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Biomedicine and Health: Bacteriology

Biomedicine and Health: Bacteriology

Introduction

Bacteriology and microbiology emerged as scientific disciplines in the nineteenth century. Some scientists use the terms bacteriology and microbiology interchangeably, although microbiology can encompass virology, mycology, botany, and zoology as well. Advances in microbiology were closely linked to nineteenth-century improvements in microscopy. Better magnifying lenses and new staining methods that enhanced visual contrast made it possible to observe, describe, and sort out the confusing world of previously invisible entities, including those that became the special subjects of bacteriology.

The term bacteriology was first used in the early 1880s, primarily to designate the new medical science devoted to the study of disease-causing germs. At this time, however, microbes were also of interest to scientists speculating about problems as abstract as the origin of life and to those studying problems as practical as making wine, beer, vinegar, and cheese. In terms of medicine and public health, bacteriology was crucial to the development of the germ theory of disease, a unifying theory that revolutionized medicine and surgery. Late-nineteenth-century studies of bacteria made it possible to understand the causes of infectious diseases and postsurgical infections. Agricultural and soil scientists discovered that bacteria played an essential role in nitrogen fixation and the breakdown of dead and decaying organic matter, processes that contribute to soil fertility.

Twentieth-century scientists found that bacteria provided valuable models for revealing the secrets of the gene, including its chemical nature, mutation, recombination, regulation, as well as the relationship between genes and their products (i.e., proteins). Although bacteria are generally thought of in terms of the diseases they cause, by the beginning of the twenty-first century scientists were creating genetically engineered bacteria that could produce valuable medical and industrial products, such as insulin, interferon, and antibiotics.

Historical Background and Scientific Foundations

What Are Bacteria?

Bacteria are unicellular prokaryotic microorganisms that vary considerably in terms of size, shape, oxygen and nutritional requirements, and motility. Although often referred to as microorganisms, bacterial cells are prokaryotes, that is, they lack a true nucleus and nuclear envelope. Moreover, except for ribosomes (tiny particles composed of RNA and protein that cells use in the synthesis of proteins), bacteria lack the subcellular organelles found in more complex life forms known as eukaryotes. Bacterial DNA, the genetic material, usually exists as circular molecules, although it can also be linear. Many bacteria strains also contain additional DNA in circular plasmids.

Despite their apparent simplicity, bacterial species have adapted to a remarkably broad variety of environments, including some whose extreme temperatures would otherwise make them seem quite hostile. Bacteria have also adapted to life with or without oxygen. Those that require oxygen are called aerobic bacteria, or aerobes. Those that live without oxygen are called anaerobes, but some species can change their respiration in response to environmental conditions.

Under a good light microscope, bacteria are generally visible as separate cells in a variety of shapes: spherical (cocci), corkscrews (spirilla and spirochetes), rod-shaped (bacilli), comma-shaped (vibrios), and threadlike (filamentous). Pleomorphic bacteria can assume different shapes depending on conditions. Almost all bacteria are enclosed in a cell wall; some have a protective capsule beyond it. Pili, tiny hairlike projections on the outer surface of many bacteria, seem to participate in their attachment to certain surfaces. Flagella, whiplike extensions on either or both ends of a bacterium, act as agents of locomotion.

In addition to studying bacteria size and shape, scientists use specific staining techniques to identify different types. Gram staining, introduced in 1884 by Danish physician Hans Christian Gram (1853–1938), identified bacteria by their reaction to the staining process. Gram-positive and gram-negative bacteria absorb dye differently, allowing researchers to identify them and predict their chemical properties, structure, and sensitivity to antibiotics.

A classification system established in the 1960s divided all living beings into five kingdoms. Bacteria belonged to the kingdom Monera; the other kingdoms contained all the eukaryotes (cells with a nucleus and nuclear envelope). In another system developed in the 1970s, the prokaryotes were divided into two distinct domains (the highest level of taxonomic rank above kingdom): the Archaea and Bacteria, with the eukaryotes placed in the third domain, Eukarya. Bacteria can also be divided into lineages based on ribosomal RNA: proteobacteria, (formerly known as the purple bacteria), green sulfur bacteria, green nonsulfur bacteria, gram-positive bacteria, cyanobacteria (formerly known as the blue-green algae), gram-negative bacteria, and spirochetes.

IN CONTEXT: GIROLAMO FRACASTORO AND CONTAGION

Girolamo Fracastoro (1478–1553), poet, physician, and mathematician, pioneered the development of the germ theory of disease, analyzing evidence to support the miasma (or miasmatic) and contagion theories of disease transmission. In general, miasmatic diseases were attributed to “bad air”; malaria, which means “bad air,” is a classic example. “Contagious” diseases were attributed to the spread of a contagion and transmitted by physical contact.

