As soon as we study animals – not in laboratories and museums only, but in the forest and the prairie, in the steppe and the mountains – we at once perceive that though there is an immense amount of warfare and extermination going on amidst various species, and especially amidst various classes of animals, there is, at the same time, as much, or perhaps even more, of mutual support, mutual aid, and mutual defence amidst animals belonging to the same species or, at least, to the same society. Sociability is as much a law of nature as mutual struggle. (Kropotkin 1902, 12)

Sociability is a characteristic of invertebrates as well as vertebrates, and is well established for ants, termites, and bees. 'Mutual aid is met with even amidst the lowest animals, and we must be prepared to learn some day, from the students of microscopical pond-life, facts of unconscious mutual support, even from the life of microorganisms' (Kropotkin 1902, 15).

The social life of microorganisms was a subject of interest among biologists during the second half of the nineteenth century. Debate focused on the so-called 'cell theory', according to which every organism, including humans, is comprised of smaller, self-reproducing organisms. Biologists are concerned with relations between the superorganism and the constituent organisms: they want to know *how* the constituents are connected (generally via evolution, anatomy, physiology) and *why* constituents are connected. When constituents are sentient entities, the 'why' answer will mention their drives, motives, or intentions. When constituents are not sentient, why answers will explain that constituent parts *enable* the superorganism to perform – this is *their function*. Moreover, when there are no satisfactory answers to how or why questions, we have a puzzle – the puzzle of 'the one and the many', 'the most central of all philosophic problem', according to William James (1907, 51).

It is a century and a half since the cell theory was introduced, and biologists are still seeking answers to the how and why questions. A popular thesis in the nineteenth century traced the evolutionary origins to primitive, free-living cells, known as 'protists'. In Ernst Haeckel's narrative of these events, protists preferring a sessile group life surrendered their independence, to create the first multicellular organisms. How and why questions were addressed via the metaphor of the 'cell state': an egalitarian 'cell republic', representing multicellular plants, and a hierarchical 'cell monarchy', representing multicellular animals, in which cells are subordinated to the central nervous system and the brain. Within the cell state, cooperation and coordination would prevail, and growth would proceed through cell division. Simple cell division would not explain embryonic development, however, and this difficulty remained unresolved.

Ultimately, beginning in the first decades of the twentieth century, the metaphor of the cell as an autonomous citizen within a larger social body lost its allure. At this time biochemical and physiological investigations began to replace morphological and evolutionary considerations of organisms and cells. As biochemistry matured as a professional discipline, another metaphor came to dominate, one more suited to the particular types of questions being pursued by the new breed of investigators, so that today one more commonly hears the cell described as a 'chemical factory' (Reynolds 2007, 74).

# Part Two: Bacterial society

This is where we left Kropotkin, the year is 1907 and he is thinking about pond life. A newly discovered free-living microorganism, the bacterium, is attracting attention. Koch and Pasteur have established the medical and industrial importance of bacteria, and significant technological developments have followed. However, misunderstandings about bacteria persist. Some biologists believe that they are not true cells, since cells must have nuclei. If bacteria are cells, it is uncertain whether they belong among plants or animals. In either case, the bacterium is a primitive form of life: 'a simple automaton, blindly following its genetic programming … [with no] personal idiosyncrasies, let alone a social life' (Gardner and Kümmerli 2008, R1021). Kropotkin wisely excluded this 'generic loner' from his book on mutualism.

Today, experts know otherwise. Bacteria are biologically complex organisms, operating in unexpected ways. For instance, the bacterial cytoskeleton regulates and executes key cellular processes in a manner analogous to the operations of organelles in the nucleated (eukaryotic) cells that compose body tissues and organs. In addition, bacteria lead complicated social lives, interacting with different species – bacterial and otherwise – within multicellular communities. When describing bacterial social life, I will rely on the language employed by contemporary microbiologists.

Microbiologists write that, within these communities, bacteria 'can glean information from the environment and from other organisms and interpret the information in an existential "meaningful" way, i.e. by building an appropriate colony structure … and [may even] learn from past experience' (Ben-Jacob and Levine 2006, 198). Their chemical communication is said to be like linguistic communication, in giving contextual meaning to bits of information connected like words into sentences, and exchanged between individuals via a dialogical process through which these bacteria assess local cell density: a procedure known to researchers as 'quorumsensing'. This arrangement tells bacteria when they are numerous enough to overwhelm the immune system defences of the host organism. Until this threshold is reached, bacteria modulate the expression of their virulence genes, thus forestalling the timely mobilisation of antibiotic defences by suppressing evidence that advertises their presence to 'target cells'.

Some quorum-sensing systems are operated by a single species (or genus), and their messages are unintelligible to outsiders. In multi-species systems, outsiders are able to 'eavesdrop' on conversations (Schertzer et al*.* 2009). In the right circumstances, this crosstalk can benefit both senders and eavesdroppers, but in other communities crosstalk provides opportunities for cheating, deception and exploitation. For example, the chemical signals or metabolites used for quorum sensing may be good to eat, and are valued by freeloaders belonging to other species, as nutriments. The free lunch ends when the target is attacked, and quorum-sensing is superfluous. Polyglot freeloaders prolong the quorum-sensing phase by circulating disinformation – underestimates of the virulent population (Sandoz et al*.* 2007; Williams et al*.* 2007).

Disinformation is also employed defensively (Bjarnsholt and Givskov 2007; Popat et al. 2008). Suicide bombers provide one more example. Pulmonary strep infections are promoted by the release of a toxin via self-destructive bursting (lysis). This would be a onegeneration solution if all of the bacteria possessing this trait in a given community or species were to self-destruct on the first opportunity. In practice, only some potential bombers self-destruct. Wholesale self-destruction is avoided by biological individuality, also known as 'phenotypic noise':

[Suicidal] microbes might be responding to differences in their personal quality: a moribund cell with nothing to lose will be more inclined towards committing suicide for the good of healthy neighbours. More sinister is the possibility that bacteria are manipulated into making the sacrifice … (Gardner and Kümmerli 2008, R1023)

# Part Three: Biofilms

Many bacterial species enclose their communities within 'biofilms'. They are densely populated communities, growing on surfaces, protected from antibiotics and predation by a thick cover made of secreted polymers, and structurally complex, with intricate channels for delivering nutriment and disposing of waste. Biofilms are also ubiquitous: responsible for many acute and chronic infections, the degradation of implanted prosthetic devices, the contamination of drinking water distribution systems, and a multitude of industrial problems. Communal relations appear to be coordinated and cooperative, and an analogy is sometimes made between biofilms and multicellular organisms.

However, multicellular animals develop from a single cell that proliferates, and constituent cells are siblings, so to speak. Most biofilms are composed of cells from different lineages or species, and many species are genotypically diverse – a consequence of spontaneous mutations and lateral transfer of DNA between species. In these heterogeneous populations, cheaters proliferate, reaping the benefits of indirect reciprocity and altruism without incurring the expenses. Strong conflicts and selfinterest compromise the biofilm's thickness and growth rate, and reduce resistance to antibiotics – a case of 'the tragedy of the commons', made familiar to us by neo-Darwinians (Claessen et al. 2014, 117–18; Nadell et al. 2009).

The structural and physiological complexity of biofilms gives the mistaken impression that they compose communities of coordinated and cooperative groups. '[Yet] biofilms can emerge without active coordination [and] species stratification and channel formation do not necessarily require that cells communicate with one another using specialised signalling molecules' (Nadell et al. 2009, 206). Biofilms and quorum-sensing systems seem impressive because bacteria were formerly misperceived as primitive and solitary. However, the systems operate over very short distances – just a few cell lengths – and, so, contrast with multicellular animals, 'where many types of differentiated cells communicate across the whole architecture to produce a highly integrated functional unit' (Nadell et al. 2007, 217).

Biofilms and multicellular organisms are certainly different from one another, but 'different' does not imply 'higher' and 'lower' or 'sophisticated' versus 'primitive'. Bacteria are not the progenitors of eukaryotic (nucleated) cells. Biofilms are not an early stage in a shared evolutionary pathway, but rather the product of a unique trajectory. 'Different' refers here to *different vital economies* – distinctive modes of production, distribution, exchange and consumption. Different means 'strange', not 'primitive', when mode of exchange includes self-transformation via lateral transfer of DNA, consumption includes predation, cannibalism, and self-sacrifice, and the biofilm economy incorporates an intercellular caste system:

[T]he chemical environment within a biofilm often differs greatly at different depths . ... [a] nutrient in the liquid surrounding a biofilm may be consumed by cells in the outermost layers such that its concentration decreases deeper in the biofilm. Meanwhile, a product secreted by the cells in the biofilm will often accumulate to its highest concentration within the biofilm's interior. Given that many bacteria use multiple growth substrates and release numerous extracellular products, diffusion limitation can produce complex vertical and transverse chemical gradients, particularly when the secretions of some cells are consumed by others. ... These gradients, in turn, generate numerous microniches within the biofilm that can induce pronounced physiological heterogeneity simply because bacteria alter their behaviour according to local conditions. (Nadell et al. 2009, 211)

Neo-Darwinian theory argues that the proportion of cheaters in a community inevitably increases, from minority to majority, in the absence of regulatory mechanisms. Communal survival requires a modicum of cooperation: once the proportion of cooperators drops beneath a critical threshold, a community collapses. Biofilms have additional worries: starvation, desiccation, predation, viral infections (bacteriophages).

Yet death can be a pathway to resurrection, via a process called 'sporulation', in which bacterial individuals are transformed into spores that are then dispersed from 'towers' into the ambient environment, to develop into free-living (plaktonic) cells, that will eventually aggregate on surfaces, and mature into biofilms. It is not a simple matter, though: life and death decisions must be made along the way.

Considerable research effort has been devoted to untangling the components of the signal transduction decision-making system that allows the individual cell to decide whether to wait, take a chance … or commit to sporulation. It is now understood that the cell decision follows careful sensing, advanced cell–cell communication using a variety of peptide pheromones … and elaborate information processing to assess information about the colony density, the collective progression toward sporulation, and the inclination to escape into competence. (Schultz et al*.* 2009, 21027)

Sporulation is an energy-intensive process and takes several hours. It is initiated while enough nutrients are available to complete the process. If other bacteria within the same niche continue to grow, there is the risk that nutrients will be exhausted before the cells committed to sporulation have completed the process (Claverys and Håvarstein 2007, 225). The choice is further complicated by the need to set priorities. What is the best investment when voracious, bacteria-eating protozoa patrol the biofilm's periphery? Bacteria may respond by postponing sporulation, and divert the resources needed for building towers into the task of engorging the bacteria living on the biofilm periphery to create a cordon of bacterial cells of inedible proportions, larger than the predators. The process of engorgement is routinely enhanced through cannibalising altruistic members of the community.

Schultz et al*.* write about a decision-making system that *allows the individual cell to decide*, while the processes described seem to be coordinated collective activities (Claverys and Håvarstein 2007). About the same time, in an essay on 'molecular autonomous agents', Stuart Kaufman identified autonomous agents as systems capable of selfreproduction and necessarily self-organisation, and able to act on their own behalf, citing the example of 'a bacterium swimming up a glucose gradient' (Kaufman 2003, 1089). Kaufman's additional interest concerns the question of fit between a presumably panbiotic tendency to selforganisation and the central dogma of evolutionary biology, i.e. the primacy of selection. Moreover, these questions can be pushed still further, to consider how the emergence of molecular autonomous agents bridges a 'willingness' to self-organise themselves into multicellular systems (and into social groups). The juxtaposed claims are not necessarily contradictory, but they require elaboration – a concept or theory for the puzzle of the one and the many, a puzzle that pervades microbial societies.

