Bacteriology History: Germ Theory, Vaccines & Antibiotic Resistance

Bacteria, along with other microorganisms, were first observed and described in 1683 by Antoni van Leeuwenhoek (1632-1723), a Dutch draper, instrument maker, and member of the Royal Society. Van Leeuwenhoek, who ground tiny lenses and built his own single-lens microscopes, called the entities he had seen ‘animalcules,’ a group that we now believe to have included bacteria as well as protozoa.

Sporadic observations of microorganisms continued through the eighteenth century. John T. Needham (1713-81), Comte de Buffon (1707-88), and Lazzaro Spallanzani (1729-99) conducted experiments and debated the possibility of spontaneous generation of microorganisms from organic matter. Linnaeus included Leeuwenhoek’s animalcules in his Systema Naturae under Vermes, in a class he called Chaos, which contained a species called Chaos infusorium.

These temporally and geographically isolated observations, descriptions, and classifications were not signs of an emerging scientific specialty. Bacteriology became an institutionalized specialty only after 1870, when the association between specific microorganisms and infectious diseases came to mean that the study of bacteria was recognized as important for medicine and public health.

Improvements in the quality of microscopes at the beginning of the nineteenth century brought ‘infusoria’ back to some scientists’ attention, but while better lenses minimized chromatic aberration, the use of the new microscopes did not necessarily lead to agreement as to what was being observed. A German naturalist and professor of zoology in Berlin, Christian Gottfried Ehrenberg, for example, devoted extensive attention to the classification and description of infusoria.

Ehrenberg believed that infusoria were by no means simple organisms, but were equipped with complex organ systems, including elaborate ‘polygastric’ digestive systems that he was able to observe with his new achromatic microscope.

Ehrenberg’s observations of the complex morphology of microorganisms fit well with his ideas about the stability of species and his opposition to notions of spontaneous generation, just as the ideas of his opponents (such as the French biologist Felix Dujardin), who disputed morphological analogies between infusoria and other organisms, depended not simply on observations under the microscope but also on their beliefs about evolution, cell theory, the genesis of life, and so forth.

Questions about classification, morphology, and generation continued to dominate interest in microorganisms in Germany from the 1840s through the 1870s. In 1845, Karl Theodore von Siebold (1804-85), a zoologist at the University of Freiburg, reclassified the infusoria by drawing a distinction between bacteria and protozoa.

A proponent of the cell theory of life, he assigned bacteria to the plant kingdom and installed unicellular microorganisms as the simplest organisms in both the plant and the animal kingdoms. General biological issues were also at stake in debates between Ferdinand Cohn (1828-98) and Carl von Nageli (1817-91), who disagreed as to whether bacteria could be divided into stable species, as well as about evolution and the possibility of spontaneous generation.

Nageli emphasized the evolutionary continuity and unity of life, and saw bacteria (or schizomycetes, as he called them) as pleomorphic and flexible, and thus also impossible to classify into distinct species. Cohn, by contrast, emphasized the stability and fixity of the bacterial species he was classifying.

Cohn’s ideas about the fixity of bacterial species were of great importance for Robert Koch’s version of the germ theory of disease: The constant association between a specific germ and a specific disease made sense only within a framework in which bacteria could be reliably classified into distinct and fixed species.

In the 1850s, Louis Pasteur (1822-95), a chemist by training, turned to the study of microorganisms, focusing his investigations initially on practical problems in the production of alcohol, wine, and beer. Pasteur’s studies, however, also addressed two more general and, at the time, contentious problems: the theory of fermentation and the (im)possibility of spontaneous generation. Pasteur was not the first scientist to suggest that fermentation was a result of the activity of living microorganisms.

Charles Cagniar de Latour (1777-1859), Theodor Schwann (1810-82), and Friedrich Kutzing (1807-93) had made such claims earlier; while Justus Liebig, the preeminent German chemist of the first half of the nineteenth century, saw fermentation as a purely chemical process analogous to the process of digestion. Pasteur established that living microorganisms were necessary for fermentation, showed that some microorganisms (like yeast) could grow and multiply in the absence of oxygen, and that different living ferments caused specific types of fermentation (lactic, alcoholic, acetic, butyric, etc.).

Defining fermentation as ‘life without air,’ Pasteur emphasized the importance of the process of fermentation and putrefaction in the general ‘economy of nature.’ Since at the time, diseases were often understood as processes of fermentation and putrefaction, Pasteur’s studies suggested an analogy for investigations of the role of microbes in disease etiology. Already in 1859, before he actually turned his attention to the study of infectious diseases, Pasteur argued that contagious diseases are likely ‘‘to owe their existence to similar causes’’ as specific fermentations.

