I. Introduction
In 2010 India found itself mired in a medical crisis of diplomatic proportions. The crisis was precipitated by a paper (Kumaraswamy et al 2010) published in a subsidiary of the eminent medical journal The Lancet. The paper detailed its findings on a newly identified genetic sequence in bacteria that conferred resistance to most extant antibiotics and could be exchanged with ease between bacterial species and genera. The crisis that ensued in the wake of this publication, and the purchase it garnered on national and international media, not only catapulted antibiotic/antimicrobial (ABR/AMR) to a crisis of global proportions but also scripted India as the alleged epicentre of the imminent/unfolding crisis. The identity of “resistance” has slowly mutated from being an instrumentalisable mechanism used in the laboratory to probe bacterial transformation (and, to a lesser extent, a mostly containable clinical quiddity) to where its material and discursive circulation, in the contemporary global health arena, signals an ongoing/imminent crisis of global proportions. In what follows I will trace, in broad strokes, this historical arc of resistance.
Antibiotics entered the therapeutic scene of modern medicine in the first half of the 20th century. The crystallisation of “the germ theory of disease,” and the subsequent institutional and epistemic hold of the notion of “causal specificity”[1] in modern medicine, furthered investment in the idea of targeted therapeutic substances which would help vanquish the newly identified etiological agents. The commercialisation of penicillin during the second world war was followed by a host of other antibiotics. During the course of the past few decades antibiotics have become “mundane technologies” (Hinchcliffe et al. 2018, p.2)—infrastructural (Chandler 2020) to the production of health and food for the growing populations. Exemplary “magic bullets” in their heyday, antibiotics are now threatened by their increasing inefficacy in the face of wily bacterial strains which have developed the ability to resist them. Antibiotic resistance is both a natural phenomenon, relaying the dynamism and relational unfolding of (microbial) life as such, and also a particular historical discourse that warrants more careful understanding. In this piece I am not concerned with how best to apportion blame for rising rates of resistance—which is all too often and too simplistically attributed to the “irrational” use of these therapeutic and prophylactic substances. Here, I contend with the historical making of a crisis of global proportions. Although resistance had been observed since the initial use of penicillin,[2] its crystallisation into a crisis that besets the global has only materialised since the late 1980s. With the articulation of resistance as a concern for global health has come the concomitant focus on the Global South, and especially India, as the prime locus of consternation.
II. The Lab and the Clinic
In a passage tucked away towards the end of the The Human Condition, Hanna Arendt compared modern motorisation to “the mutation which…goes on before our eyes in those small living organisms which we fought with antibiotics and which mysteriously have developed new strains to resist us” (1958, p. 323). Arendt wielded resistance as a metaphor but it derived its comparative force through its “mysteriousness.” In the clinic, up until the 1980s or so, this is how resistance seems to have been apprehended—a mysterious presence the recourse to which was usually to switch antibiotics or prescribe varying combinations of the drugs. If resistance remained mysterious in the clinics and something to be dealt with empirically as and when it arose in therapeutically challenging scenarios, then in the laboratories, on the other hand, with the growing recognition of bacteria in the early 1940s as genetic organisms, antibiotic resistance presented itself as the perfect modality through which to probe transformation in bacteria. Scientists used the application of sub-therapeutic quantities of antibiotics in the laboratories to select for mutant strains. The prevailing view at this time recognised selection, under antibiotic pressure, of statistically random mutant lifeforms as the primary mode of bacterial transformation. Resistance, understood to result from the colonisation of mutant bacterial strains which passed on their genetic endowment through vertical forms of hereditary transfer, was seen as exceptional and infrequent.
Soon, however, things began to change with the growing recognition of non-Mendelian or non-vertical modes of genetic transfer—referred to as horizontal or lateral gene transfer. Joshua Lederberg, a molecular geneticist based in the USA, and Tsutomu Watanabe, a microbiologist working halfway across the world in Japan, are both central to how this story unfolded. Lederberg’s experiments in the 1950s demonstrated that extra-chromosomal genetic material—smaller genetic fragments present independently of the chromosomal DNA—could be exchanged between individual bacteria. Lederberg worked with these “plasmids” that could be exchanged through various modes of horizontal transfer. During the time that the work on these non-Mendelian modes of genetic transmission was gaining ground in laboratories in the USA, on the other side of the Pacific, Japanese patients were suffering from bouts of multiple drug-resistant Shigella infections. These infections were observed to be simultaneously resistant to multiple antibiotics. The explanation for the co-incidence of these multiply resistant strains could not be sought in the occurrence of statistically random genetic mutations. What was even more perplexing about these infections was that the bacteria were often found to harbour resistance to antibiotics that they hadn’t been previously exposed to. In the 1950s, inspired by and building on the work of Lederberg, Tsutomu Watanabe (Watanabe 1963) and his collaborators were able to provide a better answer to this puzzling (and clinically significant) situation. They came to the conclusion that resistance to antibiotics in bacteria could be conferred by cytoplasmic resistance factors which were encoded in the plasmids. These resistance factors could be exchanged with ease, between different species and even genera, in bacteria.
