introduced serum therapy (toxin-antitoxin therapy). In serum therapy, antitoxins for diphtheria exotoxin that were produced in a horse were administered to the blood of diphtheria patients. This treatment was developed by applying the mechanism of passive immunization to eliminate foreign enemies from the body, in which the formation of an immune complex consisting of antigens, antibodies, and complements in the human body led to phagocytosis (opsonin effect) by macrophages. This mechanism is called passive immunization.

With respect to COVID-19, the blood of patients who completely recovered from this disease is a very important therapeutic agent. Although it may be effectively used only a few times, it is expected to be a stop-gap treatment until a vaccine is developed. The strength (quantity) of antibody substances against antigens (M-type IgM and G-type IgG) varies among individuals. When patients receive an antibody for treatment, it causes production of an antibody against the immunoglobulin of the donor. Therefore, administration of an antibody may be limited to only several doses. If this treatment triggers a rejection reaction, it may result in a lethal “cytokine storm.”

Most cold symptoms, except for influenza, are attributed to acute pharyngitis and rhinitis from gram-positive bacteria including Streptococci and Staphylococcus aureus, therefore antibiotics can be effective for these symptoms. What, then, are antibiotics? Penicillin, which would be later used as an antibiotic was discovered by Alexander Fleming. He was an assistant in the Inoculation Department for syphilis by Salvarsan at St. Mary’s Hospital in London. He was also a researcher in pathology and bacteriology. Pure culturing of bacteria in a medium is the first step in bacteria research. For example, agar is prepared in a small Petri dish-like bowl. This is called the “medium” for purification for a certain bacteria, which was contaminated and a kind of failure, he thought.

Fleming was engaged in pure culturing of Staphylococcus aureus as part of his research. At one point, he found that a blue mold, which was grown in the adjacent laboratory room, had contaminated the Petri dish where bacteria were cultured. A portion of the growing bacteria was melted by a yellowish-green mold. At first, he was discouraged, thinking “this experiment has ended up a failure.” However, he repeatedly asked himself the question, “Why did the mold melt the cultured bacteria?” Finally, an idea came to his mind that the mold had destroyed his bacteria. The name of this green mold was Penicillium notatum. It is because of this that he named the substance contained in this mold “penicillin.” He made a presentation about these findings at the British Society of Pathology in 1929. However, it was disregarded.

About ten years later, as World War II increased in severity, many soldiers died because of traumatic acute infections on the battlefield. It was a serious concern for the British General Command. Florey and others, pathologists at Oxford University, started to contrive measures to cope with infections under the order by the General Command. They thoroughly searched past medical studies, and unexpectedly found Fleming’s research paper. After the Florey group finally arrived at the importance of the substance, penicillin, they successfully developed methods for large-scale culture, analysis of extracts, a purification process, and pharmaceutical formulation for this blue mold over research of several years. During the second World War, Prime Minister Sir Winston Churchill suffered from severe bacterial pneumonia. He recovered miraculously from this infection by this penicillin. This news was rushed around the world.

Penicillin worked as a specific medicine against a wide variety of acute bacterial infections including those resulting from traumatic injury and pneumonia. This medicine caused a revolution in the world after World War II. After that, Selman Waksman suggested that the antibacterial action of blue mold indicated a fight among living organisms. This phenomenon led to naming these substances “antibiotics.” Waksman extracted streptomycin from a soil bacterium called actinomyces. Dr. Hamao Umezawa, a Japanese researcher, is famous all over the world because he found many kinds of antibiotics through studies of soil bacteria.

Penicillin was effective against special intracellular parasitic bacteria including tuberculosis, syphilis, and Hansen’s disease, which were among the most abhorrent diseases in human history. These diseases were eradicated worldwide. The pharmacological action of penicillin includes functions to destroy the mechanism that forms bacterial cell membrane polysaccharides. Therefore, this substance is effective for all bacteria which have similar cell membrane structures. Viruses are not cells, and they are not living creatures. Furthermore, they have a completely different structure and have no cell membranes, therefore, antibiotics are ineffective against viruses. Antiviral drugs can be a double- edged sword in some ways, since they can enter human cells and interfere with the formation of DNA or RNA and the accompanying proteins.

The most famous human infectious virus in human history is smallpox (Variola). This virus triggered serious infectious disease in human beings. It was a systemic disease that caused a rash spreading to all parts of the body, which resulted in systemic skin inflammation and eye problems. Smallpox was eradicated worldwide due to the smallpox vaccine developed by Jenner in England. It was an epoch-making effort in the development of vaccination therapy. He established the theory that injection of cowpox virus (Vaccinia), which is very similar to human smallpox virus, promotes antibody production in the human body. Cowpox is known as “vaccinia,” from which the word “vaccine” was adapted. This is why the rapid development of a vaccine for COVID-19 is so sought after.

Viruses are roughly categorized into two types, DNA-type and RNA-type. If a virus is likened to a cell, it would be a structure composed of only a nucleus. It attaches to a living creature, becomes parasitic in a cell, and reproduces itself. The coronavirus is an RNA virus. It has crown-shaped (corona means “crown”) protrusions (spikes) on its surface, which look like the corona of the sun, the outermost region of the Sun’s atmosphere. Viruses can be parasitic only on cells of certain animals that have antenna- like structures on their surfaces. This phenomenon is called “species specificity.” For example, when a coronavirus that infects only bats invades the respiratory system or lung cells (organ specificity), reproduces, proliferates, and destroys the host cells, arachidonic acid, mentioned in the previous essay, is released. This substance subsequently triggers inflammatory reactions. This novel coronavirus. COVID-19, mutated and became able to invade human respiratory and lung cells. The most important strategy against COVID-19 is to develop pharmaceutical products that can prevent its RNA replication. The SARS virus that caused the pandemic from 2002 through 2003, and MERS during 2012 in the Middle East, are both RNA-type and corona-type viruses. These diseases trigger systemic acute inflammation, especially in the lungs as interstitial pneumonitis, acute respiratory distress syndrome (ARDS), which is a catastrophic situation, called cytokine storm, probably treated by dexamethasone, a kind of steroid as immunosuppressant.