Robert Koch: the grandfather of cloning?

This year marks the centenary of Robert Koch's Nobel Prize for discovering the cause of tuberculosis. Koch was also the first scientist to isolate the anthrax and cholera microbes. Yet perhaps one of his greatest contributions to biology is the least appreciated: his method for propagating individual colonies of bacteria on plates, a technique that came to be called cloning.     

Robert Koch and the white death: from tuberculosis to tuberculin

The German medical bacteriologist Robert Koch is commonly considered one of the founding fathers of medical bacteriology. His investigations into the aetiology of tuberculosis uncovered the pathogen of this condition, the tubercle bacillus today known as Mycobacterium tuberculosis, in 1882. This work can be seen as a cornerstone of contemporary medical bacteriology, its technologies and methods. It has often been asked how such successful research connected to the tuberculin episode of 1890/91, when Koch produced a medicine for that disease, which spectacularly failed when applied in practice. The analysis concentrates on the path of mostly experimental investigations which Koch followed between 1882 and 1890. From Koch's laboratory notes it becomes clear that tuberculin therapy did in fact work in Koch's laboratory, even though it failed to do so almost anywhere else. The clue to this contradictory picture lies in the peculiar nature of Koch's understanding of tuberculosis as a disease e.g. his reliance an animal experiments, which essentially differed from what many of his contemporaries held as essentials of that condition.     

Robert Koch

This article traces the origins of bacteriological research, with particular attention to the role of Robert Koch, and his postulates, on infectious agents. By chronologically following Koch's work on anthrax, germ photography and tuberculosis, it shows how the visual representation of germs transformed laboratory research in medical science.     

A harmony of illusions: clinical and experimental testing of Robert Koch’s tuberculin 1890–1900

One of Ludwik Fleck’s ideas about the development of scientific knowledge is that—once a system of interpretation is in place—the process that follows can be characterised as one of inertia: any new evidence comes under a strong pressure to be incorporated into the established frame. This can result in what Fleck called a harmony of illusions (Harmonie der Täuschungen) when contradictory evidence becomes almost invisible or is incorporated into the established frame only by huge efforts.The paper analyses early explanations of the tuberculin reaction as a case study of Fleck’s argument. For Robert Koch, who had presented tuberculin in 1890, the compound was supposed to be a diagnostic tool and a cure for tuberculosis. His conception of its effect was rather peculiar, but strictly in line with ideas on the pathogenesis of infectious diseases he had developed much earlier. After tuberculin was released in late 1890, whether Koch’s conception was convincing depended on the place that a given observer had in the medical world in late-nineteenth-century Germany. Inside Koch’s group, the status of the tuberculin reaction remained stable and tuberculin retained its value as a diagnostic and curative tool. On the other hand, observers from outside that thought collective, and in particular from clinical medicine, soon pointed to flaws in its conception. These critics developed a rather different picture of tuberculin as a mysterious and dangerous drug. No reconciliation followed and what we find instead in German medicine around the year 1900 is the presence of rather contradictory concepts and practices surrounding Koch’s wonder cure.     

Consumption, silicosis, and the social construction of industrial disease.

In the wake of the bacterial revolution after Robert Koch identified the tuberculosis bacillus, medical and public health professionals classified the various forms of consumption and phthisis as a single disease--tuberculosis. In large measure, historians have adopted that perspective. While there is undoubtedly a great deal of truth in this conceptualization, we argue that it obscures almost as much as it illuminates. By collapsing the nineteenth-century terms phthisis and consumption into tuberculosis, we maintain that historians have not understood the effect of non-bacterial consumption on working-class populations who suffered from the symptoms of coughing, wasting away, and losing weight. In this essay, we explore how, in the nineteenth century, what we now recognize as silicosis was referred to as miners' "con," stonecutters' phthisis, and other industry-specific forms of phthisis and consumption. We examine how the later and narrower view of the bacterial origins of tuberculosis limited the medical professions' ability to diagnose and understand diseases caused by industrial dust. This paper explores the contention that developed at the turn of the century over occupational lung disease and tuberculosis and the circumstances that led to the unmasking of silicosis as a disease category.     