Syphilis, a sexually transmitted disease that Fracastoro described in the medical classic Syphilis, or the French Disease (1530), provided a good example of transmission by contagion. Fracastoro, like most sixteenth-century physicians, believed that syphilis was a new disease. In his major medical work, On Contagion and the Cure of Contagious Diseases (1546), Fracastoro speculated about the existence of “contagions” or “seeds” of disease and compared this with the miasmatic theory. Some diseases, he argued, were transmitted only by direct contact. Others were transmitted by direct contact and by “fomites” (inanimate articles, such as clothing, that had been in contact with the sick). Some diseases were apparently transmitted by direct contact, by fomites, and by contagion or seeds capable of infecting victims without direct contact.

Although Fracastoro has been called the founder of the germ theory of disease, his writings were more ambiguous than this honorary title would imply. In general, the idea of contagion existing in tiny germs or seeds of disease did not prove very useful in guiding medical practice until the nineteenth century. The contagion theory led to attempts to stop epidemics by quarantines, isolation, and disinfection, but these methods had little practical effect.

The establishment of germ theory is often cast in terms of a conflict between contagion theory and miasma theory, but until the late-nineteenth century medical writers often used these terms interchangeably. The term “contagion” referred to harmful material that was transmitted directly or indirectly. It was, therefore, compatible with “miasma” as disease-inducing noxious air. By 1900, bacteriologists resolved this conflict by proving that the “filth” associated with miasmas usually contained disease-causing germs.

ANTONI VAN LEEUWENHOEK (1632–1723)

Antoni van Leeuwenhoek (1632–1723) was born in Delft, the Netherlands. His mother was the daughter of a brewer. His father, a basket maker, died when Antoni was only six years old. When his mother remarried, van Leeuwenhoek was sent to grammar school at Warmond, a nearby village. At the age of 16, he was employed as bookkeeper and cashier by a linendraper (cloth merchant) in Amsterdam. He returned to Delft six years later and bought a house and shop. In 1660, he became involved in a variety of civil service positions. Despite the demands of his business and municipal duties, van Leeuwenhoek devoted so much of his time to his microscopes that he was accused of neglecting his family. He outlived two wives and all but one of his six children. As recorded on his tomb, he lived for 90 years, 10 months, and two days.

Van Leeuwenhoek's interest in lenses began when he was about 39, but his inspiration for making microscopes is uncertain. One possibility is that he got the idea while working with special lenses that linendrapers used to inspect cloth. Another possibility is that he learned about microscopes from someone conducting scientific research. He probably got some basic ideas about microscopy from English physicist Robert Hooke's (1635–1703) Micrographia (1665), which described how to make and use simple magnifiers, also known as single microscopes, and the compound or multilens microscopes that Hooke preferred.

Although overshadowed by his contemporary, the brilliant English physicist and mathematician Sir Isaac Newton (1624–1727), Hooke was one of the seventeenth century's leading physicists, mathematicians, and inventor of scientific instruments. Some of van Leeuwenhoek's early experiments seem to reproduce experiments described by Hooke. By 1674, however, he was publishing accounts of microscopic observations that were superior. Moreover, van Leeuwenhoek was interested in searching for truly novel entities, while Hooke was primarily interested in magnifying conventional objects.

Van Leeuwenhoek's first simple microscope was a tiny lens, ground by hand and clamped between metal plates, with a specimen holder attached to it. Eventually, van Leeuwenhoek made simple microscopes that were superior to most seventeenth- and eighteenth-century compound microscopes. When he died, a collection of 26 microscopes and extra lenses was sent to the Royal Society. Tests demonstrated magnifying powers from 50- to 200-fold. Unfortunately, these instruments were later lost or misplaced.

Origins of Bacteriology

Bacteriology traces its origins to the doctrine of contagion, a universal concept in ancient societies and medical writings and one that formed the biblical practice of segregating lepers. Contagion theory states that impurity, corruption, and disease can all be transmitted by direct contact. Bacteriology developed as a scientific discipline in the nineteenth century, closely related to microscopy and botany. The term “bacterium” comes from the Greek bakterion, “little rod.” Some scientists used bacterium and germ interchangeably; many nineteenth-century naturalists preferred to use older, more general terms, such as infusoria, monads, pathophytes, saprophytes, or schizomycetes.

Seventeenth-century microscopists had discovered a new world teeming with previously invisible entities, including protozoa, molds, yeasts, and bacteria. The first person to actually see and describe bacteria was the Dutch microscopist Antoni van Leeuwenhoek (1632–1723). Using his simple yet remarkable microscopes, van Leeuwenhoek was able to study plant and animal cells, spermatozoa, molds, and microbes, including bacteria and pond infusoria, as well as crystals, minerals, water from different sources, scrapings from his teeth, saliva, semen, and gunpowder. He was also interested in the life history of insects, parasitology, and the battle against the doctrine of spontaneous generation.