# Part Four: The human microbiome

Ninety per cent of cells living inside the human body or on its surface are bacteria – 100 trillion bacteria. In 2007, the National Institute of Medicine (US) created a Human Microbiome project (HMP), funding research on the composition and diversity of the microbial communities inhabiting major mucosal surfaces of the human body – the nasal passages, oral cavity, skin, gastrointestinal tract, and urogenital tract – and research on the genetic metabolic potential of these communities.2 I will use 'microbiome' in a restricted sense, to refer to the gut bacteria (enteric bacteria). While only a minority of these bacteria form biofilms, a useful comparison can be made between microbiome and biofilm societies. There are abundant and obvious similarities, but I want to begin with an important difference, concerning the quality of 'containment'. Here, and throughout this chapter, I have retained the societal terms used by microbiologists. Containment refers to factors preserving physical borders or boundaries. The biofilm's boundary is a viscous polymer covering created by the resident bacteria. A biofilm protects its resident bacteria: its job is to keep external threats out.

The boundaries of the gut microbiome are ready-made, but not its contents. The human fetus is bacteria free, and acquires its first bacterial residents during vaginal delivery, a second wave in the course of suckling, and additional bacteria via contact with the ambient environment. In the process, the immune system is educated and matures. There are three competing views of how this happens. The traditional view is that 'the immune system is educated not to react to self and to react to non-self. [The] self is good and induces tolerance … Non-self, including microbes … are evil and elicit an immune response aimed at destroying non-self' (Eberl 2010, 454). The microbiome view is that the immune system is educated to be tolerant to self through a system of microbial pattern-matching.3 The notion of self is modified: 'good' includes both the familiar, normal self plus its mutualistic microbes. The third view, now emerging, is that:

[T]he perceived duality of mutualistic and pathogenic microbes, normal and altered self … represents extremes of a continuous reality. Microbes can express different levels of mutualistic or pathogenic properties and these levels can vary during interaction with the host. [T]he state of self and of immune responses … navigate between well-described extremes, and the most likely states are combination of these extremes. (Eberl 2010, 454)

All three views posit that the immune system plays a key role in containment – restricting the resident bacteria to the confines of the microbiome. However, it is the third view that emphasises the dual character of friendly microbes, the fact that even good friends can become dangerous threats. Once past the gut's epithelial wall, microbial friends become a source of sepsis, and potentially septicaemia. It is the strategy of containment that makes this unlikely. The innermost layer of the intestine is the epithelium, and contains specialised cells that secrete mucus to lubricate the passage of food. The sheer number of intestinal bacteria makes an occasional breach inevitable. The bacteria that penetrate this barrier are generally eliminated by macrophages. Bacteria getting through this barrier are engulfed by dendritic cells (DCs) and carried alive to the mesenteric lymph nodes where their identities (chemical signatures) are decoded. A protective immunoglobulin IgA1 is released and distributed over the mucosal layer that coats the gut's epithelial cells. Thus a barrier is erected that neutralises the bacterial threat before the microbes can reach the cells (Hooper et al*.* 2012, 1269).

# Part Five: Bacteria's brain

The gut bacteria contribute to the production of neurotransmitters and neuroregulators integral to the development and functioning of the sympathetic and central nervous systems.4 Gut bacteria communicate with the brain and nervous systems through multiple pathways: the circulatory system, the vagus nerve, and the neuroendocrine circuit (hypothalamic-pituitary-adrenal axis) that underpins the stress response. The pathways are bidirectional, but the mechanisms through which the gut bacteria receive and respond to incoming chemical signals is unclear.5

The bio-behavioural effects of gut–brain signalling are studied by comparing the behaviour of germ-free (gnotobiotic) mice with normal mice under controlled conditions. Germ-free mice exhibit low anxiety behaviour when placed in novel environments, for example, they show greater inclination to exploratory behaviour. Similarly, HPA axis arousal is less intense (measured via levels of corticosterone) when germ-free mice are put into stressful situations, such as maternal separation or physical restraint. Other efforts to study gut–brain signalling focus on the influence of specific bacterial species. These experiments alter the bacterial composition of the microbiome through dietary change, the introduction of probiotic bacteria or invasive pathogenic bacteria via faecal transplants etc., and the administration of selective endogenous bacteriocins. Although it is widely presumed that social relations within the microbiome – competition for binding sites on the gut wall, and competition for nutrients needed for growth – have differential effects on the host's behaviour, cognition and mood, it remains unclear how the underlying mechanisms can be studied experimentally. Consequently, conclusions regarding the microbiome's contribution to psychiatric disorders (depression, anxiety disorders, autism spectrum disorders) are based on correlations rather than causation.

The history of the microbiome is a chronicle of efforts aimed at connecting bacterial communities and strife to organ systems, physiological processes, and popular conceptions of selfhood and sensibility. This is the background for explaining the explosive growth in biological research, science publications, journalism, and government funding focused on the microbiome. Thus, advocates for the creation, in the US, of a Human Microbiome project comparable to the Human Genome project (HGP) justified its enormous expense by arguing that the HGP, as it was originally conceived and executed, had been incomplete.

# Part Six: The social life of enteric bacteria

Over the past 5 years, studies have linked our microbial settlers to conditions as diverse as autism, cancer and diabetes … This excitement has infected the public imagination. 'We Are Our Bacteria', proclaimed one headline in *The New York Times* … Companies offer personalised analysis of the microbial content of faecal samples, promising consumers enlightening information … Faecal transplants have been proposed – some more sensible than others – for conditions ranging from diabetes to Alzheimer's disease. With how-to instructions proliferating online, desperate patients must be warned not to attempt these risky procedures on themselves. (Hanage 2014, 247)

Popular interest in the human microbiome in North America remains unbounded, notwithstanding the scepticism of many researchers and dubious evidence of its salutogenic potential. 'Eat your way to health' is an old theme. The transgressions are new. Childbirth transformed into a bacchanalian rite of passage, in which a sterile fetus drinks deeply, through mouth and nose, of germs, dirt, and vaginal excretions, and emerges a viable human being. Woe to the uninitiated child (Caesarean birth): he will be punished with obesity. This is new. Ditto the vision of vindictive Gaia: 'Like ecosystems the world over, the human microbiome is losing its diversity, to the potential detriment of the health of those it inhabits' (Brody 2014). Who would have predicted the happiness of educated Americans following the discovery that 'we' (i.e. somatic cells) occupy only 10 per cent of our manifest bodies?

While these responses are worth ethnographic attention, I want to finish by calling attention to a significant absence. I began this paper with a theme developed in a recent issue of *Current Biology*: all life is social, in some sense collective.

The evolution of collective behaviours demands intrinsic phenotypic flexibility in the behaviours of individuals and groups in response to changing social and environmental conditions and mechanisms to facilitate coordination among members of the collective (Ross-Gillespie and Kümmerli 2014). Brainless microbes satisfy these demands partly by quorum-sensing. The quorum-sensing systems favoured by bacteria rely on the diffusion of chemical signals and pooling information. To be more precise, the scientists are writing about *social information*: signals and/or cues generated by other individuals. By averaging across multiple potentially noisy informational inputs, the decision-makers (individual cells) acquire an accurate impression of their surroundings and neighbours and produce egalitarian decisions. Operations involve an intrinsic response threshold and local feedback. Once signal receptors are sufficiently stimulated, a group-coordinated shift in geneexpression is induced.

Adjustments in the signal threshold are geared to maximising adaptation to prevailing conditions. If the signal threshold is set too low, a premature collective response follows, and fitness drops at the level of the population. When set too high, it is difficult to mobilise an effective collective response. Shifts aim for either greater speed (lower threshold) or greater accuracy (higher threshold), and are produced, in the short run, via phenotypic plasticity and, in the long run, via selection (facilitated by lateral gene transfer). These effects have been observed via experiments and computer simulations.

Cooperation is impeded by conflicts of interest. Conflicts are less frequent in communities with a high degree of relatedness. Natural microbial communities involve interactions among individuals that vary widely in their relatedness to one another. The creation of disincentives for dissent and cheating helps to limit these conflicts. This solution presumes a decision-making mechanism anteceding the increased costs:

Besides destabilising cooperative actions, and the collective decisionmaking processes that underlie them, conflicts of interest can also influence selection for different forms of decision making. When conflicts are relatively minor, and where information can be pooled fairly broadly (for example, small groups) it is easy to see how leaders could emerge – typically from among those individuals for whom different decision outcomes would have strongest effects on fitness – and how an initially democratic decision process could transition into a more autocratic one. Where more substantial conflicts of interest exist, meanwhile, democratic systems of collective decision making should be the most robust, since these give rise to the most accurate decisions (i.e. best-fit compromise across all individuals). (Ross-Gillespie and Kümmerli 2014, 7)

This social dimension of microbial life, and therefore everyday life in the human microbiome, is missing in the popular accounts. Moreover, it is likewise neglected in the published rationale for the Human Microbiome project. The project's defining technology, metagenomics, is creating a distinctively desocialised version of the microbiome. The project does not overlook social relations altogether: it is committed to understanding 'how the microbiome and human host interact to support health or to trigger disease'. However, the logically antecedent question is ignored: How do enteric bacteria organise themselves; how do they compete and cooperate with one another? The NIH subsequently established an Ethical, Legal and Societal Implications programme (ELSI) whose job is to address 'the new and unexplored issues which arise from human microbiome research'. However, once more, attention focuses on relations among humans and between humans and microbes.

# Conclusion: A question and less-than-satisfactory answer

Do bacteria really have a 'rich social life', as microbiologists claim, or does this idea falsely anthropomorphise a truly asocial nature, in a way reminiscent of the metaphorical 'cell state' pictured by Haeckel, Virchow and Spencer?

The social life claim is based on two propositions: a) bacteria behave in socially patterned ways, for example, cooperating with relatives, competing against strangers; and b) bacterial behaviour is guided by bacterial cognition, the capacity to recognise and choose among alternative possibilities. Proposition b accounts for the critics' scepticism. To be meaningful, 'cognition' must include decision making. According to sceptics, bacterial 'cognition' is a physico-chemical process, based on deterministic transduction of chemical signals, while 'decision making', in the ordinary language sense, requires a brain – at the very least, a nervous system. Bacteria possess neither. But there is another possibility: decision making can function through *stochastic intelligence*, a capacity bacteria possess.

Life is a study in contrasts between randomness and determinism: from the chaos of biomolecular interactions to the precise coordination of development, living organisms are able to resolve these two seemingly contradictory aspects of their internal workings. Scientists often reconcile the stochastic and the deterministic by appealing to the statistics of large numbers … (Raj and van Oudenaarden 2008, 16)

Quorum-sensing, as described above, is one way in which bacterial social life reconciles the stochastic and the deterministic. The part played by 'leaders' in clonal communities – where individuals share a single genotype – is especially interesting in this regard. Notwithstanding the shared genotype, there is significant variation among individuals – a consequence of randomness in transcription and translation leading to cell-to-cell variations in mRNA and protein levels. During periods of collective stress, such as exposure to antibiotics, a small fraction of individuals become 'competent', able to take up DNA from the environment. Competence is a stochastic function (the result of randomness in transcription) that enables the leader to exploit noise (random variation) generated during quorum-sensing.

This chapter ends more or less where it began, with the puzzle of the one and the many. Who is the individual possessing stochastic intelligence? Is it the single cell (a bacterium), a biofilm (comprising a leader, species mates, and neighbours), or a super-organism (10 per cent 'host' and 90 per cent microbe, i.e. a 'distributed system')? Why should it matter? We are equally perplexed (since the time of David Hume) by decision making located in the brain and self-consciousness. The two puzzles are connected by stress and anxiety, and a neo-Darwinian imperative. Is there more?

# Notes

# References

# Chapter 6 Biosocial Dynamics of Multidrug-Resistant Tuberculosis: A Bacterial Perspective

Jens Seeberg

Humans have created an ideal environment for the development of antibiotic resistance (Orzech and Nichter 2008, 269).

# Increasing access to medicines

How may the spread of antimicrobial resistance to medicines for tuberculosis (TB) be understood if it is seen from the perspective of bacteria engaging with an epidemic of treatment? Moreover, how do new medicines and technologies reconfigure the biosocial dynamics of this particular epidemic, when implemented through underfunded public health systems?