Money and microbes: Robert Koch, tuberculin and the Foundation of the Institute for Infectious Diseases in Berlin in 1891

Starting from an assessment of how far Robert Koch's bacteriology had developed in the late 1880s this paper attempts to analyse different aspects of the process that led to the foundation of the Berlin Institute for Infectious Diseases in 1891. With the development of his supposed cure against tuberculosis, tuberculin, Koch attempted to give his research a new direction, earn a fortune with the profits and become more independent of Prussian government officials who, up to that point, had had a major influence on his career. In the period following the presentation of the cure in autumn 1890, however, it became clear that tuberculin's value in treatment was at most dubious. Thus, the failure of tuberculin meant that Koch had to drop his own plans and accommodate those of the Prussian Ministry of Culture. As a result he assumed directorship of the newly founded Institute for Infectious Diseases in Berlin. Even though this was definitely a prestigious position it reaffirmed Koch's dependency on Prussian government officials and was by no means the kind of institution he had aimed for at the outset.     

Historical perspectives on the etiology of tuberculosis

Robert Koch's 1882 demonstration that the tubercle bacillus was the true cause of tuberculosis established a new understanding of causation in medicine. This scientific breakthrough set in motion an etiological revolution with vast implications for the control of infectious disease, and its ramifications are still being felt today.     

Peptide chemistry at Oxford before the Second World War.

The largely unnoticed and unpublished peptide science interests of Nobel Laureate Sir Robert Robinson at Oxford during the period 1936-1939 are outlined.     

Linking cause and disease in the laboratory: Robert Koch's method of superimposing visual and 'functional' representations of bacteria

Robert Koch based his claim that specific microorganisms cause particular diseases on laboratory studies. This paper examines how Koch set up a plausible line of argument by using special methods of representing bacteria. One kind of representation consisted in making the bacteria visible; the other mode of representation was based on disease phenomena. Using a range of techniques of isolating and controlling microorganisms, Koch combined these different modes of representation in a way that made his claims convincing. Thus, the microorganism as a specific cause of disease emerged through a chain of repeated processes of selection and representation in the laboratory.     

Adaptive designs from the viewpoint of an academic biostatistician

This is a discussion of the following three papers appearing in this special issue on adaptive designs: 'FDA's critical path initiative: A perspective on contributions of biostatistics' by Robert T. O'Neill, 'A regulatory view on adaptive/flexible clinical trial design' by H. M. James Hung, Robert T. O'Neill, Sue-Jane Wang and John Lawrence; and 'Confirmatory clinical trials with an adaptive design' by Armin Koch.     

Opening the adaptive toolbox

This is a discussion of the following three papers appearing in this special issue on adaptive designs: 'A regulatory view on adaptive/flexible clinical trial design' by H. M. James Hung, Robert T. O'Neill, Sue-Jane Wang and John Lawrence; 'Confirmatory clinical trials with an adaptive design' by Armin Koch; and 'FDA's critical path initiative: A perspective on contributions of biostatistics' by Robert T. O'Neill.     

Challenges in implementing adaptive designs: comments on the viewpoints expressed by regulatory statisticians

This is a discussion of the following three papers appearing in this special issue on adaptive designs: 'FDA's critical path initiative: A perspective on contributions of biostatistics' by Robert T. O'Neill; 'A regulatory view on adaptive/flexible clinical trial design' by H. M. James Hung, Robert T. O'Neill, Sue-Jane Wang and John Lawrence; and 'Confirmatory clinical trials with an adaptive design' by Armin Koch.     

Attempts to revive Mycobacterium tuberculosis from 300-year-old human mummies

Environmental persistence of Mycobacterium tuberculosis is subject to speculation. However, the reality that infected postmortem tissues can be a danger to pathologists and embalmers has worrisome implications. A few experimental studies have demonstrated the organism's ability to withstand exposure to embalming fluid and formalin. Recently, a failure was reported in an attempt to resuscitate an original isolate of Robert Koch to determine the lifetime of the tubercle bacillus. The present study also considers a historical approach to determine persistence under favorable environmental conditions. It asks whether acid-fast forms observed in tissues of 300-year-old Hungarian mummies can be resuscitated. Finding organisms before the advent of antibiotics and pasteurization may yield valuable genetic information. Using various media modifications, as well as guinea pig inoculation, an attempt was made to culture these tissues for M. tuberculosis. In addition, a resuscitation-promoting factor, known to increase colony counts in high G+C bacteria, was applied to the cultures. Although an occasional PCR-positive sample was detected, no colonies of M. tuberculosis were obtained. Our results may indicate that the life span of the tubercle bacillus is less than a few hundred years, even though in the short run it can survive harsh chemical treatment.     

