Adaptation or selection? Old issues and new stakes in the postwar debates over bacterial drug resistance
Introduction
The development of antimicrobial drugs, particularly antibiotics, has long been touted as one of the great medical success stories of the twentieth century. In 1935, publication of the effectiveness of Protonsil against streptococcal infection ushered in the rapid development of sulfa drugs, overtaken within a decade by the promise of penicillin and streptomycin.1 Yet troubling observations that infectious agents could become resistant to such drugs surfaced early on in bacterial chemotherapy.2 As William Summers has remarked, ‘No sooner were new antibiotics announced than reports of drug resistance appeared: sulfonamide resistance in 1939, penicillin resistance in 1941, and streptomycin resistance in 1946’ (Summers, 2002, p. xix).3 Thus, even as observers at the end of World War II hailed the end of infectious diseases, drug resistance was already a recognized problem—and its origin, like the mechanism of antibiotic action, remained unknown.
In the early postwar period, the antibiotic resistance problem became a testing ground for different views on bacterial variation. Many scientists resorted to explanations of ‘adaptation’ and ‘training’ to account for microbial drug resistance. Throughout the 1930s, bacteriologists had shown that microbes could adapt to their nutritional environment by synthesizing new enzymes. These acquired characteristics could persist for several generations, and some researchers thought they could become hereditary. Yet these changes were regarded as induced, not mutational, and there was little reason to differentiate between individual cell and culture in conceptualizing the adapted bacteria. In the 1940s, a new generation of bacterial geneticists began challenging the adaptationist explanation for bacterial variation in general and drug resistance in particular, arguing that the trait appeared by random mutation as a strictly heritable trait in microbes, and that exposure of a population of bacteria to antibiotics simply selected for this pre-existing variant.
At stake in this debate over drug resistance was the nature of bacteria as organisms. Bacteria had not previously been regarded as ‘genetic’ organisms—they did not possess chromosomes, nor could they exhibit Mendelian patterns of inheritance, since they lacked the morphological apparatus associated with the genetics of sexual reproduction. As Julian Huxley described bacteria in 1942,
Microbiologists did not need evidence of the same sort of hereditary determinants found in higher organisms to classify and characterize bacterial species.5 Yet bacteriologists’ interests in ‘physiologic plasticity’ had long been a source of frustration to some geneticists; in 1916, L. J. Cole and W. H. Wright contended that bacteriologists, by believing that conditions could induce changes in bacterial cultures and that these could become fixed, refused to abandon Lamarckianism.6They have no genes in the sense of accurately quantized portions of hereditary substance; and therefore they have no need for the accurate division of the genetic system which is accomplished by mitosis. The entire organism appears to function both as soma and germplasm and evolution must be a matter of alteration in the reaction system as a whole. That occasional ‘mutations’ occur we know, but there is no ground for supposing that mutations are similar in nature to those of higher organisms, nor, since they are usually reversible according to conditions, that they play the same part in evolution.4
Bacterial geneticists of the 1940s echoed Cole and Wright’s characterization, but in a changed context. The Lysenko affair—which resulted by 1949 in the Soviet suppression of Mendelian genetics as a manifestation of capitalist ideology—politicized debates everywhere over heredity and made charges of Lamarckianism especially polemical. At the same time, the neo-Darwinian synthesis provided a new theoretical framework for viewing drug resistance as the selection of random resistant mutants in a population of sensitive bacteria. Growing support for the genetic explanation of resistance fits well with what Stephen Jay Gould has called the ‘hardening of the modern synthesis’, as more pluralistic views of evolutionary change gave way to a strict emphasis on natural selection working on genetic variation as the mechanism for evolution at all levels (Gould, 1983).
Indeed, microbial drug resistance became an oft-cited exemplar of the principles of Darwinian genetic selection in the decades after World War II, marginalizing alternative explanations of resistance. The very language of the neo-Darwinian synthesis conflicted with a long tradition of bacteriological explanation: the evolutionary meaning of adaptation, now with strongly genetic overtones, threatened to displace the physiological meaning of adaptation, as bacteriologists had long used the term in discussing acquired traits.7 Yet, ironically, the thorough-going geneticization of bacteria by the 1960s ended up having a subversive effect on genetic orthodoxy, with its ‘nucleocentrism’ (Sapp, 1994). Although bacterial geneticists called upon their experiments on the origin of antibiotic resistance to demonstrate that mutation and selection could account for any bacterial variation, researchers eventually determined that most genes for antibiotic resistance were not carried on bacterial chromosomes. The understanding of gene had to be recast in order to include the extrachromosomal pieces of nucleic acid that carry resistance genes and are laterally transmitted between bacteria, even those of different species. This revised notion of the gene became operationalized in the use of engineered drug-resistant plasmids for cloning genes in the 1980s.