Extensive observations of intestinal parasites, insects, spermatozoa, and other creatures thought to be generated spontaneously convinced van Leeuwenhoek that even the smallest microscopic creatures were produced by parents like themselves. Assuming that motility was characteristic of living beings, he concluded that the tiny moving things that he had first observed under the microscope in 1674 were a new form of life. He was quite sure that he had discovered very tiny, but remarkably lively “little animals,” which he called animalcules. About 30 of his letters to the Royal Society dealt with microscopic organisms, including rotifers, protozoa, and bacteria. His reports generated a great deal of excitement as well as some skepticism in the scholarly community. Van Leeuwenhoek responded to skeptics by sending testimonials from doctors, jurists, ministers, and other reliable witnesses.

Eighteenth-century naturalists acknowledged the existence of microorganisms, but found them very difficult to characterize and classify. The great Swedish taxonomist Carl Linnaeus (1707–1778; also known as Carlolus Linnaeus or Carl Linné), placed all the “infusoria,” a term commonly applied to all types of microorganisms, in the category he called Vermes (worms). German naturalist Christian Gottfried Ehrenberg (1795–1876) believed that the infusoria were complex creatures with internal organs, analogous to those of larger beings. Attempting to demonstrate these minute organs, he interpreted staining patterns as evidence of multiple stomachs. These observations actually

represent differential staining, that is, the inner portions of certain microscopic organisms absorbed dyes while other parts did not. Like van Leeuwenhoek, Ehrenberg opposed the idea that the infusoria were produced by spontaneous generation.

Crude staining methods made it difficult for microscopists to identify and characterize the different kinds of infusoria. Microscopists eagerly adopted the synthetic dyes that became available in the nineteenth century. Natural dyes, such as indigo, carmine, and blueberry juice, had, of course, been in use for thousands of years as stains for clothing and textiles. In 1856 William Henry Perkin (1838–1907) discovered the first of many aniline dyes while trying to synthesize quinine, a drug used to treat malaria. By the 1860s, aniline dyes were being used as biological stains, although impurities in commercially available preparations made it difficult for bacteriologists to obtain consistent results.

The German botanist and naturalist Ferdinand Cohn (1828–1898) was the first prominent scientist to take a special interest in bacteriological research. In the 1850s he suggested that bacteria should be considered microscopic plants. Many scientists, however, thought that bacteria were too primitive to fit into traditional botanical or zoological categories. Even the boundary between bacteria and inanimate matter was ill defined, and the question of the spontaneous generation of infusoria from inanimate materials remained controversial.

Karl von Nägeli (1817–1891), the German botanist who gave bacteria the name schizomycetes (fission fungi), rejected the idea that bacteria could be characterized by morphology like plant and animals species. He assumed that schizomycetes were pleiomorphic, that is, capable of changing from one form to another under different conditions. Moreover, he thought that these microscopic entities could arise by spontaneous generation and, therefore, were too insignificant to be worthy of a special place in the plant kingdom. Nägeli, who is primarily remembered as the distinguished botanist who failed to appreciate the Austrian botanist Gregor Mendel's (1822–1884) landmark paper on the laws of inheritance, paid little attention to the nature of bacteria and other microbes.

Despite unresolved debates about the nature of infusoria, Cohn's work defined bacteriology in the 1870s. Cohn placed bacteria into four groups, based on shape: sphaerobacteria (round forms, later cocci); bacteria (rod-shaped); desmobacteria (thread- or filament-like, later bacilli); and spirobacteria (motile forms with screw-like tails, later spirilla and spirochetes).

Louis Pasteur and Robert Koch, the Founders of Bacteriology

By the 1880s, bacteriology was emerging as a discipline within medical science, primarily through the research conducted by French chemist Louis Pasteur (1822–1895) and German physician Robert Koch (1843–1910). Bacteriology's early techniques were fairly crude, which made the identification of pure strains extremely difficult and tedious. Pasteur, Koch, and others had to find both substances and experimental animals in which different bacteria would grow. Laboratory media included various forms of chicken or meat broth, blood, urine, and even aqueous humor from the eyes of large animals. Finding the temperature range in which different bacteria would grow and preventing the growth of contaminant was, and still is, a major problem. Pasteur and his associates developed methods for removing or killing bacterial contaminants found on equipment and in liquids, including various forms of filtration and the autoclave, which provides steam heat under pressure.

By growing pure strains of bacteria in laboratory cultures and observing their characteristics and their ability to grow in suitable experimental animals, Pasteur, Koch, and their disciples clarified the relationship between specific “germs” and specific diseases. They established the theoretical and methodological foundations of the new science of microbiology. Moreover, their lives, their work, and their conflicts reflect the interplay between scientific research, both basic science and applied, and the political and social milieus within which scientists are embedded.