A call was put forward during the 1990s and 2000s for universal access to existing and effective treatment against common diseases such as TB and HIV. Paul Farmer (2001, 2005) consistently and forcefully argued that the denial of such treatment was an expression of a global war against the poor, fought through mechanisms of structural violence. The call for global access to treatment is a strong moral imperative. Indeed, whether at the individual level when facing a patient or at the level of public health, the argument regarding access to life-saving medicine is well justified. Concurrently, new global funding mechanisms have come into place since the 1990s to support access to drugs. An example of this is the financing of the global TB control programme known as directly observed treatment, short-course (DOTS) through a combination of government and donor funding. In India alone, millions of patients were treated under DOTS, and by 2006, the government of India estimated that the lives of 2 million TB patients had been saved (Government of India 2006). For this reason, DOTS was celebrated as a success in India during the 2000s. Two ticking clocks were placed on the website of the government's control initiative, the Revised National TB Control Programme (RNTCP): one for patients put on treatment and one for lives saved. These clocks have since been removed, though their traces remained visible for a long time afterwards, perhaps indicating a general lack of resources for the programme. Despite the emergence of new funding mechanisms globally, however, the effective improvement of health systems necessary to safeguard the quality of programmes such as DOTS and other medicine-intensive global health programmes did not materialise. Increasingly, healthcare is privatised, and state-funded health provision is under pressure, in India and elsewhere.

From its inception, the RNTCP in India had a substantial interest in the production of 'success stories' demonstrating the curability of TB with DOTS. Such messages were intended to decrease the stigmatisation of TB patients and stimulate passive case finding. Gradually, success stories became moderated a little by growing attention to treatment failure related to antimicrobial resistance. It was clear from the beginning that DOTS was a complex strategy that would also involve limited strengthening of the health system. Even if, in the later Stop TB strategy, this was given some attention as an area where investments were needed, the dominant line of thinking assumed that the general health system would somehow automatically be strengthened once scarce resources were flowing to the vertical TB treatment programme. This assumption disregarded evidence that the simultaneous existence of many competing vertical programmes resulted in a compartmentalised, fragmented and unevenly funded health system. So far, the priorities of dominant funding mechanisms, which see the solution to these epidemics in terms of physical access to pharmaceuticals and diagnostic technologies, have failed to address the biosocial dimensions of the disease. An understanding of biosocial dimensions would take as its starting point the lives of humans and of bacteria. In what follows, I shall pursue an understanding of the social co-existence of bacteria, their human hosts, and the anti-TB medicines with which both engage, in an analysis that seeks to incorporate three different scales across which social practices play out and interlink: the microbial, the human, and the global.

# Phages

The constant engagement of a bacterial cell with whatever inhabits its environment may at any point in time result in the cell's death, engagement in relations of symbiosis, or resilience (i.e. resistance). From this perspective, the presence of anti-TB medicine in the host organism may be likened to the presence of viruses capable of infecting bacteria, so-called bacteriophages; or in the case of mycobacterial hosts, mycobacteriophages. A phage that infects Mycobacterium TB (M. TB), which causes TB, was first discovered in 1947, and hundreds of such 'TB viruses' have subsequently been identified. Once they are hosted by M. TB, they communicate their genetic material to the TB cell, affecting different aspects of its genetic code. Little is known about the complex relationship between phage infection and bacteria behaviour, but some phages seem to enhance the ability of bacteria to produce biofilm, while only a few have the potential to kill their hosts.1

Napier has argued in favour of a new sociobiology that prioritises 'organic relatedness over organic autonomy', where the self – the somewhat bounded organism – is as much xenophilic, i.e. seeking engagement with its organic environment, as xenophobic, defending itself against it (Napier 2013, 20; see also Young (this volume) for an overview of similar positions). A metaphor of travelling through an organic landscape could perhaps replace the traditional immunological metaphor of warfare as an appropriate trope for capturing this engagement of organisms, as in microbiologist Graham Hatfull's description of mycobacteriophages' search for suitable host cells:

Thus, the observed phage diversity can be explained by assuming that wherever broad and diverse ranges of hosts are present, the phages can rapidly dance across the microbial landscape, using the hosts as 'stepping-stones'. Migration across this landscape requires that the 'stepping-stones' be spaced sufficiently close (genetically) to enable a host-range transition jump with either very few mutations or a gene acquisition event. (Hatfull 2014, 1)

Hatfull proceeds to talk about certain phages as 'merely accidental tourists in the Mycobacterium locale'.

From the perspective of the mycobacteria, such encounters with viral travellers constitute both communicative opportunities and risks. Whether a xenophobic or a xenophilic response would be advantageous is determined through engagement. For some mycobacteria, engagement with phages has been shown to influence their physiology in ways that increase virulence through expression of phage-encoded proteins or integration of the phage genome into the host gene, the so-called lysogenic cycle, potentially affecting the ability to create biofilm and hence giving host cells with a particular phage infection a selective advantage (Hatfull 2014, 2). Another process of viral replication, known as the lytic cycle, allows the phage's DNA to exist as a separate molecule and replicate in a process that eventually kills the host cell when the cell membrane bursts and multiple new phages are released. Using a more conventional metaphor for the co-existence of bacteria and phages and the mechanisms of resistance to phage infection developed by the former and the counter-mechanisms to overcome resistance developed by the latter (and so on), Labrie et al. have described such processes as the 'arms race between bacteria and phages' (Labrie et al. 2010, 321); they describe the blocking of phage receptors as one of several resistance mechanisms developed by bacteria. Though an 'arms race' metaphor is open to differing interpretations, it seems to imply a war that can be won. I suggest that a 'traveller' metaphor takes us further in reflecting on organic interactions that involve risk and (evolutionary) development potentials, and hosts that are more or less welcoming along with guests that are more or less intrusive and influential and that sometimes become part of the family, so to speak. Less metaphorically, perhaps, we see that the longterm interaction of bacteria and phages has resulted in a flexibility for both that is crucial for their survival and continuous adaptation to everchanging environments. Development of phage resistance is, therefore, a daily routine for bacteria, as are the other possible outcomes of the interaction, i.e. death and incorporation.

From the perspective of M. TB, anti-TB drugs have certain similarities to phages, but they are also dissimilar in important ways. Most importantly, the standard treatment drugs are not viral, i.e. they do not contain genetic material capable of replicating in the host cell, and the person under treatment must therefore consume them for a long period. If naturally occurring, phages contrast with the sudden and prolonged high concentration of engagement achieved through medical treatment and, in the case of combination therapy, the simultaneous presence of several antibiotics. Nevertheless, medicines may be considered similar to phages in terms of the natural response of the cell to develop, through mutation, mechanisms that enable the cell to resist the specific mode of operation of a given drug. Bacterial stress (for example, during antibiotic treatment) increases the mutation rate (Martinez and Baquero 2000). However, resistance can also occur by acquisition of resistance genes carried by other 'tourists', i.e. plasmids or transposons, across the microbial landscape, or by recombination of foreign DNA into the chromosome (Martinez and Baquero 2000) further supporting the use of a viral metaphor for the spread of drug resistance among bacteria. The chances for development of resistance in M. TB to a single drug vary depending on the drug (Zhang and Yew 2009), but are invariably much higher than those of simultaneous development of resistance to several drugs. This is the logic behind the multidrug treatment regimes. Theoretically, if three or more drugs are present in the host body, the possibility of simultaneous development of drug resistance to all drugs is virtually non-existent. However, once resistance is developed, the genetic material of the TB cell has changed, and hence that drug resistance is replicated through standard processes of cell division. This allows for a new resistant strain of TB to spread, both within the human host (known as 'acquired' or 'treatment-induced' drug resistance) and, if it is pulmonary TB, to other people (known as 'primary' or 'transmission-generated' drug resistance).

Multidrug-resistant TB (MDRTB) is rapidly increasing worldwide. With approximately 25 per cent of the global TB burden, India is one of the most important geopolitical spaces for the TB epidemic and for the development of MDRTB.2 In what follows, I shall discuss MDRTB in the context of the TB control programme in India.

# TB control in India

'Directly observed treatment, short-course' (DOTS); 'short' in this context means 6 months of uninterrupted treatment. The World Health Organization (WHO) developed this treatment regime in the 1990s in response to problems with patient compliance with the former treatment, which was of even longer duration and was unsupervised. A multidrug regimen, it was intended to control the risk of drug resistance. Even though WHO advocated DOTS as a globally uniform treatment strategy, in the event, it was implemented with some variations across countries; this chapter focuses on DOTS in India.3 In 'directly observed treatment', a so-called DOT provider (DP) was in charge of the full amount of tablets for the duration of the treatment. During the initial two months' 'intensive phase', the patient had to visit the DP three times per week (this was known as intermittent treatment) and take the medicine under 'direct observation'. In addition to directly observed treatment and availability of the entire course of treatment from the outset, earmarked for individual patients, the DOTS regimen also included an extensive monitoring system. Each individual patient visit to the DP and each intake of drugs were registered, and the information fed into a surveillance system that aggregated data at relevant administrative units up to the national level.

From its inception, and throughout high-burden countries, DOTS was a highly complex strategy that depended on the success of many simultaneous interventions at all levels of a given health system (Gericke et al*.* 2005). A vertical programme, it was semi-integrated with the existing health infrastructure and hence depended on the quality and stability of that infrastructure to achieve the desired effect on TB control. The programme rested on a calculation indicating that achieving a case detection rate of at least 70 per cent of all actual cases and a cure rate of at least 85 per cent could cut the TB caseload by half within a decade (Elzinga et al*.* 2004). This constituted a strong selling point for the adoption of the DOTS strategy as a major public health intervention by governments globally. In India, the National TB Control Programme had failed to manage the TB epidemic effectively during the 1980s and 1990s (Brimnes 2016). There was an urgent need for policy change, and WHO was advocating DOTS as an answer to the problem. This approach was eventually accepted by the government of India (GOI) and incorporated in the RNTCP, which was launched in 1993 as a pilot project. The programme was gradually scaled up from an initial coverage of 2.35 million people to cover a population of 20 million in 1996, the year in which World Bank funding was introduced, and a plan for rapid nationwide scaling-up of the programme was developed. Within the next 10 years, by March 2006, DOTS had been expanded to cover the entire Indian population, even if coverage as defined by GOI did not imply that all TB patients were treated under DOTS; rather, it meant that the formal DOTS structure was nationally accessible as per the norms established by the programme (Seeberg 2014).

# Contamination and configuration: TB treatment as an epidemic

Rosenberg uses the concepts of 'configuration' and 'contamination' to describe two distinct approaches historically used to explain the occurrence of epidemics (Rosenberg 1992). Configurationist explanations assume a normal health-maintaining steady state of 'climate, environment and communal life', and Rosenberg suggests that such 'holistic' explanations dominated before the appearance of medical knowledge about specific infectious agents (Rosenberg 1992, 295). Contamination designates the idea of 'person-to-person contagion, of the transmission of some morbid material from one individual to another', or 'an event or agent that might subvert a health-maintaining configuration' (Rosenberg 295). Even if these explanatory models contrast, they are not mutually exclusive; rather, as Rosenberg points out, they weigh differently in different cases of epidemics and at different times. Using these concepts as analytical categories (Seeberg and Meinert 2015) rather than as contrasting types of explanatory models allows for us to explore the configuration of an epidemic of contamination of drug resistance (see also Seeberg 2019). Furthermore, if we adopt the perspective of TB bacteria, TB treatment in the age of global health becomes a pandemic of contamination that is potentially fatal for M. TB. Studying the configuration of this pandemic (i.e. global TB governance and its implementation in specific contexts) enables us to explore from a new angle, ways in which the bacteria have been able to transform into drug-resistant strands, seemingly successfully surviving the global health 'treatment pandemic'.