The blood from Auschwitz and the silence of the scholars

The Kaiser Wilhelm Institute for Anthropology, Human Genetics and Eugenics in Berlin-Dahlem was the centre of scientific racism in Nazi Germany. Its bad history culminated in a research project to analyse the molecular basis of racial differences in the susceptibility to various infectious diseases such as tuberculosis. Josef Mengele, a former postdoc of the director of the institute, Otmar von Verschuer, collected blood samples and other material in Auschwitz from families and twins of Jews and Gypsies. The blood samples were analysed by Günther Hillmann in the Berlin laboratory of Nobel Prize winner Adolf Butenandt. Butenandt had just moved to Tübingen. The project was paid for by the Deutsche Forschungsgemeinschaft. Butenandt, Hillmann and von Verschuer made scientific careers in the Federal Republic. To the present day this past has not been acknowledged by the Max-Planck-Gesellschaft as part of its history.     

In vitro fertilization, the Nobel Prize, and human embryonic stem cells

Robert Edwards was awarded the 2010 Nobel Prize in Physiology or Medicine for the development of human in vitro fertilization. His work not only provided the means to overcome many forms of infertility, but it also enabled research on early stages of human embryos and the derivation of human embryonic stem cells.     

A consultant's perspective on the regulatory hurdles to adaptive trials

This is a discussion of the following two papers appearing in this special issue on adaptive designs: 'A regulatory view on adaptive/flexible clinical trial design' by H. M. James Hung, Robert T. O'Neill, Sue-Jane Wang and John Lawrence and 'Confirmatory clinical trials with an adaptive design' by Armin Koch.     

Methodological developments vs. regulatory requirements

This is a discussion of the following three papers appearing in this special issue on adaptive designs: 'FDA's critical path initiative: A perspective on contributions of biostatistics' by Robert T. O'Neill, 'A regulatory view on adaptive/flexible clinical trial design' by H. M. James Hung, Robert T. O'Neill, Sue-Jane Wang and John Lawrence; and 'Confirmatory clinical trials with an adaptive design' by Armin Koch.     

Epidemiological causality

Epidemiological methods, which combine population thinking and group comparisons, can primarily identify causes of disease in populations. There is therefore a tension between our intuitive notion of a cause, which we want to be deterministic and invariant at the individual level, and the epidemiological notion of causes, which are invariant only at the population level. Epidemiologists have given heretofore a pragmatic solution to this tension. Causal inference in epidemiology consists in checking the logical coherence of a causality statement and determining whether what has been found grossly contradicts what we think we already know: how strong is the association? Is there a dose-response relationship? Does the cause precede the effect? Is the effect biologically plausible? Etc. This approach to causal inference can be traced back to the English philosophers David Hume and John Stuart Mill. On the other hand, the mode of establishing causality, devised by Jakob Henle and Robert Koch, which has been fruitful in bacteriology, requires that in every instance the effect invariably follows the cause (e.g., inoculation of Koch bacillus and tuberculosis). This is incompatible with epidemiological causality which has to deal with probabilistic effects (e.g., smoking and lung cancer), and is therefore invariant only for the population.     

Prediction of the Most Probable B Cell Epitopes from (DnaK) Adhesin of Mycobacterium tuberculosis Using Immunoinformatic tools

International Journal of Peptide Research and Therapeutics - Tuberculosis is a contagious bacterial infection disease caused by the Koch bacillus (Mycobacterium tuberculosis: M.tb) that usually...     

Pasteur, Koch and American bacteriology

This study traces American awareness of the work of Louis Pasteur and Robert Koch from the 1860s to the 1890s. In the years before the Civil War, American interest in germ theories had appeared at times of epidemics and persisted to a limited extent among physician-microscopists. Discussions of Pasteur's work occurred primarily in the context of spontaneous generation and antisepsis. Few Americans imitated his work on immunology or studied with Pasteur, but his work on immunity influenced their faith in the potential of bacteriology as a solution to problems of infectious disease. Koch's discoveries of the bacterial agents of tuberculosis and cholera stimulated American medical and public health interest in bacteriology in a more practical way. Americans learned Koch's methods by taking his courses and imported them directly into their own laboratories. A context of enthusiasm for science, educational reform, and problems of infectious disease associated with urbanization and changes in agriculture aided the growth of bacteriology in the American context.