IN CONTEXT: THE LIGHT MICROSCOPE

During the seventeenth century, several important instruments, including the telescope, microscope, air pump, and barometer, were either invented or adopted by experimental scientists. The telescope granted a better view of objects that had fascinated human beings for thousands of years, but the microscope gave observers a new way of seeing, and access to an entirely new and previously invisible world. This led to revolutionary changes in science.

The images described by scientists using telescopes and microscopes were often greeted with skepticism or hostility. Critics insisted that such unnatural devices generated bizarre images of unnatural objects. Physicians of the time were generally indifferent to microscopy, probably because the findings did not help them diagnose or treat disease.

Credit for the invention of the microscope has been attributed to three Dutch spectacle makers: Hans Janssen, his son Zacharias (c.1580–1638), and Hans Lippershey (c.1570–1619). Cornelius Drebbel (1572–1633) and Lippershey may have added significant improvements to the first microscopes. Even with magnification no greater than 10-fold, they provided exciting images. Fleas, mites, and other creatures just visible to the naked eye became complex and bizarre monsters. Although many seventeenth-century scientists made some use of the microscope, van Leeuwenhoek, a man of immense energy and curiosity, was clearly the most ingenious microscopist of that era.

Improvements in the microscope in the nineteenth century, as well as new methods of sample preparation and staining, made it possible to distinguish bacteria from other types of cells. By the 1930s, however, the theoretical limits of the light microscope had been reached. To obtain higher magnification and resolving power, microscopists had to find ways of working with rays of a shorter wavelength than ordinary light. The development of the electron microscope in the 1930s made it possible for scientists to explore the fine structure of bacteria.

Koch preferred the term bacteriology to describe his work, which was appropriate given that his greatest successes were to identify the bacteria that cause anthrax and tuberculosis. In France, where Pasteur's influence was dominant, the study of bacteria was considered part of the discipline of microbiology. Bitter and disruptive disputes between the two were not uncommon and, at least in part, reflected the hostilities between their countries. Deeply troubled by the French defeat in the Franco-Prussian War (1870–1871), Pasteur hoped that his work would raise the status and productivity of French science and industry. Pasteur particularly disliked the term bacteriology, which he considered too restrictive and “too German.” Indeed, Pasteur's most famous discoveries involved diseases caused by the agents now known as viruses, as well as fermentation processes and diseases caused by bacteria.

Generally involved in several major lines of research at the same time, Pasteur made major contributions to the study of fermentation, spontaneous generation, and the diseases of wine, beer, silkworms, farm animals, and humans. During his investigation of chicken cholera, Pasteur isolated bacteria from sick chickens and accidentally discovered that it was possible to produce weaker cultures of the microbe that could be used as vaccines. Clearly this supported one of Pasteur's favorite aphorisms: “Chance favors only the prepared mind.” Just as the English surgeon Edward Jenner's (1749–1823) cowpox vaccine protected people from smallpox, Pasteur's laboratory vaccines provided protection against chicken cholera, anthrax, swine erysipelas, and rabies.

Troubled by what he saw as careless, inaccurate, and speculative work by previous investigators, Koch argued that modern bacteriology must be grounded in the identification of individual species, constant in form and function, and in their pathological effects. Only by adhering to the most rigorous methods, Koch insisted, would it be possible for bacteriology to take its rightful place among the sciences. Properly grounded, bacteriology was the key to improving public health and hygiene.

His early work and the institutions established in Germany to further such research provided a model for the development of bacteriology. The Institute of Hygiene (1885) and the Institute for Infectious Diseases (1891) were established to honor Koch's achievements and to further his research. The latter offered classes and diagnostic services to clinicians and provided facilities for bacteriological research. Koch's methods were successfully exploited in the search for the agents of typhus, diphtheria, tetanus, pneumonia, dysentery, relapsing fever, and other infectious diseases. In 1912, two years after his death, the Institute for Infectious Diseases was renamed the Robert Koch Institute.

Between 1876 and 1882, Koch produced convincing evidence that specific bacteria caused anthrax, septic infections, and tuberculosis. Anthrax, primarily a disease of sheep and cattle, can cause severe, localized skin ulcers known as malignant pustules in humans, as well as a dangerous condition known as gastric anthrax, or a virulent pneumonia known as wool-sorter's disease. The German physician Franz Pollender (1800–1879) and French physicians Pierre Rayer (1793–1867) and Casimir Joseph Davaine (1812–1882) had previously reported finding bacteria in the blood of anthrax victims, but Koch was the first to provide unequivocal proof that the disease was caused by a specific microbe now known as Bacillus anthracis. Koch also proved that the spores formed by B. anthracis could survive under harsh conditions to serve as a reservoir of disease.