Due to its strong walls, M. TB is a very robust cell, capable of surviving in dry environments for years, and in air for days. Its cell walls have enabled it to develop a 'complex parasitic relationship with its host's immune system' and 'down-regulate its host's immune response, allowing the pathogen to protect itself from attack by the immune system and thus to survive in a latent state for decades' (Nightingale 2010, 167). It is this capability that explains how an estimated one-quarter to one-third of the world's population can be infected with latent TB, capable of subsequently producing disease if the immune system is compromised, for example, with HIV co-infection or malnutrition. As is the case with the TB cell's evolutionary relationship with phages, the cell's relationship to its human (or non-human) host is one of biological co-evolution. With the configuration of urbanisation from the sixteenth century onwards, the disease gradually changed from rare to epidemic (Nightingale 2010) because of the combination of high population density, poor hygienic conditions and widespread undernutrition. The relative disappearance of TB from the Global North and its epidemic proportions in the Global South can be seen as expressing global reconfigurations of these three factors, further fuelled by its syndemic relations to HIV (Singer 2009).

If the TB control programme creates, from a TB bacteria perspective, an epidemic of contamination, it is potentially a very serious one. DOTS used a combination of four drugs – Isoniazid, Rifampicin, Pyrazinamide and Ethambutol – in the first 2 months of treatment. If the medicines had the desired effect, demonstrated by a negative sputum test, the dose was reduced during the following 4 months of treatment with only Isoniazid and Rifampicin, where the patient was given treatment to take home for a week at a time.4 Isoniazid, Ethambutol and probably Pyrazinamide attack the cell wall, whereas Rifampicin inhibits the cell's ability to perform RNA (ribonucleic acid) polymerase (Laurenzo and Mousa 2011). If all these drugs are administered together, and for an extended period, a treatment-naïve TB cell has virtually no chance of survival, since it depends on mutation to develop the appropriate forms of resistance for each drug independently. Patients who resumed treatment after an interruption of 2 months or more (so-called 'defaulters') and relapsing patients were categorised as Category II patients; in these cases, intravenous Streptomycin was added to the regimen and intensive and continuation phases were increased to 3 and 5 months respectively, resulting in an additional 8 months of treatment. In spite of this chemical carpet-bombing of the TB cell's walls and interior, similar to a contamination syndemic (the mutually reinforcing dynamics of two or more concurrent epidemics in a population) (Singer and Clair 2003) with quadruple exposure to pathogens for the TB cell, multidrug resistance still happened; conversely, the reduction of incidence that had been calculated as the desired public health outcome (i.e. cutting TB by half in a decade) did not result. Figure 6.1 shows the trends over the period 2005–18 for notified cases of TB (the flat graph) and MDRTB (the rising graph, note: logarithmic scale) in India.

Estimated numbers are much higher than notified numbers, and so it seems that M. TB is so far able to adapt to this syndemic of anti-TB medicines. Keeping in mind Napier's call for a sociobiology that focuses

**Figure 6.1** Trends for notified TB and MDR/RR-TB cases in India. Data source: http://www.who.int/tb/data.CCBY-NC-SA 3.0 IGO.

on the communication between organisms, it seems that the TB bacteria engage in similar ways with drugs and phages, with outcomes that may be positive (resistance or adaptation) or negative (death), but in specific cases are unknown and perhaps unpredictable. To understand how the TB cell is able to resist contamination, so to speak, I return to the trope of configuration. How is the 'epidemic of anti-TB medicines' configured?

# Configuring the spread of TB treatment

Most public health studies on the occurrence of drug resistance under the DOTS programme either take a standard epidemiological approach involving the identification of risk factors for 'defaulting', or (more seldom) take a qualitative approach and ask 'defaulters' about why they have left treatment. 'Defaulters' constitute by definition the category of patients who have interrupted treatment for two or more consecutive months. A frequently held view on acquired drug resistance in TB in public health literature would state that MDRTB 'for the most part [is] due to inappropriate treatment protocols, non-compliance or inappropriate dosing schedules' (Laurenzo and Mousa 2011, 6). I shall return to inappropriate treatment below; here I focus on non-compliance. Given that DOTS, by definition, used correct treatment protocols and appropriate dosing schedules, it is hardly surprising that attention initially concentrated on the category of 'defaulters' in attempts to understand their 'non-compliance' or 'non-adherence'. For example, a hospital-based study in South India identified patients 'vulnerable to default such as males, alcoholics,5 smear positive cases, and DOT being inconvenient' (Jaggarajamma et al*.* 2007, 130). The authors felt that 'Intensifying motivation and counselling of this group of cases are likely to improve patient compliance and reduce default' (Jaggarajamma et al*.* 2007, 130). Other study designs have allowed for a more nuanced discussion of the issue, and suggested that the category of 'defaulter' be reconsidered (Jaiswal et al*.* 2003), a revision of terminology that was embraced by WHO in its 'End TB Strategy' (WHO 2014b).

Seeing the issue from the bacterial perspective, and hence perceiving treatment as a contamination epidemic, makes it possible to ask a somewhat different set of questions. What is 'access' combined with 'non-compliance' in a global health perspective now becomes a question of exposure. A number of situations could offer TB bacteria some relief from exposure to the toxic treatment. As mentioned earlier, India had from the beginning decided to implement so-called intermittent treatment, with administration of medicines three times per week during the intensive phase, whereas most other countries had implemented DOTS with daily medicine administration.6 The reasons for intermittent treatment were economic and managerial, but the risk of adverse side effects was also reduced (Saltini 2006). It was cheaper to manage a system with patient–provider contact reduced to less than half that required for a daily regime. It meant, however, that missing one dose equalled missing close to 3 days' medication. If this happened regularly, bacterial exposure was reduced and the risk of Rifampicin resistance increased (Saltini 2006, 2089). Another cause of interruption of treatment was the gap that often arose between the intensive and continuation phases. After the intensive phase, the patient had to travel to the diagnostic centre for a sputum test. Whereas the distance between patient and DP was supposed to be less than 2 kilometres, the distance to the microscopy centre could be considerable, and it could be difficult to organise the journey due to work and social obligations. Even if the journey was made, there was no guarantee that health staff were available. With effective treatment, the sputum test would be negative (sputum conversion) and the patient would be shifted to the less aggressive 'continuation' regimen, whereas patients with a positive test would remain on intensive phase treatment. Depending on the stability of exposure during the intensive phase, this window between the intensive and the continuation phases established another systemic risk of interruption. The pressure to ensure that the patient went for the sputum test fell on the DP, adding to the need for a trusting relationship between DP and patient.

Furthermore, in many cases, the assumption that a trained DP would be within reach of any patient across the subcontinent was rather optimistic. For this reason, two emergency measures were routinely taken. One of these was 'spot training' of a relative or neighbour, who in place of a full day's DP course would be given a briefing on how to give the medicine, how to complete the patient card and whom to report to. This was not necessarily a less effective approach, since as many as 50 per cent of trained DPs at a given point in time did not treat any patients for years after their training was completed (Hjalsted 2003). If spot training was not possible, for instance, if no volunteers were available, a second measure was for the medicine box to be given to the patient, who would be given similar on-thespot instructions. Faced with the alternative of denying sick patients treatment, dedicated frontline health workers who were used to 'improvising medicine' (Livingston 2012) in difficult situations in order to make sense of their work were squeezed between rigid programme guidelines and rough realities. Patient-administered TB treatment was often practised in areas very far from functioning health clinics with trained staff. A study from Odisha – a state in India with a large population classified as 'scheduled tribes', who have historically been pushed into hilly and mountainous areas with poor infrastructure – found that in 2001, only 68 per cent of patients registered in the DOTS programme received directly observed treatment (DOT) throughout the intensive phase of treatment. One of the main reasons for not having DOT among patients even when a DP was available was 'reluctance to have nine tablets on an empty stomach in the morning' (AIMS Research 2002, viii). A comparison of 'community DOT' provided by health workers and 'family DOT' given by a relative showed that more patients completed treatment with family-based supervision and support (Newell et al*.* 2006). A study from Kerala, India, found that 27 per cent of those patients who were reported to receive observed treatment in fact did not and that they accounted for 86 per cent of treatment failures or relapses (Balasubramanian et al*.* 2000, 410). Given that approximately 70 per cent of registered TB patients in India were male and that the vast majority of DPs (80–90 per cent) were female (Hjalsted 2003), the idea that maleness could be constructed as a risk factor for defaulting as quoted above is hardly surprising. However, this observation should be placed in a context where it was often difficult for female DPs to operate and assume the authority necessary to personify a very paternalistic treatment system in a society with pronounced gender inequality. In addition, DPs without other health training frequently faced problems when trying to obtain the medicine from and otherwise interact with health personnel at the TB centre (Hjalsted 2003). The implementation of a programme that forcefully interfered with patients' daily lives in a strict treatment-cum-control regimen was highly dependent on local context and existing power structures to assert itself. In the fast and target-driven expansion of DOTS in India, such dynamics were ignored or assumed to be unproblematic. The speed with which DOTS was expanded and the necessity of disregarding local solutions to implementation problems in favour of easy-to-manage uniform policies pushed by the World Health Organization was itself an important part of the configuration. These factors created a context in which reports of dysfunctional health posts, untrained personnel and longterm vacancies at key posts in peripheral districts were highly unwelcome among state-level and national-level TB administrators who were engaged in the race against time to complete full DOTS coverage by March 2006 (Seeberg 2014). In many places, DPs and lab technicians were trained in large numbers, but the system's internal supervision and monitoring practices could not be uniformly sustained, at least not for an extended period of time. The logic of the surveillance system focused on registering the moment at which the patient was supposed to swallow the tablets.

Hypothetically, one could imagine a different kind of monitoring system, one that not only registered 'missed doses' but that monitored the quality of the health system: days without the presence of a medical doctor or a lab technician due either to 'other work' (a euphemism commonly used for personal business elsewhere) or long-term vacancies; periods with defective microscopes; lack of fuel for supervisors to conduct field visits; or periods where the DP would travel to other places, and so on. This kind of workplace monitoring would have its own practical, ethical and social problems, and supporting an underfunded public health system seems more important than adding new control mechanisms. Still, it seems a valid point that the existing monitoring system was not designed to demonstrate the need to invest more resources in the public health system, and it failed to connect its structural shortcomings more directly to the phenomenon of drug resistance. The 'faults' of 'defaulters' were given privileged visibility by the monitoring system and therefore in policy discussions, especially at the district and lower administrative levels, where the blame for health system inadequacies was typically directed (Seeberg 2014). In this configuration, the DOTSbased 'epidemic of antibiotics' proved less fatal to TB bacteria than had been calculated, as the meeting with ground realities offered sufficient opportunities for M. TB to develop drug resistance.

If, despite the tremendous efforts and resources invested in the programme, the DOTS strategy failed to take into account the living conditions of and social dynamics between providers and patients on the ground, it also had another serious problem. The rapid expansion of DOTS did not take place in a context free from pre-existing TB treatment. On the contrary, in an Indian health system dominated by commercial health clinics, DOTS had primarily found its takers among poor patients in rural areas of India where government-run health clinics were fully or partially functional. In the large cities, government services at primary and secondary levels were largely absent and patients generally had to rely on commercial healthcare services. TB management in the commercial healthcare sector was, however, rather flawed. Uplekar and Shepard showed in 1991 that in Mumbai, 100 private practitioners prescribed 80 different regimens that were generally expensive and inefficient (Uplekar and Shepard 1991). In 1998 the situation was largely unchanged (Uplekar et al*.* 1998). This situation contributed substantially to the development of MDRTB in India (Udwadia 2001). The booming pharmaceutical industry's engagement with and monitoring of private providers was the main driver of healthcare services in the commercial sector (Kamat and Nichter 1997, 1998; Seeberg 2012). The Indian drug company Lupin, with a dominant market share in anti-TB drugs, had a substantial influence on 'continued medical education' in the commercial sector, where doctors had few other options for keeping up to date with pharmaceutical developments. Ecks and Harper have shown that 'big doctors' (specialists, such as, pulmonologists) were opposed to DOTS because they considered the guidelines too inflexible for the management of individual patients: they saw a need to experiment in individual cases so as to reduce side effects and match dosage with the weight gain that typically accompanied successful treatment (Ecks and Harper 2013). General practitioners were less concerned with TB, since it was perceived as affecting only a small proportion of the cases they saw in their clinics. Therefore, they were less susceptible to the medical representatives'(MRs) 'education' about TB even if this, according to the MRs, might save doctors from engaging in malpractice (Ecks and Harper 2013, 266–7). The vast population of registered (or rural) medical practitioners (RMPs, often labelled 'quacks' by medically qualified doctors) also constituted an important outlet for Lupin's medical representatives, as for most Indian-based drug companies, even if these practitioners did not 'understand the quality' of the medicines (Ecks and Harper 2013, 267). While active TB infection was already disproportionally affecting the poor, the differential costs involved in consulting these practitioners clearly favoured opportunities for M. TB to develop drug resistance among poor patients, who had no option but to choose the short-term treatment of RMPs for economic reasons, unless they were enrolled in DOTS. Add to this the circulation of expired, substandard and spurious drugs in a potentially illegal medical economy with few or no quality checks in place among the non-specialised and non-qualified practitioners more often frequented by poor patients.

