Adaptation or selection? Old issues and new stakes in the postwar debates over bacterial drug resistance

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Abstract

The 1940s and 1950s were marked by intense debates over the origin of drug resistance in microbes. Bacteriologists had traditionally invoked the notions of ‘training’ and ‘adaptation’ to account for the ability of microbes to acquire new traits. As the field of bacterial genetics emerged, however, its participants rejected ‘Lamarckian’ views of microbial heredity, and offered statistical evidence that drug resistance resulted from the selection of random resistant mutants. Antibiotic resistance became a key issue among those disputing physiological (usually termed ‘adaptationist’) vs. genetic (mutation and selection) explanations of variation in bacteria. Postwar developments connected with the Lysenko affair gave this debate a new political valence.

Proponents of the neo-Darwinian synthesis weighed in with support for the genetic theory. However, certain features of drug resistance seemed inexplicable by mutation and selection, particularly the phenomenon of ‘multiple resistance’—the emergence of resistance in a single strain against several unrelated antibiotics. In the late 1950s, Tsutomu Watanabe and his collaborators solved this puzzle by determining that resistance could be conferred by cytoplasmic resistance factors rather than chromosomal mutation. These R factors could carry resistance to many antibiotics and seemed able to promote their own dissemination in bacterial populations. In the end, the vindication of the genetic view of drug resistance was accompanied by a recasting of the ‘gene’ to include extrachromosomal hereditary units carried on viruses and plasmids.

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,

They 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

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.6

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

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