Moreover, the demonstration that different microbial organisms are responsible for different types of fermentation established the notion of specificity, which became a central idea in the germ theory of disease. (In 1897, Eduard Buchner isolated an enzyme he called zymase and showed that, contrary to Pasteur’s claims, fermentation can in fact take place outside of a living yeast cell.)

Pasteur’s studies of fermentation were in part motivated by his belief that life processes are fundamentally distinct from the processes taking placed in inorganic matter. Just asfermentation required the action of live yeast ‘globules,’ so, according to Pasteur, even the smallest and simplest living organisms could originate only from other living beings, and any form of heterogenesis was impossible.

Historically, support for spontaneous generation in France was associated with materialist, atheist, and revolutionary ideas; and given this history, Pasteur’s debate with F.A. Pouchet (1800-72), who claimed to have observed the generation of microorganisms from organic matter and pure air, had scientific, religious, philosophical, and political implications. Pasteur’s elegant series of experiments - including demonstrations with swan-necked bottles and the incubation of microorganisms in pure mountain air - was designed to show that if the hay infusion and air were indeed sterile, no microorganisms could be recovered.

Pasteur’s victory ended the spontaneous generation debate in France. However, the controversy erupted again in the 1870s in Britain, when H.C. Bastian’s claims of heterogenesis in his book on The Beginnings of Life were disputed by John Tyndall in his studies on sterilization. Though Pasteur’s work on spontaneous generation, like his work on fermentation, was not medically motivated, acceptance of the belief that bacteria originate from other bacteria (and breed true) was crucial for the establishment of the bacterial etiology of diseases.

Pasteur turned to the study of the association between microorganisms and disease only in the mid-1860s when he investigated pebrine, a disease of silkworms, and again in the 1870s and 1880s when he investigated chicken cholera, anthrax, and rabies, and developed vaccines against these diseases.

As a scientific accomplishment, the bacteriological revolution rested on the assertion that specific microorganisms cause specific diseases and that no infectious disease originates de novo, without the presence of a causative pathogenic organism. In this formulation, the germ theory of disease has been traditionally associated with the work of Pasteur, Robert Koch (1843-1910), and Joseph Lister (1827-1912).

However, its establishment was a long and protracted process, and what is today understood as ‘the’ germ theory of disease was in the middle decades of the nineteenth century far from a single unified theory. Scientists as well as practicing physicians, veterinarians, and epidemiologists commonly explained infectious or contagious diseases as resulting from some particulate, usually organic, and occasionally even living matter (which could be described as a poison, a germ of disease, a microzyme, a fungus, a bacillus, or a vibrio) that was either generated in particular locations (for example, from decomposing organic matter), transmitted directly from person toper- son, or passed on indirectly via water or ‘fomites.’

Many diseases were seen as forms of putrefaction and fermentation; and when the chemical theory of fermentation was still generally accepted, the pathological process was believed to be initiated by chemical changes affecting organic matter that made it ‘zymotic’ and allowed for the transmission of its fermentative powers to new sufferers.

Although they shared a belief that infectious diseases were distinct entities and that specific microorganisms were causally implicated in their origin and spread, the germ theory developed by Pasteur and his students was significantly different from that of Koch and his collaborators. Because of his work on fermentation, Pasteur tended to view microorganisms as adaptable to their environment and physiologically flexible.

Accordingly, in his research on infectious diseases he focused on modifications of virulence and immunity and the development of vaccines (most famously against anthrax and rabies). In contrast, Koch’s medical perspective, and perhaps also his military experience (he had served in the Franco-Prussian War and later surrounded himself with other army doctors), led him to view microorganisms as deadly enemies to be hunted down in all nooks and crannies and eradicated.

Moreover, Koch’s commitment to the idea of the specificity, stability, and distinctiveness of bacterial species played a key role in his and his collaborators’ etiological investigations, which associated specific and stable bacterial species with specific diseases.

Koch began his bacteriological experiments while working as a country doctor in eastern Prussia. In 1876, hedescribed the entire life cycle (including the spore stage) of the anthrax bacillus, and demonstrated how to grow pure cultured colonies of the anthrax bacteria on solid media.

Though Koch was not the first to suggest that anthrax was caused by bacilli (he was preceded by the Frenchman Casimir Devaine, 1812-82), the presentation of his experiments in the Breslau laboratories of Ferdinand Cohn generated enthusiasm not only because it posited a credible mode of transmission of anthrax and explained the known epidemiological facts about this disease, but also because Koch’s new experimental techniques advanced the researchers’ ability to manipulate microorganisms in the laboratory and suggested new ways to conduct etiological investigations.