Especially in urban slums, it was difficult to implement DOTS (Seeberg 2013; Das 2015). Inhabitants had plenty of unpleasant experiences with state representatives and often lived under a general fear of eviction, another bureaucratic constraint that could lead to treatment delay or treatment refusal, since proof of residence was a prerequisite for assigning a DP (Seeberg 2013). Furthermore, primary-level government health services were virtually non-existent in urban India. This meant that the health infrastructure was insufficient to support DOTS (Seeberg 2012), working as it was against the systematic anti-DOTS campaign among practitioners in the commercial sector (Ecks and Harper 2013), further supported by MRs from companies who saw DOTS as a potential threat to their business. In this context, with only around 0.25 per cent of medically qualified private practitioners involved, it was not surprising that the response of 'public–private mix', as a strategy to expand DOTS and control the unstandardised treatment regimes in the commercial health sector, had very limited success (Seeberg 2014). With a 46 per cent share of TB drugs in India, and with 74 per cent of the TB drugs consumed in India being dispensed by the commercial health sector and only 26 per cent by DOTS (Ecks and Harper 2013, 254), the dominant pharmaceutical company Lupin seemed to ignore the rise of drug resistance in the interest of short-term profit rather than engaging in a long-term collaboration with the state to promote DOTS. This apparent strategy was pursued despite the consideration that changes in global treatment regimens are likely to develop faster than any single drug company can adapt to such change, thereby creating space for new and competing pharmaceutical companies to become dominant.

From the perspective of the TB bacteria, it is obviously immaterial whether the host is engaging with drugs that pass through the commercial or public healthcare sector. From its perspective, this is one syndemic (Singer and Clair 2003) involving multiple contaminants distributed along socio-economic differentials among their hosts in their immediate organic environments. Viewing this as configuration rather than contamination, however, the political and economic separation of these sectors works to optimise the opportunities for TB bacteria to develop resilience. Conversely, this has a negative impact in the form of an escalating epidemic of MDRTB as seen from a human perspective.

# Multidrug-resistant tuberculosis in India

Multidrug-resistant tuberculosis is defined as drug resistance to at least two of the four first-line drugs used in standardised TB treatment. For an extended period during and after the expansion of DOTS, the GOI refuted that drug resistance among DOTS patients was a problem. Lack of access to diagnostic facilities to test for drug resistance allowed MDRTB to remain invisible. As these facilities became more accessible and with a growing number of alarming studies showing an escalation of MDRTB patients (for example, Almeida et al. 2003), the GOI eventually incorporated the so-called DOTS+ regimen in the TB control programme, following a 'consensus statement' issued jointly by the government and leading TB research centres in India on MDRTB in 2007 (Engel 2013). DOTS+ was not only much more expensive; with a treatment duration of 2 years of chemotherapy, its management added exponentially to the complexity of an already complex public health intervention.

Furthermore, in India, because access to drug susceptibility testing during the 1990s and 2000s had been poor, it was generally not known whether drug resistance or other factors caused treatment failure. Towards the end of this period, however, upgrading of laboratories and availability of medicines for patients who tested positive for drug resistance, classified as CAT IV treatment, changed this situation in parts of India. This also led to dramatic changes in the figures involved: an estimate of 99,000 new MDRTB cases annually by 2011 was quoted by a leading national expert (National DOTS+ Committee 2011). Compare this with figures saying that 4,217 patients had been placed on CAT IV treatment by end of 2009, of whom only 756 were alive 12 months later. The rapid expansion of the DOTS+ programme (meanwhile renamed to 'programmatic management of drug-resistant TB' (PMDT)) is visible when these figures are compared with the STOP TB India country profile for 2012, with 64,000 notified cases of MDRTB and 14,143 (22 per cent) patients started on MDRTB treatment (WHO 2014a).

The challenges posed by this iatrogenic epidemic for public health are formidable. Not only are individual patients and their families forced to realise that the kind of TB they have is very difficult to treat successfully and likely to cause individual death, household disaster and community-level distress. The rise of MDRTB turns the image painted by the commercial healthcare sector of DOTS as a failed government programme into a self-fulfilling prophecy, even if the commercial sector contributed substantially to the development of drug resistance.

Lock and Nguyen have pointed to the 'military-like organisation' (not to mention, rhetoric) adopted in large-scale public health campaigns developed in continuation of colonial medicine in Asia, Africa and Latin America (Lock and Nguyen 2010, 153). DOTS, with its strongly hierarchical organisation and emphasis on disciplining both patients and peripheral providers through supervision, monitoring and 'motivation', was an example of this. With its near-exclusive emphasis on drug delivery, the system was a carefully designed attack on TB bacteria. Patients were at best passive vessels through which the medicines had to pass, at worst obstacles to the success of the attack due to epidemiologically constructed risk factors of non-compliance such as being uneducated or consuming alcohol. Gradually, however, this medicine-centred approach was seen to conflict with rights-based approaches, which began to influence discourses about healthcare delivery globally. In particular, the need to address the TB–HIV syndemic brought into closer contact two treatment systems that had hitherto viewed the issue of patient rights very differently. In India, confidentiality regarding information about TB patients was not routinely maintained at the community level; anybody in a village would be able to point a treatment supervisor to the house of a TB patient. At the same time, the discrepancy between policy changes and actual implementation was increasing, since 'policy translation' is a time-consuming process of negotiations, adaptations and (un)learning. Hence, while DOTS was rapidly being scaled up in India under the initial strategy, the then-new STOP TB strategy was being launched in Geneva in 2001. As DOTS reached national coverage in India, the Global Plan to Stop TB 2006–15 was published, calling for 'human rights imperatives' to be incorporated. However, the route from policy changes made in Geneva to the practising of TB treatment in a remote Indian village is very long.

Harper has pointed to a growing tension between problems with drug resistance and the patient-centred approach as advocated by the STOP TB partnership (Harper 2010). This tension was even more pronounced in connection with extensively drug-resistant TB (XDRTB), where additional resistance to second-line drugs made the disease untreatable in most settings. The dramatic rise in drug-resistant strains of TB created a situation where not only the prognosis, but also the rights of patients could vary depending on the type of TB, while it remained difficult in some contexts to determine the existence and extent of drug resistance.

Disregarding the classificatory issues mentioned above as well as the other barriers to treatment initiation that sometimes occur with standard TB, all patients identified by the DOTS programme were presumably placed under DOTS treatment. According to the Patients' Charter for TB Care, patients have a right to free and equitable access to services, including treatment, care and information; and they also have the responsibility to comply with the prescribed treatment plan. However, in the face of MDRTB and XDRTB, documents originating from WHO have begun to discuss more restrictive measures, including a return to isolation practices and the consequent risk that such measures could jeopardise the treatment programme as a whole and add to the stigmatisation of patients (Harper 2010, 210).

# Resistance-driven technologies

The DOTS+ strategy seemed unduly optimistic because it was essentially based on an idea of 'more of the same', i.e. more toxic drugs for a fourtimes-longer period compared with the regimen that had failed in the first place. Dr Mel Spigelman, President and CEO of the Global Alliance for TB Drug Development (TB Alliance), talking in 2014 about the promises of a new drug combination going into phase three clinical trials, stated:

Many of the problems with today's MDRTB treatment are due to the fact the regimens were assembled as an emergency reaction to the problem – an approach of treating patients with the 'kitchen sink' of available drugs to find something that works [and] an approach whereby you throw what you have, flawed as it may be, at the problem and hope for the best. (Prasad 2014)

This may be seen as a somewhat arrogant description, given the substantial resources that had gone into convincing governments that DOTS+ was the necessary answer to the MDRTB epidemic and into the subsequent revamping of the programme in order to enable the system to apply this 'kitchen sink approach'. Nevertheless, Spigelman illustrates that the response to the crisis of MDRTB was one of more drugs, rather than one of addressing health-system failures leading to the development of drug resistance in the first place.

One would like to share the optimism that the answer to drug resistance is new drugs: that we can solve the problem with yet another technological fix. One of the most prominent candidates for such new treatment, according to Bill Gates in 2014, and depending on the outcome of phase three trials partially funded by the Bill and Melinda Gates Foundation, was a new combination therapy known as PaMZ. This regimen was linked to promises to reduce treatment periods for TB to 4 months and for (susceptible) DRTB to 6 months, with fewer tablets to take for patients (Gates 2014). Both were important dimensions of potentially less troublesome treatment regimens. But two years later, TB Alliance decided to close enrolment to the trial in favour of a more promising Bedaquiline trial known as BPaMZ. Important as new anti-TB medicines are, they are also goods circulating in the economy of technological hope; by contrast, improvements of the public health infrastructure with well-established positive effects remain underfunded.7

The role of the phages in the above discussion was to launch the idea that from a bacterial perspective, anti-TB medicines could be seen as an epidemic of contamination, that the bacteria had to relate to in order to either die, survive as self, or transform into a new (drug-resistant) strain. However, phages too may become medicine. The landscape of phages could constitute another potential frontier for treatment-orientated developments. Phage-based therapies have been tested in treatment of MDRTB patients in some countries of the former Soviet Union, where the breakdown of the health system in the wake of the collapse in 1989 of the state, along with abysmal conditions and treatment practices in prisons, resulted in widespread drug-resistant TB (Farmer 2001). Phage therapies have the theoretical advantage over standard antibiotics that they target specific bacteria and, therefore, do not have the generalised negative impact on the bacterial fauna that antibiotics have; indeed, for the same reason they are self-limiting – they can only exist in the body for as long as the host cell is present. Problems include high immunogenicity that may result in their rapid clearing by the body, as well as the risk of production of high levels of endotoxins from lysed bacteria.8 However, addressing such biotechnical issues is generally not considered interesting by a pharmaceutical industry that is nervous about intellectual property rights, given that phage therapy has been used in the public domain for a century and that individual phages are unlikely to be patentable (Clark and March 2006). Thus, a major obstacle to pursuing this potentially less harmful and more specific (although, so far, not very effective) treatment directed at a major health problem is that it does not fit the dominant business model of present-day global health financialism (Erikson 2012, 2015).

Using the standard treatment in environments with high but unknown levels of Rifampicin and Isoniazid resistance can lead to the so-called 'amplifier effect', whereby resistance to the other first-line drugs develops faster (Harper 2010), since the effect of having a combination of four drugs in this situation is significantly reduced. For this reason, the difficulties involved in testing for MDRTB combined with a uniform approach to DOTS implementation in a context such as India, in which most commercial-sector TB treatment is insufficient, has in itself potentially contributed to fuelling the MDRTB epidemic. Therefore, WHO approval in 2011 of a new technology to rapidly test for resistance to Rifampicin, known as Xpert MTB/RIF, which reduces the time for such testing from months to hours, was met with high expectations. The machine was designed for district-level implementation and was rolled out worldwide with support from USAID and the Gates Foundation, among others. The number of machines distributed in this approach has become a measure of success in itself. As pointed out by Adams, global health 'envision[s] a world in which, interventions can be mapped out as problems of scale and measurement (or specifically as counting practices) rather than as problems of custom, culture or national political will' (Adams 2016, 6). Riding the hope of improved TB control, such interventions allow for the continuation of an exclusively pharma-technical understanding and management of what should in fact be regarded as a biosocial complex, with very selective and specialised 'vertical' support mechanisms to health systems in dire need of general strengthening (Biehl and Petryna 2013).

