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It was long suspected that living things were the agents of disease. In volume 6 of his epic poem De Rerum Natural (On the Nature of the Universe) written sometime around 50 B.C., Titus Lucretius Carus speculates about invisible atoms causing disease. This was only one idea among many and some thought that an imbalance in humors caused illness, while others felt that supernatural forces were at work. The prevailing theory held by most doctors of the 19thcentury was that chemical toxins were carried from an ill patient to others, causing them to contract the same malady. The bacteria that were known to be present were seen as a symptom of the disease and not its cause.
Ignaz Semmelweis, pictured in Figure 1.14, a Hungarian physician working in Vienna, made the first breakthrough in the true nature of disease. He realized that asepsis in obstetrical wards could prevent the transmission of childbirth fever from patient to patient. He therefore instigated a policy for all attending physicians to wash their hands with chloride of lime (a mixture of calcium chloride hypochlorite, CaCl(OCl); calcium hypochlorite, Ca(OCl)2; and calcium chloride, CaCl2) between patients. This innovation dropped the mortality rate from 18% to 2.4%.
Figure 1.14. Ignaz Semmelweis. The Hungarian Ignaz Semmelweis. Drawing by Tammi Henke
Ignaz became a vigorous proponent of his ideas, but the Hungarian doctor's efforts were opposed by many who could not accept that physicians themselves could be responsible for spreading bacterial infection. Ridicule of his idea caused him to move from Vienna to Pest, Hungary and ultimately played a role in a nervous breakdown. Ironically Semmelweis died from an infection that he contracted during a surgery he performed, while recovering from his nervous breakdown.
Before his death he published his ideas in a paper The Cause, Concept, and Prophylaxis of Childbed Fever in 1861.The poor writing of the paper contributed to the obscurity of his ideas, with the work being ignored for 17 years. This raises an interesting point about the culture of science. Radical ideas, even those that are correct and can save lives, are sometimes ignored. It takes time to overcome the dogma of the day. The personalities involved and the negative light it might throw on past practices play a large role in the rate of acceptance of a new idea.
In a seemingly unrelated event, Louis Pasteur found something interesting while working on wine souring, a problem where wine fermentations produce a sour taste and very little alcohol. Fermentation of alcoholic beverages was thought to be a simple chemical reaction. Heating, common in most beverage preparations, was thought to cause the breakdown of sugar into alcohol. Pasteur was asked to help out the wine industry in France because wine souring was pushing it close to ruin. His work on wine-making revealed that the process of converting sugar to alcohol is actually performed by various yeast strains. He then showed that the wine was going bad because a contaminating microbe was generating lactic acid instead of alcohol from the sugar. This idea was controversial, but gained credibility when Pasteur solved the problem by heating the wine and killing the contaminant. The heating process was named pasteurizationin his honor and is still widely used today. In a brilliant step of generalization, Pasteur realized that souring of wine and infectious disease shared a common thread in that they both might involve infection by a microorganism. His suggestion that microbes cause disease became known as the germ theory of disease.
Joseph Lister became aware of Semmelweis's work and together with Pasteur realized the true nature of disease. He then recognized that he could use this idea to help his surgery patients. At this time, major injuries, broken bones or surgery would often result in infection of the damaged area, sometimes leading to amputation or death. Lister found he could greatly reduce the number of microorganisms on wounds and incisions by using bandages treated with phenic acid, a compound that killed microorganisms (phenic acid, now known as phenol, is the active ingredient in Listerine). During surgery he began the practice of spraying the wound with a fine mist of phenic acid to kill microbes. These practices greatly reduced the rate of infection and mortality of surgery patients, lending further credence to the germ theory of disease.
In 1876 Robert Koch provided definitive proof of the germ theory by isolating the cause of anthrax and showing it to be a bacterium. From this came the development of Koch's Postulates, a set of rules for the assignment of a microbe as the cause of a disease:
The postulates are Koch's most famous contribution to science and it is a testament to the utility of these postulates that they are stilled used today to discover the cause of new emerging diseases. Koch went on to apply these principles in the study of many other diseases including tuberculosis, cholera and sleeping sickness. It should be pointed out that Koch's postulates cannot be applied to all diseases. For example if a disease-causing microbe has humans as its sole host and has a significant possibility of causing death, it would be unethical to apply this microbe to test humans as dictated by postulate 3. Also, it is not always possible to obtain a disease-causing microbe in pure culture.
While attacking the problem of disease, Koch developed the tools for obtaining pure cultures. Advances in science often come from innovations in the available technology. Robert Koch was an important microbiologist because his pioneering work in the isolation and characterization of bacterial diseases helped to identify the causes of many of the maladies plaguing humanity. Further work by other scientists then began the long road to conquering them.
The ensuing years brought numerous discoveries about the nature of disease. In the latter half of the 19thcentury, the causative agents for anthrax, tuberculosis, gonorrhea, diphtheria and many more were discovered. Great strides in understanding maladies caused by bacteria were made at this time, including the solidification of the germ theory of disease. However, some illnesses seemed not to have bacterial origins. Microscopic examination of serafrom ill patients revealed no organisms and the causative agents could not be grown on any known medium. Yet if these sera were injected into a susceptible host, disease resulted.