In 1880, Koch moved to Berlin and continued both his etiological research and his methodological innovations. In 1882, hedescribed the bacilli responsible for tuberculosis and formulated his famous postulates, the criteria to be met when establishing a bacterial etiology for any disease (Koch, 1882).

In the last two decades of thenineteenth century, Koch and his students and collaborators identified the specific microorganisms responsible for diphtheria (Loeffler, 1884), glanders (Loeffler, 1882), typhoid (Gaffky, 1884), cholera (Koch, 1884), and tetanus (Kitasato, 1889).

Others, using Koch’s methods of isolation, pure culture, and inoculation, identified and described the specific organisms responsible for the plague (Yersin, 1894), dysentery (Shiga, 1898), gonorrhea (Neisser, 1879), leprosy (Hansen, 1873; Neisser, 1880), and pneumonia (Sternberg and Pasteur, 1881), among others. In 1905, Fritz Richard Schaudinn (1871-1906) and Erich Hoffman (1868-1959) identified aspirochete now known as Treponema pallidum as the microorganism responsible for syphilis. Koch’s etiological endeavor was extended in the late nineteenth/early twentieth century to the identification of specific viruses responsible for human, animal, and plant diseases and to infections transmitted by microorganisms carried by animal vectors.

Discoveries of such associations between bacteria and disease continue to this day. In the 1980s, forexample, Willi Burgdorfer isolated a specific spirochete (now known as Borrelia burgdorferi) as the causative agent of Lyme disease, and two Australian researchers, Robin Warren and Barry Marshall, showed that Helicobacter pylori, ahelicalbacterium found in human stomachs, was a cause of stomach ulcers.

The bacteriological revolution of the late nineteenth century led not only to changes in the way in which diseases were understood, but also to changes in the organization of medical research. Within a few decades, bacteria became the central preoccupation of a variety of medical researchers and physicians working in hospitals, public health laboratories, and medical schools and faculties. The precise institutional location of bacteriology differed in different countries: In Germany, for example, bacteriologists tended to be appointed to chairs of hygiene, while in the United States they were more likely to be employed in departments of pathology.

But while finding an appropriate institutional setting for bacteriology took time, the hope for medical progress generated by bacteriological discoveries was a stimulus for the establishment of a number of major medical research institutes such as the Pasteur Institutes (1888), the Lister Institute in London (1893), the Koch Institute in Berlin (1892), and the Rockefeller Institute in New York (1902). All of these institutes shared a commitment to laboratory studies of disease, although they differed in the scope of the research that was envisaged and performed.

In addition to sponsoring research, these institutes disseminated the knowledge of medical bacteriology to clinicians and public health professionals, and taught the laboratory skills and methods of sterilization, bacterial cultivation, staining, and identification essential to all bacteriological work. Of special importance here were the courses offered by Koch and his collaborators.

Although the scientific successes of bacteriologists were publicly acclaimed and widely celebrated, the new understanding of infectious diseases did not lead to immediate or dramatic changes in clinical approaches to specific diseases or in public health measures. Generalizations here are made more difficult by the fact that changes in public health measures were local events, and the policies implemented in London were not the same as those followed in Paris, Berlin, or New York, not to mention the whole wide world beyond such metropolitan centers.

Moreover, the introduction of bacteriologically informed policies directed against a particular disease (e.g., diphtheria) or a specific mode of transmission (e.g., via contaminated water) cannot be taken as representative of measures designed to combat other conditions (e.g., tuberculosis) or modes of transmission (e.g., contaminated food). It is clear, however, that there was much continuity in the sanitary measures taken before and after the 1870s.

Many sanitation measures taken against disease in the 1850s and 1860s were premised on the idea that illness was due to the transmission of some kind of organic poison, ‘seed,’ ‘ferment,’ or ‘germ’ that could be carried by water or air. The discovery that that seed or germ was a specific bacterium did not necessarily change the methods used to guard against contamination or transmission.

Accordingly, efforts to provide safe water predated the identification of the cholera vibrio or the typhoid bacillus (and were not uniformly successful either before or after that identification), and the disinfection of houses following a case of measles or scarlet fever was a common procedure both before and after it was known that specific microorganisms caused these childhood afflictions.

The new knowledge also did not eliminate some of the older fears of the dangers posed, for example, by bad odors or sewer gas, even if in the 1880s and 1990s ‘sewer gas’ was believed to carry dangerous microbes rather than the unidentified poisons or miasmas it was supposed to have carried in the 1850s or1860s.