# Between nature and culture

The initial treatment standards of DOTS, with at least 70 per cent case detection and 85 per cent treatment completion, held out the promise that the caseload of TB would be reduced by half in a decade. This bioeconomic calculation shaped the projections of a regimen onto the complex dynamics of daily living for TB patients, health providers and bacteria alike. Among the many thousands of people involved in TB treatment globally, two interpretations of these standards can be imagined. One interpretation sees such targets as minimal quality criteria that must be fulfilled by any TB control programme. However, an alternative interpretation sees these as programme targets to be achieved. The two interpretations thrive alongside one another, even if target-orientated systems tend to favour the latter. A central question concerned the remaining 15 per cent of patients whose treatment completion was, so to speak, outside the target. The production of so-called 'defaulters' was a by-product of this target (Seeberg 2014), explained through the projection of certain characteristics (for example, being male, alcoholic, uneducated) onto systemic programme failure. For many years, this contributed to the configuration of the MDRTB syndemic by establishing a reservoir of TB cells that had better chances of developing drug resistance among those human hosts least able to follow the standard TB treatment, much less treatment for MDRTB.

From the perspective of the TB cell, medical treatment is a potentially fatal source of toxic contamination. The DOTS programme was a pandemic of such contamination, configured in particular ways that varied according to context. I have focused on India; but within India, configurations of DOTS varied across state and district boundaries, social classes, castes, gendered inequities, urban and rural settings, households, and individual patients, as well as density and performance of both government and private-for-profit providers. The projection of DOTS as a universal TB control programme and its rapid expansion in need of a one-size-fits-all logic was blind to the political economy of which it was itself a part. The relevance, if not the existence, of all these variations was forcefully denied. Revised global and national TB control strategies may have strengthened their focus on both DRTB and patient rights in certain limited ways, but in contexts of serious resource constraints in government health facilities as well as in the households of most TB patients, it is likely that M. TB will continue to find successful ways to engage with the pandemic of medical contamination. Indeed, in this Waddington-like landscape (see Lock, this volume; Petryna, this volume), it seems likely that TB cells will continue to produce drug resistance faster than biomedicine can 'mutate' into new drugs and renew the efficacy of treatment. From this perspective, new drugs – and global access to them – may buy some time for humans in the ongoing engagement with bacteria such as M. TB. Biomedical optimism holds that this time will be sufficient for biotechnology to develop new vaccines of high potency, thereby solving the problem of antibiotic drug resistance en route to 'End TB'. While we wait to see what is on the 'blindsided' fold of this hopeful horizon (see Petryna, this volume), beginning to understand the biosocial dimensions of TB could help us to prepare better for yet another disappointment, perhaps even to learn from past failures about how to take the life circumstances of patients, providers and bacteria seriously when trying to help the former.

# Notes

# References

# Chapter 7 When Sickness Comes in Multiples: Co-morbidity in Botswana

Julie Livingston

# Introduction: Situations of complexity

Biology is often assumed to determine much about how illness and medicine are experienced. Yet what are we to make of situations in which biology points in multiple directions simultaneously? Botswana, like many places, is rife with co-infection and co-morbidity. The complexity is overwhelming. Simultaneous epidemics of tuberculosis (TB), HIV/AIDS, and cancer are deeply entangled and fuelling one another in this small Southern African nation. There are also ongoing epidemics of diabetes and hypertension to consider as well (Young et al. 2009; Haregu et al. 2012).1 The situation is creating great challenges for both patients and their clinicians. They are seeking diagnosis and treatment in a health system whose institutional and intellectual architecture was to some extent designed to separate these three disease categories even as health planners and clinicians alike recognise how TB, HIV, and cancer continually clot back together, aggregating in the human body, clinical thought, and the social imaginary. The challenges are compounded by the potential for a silent or latent stage of each disease, the nature of AIDS as a disease of co-infection, the plurality of disease contained under the rubric of cancer, the historical freight of TB in the region, and the dissonance brought by the relative novelty of cancer in the country.

This kind of complex epidemiological landscape calls our analytical capacities into question. It troubles disease-centred social and medical science. It is local biology that at once threatens and reveals the taxonomic project at every level of iteration (see Lock and Nguyen 2010 this volume for an extended discussion of local biology).

It is not that disease specificity, that legacy of the bacteriological revolution, is absent entirely. Historians use the term 'disease specificity' to refer to a fundamental transition in medical reasoning that took place over the course of the nineteenth century. Charles Rosenberg (2002, 242) explains: 'In traditional [Western] medicine, disease concepts were focused on the individual sufferer. They were symptom orientated, fluid, idiosyncratic, labile, and prognosis orientated. Diseases were seen as points in time, transient moments during a process that could follow any one of a variety of possible trajectories.' By the early twentieth century, this idea had given way to 'the more abstract notion of disease entity as ideal type abstracted from its particular manifestations. A legitimate disease had both a characteristic clinical course and a [discrete, causative] mechanism.' However, while this sense remains, the presence of comorbidities mean that the complexities of experience must be continually and artificially disentangled and sorted along biological, institutional, and intellectual grids in order to support such analytics. Clinical decision making around drug and radiation dosage, timing, and interactions necessitates great care in a medical system that is overwhelmed by the volume of patients and their biological intricacies. The stable, normative biomedical body within which disease is imagined, is not available. Nor are the ontological certainties that separate diseases from one another. In some cases, the ontological barriers make little sense: Kaposi's sarcoma (KS) in women is so extremely rare that it is almost thought not to exist without HIV, so are these two diseases or one? However, the political, economic, moral, and institutional projects that arise around specific diseases continue to matter tremendously.

Here is a quick glimpse at what that complexity looked like 10 years ago, in January 2007. At the time I was working as an ethnographer in the oncology service in Princess Marina Hospital, Botswana's central referral hospital, located in the capital city, Gaborone. I made the following entry in my field notes.

A woman arrives dizzy and weeping. We see her sitting on the floor by the waiting bench and Dr P, the oncologist, has her put into a bed. She is *very* miserable. There is a man accompanying her. Is this her husband? Brother? She has HIV. Her CD4 is 251 and she is not yet on antiretroviral therapy. They have been treating her for TB for one month even though she has two purple KS lesions in her mouth and a big one on her arm and her lung x-ray shows the symmetrical, butterfly shaped pattern that is typical of KS. Dr P does a fine needle aspiration from the swelling in her neck to see if maybe she also has non-Hodgkin's lymphoma, but meanwhile, given the urgency of her lungs, will begin chemotherapy for the KS.

Or another from that same month.

A man arrives on a stretcher. It turns out this patient is a nurse. He is in his late 20s and has HIV, TB, and KS – three wasting diseases. He is gaunt. He arrives from one of the provincial hospitals via the dental clinic, brought by Dr O, the maxillofacial surgeon, who wants Dr P to have a look. This patient has defaulted chemotherapy twice and he has big KS lesions inside his mouth, Dr O explains. No. The nursing assistant who has accompanied the patient from the provincial hospital corrects Dr O. This man has been hospitalised since June so it can't be his fault if he 'defaulted'. Now he is being referred by the doctor at the provincial hospital who is asking for a resection. But, as Dr O says 'No way – you can't cut KS out, it will bleed like mad' (KS, like other sarcomas is a very vascular cancer). Dr P agrees. They are frustrated with the doctors back at the provincial hospital, as is the nursing assistant. The patient will need to begin chemotherapy for a third time. The next day he was back, now accompanied by a nurse. It turns out he has multidrugresistant TB (MDRTB). Dr P says to put him outside on the veranda where the ultraviolet light from the sun will kill the bacteria, while he waits for his chemo, but no one does it. Instead the stretcher is in the crowded hallway where cancer patients sit waiting for their chemotherapy and clinic appointments.

As you can see, some patients arrive in Botswana's oncology ward suffering from HIV, KS and TB. Some patients have been on TB treatment for months to no avail, before they are able to get the cancer in their lungs diagnosed, while others have to let their cancer wait while hopefully their TB and HIV are brought under control enough to give them the strength to undergo chemotherapy. Some patients have scar tissue in their lungs from previous TB infections, which increases their susceptibility to lung cancer (Vento and Lanzafame 2011). Sometimes the oncologist (who in the time of my research also served as the ward cytologist) finds lymphoma cells and TB bacilli in the same lymph node. Some HIV patients are co-infected with cancers, meaning they have multiple malignancies at once and of course some patients have cancer and TB but not HIV.

This chapter uses the particular vantage point of the cancer ward to try to understand how the meaning of co-morbidity and the densities of entanglement between HIV, TB, and cancers shift over time and across scale in this context of intersecting and accumulating epidemics. Epidemic multi-morbidity challenges the institutional capacity of the health service, the intellectual and technical capacity of hospital and clinicians, and the social, emotional and existential capacities of patients and relatives. In this way, it provides a key site for elucidating biosocial complexities and the need to refuse any false separation between nature and culture (see Lock, this volume) at all scales of analysis. For example, in the case of co-morbidity in Botswana, ethnographic attention to the medical institution as social environment further reveals contradictions between biomedical reasoning and the institutional organisation of both the hospital and larger health system. The biology with which the co-morbid patient lives is in contradiction to the environment designed to heal her. Ethnographic methods reveal the dilemma of the biosocial patient and the limits of the biological purchase of the clinician.

In what follows, even as I pursue the logic of co-infection, and given that approximately 40 per cent of the patients who arrive at the cancer ward are HIV negative, I also want to push a bit against an easy assumption that HIV is the index disease around which TB and cancers appear as co-morbidities (Valderas et al. 2009). While the production of knowledge (not to mention the political and funding impetus) in Botswana is to some extent organised around HIV, and while there is great truth to understanding HIV as a disease of co-infection, a model that overly privileges HIV is too limited to capture the complexities on the ground. Viewing cancer in Botswana mainly as an epidemic of co-infection risks subsuming the politics of oncology within those of HIV, even as they point in somewhat different, if overlapping directions. Cancer (like TB) asks us to think about labour migration in terms of occupational health and not only as the historical structuring force behind contemporary sexual and care-giving norms. It points to questions of toxicity and environmental health and cancer shifts the economic dynamics of the pharmaceuticalisation of public health (Biehl 2007).

I also want to push back against an assumption that co-infection, rather than co-morbidity is what matters. The majority of diabetic patients in Botswana are also hypertensive. While this relationship is often explained by its predication on shared risk factors (obesity, physical inactivity) what are the results of diabetic and hypertensive co-morbidity? What meaning does this articulation have for the patient who must attend two clinics, manage two pharmaceutical regimes, etc.? Or, given that not all cancers have an infection component, what might it mean to rethink our taxonomy of infectious versus non-infectious disease? How might upending taxonomy help us to contemplate the presence of HIV in patients on antiretrovirals? These are persons whose viral load is contained so well as to be negligible in terms of transmission, even as the effects of the drugs themselves are somatic and enduring, and whose sexual activity nonetheless proceeds under the sign of HIV. What if as a thought experiment, and given the high rates of diabetes in Botswana, we reimagined this epidemiological landscape as one united around metabolism, tumour necrosis factor and wasting, rather than privileging the paradigm of infection? Or what if we rethought diabetes and hypertension as an epidemiology significantly determined through vascularity rather than through obesity? What happens if we triangulate dyadic diabetic and hypertensive co-morbidity through HIV, recognising that HIV infection raises rates of both? Might foregrounding co-morbidity open new sightlines in aspects of disease and illness that are currently overdetermined by the infectious disease paradigm?

Such thought experiments abound once one gives them free rein. What I am suggesting is that by paying attention to patient experiences and to clinician's frustrations at the contradictions that they must navigate, one finds places where the human body overspills or does not quite fit biomedical categories. These experiences can thereby be the basis for biomedical theorisation or question raising. As the editors of this volume observe in their introduction, and as the chapters demonstrate, anthropological perspectives on biosociality can speak to and resituate biological inquiry and practice in vital ways.