III. Emergent Resistance
The work on resistance factors or R-factors, however, remained relatively obscure during Watanabe’s initial publication even though it foresaw what a nuisance this could be for public health. Resistant infections were still to register as clinically and politically significant bones of contention. The faith in the advances of the biosciences and public health strategies in mitigating infectious diseases remained quite sturdy through the first three quarters of the 20th century. The imaginary of the “epidemiological transition” still exacted a hold—the UN had issued an accord in 1978 attesting to its faith in this model of transition from infectious diseases to chronic diseases as the indices of development were increasingly witnessed globally. Starting from the late 1980s, however, the sense of prevailing complacency began to erode. In the face of the AIDS pandemic and other novel and resurgent—oftentimes in resistant forms—infections, the truce (which was at least thought to have been effected in the Global North) between microbial lifeforms and humans became at best questionable. During this time, ecological strands of infectious diseases research became increasingly prominent in their bid to try and offer a way to understand the shifts stemming from the ease of mobility—of germs, people, commodities and imaginaries—that an increasingly globalised world came to facilitate. Ecological strands of infectious disease research, which had prior to this remained a relatively fringe concern,[3] rose to prominence in the late 1980s and 1990s around the reigning concept of “emergence.” Coined by the virologist Stephen Morse, the concept of disease emergence argued for a more dynamic relationship between host and pathogen interactions by locating the emergence of diseases in the transmission of pathogens into novel host populations. The “emerging diseases worldview,” as historian Nicholas B King (2002) describes it, came to quickly dominate understandings of international health. ABR/AMR also received more political and social purchase during the time and came to be reckoned with as an impending crisis of a global scale (Podolsky 2018). The document titled “Emerging Infections: Microbial Threats to Health in the United States,” edited by Lederberg et al., which came out of a seminal meeting convened by the Institute of Medicine (IOM) “serve[d] as a crucial inflection point in turning attention to the problem of antibiotic resistance” (Podolsky 2018, p. 4). Initially the report focused its attention on viral diseases but ABR/AMR was later added to the report as well.
The emerging diseases worldview was not just a response to the shrinking world and its increasing traffic of germs but also to its shifting geopolitical balance. The post-Cold War era witnessed the congealment of the notion of “emergence” and its political valence due to the increased conceptual traffic between the spheres of security strategy, infectious diseases research and neoliberalism (Cooper 2008). The post-Cold-War climate in the USA came to be marked by a growing unease with non-sovereign threats that were unamenable to the logic of mutual deterrence[4] that had previously animated defence strategies and foreign policy. The anthrax attacks in the 2001 precipitated a fear of what Cooper calls the “generic bio-threat.” It was the extremely productive elision between intentional acts of bioterrorism and (re)emergent infections that made emerging infectious diseases a global health and security concern. The emerging diseases worldview, with its focus on the ever emergent threat, has animated the regime of global health security (Lakoff 2010).
IV. Resistance Becomes Global
A significant amount of scholarly attention in anthropology has been paid to disease emergence in its association with viral mutability (Caduff 2015, Keck 2020), but less has been written about lateral gene transfer. Lateral gene transfer, I contend, is the material fulcrum and epistemic hinge around which discourses of the global threat of resistance have come to cohere. These infectious modes of heredity (Lederberg 1988, 1996) started gaining traction as antibiotic resistance became increasingly recognisable in clinical settings. Towards the end of the 20th century—and thanks, in no small part, to the productive nature of the emerging diseases worldview—these speedier processes of genetic transmission came to portend disasters of epidemic and pandemic proportions. Scientists in their increasing pursuit of resistant gene trails are now of the opinion that horizontal gene transfer is the rule rather than the exception in the bacterial world. In light of this, bacteria have been reconfigured as exceedingly promiscuous entities. If ontology is existence (and not essence), these social and sociable single-celled microbial beings can be seen “…as one huge multicellular organism in which cells exchange their genes with ease” (Levy 1998, p.48). Lateral modes of genetic transmission “potentially make all genes in the microbial biosphere a single, common, and shared resource” within which bacteria can “mobilize and transfer genes across physical and phylogenetic distance very rapidly” (Stokes and Gillings in Landecker 2016, p. 40). Scientists have christened the common genetic resource from which bacteria can draw the bacterial “pangenome.” The resistome is the subset of this pan-organismic genome that comprises all the resistant and potentially resistance conferring genes (D’Costa et al., 2006). These resistant genes are omnipresent in any given ecosystem and decades of extensive antibiotic use has amplified their presence. Both commensal and pathogenic bacteria can draw from this reservoir of genetic material under the selective pressure of antibiotics—throwing micro-biopolitics[5] out of joint.