In 1886 John Brown Buist devised a method for staining and fixing liquid from a cowpox vesicle. Observations of this slide showed tiny bodies that he believed were spores. Although he did not realize it, he was the first person to see (and photograph) a virus. It was not until the middle of the twentieth century with the invention of the electron microscope that the true shape and structure of viruses was understood.
In 1884 Charles Chamberland in Pasteur's laboratory created an unglazed porcelain filter that had pores much smaller than bacteria (0.1-1 µm). It was possible to pass a solution containing bacteria through these filters and completely remove them from the solution. This enabled the creation of sterile medium without the use of heat, and also became a standard test for the removal of all bacteria, especially when testing transmission of disease. By removing the microbes, Chamberland clearly demonstrated that an infectious agent, and not the solution, was causing the illness. This concept seemed reasonable until scientists began to investigate a tobacco infection.
Tobacco mosaic disease is characterized by light and dark green areas on plant leaves in a mosaic pattern. The disease stunts the growth of the plant, therefore reducing yields. Europeans recognized the effects of this disease soon after tobacco was introduced from the New World in the 17th century. Adolph Mayer first described transmission of the disease by injecting fluid from a diseased plant into a healthy one. Nine out of ten times the healthy plant would become heavily diseased. In 1892 Dmitrii Ivanowski extended this research by the shocking discovery that the causative agent could pass through Chamberland's porcelain filter. He reported his findings, but the idea that the causative agent could pass through the filter was so troublesome to Ivanowsky he attributed the phenomenon to a cracked filter or to small spores that passed through the pores. It was Martinus Beijerinck in 1898 who realized the true nature of these particles, making the intellectual leap that the causative agent of the disease must be so small as to pass through the filter known to trap all bacteria. He coined the term contagium vivum fluidum a contagious living fluid.
Some scientists thought these agents were toxins in the fluids of the hosts, but further study revealed that tobacco mosaic disease could cause illness through many transfers from plant to plant. A toxin might cause damage on the first plant, but subsequent transfers should make it so dilute that it would no longer have any effect. These filterable entities were different from bacteria and appeared to depend on their host in order to multiply. The term ultrafiltrable viruses and later just viruses (virus means poison in Latin) was coined to describe these tiny pathogens.
Bacteria are also vulnerable to viruses. Bacterial viruses were described by Frederick Twort in 1915 and independently by Felix d'Herelle in 1917. Felix d'Herelle was studying a plague of locusts in Mexico when he noticed that the locusts were being killed by a microorganism. During experiments to characterize this microbe, d'Herelle noticed the appearance of clear, circular spots two or three millimeters in diameter on cultures growing on agar. At this point d'Herelle studied the spots enough to determine that they came from an agent small enough to pass through a porcelain filter. He dropped the investigation, but recalled these observations while studying dysentery in 1915. The illness was affecting soldiers fighting in World War I and he soon determined the cause to be the bacterium Shigella dysentery. In the process of investigating Shigella, similar areas of clearing were observed. d'Herelle realized that something in these areas of clearing was killing the bacterium. He eventually determined these were viruses of bacteria, coining the term bacteriophage (devourer of bacteria). Table 1.4 lists these and other significant events in the discovery of the cause of disease.
|1840s||Ignaz Semmelweis shows that hand washing between visiting mothers can prevent childbirth fever.|
|1854||Dr. John Snow studies a cholera outbreak in the Soho neighborhood of London and determines it was caused by contaminated water at the Broad Street pump. His methods found the field of epidemiology.|
|1857||Louis Pasteur develops the germ theory.|
|1867||Joseph Lister develops the use of phenic acid (phenol) to treat wounds and for antiseptic surgery.|
|1873||Gerhard Henrik Armauer Hansen discovers the leprosy bacillus (Mycobacterium leprae) and demonstrates that leprosy is a contagious disease and not inherited as was the popular belief. In many countries leprosy is still called Hansen's disease in his honor.|
|1876||Robert Koch and Cohn identify a bacterium, Bacillus anthracis as the cause of anthrax and publish their research.|
|1882||Koch isolates the Tuberculosis bacillus, Mycobacterium tuberculosis.|
|1884||Koch puts forth his postulates, which are standards for proving that a microorganism is the cause of a disease. Application of Koch's postulates continues to reveal the association of many diseases with pathogens.|
|1886||John Brown Buist is the first person to see a virus.|
|1892||Dmitri Ivanowski publishes the first evidence of the filterability of a pathogenic agent, the virus of tobacco mosaic disease.|
|1899||Martinus Beijerinck recognizes the unique nature of Ivanowski's discovery. He coins the term contagium vivum fluidum - a contagious living fluid.|
|1899||Friederich Loeffler and Paul Frosch discover that foot and mouth disease is also caused by a filterable agent.|
|1915-1917||Frederick Twort and Felix d'Herelle discover bacterial viruses.|
|1918||In the fall of 1918, as World War I was ending, an influenza pandemic of unprecedented virulence swept the globe, leaving some 40 million dead in its wake. A search for the responsible agent began in earnest that year, leading to the first isolation of an influenza virus by 1930.|
|1957||D. Carleton Gajdusek proposes that a slow virus is responsible for the wasting disease kuru. In subsequent years several diseases are shown to be caused by slow viruses (later renamed prions) including mad cow disease.|
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