Although it was Koch who demonstrated the bacterial etiology (cause) of anthrax and the critical problem of spore formation, it was Pasteur who developed a successful vaccine. He publicly demonstrated the efficacy of anthrax vaccine in 1881, a demonstration closely watched by doctors, veterinarians, supporters, and critics.

Through his studies of wound infections and tuberculosis, Koch formulated the criteria, now known as Koch's postulates, that must be satisfied to prove that a specific microbial agent causes a specific disease. In their classical form these postulates include: 1) prove that a specific microorganism is found in infected tissues; 2) isolate and cultivate the microbe; and 3) transmit the disease by administering pure cultures to healthy experimental animals. (A fourth postulate, isolating the microorganism in the experimental subject, was added later.) Although carrying out this proof for human diseases that lack animal models (such as typhoid fever, leprosy, and cholera) was difficult, Koch confidently predicted that progress in bacteriology would soon lead to the control of the epidemic diseases.

The Fight against Tuberculosis

In 1882, tuberculosis was a much feared and highly prevalent disease. Its effect on society was amplified by the fact that it was particularly likely to claim victims in what should have been their most productive adult years. Identifying the microbe that caused this devastating disease, Mycobacterium tuberculosis, was the high point of Koch's career.

To visualize the tuberculosis bacteria, special fixation and staining methods, as well as rigorous technique and patience, were needed. The tubercle bacillus is only one-tenth the size of the anthrax bacillus and is covered by a waxy layer that made staining very difficult. To complicate matters further, the tubercle bacteria grew exceptionally slowly. Koch proved that M. tuberculosis could be isolated from the tissues of patients suffering various disorders known as phthisis, consumption, scrofula, miliary tuberculosis, and others. Nevertheless, Rudolf Virchow (1821–1902), Germany's most famous physician and the founder of cellular pathology, continued to doubt that clinical patterns as complex and different as miliary tuberculosis and consumption could really arise from the same causative agent.

Pulmonary tuberculosis, the most common form of the disease in humans, provided the most efficient means of transmission, because its victims coughed up large quantities of germ-laden sputum. In poorly ventilated, dirty, dusty tenement rooms, tubercle germs remained viable for days or even months. When other bacteriologists warned that milk from cows with bovine tuberculosis was a danger to children, Koch insisted, quite incorrectly, that humans could not be infected with the bovine tubercle germ.

In 1890, Koch announced that he had found a substance, which he called tuberculin, that could inhibit the growth of the tubercle bacillus in laboratory cultures and in guinea pigs. Although tuberculin was immediately lauded in newspapers throughout the world as the long-awaited cure for tuberculosis, it did not cure the sick. Tuberculin, essentially a glycerine extract of tubercle bacilli, actually detected latent infections and, in some cases, even activated the disease process.

Despite all the clinical evidence, Koch insisted that tuberculin, if properly used, was a valid cure for tuberculosis. Immunologists later identified the tuberculin response as part of the complex immunological phenomenon called delayed-type hypersensitivity. Other bacteriologists attempted to create preventive vaccines by testing different strains of tubercle bacilli. The most widely used vaccine, known as BCG (Bacille Calmette-Guérin), was derived from a live, attenuated strain produced by French bacteriologists Albert Calmette (1863–1933) and Camille Guérin (1816–1895) in the 1920s. The resurgence of tuberculosis in the 1990s and the global emergence of virulent, multidrug-resistant bacteria reflect the misplaced optimism that led to the neglect of the bacteriology laboratories within the public health system.

Serum Therapy, Salvarsan, Sulfa Drugs, and Antibiotics

In addition to hunting for microbes, nineteenth-century scientists also began to investigate the ways in which the body fights off pathogens and responds to vaccines. These studies led to the development of preventive and curative serums and antitoxins that promised to conquer diseases like diphtheria and tetanus. At the Pasteur Institute in 1889 Émile Roux (1853–1933) and Alexandre Yersin (1863–1943) discovered that diphtheria bacteria generally remained localized in the throat, but released deadly toxins into the bloodstream. Shibasaburo Kitasato (1953–1931) isolated the tetanus bacillus and proved that it also produced a specific toxin.

In 1890 Emil von Behring (1854–1917) and Kitasato initiated a new era with a therapeutic approach generally known as serum therapy. At the time, “serum” (the fluid portion of the blood that remains when blood cells and clots are removed) was often used as a synonym for immune serum, antiserum, or antitoxin. Immune serum was prepared from the blood of animals that had been inoculated with diphtheria or tetanus toxin. The blood of animals that survived this challenge contained antibodies that could be used to protect other animals or humans. To provide sufficient qualities of immune serum, horses were used as “antitoxin factories.” Similarly, serum, or specific fractions of the blood (usually gamma globulin) from people or animals who have survived a disease can be used to treat others.