Botswana is a middle-income country with an agentive and forwardthinking ministry of health. For nearly 50 years, the post-independence state has steadily invested in infrastructure and social services, developing capacity in their system of universal healthcare. However, Botswana is not without its problems. While the GDP has gradually risen over the past four decades, the United Nations Development Programme (UNDP) estimates that about a third of Batswana (as citizens of Botswana are called) live below the poverty line, as the gap between rich and poor expands across the globe (Republic of Botswana and United Nations 2010). Quality of care and capacity remain a problem as the health system struggles to keep up with a challenging national epidemiological profile. Human resources and technological capacity are uneven and strained, and as in many medical systems, bureaucratic requirements often hamper delivery of efficient, effective care. Nonetheless, given the degree of state commitment to health, in recent years Botswana has become one site in the region where new health policies and clinical modalities are developed and piloted, including most notably, the first public antiretroviral programme on the African continent. From Botswana, we can begin to see the thicket of intellectual, infrastructural, technical, and social challenges posed by the complicated relationship between ongoing epidemics of cancer, HIV, and TB.

I observed the brief scenes described above only 5 years into the start and scale up of Botswana's public antiretroviral programme. From its inception in 2002, the national programme triaged enrolment on antiretroviral therapy, to ensure that the sickest patients were covered first and then gradually scaled up from there. In 2007, the criteria for initiating Highly Active Antiretroviral Therapy (HAART) for a Motswana patient with a confirmed HIV diagnosis, were a CD4 count of 200 or below or an AIDS defining condition as established by the US Centers for Disease Control (CDC). In 2008, the threshold was raised to a CD4 count of 250 (and has continued to scale up to the current level of 350) and a shift was made from CDC clinical staging to WHO staging. In both staging systems, the presence of KS, invasive cervical cancer, non-Hodgkin's lymphoma, and/or TB (pulmonary or extra-pulmonary) indicated that HAART should be initiated regardless of CD4 count, though as we can see from my ethnographic vignettes, in practice this was not always done.

January 2007 also marked 5 years into the opening of the cancer ward and the beginnings of public oncology care in Botswana. The Botswana Ministry of Health had anticipated that the new antiretroviral programme would amplify the effects of HIV/cancer co-infection and so they planned accordingly. As HIV undermines the immune system, it makes patients more susceptible to a range of virus-associated cancers – most notably KS, non-Hodgkin's lymphoma, genital cancers, head and neck tumours, and other lymphomas. Before antiretrovirals were provided, AIDS patients with these cancers often died fairly rapidly from other opportunistic infections. But now as patients were put onto HAART, they began to survive longer, but with a new set of complications brought by their cancer. Experience in the US also shows that patients who do not have a cancer when beginning their antiretroviral treatment, nonetheless appear to develop cancers at higher rates over time even if they remain on antiretrovirals (Shiels et al. 2011). Botswana's lone oncology service was set up in a separate part of the central referral hospital from the Infectious Disease Care Clinic (IDCC) (as the HIV clinics in Botswana are called), and yet in some sense also as a response or supplement to it.

# Botswana's epidemiology of co-infection

Since the mid-1990s, Botswana has had one of the highest rates of HIV prevalence globally. A national survey in 2008 indicated an HIV prevalence of 17.6 per cent among the general population and a 40 per cent prevalence among people aged 30–44 years. In 2009, an estimated 331,000 people were infected with HIV, and there were over 8,700 HIV/ AIDS-related deaths, and an estimated 18,000 new infections annually in this nation of 2 million citizens (Republic of Botswana 2011, 6). TB rates have also been consistently high since the mid-1990s. In 2008, Botswana had the sixth highest TB rate globally (536 per 100,000). As part of this unfolding epidemic, the rates of multidrug-resistant TB (MDRTB) are also rising, with a reported 'increase in new cases of MDRTB from 0.2 per cent in 1995 to 2.5 per cent in 2008' (Republic of Botswana Ministry of Health 2011, 8). Meanwhile, rates of cancer are also on the increase. Botswana has been building its cancer registry for the past decade, but its capacity for diagnosing and counting cancers remains much thinner than the epidemiological apparatus necessary for counting TB and HIV. Therefore, figures for cancers are necessarily more tentative than those for HIV or TB. Nonetheless, we know that 8,494 cancers were diagnosed between 2003 and 2008 (Dryden-Peterson et al*.* 2012; Suneja et al*.* 2013). We can be fairly certain this is an under-reporting of the true burden of cancer in the country.

A dense picture emerges from tracing connections between these figures. In a revealing limitation of logic in the health system (one I am told that the Ministry of Health is actively seeking to change), I could not find figures for TB/cancer co-morbidity, or for TB/cancer/ HIV multi-morbidity, only for dyadic co-infections with HIV.2 Recent, preliminary studies suggest that over 60 per cent of Botswana's cancer patients are co-infected with HIV (Dryden-Peterson et al. 2012; Suneja et al. 2013). They also suggest that even as patients are initiated onto HAART with relatively higher CD4 counts (remember the rise from 200 to 350), high rates of cancer persist. While rates of KS are dropping slightly, those for non-Hodgkin's lymphoma and HPV-related cancers have risen.3 Meanwhile, epidemiological research in Botswana suggests HIV co-infection rates of 60–80 per cent in patients with active TB.

'Moreover,' researchers in Botswana have noted, 'the clinical presentation and natural history of TB differs between HIV positive and negative individuals. People living with HIV are more likely to be sputum smear negative and have atypical clinical and radiographic evidence of TB disease, especially with advanced immune suppression. Treatment of patients with TB/HIV is also challenging, due to the frequency of immune reconstitution inflammatory syndrome (TB–IRIS), drug interactions and toxicity' (Republic of Botswana Ministry of Health 2011, 9). The same could be said for atypical clinical presentations of cancers in HIV positive people as well as the problem of drug interactions and toxicity. This is an epidemiology that resituates the 'normal' body.

The situation in Botswana is this. There are three epidemics at present: TB, HIV/AIDS and cancer. One of these epidemics is emergent (cancers). One is the resurgence of a long-standing problem (TB). One is an epidemic of co-infection (HIV) that acts as an accelerant and an amplifier of the other two, even as it generates an unstable clinical profile among co-infected patients. Meanwhile the other two (TB and cancers) also enjoy a synergy independent of HIV. The epidemic and historically familiar nature of TB causes a misrecognition and thereby delayed (or absent) diagnosis of many cancers. Yet the presence of an oncologist who does fine needle aspirations facilitates the diagnosis of extra-pulmonary TB. The public health apparatus and resources brought by one epidemic (HIV) facilitate and force the recognition of the other two epidemics. However, the configuration of the health service makes co-morbidity difficult to manage – and parses infections by citizenship. Non-citizens are covered by the national programme for TB, but unlike Batswana they are not otherwise covered under the system of universal care and so they must pay for antiretroviral drugs (ARVs) and oncology out of pocket. In order to understand the syndemic roots of the situation (Singer 2009; Meinert and Whyte, this volume), let me step back and explain how this problem has unfolded over time in the briefest of terms. What we will see is a field of synergistic complexity and widespread distress similar to the case described by Meinert and Whyte (this volume) in Uganda, in which caregiving resources are overstretched, existential angst is widespread, and no one therapeutic domain is sufficient to apprehend, much less tend to, the syndemic field.

# Tuberculosis: The colonial epidemic

Tuberculosis was the great scourge of Southern Africa, including Botswana (previously Bechuanaland) for much of the twentieth century. European observers in the nineteenth century had remarked on the seeming absence of consumption/phthisis in the region, but this would soon change. In the late nineteenth century, the British colonised Bechuanaland and eventually ran the country as a migrant labour reserve for the South African mining industry, a labour regime structured by the institutionalised racism that would reach its fullest expression under apartheid. As historian Randall Packard has described, in the late nineteenth and early twentieth centuries the mines became an engine for the introduction and then dissemination of TB, which reached epidemic proportions in places like Bechuanaland by the 1930s (Packard 1989).

Tuberculosis remained endemic at very high rates even after Botswana gained its independence in 1966. The new nation inherited a handful of mission hospitals and clinics, but essentially had to build a health system from the ground up. By the 1970s and 1980s, a now independent Botswana had developed enough reach in its new primary care system to begin expanding access to antibiotics for TB patients. In 1975 they launched the National Tuberculosis Control Programme, introducing short-course chemotherapy in 1986, which was already making significant progress when they began implementing the directly observed treatment, short course (DOTS) therapy in 1993. The annual risk of infection declined from 5.8 per cent in 1956 to 0.1 per cent in 1989 (Republic of Botswana Ministry of Health 2007, 11). Tuberculosis notification rates declined from 506/100,000 in 1975 to less than half that figure by the end of the 1980s. Undoubtedly, this decline in TB rates was also facilitated by rising incomes and expanding social welfare programmes which together meant a rise in general nutrition. Unfortunately, this decline in TB was short lived. As outlined above, TB rates soon began to rise again in the face of widespread HIV infection, but the point here is that TB policy was foundational to the public health system in the country.

As I have described elsewhere, the history of TB was a fraught one in Botswana.  Improper sexuality (often an issue of timing and purification) was understood to produce illness in children and partners, even as the migrant labour economy exposed women to overwhelming caregiving burdens and extreme economic vulnerability. The symptoms of pulmonary TB overlapped with those of a Tswana disease *thibamo* that resulted from the violation of sexual and parenting expectations (in terms of timing of liaisons, modes of purification, etc.) and thereby carried some moral tinge.

Meanwhile, throughout the colonial and post-colonial period, the biomedical establishment focused on *pulmonary* TB when designing diagnostic, preventive, epidemiological and therapeutic interventions (Livingston 2005). Yet in the mid-1950s, extra-pulmonary TB accounted for fully a third of registered cases of TB. Extra-pulmonary TB has continued to account for a significant portion of the known burden of TB infection in Botswana, despite an epidemiological system premised on sputum smears and x-ray technology that is designed to identify and count pulmonary cases.

# HIV/AIDS: The epidemic of national existential emergency

The HIV/AIDS epidemic in Southern Africa was seeded through the high mobility and economic inequality of the population which began under the colonial migrant labour system. It built upon its legacy of sexual suspicion and overwhelmed caregiving networks. Like the TB epidemic that preceded it, HIV/AIDS too hit people in their prime. Young children, young adults, and the middle-aged formed the bulk of the patient population. Despite preventive efforts by the Botswana Ministry of Health, by the mid-1990s, the epidemiological scale of the HIV/AIDS epidemic had overwhelmed the health service which was designed to prioritise primary care. Hospitals, clinics, and private homes buckled under the weight of long-term, terminal illness. HIV brought TB back with a vengeance. Within a few years of the declared success of the national TB programme, the disease was palpably present and its prevalence escalated at an alarming rate. Meanwhile, the scope and scale of illness and death presented a grave moral crisis within the country and an existential crisis for the nation itself.

In 2002, when Botswana began its national antiretroviral programme, TB had already resurged and gained visibility as an epidemic of co-infection. Batswana to some extent made sense of HIV/AIDS through older understandings of existential crisis, epidemic, latent infection, and toxic sexuality through their historical experience with pulmonary TB/*thibamo*.  The incredibly high death rates amplified and added new vital dimensions to the problems of social toxicity associated with the disease as families and communities struggled to make sense of and cope with the impossibly high volume of death and caregiving needs in their midst.

The Botswana government, reeling from the scale of the HIV/AIDS epidemic, publicly feared the long-term viability of the nation (Mogae 2001). By the mid-1990s, the government had already begun to parlay this epidemiological crisis into new transnational research partnerships and investments, successfully marketing themselves as a clinical research and training hub. Over time, the government would expand these partnerships significantly, first around TB and then HIV/AIDS and then eventually cancer.