Bacterial change is now better understood through a neo-Lamarckian lens—bacterial transformation brought on solely by statistically random mutations passed on through vertical modes of hereditary transfer has been usurped by this understanding of mutual exchange and horizontal modes of relationality between bacteria. Episomes and plasmids that are frequently used in laboratories as biotechnologies have, outside the artifactual setting of the laboratory, come to stand for an imminent disaster (Landecker 2016). And resistance itself has become infective, dis-locatable and easily transmissible.
V. The Promiscuous Plasmid, The Itinerant Patient and the Making of a Global Crisis
The emerging diseases worldview and the epistemic hold of the concept of lateral gene transfer ripened the conditions for the crisis that ensued as a result of the publication of that now (in)famous paper, the reference to which opens this piece, in The Lancet Infectious Diseases in 2010. The paper reported its findings on a newly identified enzyme, belonging to the larger class of enzymes called carbapenemases, which made bacteria resistant to most extant second and third line antibiotics. The gene sequence had allegedly originated in India and had reached the West via the bodies of unsuspecting itinerant patients who, having travelled to India for surgical procedures, had picked up the bugs from Indian hospitals. The paper controversially christened the identified enzyme New Delhi metallo-beta-lactamase-1 after the capital city of India—affixing its purported origin to its name. A bug carrying this enzyme was first identified in a Swedish patient of Indian origin. The Swede had traveled to India for a surgical procedure and ostensibly had picked up the dreaded superbug in the hospital where they had been admitted. The researchers justified the christening by stating that some of the patients in whom bugs carrying the enzyme were later identified in the UK had also travelled to India for medical and cosmetic procedures.[6] The naming of the bug after the city of New Delhi, and the badnami or ignominy (Bharadwaj 2015) that followed in its wake, led to a massive nationalistic backlash from the government and from the medical community in India.
What made NDM-1 especially concerning, the paper reported, was its location on particularly
“plastic plasmids.” Timothy Walsh and Mark Toleman, two of the lead authors of the paper, stated in later commentaries and interviews that the threat posed by these menacingly agile and “highly promiscuous” plasmids is compounded by the Indian who has an equally threatening confusion of boundaries. Indians are unable to adhere to the easy concept of “separating dirty from clean,” which has allowed the transmission of these bugs to progress unchecked from the environment/community to the hospital and vice versa. This recalls a more familiar trope in which medical-scientific and cultural collusions of this kind script particular locales as hotspots and epicentres through what has been described in critical literature as a “geography of blame.” A particularly contentious paragraph concluded the 2010 paper in which the authors advised UK citizens against opting for medical interventions in India. This concluding sentiment was at the receiving end of much of the ire of the government and the medical community in India. For these Indians, it was a burgeoning medical tourism industry which was the perceived target of these statements. It was a time when India’s medical tourism industry was at a tremendous rise. For a sense of the size of India’s medical tourism industry it is helpful to recall here that in 2022 India’s medical tourism sector was estimated to be worth US$9 billion. At a time when this booming industry was at its height, affixing the name of India’s capital city to the “superbug” enzyme and asking patients to not travel to India for medical procedures was appraised as “…well orchestrated badnami” with its threatening “…ability to truncate names and indelibly attach itself to people and places” (Bharadwaj 2015).
Initially the recognition of ABR/AMR as a clinically relevant phenomenon had arisen in the Global North. These concerns had, however, been more located in texture i.e. of a more local provenance and relevance. Methicillin-resistant Staph aureus[7] (MRSA) served as the “model” (Podolsky 2018, p. 2) for these earlier concerns with clinically relevant bouts of resistant infections. Many in the medical community maintain that there are fewer concerns with MRSA because the gene that confers resistance has been confined to a specific species of bacteria. With NDM-1, however, resistance itself took a form that is highly infectious and dis-locatable. What is often left out in this story is that it is the concurrence of the promiscuous plasmid and the figures of the itinerant patient, and the irrational native with their inability to distinguish between clean and dirty, that has given resistance the affective force of a crisis that now besets the global.
VI. Conclusion
The foregoing discussion delineates the historical arc of “resistance” and attempts to situate it at a time marked by its heightened material and discursive circulation as an ongoing/imminent crisis of global proportions. The emergent diseases worldview created the conditions ripe for the recognition of ABR/AMR as an imminent global health crisis. The epistemological shift from vertical-Mendelian modes of genetic transfer to horizontal/lateral gene transfer as the dominant mode of appraising bacterial transformation makes the spectre of resistance potentially ever-present: much like that of emergent viral forms. As concepts such as pan-genomes and resistomes take hold, the breadth of the network of resistant genes seems to increasingly encompass the “global” across geographical and ecological boundaries. The epistemic hinge and material process of lateral gene transfer has dovetailed with figures of the itinerant patient and the irrational native to (re-)inscribe India as the epicentre of the ongoing/imminent threat of resistance.