When Behring won the first Nobel Prize in physiology or medicine in 1901 he predicted that serum therapy would lead to complete triumph over the infectious diseases. Indeed, by the end of the twentieth century, at least in wealthy industrialized nations, massive immunization campaigns had almost eliminated the threat of diphtheria. No other major epidemic disease of bacterial origin has been so successfully managed by preventive immunizations. Nevertheless, although serum therapy stimulated the establishment of a new scientific disciple known as immunology, it did not provide the universally effective weapon in the battle against infectious diseases that bacteriologists had hoped for.

Despite significant success with preventive vaccines and antitoxins, in the early twentieth century there were still very few drugs that were useful in the treatment of bacterial diseases. In 1910 German medical scientist Paul Ehrlich's (1854–1915) work on chemical derivatives of an arsenical compound led to the discovery of Salvarsan, a drug that was effective against the spirochetes that cause syphilis, but relatively safe for people. Ehrlich called Salvarsan a “magic bullet,” because it destroyed spirochetes without significant harm to the patient. Ehrlich hoped to synthesize or discover other drugs that would destroy virulent bacteria when the body was not fast enough or effective enough in making its own bullets (antibodies). Chemists could synthesize many drugs that killed pathogens in the test tube, but magic bullets were rare indeed, because most of the drugs that killed bacteria also damaged the patient.

Unfortunately, scientists had little success in finding other drugs that were safe and effective against bacteria until German bacteriologist Gerhard Domagk's (1895–1964) work on dye substances led to the discovery of sulfa drugs. Following the model established by Ehrlich, who had investigated the effect of various dyes on bacteria, Domagk conducted systematic tests of the aniline dyes. He discovered that the red dye called prontosil was effective against streptococcal and staphylococcal infections. Other scientists discovered that the antibacterial activity of prontosil was due to its sulfonamide portion. Eventually thousands of sulfonamide derivatives were synthesized, although very few of them proved to be safe and effective enough for use in patients. Although some of sulfa drugs were effective in the treatment of pneumonia, scarlet fever, and gonococcal infections, drug-resistant strains of bacteria began to appear almost as rapidly as new drugs.

In 1928, Scottish bacteriologist Alexander Fleming (1881–1955) discovered that the mold Penicillium notatum produced a substance that inhibited the growth of certain bacteria. Six years earlier, Fleming had discovered lysozyme, a powerful antibacterial agent found in nasal secretions, tears, saliva, and egg white. Unfortunately, although lysozyme destroyed the wall of certain types of bacteria, it did not seem useful as a therapeutic agent.

Fleming prepared crude extracts of penicillin, but was unable to purify the active principle and perform clinical tests. During World War II, Australian pathologist Walter Florey (1898–1968) and German-born British biochemist Ernst Boris Chain (1906–1979) isolated penicillin and proved that it was a chemotherapeutic agent with unprecedented activity against streptococci, staphylococci, pneumococci, and the bacteria that cause syphilis and gonorrhea. The large-scale production of penicillin became a major priority during the war.

After the war ended, penicillin was greeted with great hope and enthusiasm throughout the world as a revolutionary new therapeutic agent. By 1948 it was widely available. The search for other “miracle molds” led to the discovery of streptomycin, neomycin, chloramphenicol, aureomycin, erythromycin, nystatin, and other valuable drugs. Streptomycin, a product of Streptomyces griseus, was especially valuable, because it was effective against tuberculosis. Ukranian-born American biochemist Selman A. Waksman (1888–1973), who discovered streptomycin, defined “antibiotics” as compounds produced by microorganisms that inhibit the growth of other microorganisms. Most antibiotics are the products of fungi, like Penicillium notatum, but soil bacteria belonging to the actinomycete group, such as those studied by Waksman, also produced important antibiotics.

After 1900, medical bacteriology was complicated by the discovery of unusual bacteria that proved difficult or impossible to culture in the laboratory, bacteria that could exist as different types or strains, and bacteria that were transmitted by insect vectors. The rickettsiae, a group of bacteria named after the American pathologist Howard Taylor Ricketts (1871–1910), seemed to multiply inside living cells. Rickettsiae cause typhus, trench fever, and Rocky Mountain spotted fever. Arthropods, such as lice, ticks, mites, and fleas serve as vectors. Fortunately, the diseases caused by these unusual bacteria respond to antibiotics. The “filterable-invisible viruses” associated with diseases such as smallpox, rabies, and yellow fever caused considerable confusion, but in the 1930s virology finally emerged as a discipline separate from bacteriology.