Section snippets
The problem of bacterial variation
Behind the skepticism about bacteria as true genetic organisms was an older controversy regarding the biological stability of bacterial cultures. At one level, the germ theory established—or, more accurately, posited—the biological constancy of bacteria as organisms. Robert Koch’s ‘postulates’ hinged on the assumption that a single bacterial species caused a single infectious disease. Koch made use of the taxonomic system for bacteria published in 1872 by botanist Ferdinand Cohn, who took
The fluctuation test
In the early 1940s, research by Max Delbrück and Salvador Luria offered a very different understanding of the source of bacterial variation.18 These two émigré researchers met in 1940 and began a fruitful collaboration on bacteriophage research, joining forces during the summers of 1941 at Cold
Drug resistance and debates over bacteria as genetic organisms
Bacterial geneticists were staking a greater claim than simply the mutational origin of antibiotic resistance. As Luria stated in 1946,
If a case could be made … for similarity of the processes of mutation in bacteria and in higher organisms—that is, for the existence of discrete, gene-like hereditary units in bacteria—then these organisms might prove to be invaluable material not only for the study of physiological genetics, but also for an attack on the problems of gene structure and
Plasmids from explanation to technology
Antibiotic resistance was not only a topic of scientific debate and public concern, but also a resource for manipulating bacteria in the laboratory. Because one could select positively for drug resistance (resistant variants being the only bacteria to multiply in culture media containing an antibiotic), antibiotics were used widely in laboratories of microbial genetics as a means of selection. In fact, even in sensitive bacteria, penicillin could be used to selectively promote the growth of
Conclusions
In the end, ‘adaptation versus mutation’ turned out to be a false dichotomy. In 1960, Jacob and Monod’s ‘operon’ model enabled a fruitful separation of questions of gene mutation from the cell’s response to the environment, or gene regulation.
Acknowledgements
Research on this project was supported by the author’s NSF CAREER grant, ‘Life science in the atomic age’, SBE 98-75012. Joshua Lederberg offered many excellent suggestions on earlier versions of this paper, and Evelyn Witkin provided valuable guidance to the literature and first-hand recollections. Attendants of presentations of this paper at Johns Hopkins’ Department of Science, Medicine, and Technology (2002), Princeton’s History of Science Program Seminar (2004), and UCLA’s Center for
References (179)
- et al.
Further observations on penicillin
Lancet
(1941) Bacterial plasmids: Their extraordinary contribution to molecular genetics
Gene
(1993)- et al.
Genetic regulatory mechanisms in the synthesis of proteins
Journal of Molecular Biology
(1961) Inheritance, variation, and adaptation
Plasmid (1952–1997)
Plasmid
(1998)Science, ideology, and structure: The Kol’tsov Institute, 1900–1970
- et al.
On the mechanism of the development of multiple-drug-resistant clones of Shigella
Japanese Journal of Microbiology
(1960) Medical and biological constraints: Early research on variation in bacteriology
Social Studies of Science
(1987)Stabilizing instability: The controversy over cyclogenic theories of bacterial variation during the interwar period
Journal of the History of Biology
(1991)From pneumonia to DNA: The research career of Oswald T. Avery
Historical Studies in the Physical and Biological Sciences
(1993)
Variation in bacteria in relation to agglutination both by salts and by specific serum
Journal of Pathology and Bacteriology
Studies on the chemical nature of the substance inducing transformation of pneumococcal types
Journal of Experimental Medicine
Antibiotics
Annual Review of Microbiology
A history of research on yeasts 7: Enzymic adaptation and regulation
Yeast
Biochemical genetics
Chemical Reviews
Sex cells: Gender and the language of bacterial genetics
Journal of the History of Biology
Construction and characterization of new cloning vehicles, II. A multipurpose cloning system
Gene
DNA restriction and modification mechanisms in bacteria
Annual Review of Microbiology
The emergence of bacterial genetics
Penicillin and the new Elizabethans
British Journal for the History of Science
Indirect selection and origin of resistance
Isolation of pre-adaptive mutants in bacteria by sib selection
Genetics
The development of bacterial chemotherapy
Antibiotics & Chemotherapy
Terminology of enzyme formation
Nature
Application of the pure-line concept to bacteria
Journal of Infectious Diseases
The life of a virus: Tobacco mosaic virus as an experimental model, 1930–1965
Mapping genes in microorganisms
Actions of antibiotics in vivo
Annual Review of Microbiology
Heredity, development and infection
Nature
Isolation of biochemically deficient mutants by penicillin
Journal of the American Chemical Society
Aspects of the problem of drug resistance in bacteria
Designs for life: Molecular biology after World War II
Genetic aspects of changes in Staphylococcus aureus producing strains resistant to various concentrations of penicillin
Annals of the Missouri Botanical Garden
Origin of bacterial resistance to antibiotics
Journal of Bacteriology
Bacteriophage resistant mutants in Escherichia coli
Genetics
Sur la fermentation du galactose et sur l’accutoumance des levures à ce sucre
Annales de l’Institut Pasteur, Paris
Fighting infection: Conquests of the twentieth century
Microbiology
Annual Review of Biochemistry
The bacterial cell in its relation to problems of virulence, immunity and chemotherapy
Drug resistance
Annals of the New York Academy of Sciences
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