In the longer run, however, public health measures didcome to be informed by the new knowledge of bacteriology. The diphtheria antitoxin developed in the 1890s by an associate of Koch’s, Emil Adolf von Behring (1854-1917), and by Pasteur’s collaborator Emile Roux (1853-1933) became available to doctors relatively quickly. Campaigns against spitting, the establishment of sanatoria, and the isolation of advanced cases were directed at combating tuberculosis.

Water testing gradually shifted towards bacteriologically informed approaches and came to focus more specifically on fecal contamination - even if the criteria of what constituted such contamination continued to be debated. The discovery of healthy carriers of diphtheria and then of typhoid bacilli was rapidly incorporated into public health policies in Germany and the United States.

In 1903, a systematic campaign to isolate typhoid sufferers and others harboring the bacilli was conducted in Germany, while the most famous of the healthy carriers was Mary Mallon, an Irish cook popularly known as ‘‘Typhoid Mary,’’ who was imprisoned in New York for more than 30 years because she was considered a danger to public health. Although Mallon’s imprisonment was unusual, her case is often taken as symptomatic of the general narrowing of concerns that the bacteriological revolution brought to public health policies.

As the ‘new public health’ gradually replaced all hygienic or sanitarian reforms, policies became more focused on the specific modes of transmission of germs and sources of infection than on general social and environmental conditions. Bacteriologically informed approaches tended to be more reductionistic in their biological understanding of infectious diseases, and more focused on (immune or susceptible) individuals than on populations and environments.

Bacteriological research in the first half of the twentieth century focused chiefly on studies of immunity to bacteria, on immunological methods of diagnosing bacterial infections (as in the Widal agglutination test for typhoid developed in 1896, or the Wasserman test for syphilis discovered in 1906), and on investigations of chemical and immunological aspects of bacterial specificity (e.g., Oswald Avery’s multifaceted research on the pneumococcus, or the streptococcus classification work by Rebecca Lancefield).

Scientists interested in microorganisms in this period also began to investigate bacterial physiology, biochemistry, and genetics (e.g., Marjorie Stephenson, Albert Jan Kluyver, Paul Fildes). These developments were continued in the post-World War II period, when microorganisms became the favorite experimental objects for molecular biologists and geneticists. Others attempted to combine bacteriological and epidemiological approaches (e.g., W.W.C. Topley and Major Greenwood in the United Kingdom, and Leslie Webster in the United States).

New chemotherapeutic substances to treat infectious diseases included salvarasan, shown in 1910 by Paul Ehrlich to be active against syphilis and trypanosomiasis, followed in the 1930s by sulfanilamide, which Gerhard Domagk (1895-1964) and his coworkers at I.G. Farben showed to be effective against a whole range of infections. Penicillin first became available during World War II, and other antibiotics, such as streptomycin, were isolated in the years after the war.

The so-called epidemiological transition - the change from infectious to degenerative diseases as major causes of mortality in Europe and North America - brought with it hopes of similar control and eradication of infectious diseases in the developing world. The immediate causes of the transition (as well as its evolutionary assumptions) - particularly the role of technologies based on microbiological knowledge, including immunization and chemotherapy - continued to be debated.

The discussion was stimulated by the writings of the British demographer and epidemiologist Thomas McKeown (1976), who argued that the epidemiological transition in Europe and the United States was a result of better nutrition, changes in family size, and better living conditions rather than an outcome of any medical measures targeted at specific diseases or their causes.

While many scholars agreed that specific therapies (such as the use of diphtheria antitoxin or the introduction of antibiotic treatment for tuberculosis) became available only after the mortality from these diseases had begun to decline, others used historical and demographic studies to show the significance of public health and sanitation measures as well as some vaccines. Moreover, whatever the historical precedents, in the decades following World War II mortality from infectious disease appeared to be declining in the developing world.

The optimistic hope of achieving worldwide control over infectious diseases gave way to a new concern about the emergence of new diseases (such as AIDS) and the reemergence of certain old infections such as tuberculosis or dengue fever.

Initially brought to public attention by Stephen Morse (1995) and Joshua Lederberg et al. (1992), the concerns about emergent and re-emergent infectious diseases signaled a number of distinct dangers (the antibiotic resistance of an increasing number of pathogens, the AIDS epidemic, transfer of infections across species, the effects of encroachments on natural habitats, etc.) whose causes were social (travel, globalization, man-made environmental change, the use of antibiotics, privatization of health care, and the collapse of some public health systems) as well as biological, and whose consequences were seen to be global, potentially affecting developed as well as developing countries.

To this day, however, the effects of these new threats are distributed among developed and developing countries as unequally as ever.