New Directions in Bacteriology

Although the role of bacteria in disease remains a major focus of bacteriology, by the mid-twentieth century some scientists called for a greater emphasis on basic questions about the intrinsic nature of bacteria—their physiology, metabolism, genetics, evolution, and place in nature. Just as scientists in other twentieth-century fields, such as genetics, molecular biology, ecology, and biotechnology had learned to use bacteria as model systems and tools, bacteriologists increasingly used the methodology of other fields to further their own theoretical and practical studies.

For example, following the rigorous methodology developed by Koch, bacteriologists typically worked with pure cultures. Nevertheless, bacteriologists knew that the growth rates of bacteria in pure laboratory cultures were very different from those in natural environments and communities. Electron microscopy of samples of natural aggregates of bacteria shows complex interconnections and adhesions to surrounding substrates. Studies of natural communities, or experimental laboratory communities of microbes, may yield new insights into interactions among different species.

Scientists who are interested in understanding the diversity of life on earth suggest that there may be many hundreds of thousands of different species of bacteria. So far, bacteriologists have discovered and characterized only a small fraction of all bacteria that may exist and may have interesting properties. Since the 1980s, advances in molecular biology have made it possible to engineer bacteria that produce insulin, human growth hormone, specific enzymes, and other useful products. Bacteria that are adapted to life in extreme environments—acidity, alkalinity, high and low temperatures—may prove especially valuable in biotechnology.

Modern Cultural Connections

By the 1960s, many physicians were convinced that antibiotics had eliminated the threat of bacterial diseases and that viral diseases could be eradicated by vaccines. Newspaper articles, popular books, magazine articles, radio and television programs regaled the public with accounts of the “breakthroughs” and “miracle drugs” that were eliminating the threat of infectious diseases. At the same time, physicians and science reporters were warning the public of the rising threat of heart disease, cancer, and other chronic, degenerative diseases of an aging population.

Overly optimistic predictions about the end of infectious diseases were quickly discredited by the rise of multidrug-resistant bacteria and the emergence of new diseases. Since the 1960s, new pathogens have appeared, and many bacteria have become drug resistant. For example, by 2005, antibiotic-resistant strains of the bacterium Staphylococcus aureus, which causes skin infections, abscesses, joint infections, and death, had become a significant source of nosocomial (hospital-acquired) infections. Antibiotic-resistant bacteria have even become a problem for pets, schools, and fitness centers.

As the number of people with weak immune systems increases, as a result of HIV/AIDS and the drugs used to fight cancer or allow organ transplantation, the danger of drug-resistant bacteria also increases. One of the most dangerous bacterial pathogens associated with the HIV/AIDS pandemic is drug-resistant Mycobacterium tuberculosis. From 2000–2004, according to the Centers for Disease Control and Prevention (CDC), 20% of tuberculosis cases in the United States were resistant to commonly used first-line antibiotic treatment, and approximately 2% were resistant to the more potent and more expensive drugs employed as a next step. In May 2007, the CDC isolated an airline passenger who flew on two commercial overseas flights after it learned that the passenger (who did not have HIV infection) harbored a resistant form of tuberculosis. This action marked the first order for quarantine issued by the CDC in over 40 years. In a follow-up investigation, passengers who sat beside the infected traveler were notified and advised to be tested for the disease; airlines reviewed their cabin air quality standards; and the issue of resistant tuberculosis and quarantine received much consideration both in the scientific community and the media.

Another extremely drug-resistant form of Mycobacterium tuberculosis (XDR-TB) is also an emerging threat, according to the World Health Organization (WHO), and is virtually resistant to all readily available antibiotics. As of 2007, identified XDR-TB is rare in developed countries. Yet, WHO estimated that in 2006, there were over 500,000 cases worldwide and that this number will rise in the coming years. The increased expense of treating XDR-TB will become a significant issue for poorer nations. By 2015, according to WHO, treating tuberculosis will cost $650 million each year, in part due to elaborate and necessary airborne precautions in hospitals that include isolation rooms with specialized air exchanges and masks that serve as a barrier for the extra-small bacteria that cause tuberculosis. More than $600 million will also be needed for programs aimed at curbing the spread of the multidrug-resistant bacteria. As of late 2007, the funds budgeted by various governments around the world to battle tuberculosis total $250 million—$400 million less than the projected $650 million needed. In 2006, the WHO spearheaded the Stop TB Partnership, an initiative that aims to save 14 million lives by 2015, partly by encouraging nations worldwide to commit the needed money. The campaign also seeks to increase access to treatment for nations most in need, and to reduce the economic burden associated with the costs of tuberculosis health care and the work force losses due to the disease.

Although the medical bacteriology established by Koch and Pasteur was dedicated to proving the relationship between specific pathogens such as Mycobacterium tuberculosis and its link to specific diseases, recent medical research suggests that a more subtle and complex relationship also exists between microbial infection and human health. Some studies suggest that discreet infections and inflammation may be related to various chronic and autoimmune diseases, such as asthma, atherosclerosis, ulcers, type 1 diabetes, multiple sclerosis, Crohn's disease, cancer, and others. If such relationships are found, treating an underlying infection might control or cure previously intractable chronic conditions.