[1] Hitherto in medicine a corpus of sufficient causes had sufficed. For an extended inquiry see Codell Carter 1991.
[2] Alexander Fleming had already warned that the incorrect use of antibiotics could lead to bugs becoming resistant from them in his Nobel acceptance speech in 1945.
[3] See Anderson 2004.
[4] The doctrine of mutual deterrence is animated by the logic of rational deterrence which holds that two nuclear powers, here the Soviet Union and the United States of America, will not escalate situations to a full-scale war because it would result in the complete annihilation of both the attacker and the defender.
[5] Microbiopolitics is a term coined by Heather Paxson as a way to build on the Foucauldean concept of biopolitcs. By “microbiopolitics” Paxson means “the creation of categories of microscopic biological agents; the anthropocentric evaluation of such agents; and the elaboration of appropriate human behaviours vis-a-vis microorganisms engaged in infection, inoculation, and digestion” (Paxson 2008).
[6] The editor of Lancet later called the controversial naming an “error of judgement” but the lead authors refused to rescind the name stating that it had followed the scientific conventions of naming this class of enzymes.
[7] This is a gram positive bacteria that is commonly found on the skin and in the nasal passages.
References
Anderson, Warwick. 2004. “Natural Histories of Infectious Disease: ecological vision in twentieth-century biomedical science.” Osiris 19: 39-61.
Arendt, Hannah. 1958. The Human Condition. Chicago, IL: University of Chicago Press.
Bharadwaj, Aditya. 2015. “Badnam Science? The Spectre of the ‘Bad’ Name and the Politics of Stem Cell Science in India.” South Asia Multidisciplinary Academic Journal 12:1-18.
Caduff, Carlo. 2015. The Pandemic Perhaps: Dramatic Events in a Public Culture of Danger. CA: University of California Press.
Carter, Codell K. 1991. “The Development of Pasteur’s Concept of Disease Causation and the Emergence of Specific Causes in Nineteenth-Century Medicine.” Bulletin of the History of Medicine 65(4): 528-548.
Chandler, Clare I R. 2020. “Current accounts of antimicrobial resistance: stabilisation, individualisation and antibiotics as infrastructure.” Palgrave Communications 5(53):3-13.
Cooper, Melinda. 2008. Life as Surplus: Biotechnology and Capitalism in the Neoliberal Era. Seattle: University of Washington Press.
D’Costa, Vanessa et al. 2006. “Sampling the antibiotic resistome.” Science 311(5759): 374–377.
Hinchcliffe, Steve et al. 2018. “The AMR Problem: Demanding Economies, Biological Margins, and Co-producing Alternative Strategies.“ Palgrave Communications 4:142.
Keck, Frederic. 2020. Avian Reservoirs: Virus Hunters and Birdwatchers in Chinese Sentinel Posts. Durham: Duke University Press.
King, Nicholas B. 2002. “Security, Disease, Commerce: Ideologies of Postcolonial Global Health.” Social Studies of Science 32(5–6): 763–789.
Kumaraswamy, Karthikeya K et al. 2010. “Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study.” The Lancet Infectious Diseases 10(9): 597 – 602.
Lakoff, Andrew. 2010. “Two regimes of global health.” Humanity 1:59–80.
Landecker, Hannah. 2016. “Antibiotic Resistance and the Biology of History.” Body and Society 22(4): 19-52.
Lederberg, Joshua. 1988. “Medical Science, Infectious Disease, and the Unity of Humankind.’ Journal of the American Medical Association 260: 684–85.
Lederberg, Joshua. 1996. “Infection Emergent.” Journal of the American Medical Association 275: 243–45.
Levy, Stuart. 1998. “The challenge of antibiotic resistance.” Scientific American 278(3): 32–39.
Paxson, Heather. 2008. “Post-Pasteurian Cultures: The Microbiopolitics of Raw-Milk Cheese in the United States.” Cultural Anthropology, 23(1): 15-47.
Podolsky, Scott. 2018. “The evolving response to antibiotic resistance (1945–2018).” Palgrave Communications 4:124.
Walsh, Timothy R et al. 2011. “Dissemination of NDM-1 positive bacteria in the New Delhi environment and its implications for human health: an environmental point prevalence study.” The Lancet Infectious Diseases 11: 355–62
Watanabe, Tsutomu. 1963. “Infective Heredity of Multiple Drug Resistance in Bacteria.” Bacteriological Reviews 27:87–115.