Research conducted in the 1980s to explore the alleged link between bacteria and ulcers provides an interesting example. In 2006, Australian physician Barry J. Marshall (1951–) and Australian pathologist J. Robin Warren (1937–) were awarded the Nobel Prize for physiology or medicine after they demonstrated that Helicobacter pylori caused peptic ulcers and led to stomach cancer. Several investigators had suggested a relationship between H. pylori and ulcers, but doctors generally believed that ulcers were caused by stress or diet rather than a bacterial infection. The discovery led to an entirely new, simple, and relatively inexpensive treatment regime for stomach ulcers caused by H. pylori that consists of two different antibiotics taken simultaneously.

Bacteria are continuously producing, exchanging, and collecting genes for virulence, toxins, and resistance to antibiotics. With the development of multidrug-resistant bacterial pathogens, future bacteriologists are likely to turn their focus to fundamental aspects of bacterial physiology, metabolism, and genomic studies in the search for targets that are specific to bacteria. Clearly, basic knowledge of bacteriology will be essential to the development of new generations of “magic bullets” that can attack pathogenic bacteria—whether they cause acute or chronic diseases—without damaging human beings.

See Also Biomedicine and Health: Antibiotics and Antiseptics; Biomedicine and Health: Prions and Koch's Postulates; Biomedicine and Health: The Germ Theory of Disease; Biomedicine and Health: Virology; Physics: Microscopy.

bibliography

Books

Brock, Thomas D. Robert Koch: A Life in Medicine and Bacteriology. Madison, WI: Science Tech Publishers, 1988.

Bud, Robert. The Uses of Life: A History of Biotechnology. Cambridge, UK: Cambridge University Press, 1993.

Caldwell, Mark. The Last Crusade: The War on Consumption, 1862–1954. New York: Atheneum, 1988.

Carter, K. Codell, ed. Essays of Robert Koch. Translated by K. Codell Carter. New York: Greenwood Press, 1987.

Croddy, Eric. Chemical and Biological Warfare: An Annotated Bibliography. Lanham, MD: Scarecrow, 1997.

Daniel, Thomas M. Pioneers in Medicine and Their Impact on Tuberculosis. Rochester, NY: University of Rochester Press, 2000.

Debré, Patrice. Louis Pasteur. Baltimore, MD: Johns Hopkins University Press, 2000.

Drexler, Madeline. Secret Agents: The Menace of Emerging Infections. New York: Penguin Books, 2002.

Farmer, P., ed. The Global Impact of Drug-Resistant Tuberculosis. Boston, MA: Harvard Medical Schools, 1999.

Foster, William Derek. History of Medical Bacteriology and Immunology. London: William Heineman, 1979.

Hamlin, Christopher. A Science of Impurity: Water Analysis in Nineteenth Century Britain. Berkeley, CA: University of California Press, 1990.

Hare, Ronald. The Birth of Penicillin and the Disarming of Microbes. London: George Allen & Unwin, 1970.

Koch, Robert. “The Aetiology of Tuberculosis.” Translated by Dr. Max Pinner and Mrs. Berna Pinner. In American Review of Tuberculosis (March 1932). Reprinted in Source Book of Medical History, edited by Logan Clendening. New York: Dover Publications, Inc., 1942.

Lechevalier, Hubert A., and Morris Solotorovsky. Three Centuries of Microbiology. New York: Dover, 1974.

Margulis, Lynn. Symbiosis in Cell Evolution: Microbial Communities in the Archean and Proterozoic Eons. New York: W.H. Freeman, 1992.

Parascandola, John., ed. The History of Antibiotics: A Symposium. Madison, WI: American Institute for the History of Pharmacy, 1980.

Sagan, Dorion, and Lynn Margulis. The Garden of Microbial Delights: A Practical Guide to the Subvisible World. New York: Harcourt, 1988.

Silverstein, Arthur M. A History of Immunology. New York: Academic Press, 1989.

Tomes, Nancy. The Gospel of Germs: Men, Women, and the Microbe in American Life. Cambridge, MA: Harvard University Press, 1998.

Worboys, Michael. Spreading Germs: Disease Theories and Medical Practice in Britain, 1865–1900. New York: Cambridge University Press, 2000.

Web Sites

Quill Graphics. “Cells Alive!” http://www.cellsalive.com (accessed April 4, 2008).

Florida State University. National High Magnetic Field Laboratory, Tallahassee, Florida. “Molecular Expressions: Exploring the World of Optics and Microscopy.” http://micro.magnet.fsu.edu (accessed April 5, 2008).

Lois N. Magner

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