The new ARV programme, at once a political and a public health innovation, introduced the question of citizenship directly into the heart of Botswana's public health system. It did so just at a moment when high numbers of undocumented immigrants were arriving in Botswana fleeing economic and political collapse in neighbouring Zimbabwe. Whereas TB treatment had long been extended to immigrants in accordance with WHO recommendations, access to free care in the new ARV programme (like other medical services in the country) was limited to those who could provide proof of citizenship. Over time, experience with the ARV programme, like the TB programme a generation earlier, began to produce a cautious, and no doubt fragile therapeutic optimism among many patients and relatives, and an attendant politics around expanded access to biomedical technologies.

# Cancer: The emerging epidemic

While there were well-documented cases of cancer in Bechuanaland/ Botswana going back to the mid-century, the disease was not well accommodated by the public medical system until the cancer ward in Princess Marina Hospital (PMH) was opened in late 2001. Before this, patients with diagnosed cancers were either sent to Zimbabwe (previously a site of high quality medicine) or South Africa for oncology treatment, and/ or sent home to be tended by family until death. However, in the face of the escalating HIV/AIDS epidemic, and the new ARV programme, and with cervical cancer gaining increased international attention, Botswana developed a new oncology service in PMH (Livingston 2012). This was quickly expanded through a domestic public–private partnership with the Gaborone Private Hospital, which the Ministry of Health supported in their bid to acquire and run the national radiotherapy service. Eventually, access to clinical oncology was expanded to the north of the country as well. An oncologist from China was brought, through a bilateral agreement, to work in the medical ward of Botswana's second referral hospital, which served that region.

The development of an oncology service enhanced diagnostic capacity for cancers in the country. Not only were the expected cancers among patients with HIV now emerging in growing numbers, but also a significant HIV negative patient population began arriving at the PMH oncology ward, and soon the service was overwhelmed by patient volume. In recent years, efforts have begun to train doctors in the primary and provincial hospitals to diagnose and treat routine cases of KS, and efforts are underway to diagnose and treat cervical cancers early through new see-and-treat technology beyond the two referral hospitals. However, for the most part, cancer diagnosis remains highly centralised and the pace, volume, and quality of cancer diagnoses (which in turn feeds into epidemiological knowledge) is constrained by the limits of laboratory, surgical, and imaging capacity in the country.

The combination of a centralised and over-stretched diagnostic capacity, the lack of screening services (except for new cervical cancer screening programmes for HIV positive women), bottle-necks in the referral system, the novelty of the disease category in the country, and the problem of coinfection with HIV, which both makes cancers more aggressive and also limits treatment options, means that the majority of cancers are diagnosed at an already late stage (stage 3 or 4), and mortality rates are high.

It is now possible to see that the epidemic of HIV clarifies the presence of the co-morbidity. HIV makes cancer visible – institutionally and epidemiologically. It has also made TB visible again after a period of dormancy. Meanwhile, the presence of an oncologist/cytologist in the hospital who performs fine needle aspirations on swollen lymph nodes helps to diagnose extra-pulmonary TB, thereby making it more visible. Yet at the same time, the epidemic of TB often delays or confounds the diagnosing of cancer, since most clinical staff have rightly learned to suspect TB when faced with persistent cough and wasting, or swollen lymph nodes. There are three vertical programmes in the health system one for each of these diseases, even as each programme acknowledges and attempts to grapple with the problem of co-infection.

# Receiving a differential diagnosis

Within the oncology clinic, historical experiences begin to layer onto one another. Though there have long been cancers in Botswana, the novelty of oncology combined with the rapidly emerging epidemic scale of morbidity make the disease category a protean one in the popular imagination. Patients make sense of their cancer through historical experiences of TB and HIV/AIDS. In 2006, 2007 and 2008, this meant that TB was known, shameful and feared, while cancer was neutral. It also meant that relatives often assumed cancer patients really had HIV, when they might actually not, and it meant that patients with HIV who were now receiving a cancer diagnosis at first might not understand that this was an entirely separate disease with which they were now additionally faced. These ideas were further confused by the regular blood counts that were taken for cancer patients, since neutropenia meant that a scheduled dose of chemotherapy would have to be delayed. Such routinised tests and the continual talk of the strength of the patient's blood, made cancer resonate with clinical practice and communication around HIV. Key symptoms – lumps, wasting, coughing and dyspnea – meanwhile, also resonated with TB.

Over time, cancer is gradually becoming more familiar in popular experience, so these dynamics are in flux. However, here is how they appeared in my field notes from the oncology clinic in 2007 and 2008.

A young woman with enlarged lymph nodes comes for a second fine needle aspiration. Before beginning the procedure, Dr P thinks it looks like TB and tells her this. She gets very upset and begins to cry. She has had a fever for a few days now. Dr P reassures her, 'TB is *good* it can be treated. It is better then *kankere* (cancer). In 6 months you are cured.' Perhaps the fever is part of what is making her so emotional.

A young guy comes in to collect the results of his fine needle aspiration. He speaks excellent English (suggesting his level of education). He lives in a neighbourhood of Gaborone. The test was done in the parotid area. It turns out he has TB and so he is told he should also get tested for HIV. He looks so upset – quiet but upset. We try to explain to him that this is good news. 'You do *not* have cancer,' but he doesn't seem to believe us that this is a positive thing. The 47-year-old woman who looks miraculously young and wore that beautiful *tukwi* (headscarf) and black and white shirt finally comes back to gets her results from the fine needle aspiration (the original slide was lost by the medical ward). She has TB and looks a bit upset especially for someone who was so calm through everything. Again I am struck by this incredible contrast between the cancer diagnosis and the TB diagnosis in popular reactions.

A young guy 33 years old comes with KS in his lungs, hand, groin, mouth, tongue, and palate. He has HIV.

Dr P asks 'Do you know what your problem is?'

'*Yes'* he says, 'I know what my problem is.'

Clearly, he is already tired of all the questions and the counselling (the IDCC clinics and HIV testing and treatment use a didactic counselling script in which the patient learns to repeat their status, CD4 count, etc.) (Brada 2013).

'I am HIV positive.'

'No. Do you know why you are *here?'* (Meaning the oncology ward.) '*Yes.* It is on the card.'

The nurse pursues further. 'No. Not what's on the card. Do you know what is this place?'

'They told me that side – at the clinic.'

'What?'

'They just used some big words. I don't know.'

'You have skin cancer (*kankere ya letlhalo*) or KS. This problem is also in your lungs and in your mouth.'

He says, 'Doctor, I am suffering. I walk 50 metres and it feels bad like I ran 100 metres.'

'We know.' I finally interject and also try to explain. '*Wena, nyaa* – you have two problems, *di le pedi*. These problems are friends*. Kankere* and *mogare* (HIV) are different, but they can go together.' He looks like he doesn't want to know this.

A man in his 30s, well dressed but imperfect English. His KS is mild, but it is how he is learning that he has *mogare*. I think he is stunned – quiet, but stunned.

The woman from Phakalane with the one big KS lesion on her heel is back a week early. She and Dr P have a debate as to whether it is better or not. It is half the size it was before but now it is infected so she has a lot of pain in her ankle. This is because of the infection not the KS so they disagree. To Dr P, the pain is from the cellulitis but the KS is better. To the patient it hurts more so clearly she is worse. The nurse (Christine) struggles to explain that there is *kankere* (cancer) and *mogare* (HIV – the virus) and *megare* (bacteria/ germs/virus). I pitch in, and so does the student nurse.

A woman comes to get her results. She is in her mid-20s, on HAART and has been taking the TB prevention programme (IPT) for 6 months. Her fine needle aspiration shows she has TB. When told this she starts to cry, and she really cries for a few minutes. Dr P tries to console her. 'No, this is not a big *mathata*. You will be fine.' But she leaves in tears.

There is a man in Male A bed 2 with Hodgkin's who is HIV negative, but emaciated. He wants to be checked for TB. Dr P says he is smart. We should not be fooled into assuming we know why he's so thin, even though Hodgkin's is a wasting disease.

Patients stood in a thicket of cross-referencing between the three diseases as they attempted to understand their situation and navigate treatment. Making sense of cancer meant separating it from TB and HIV, but it also meant putting them back together. Yet such ontological exercises were necessary in order to navigate the treatment landscape. One could not 'default' on chemo or antibiotics just because they were diligent about their antiretrovirals, at least not without serious consequences.

From the perspective of the oncology ward a simple TB diagnosis was terrific news. For many patients, it was the opposite. At that point, cancer was still relatively unknown to them, while TB had long been feared and was perhaps shameful. Furthermore, TB was often the vehicle by which someone learned that they had HIV, which carried its own burden of fear and perhaps stigma. However, as they developed experience as a cancer patient, they came to realise how awful it was, with some patients remarking to me that even HIV was much better than cancer.

Within the hospital, differential diagnosis had other effects. Whenever bed space was available a cancer patient would be housed in the cancer ward. Though the oncology ward was greatly overworked, it was quieter, less chaotic, and more orderly than the medical wards where most TB and/or AIDS patients would be. In the medical wards, many patients were on gurneys packed into hallways or on mattresses crammed into empty spaces on the floor. In the cancer ward, space was tight, but the oncologist simply did not allow floor beds. Patient-to-nurse ratios were smaller in the cancer ward, and staff became familiar with patients and their relatives over the cyclical process of their care. Furthermore, pain medicine was more readily dispensed and fewer people got lost in the shuffle. More than once I remember the medical officer, faced with a patient co-infected with cancer and AIDS, who lay dying in the medical ward, deciding to transfer this patient to oncology, calling her 'our patient'. This transfer was meaningful, intended as a final gift to her and her family, allowing her to die from cancer and not from AIDS.

Meanwhile, different drug regimes seemed to create an overlapping intelligibility but in fact were often misleading in their cross-references. Second line cancer treatment is less efficacious than first line, in contrast to second line antibiotics. Prophylactic isoniazid as a public health programme to some extent mirrors the logic of the new prophylactic antiretroviral programme (PrEP), while chemotherapy drugs, by contrast, have lifetime limits. The nausea that often accompanies ARVs tends to fade for patients over time, while the nausea that results from chemotherapy tends to escalate with each new cycle.

Mma T, a nurse counsels a patient with KS – a young woman. She tells her, 'This medicine will make you nauseous, you will lose your hair, but this is temporary.' The patient is visibly upset about this, but Mma T says, 'Look with TB you take a pill a pill a pill. With *kankere,* the drug is *so* strong you take an injection every few weeks instead.'

The same extrapolating logic can also go in reverse.

In the oncology clinic G, the young woman with Hodgkin's is still here. She is in remission but coughing – is it TB? She and I go together to see if we can find Michelle to do a sputum smear, and on the way it is clear she knows less than we think. Dr P said to her earlier, 'I think you have TB my friend' and when the nurse starts to translate he says, 'No she speaks English!' I explain to her about what TB is and what it would mean for treatment. It turns out she is worried that it would be like cancer medicine but every day for months. I say, 'No. It is much easier – the pills, it is just that it lasts for months, but there should be fewer side effects.'

# Clinical intelligibility

In this context of rampant co-infection, differential diagnosis and the charting of a clinical strategy were blurrier than the moments of clinical communication presented above would suggest. An enlarged lymph node could contain both lymphoma cells and tubercle bacilli. Lungs could be plagued with both TB and lung cancer or TB and KS. The unevenness of the technological infrastructure further contributed to the diagnostic and treatment challenges. Even if there was only one disease present, it could be hard to come to a definitive diagnosis (Vento and Lanzafame 2011). Without the normative body available, and faced with an unstable technological field, the oncologist and other doctors were often left working empirically.

Consider, for example, this scene in the cytology lab from my field notes in June 2008.

Dr P, Dr S, and I are in the lab using the teaching microscope to try to make sense of what is happening to a middle-aged woman with Burkitt's lymphoma who has just had a spinal tap. Dr P explains the problem. 'Here you spin, then take the upper part off and put the bottom part in. But here, there is no cytology centrifuge, which would spin directly onto the slides and this is part of why the slides are destroyed. You can see that there are lots of cells here, which does suggest central nervous system involvement of her lymphoma but the cytoplasm is destroyed in those cells.' We search the two slides for intact cells. Dr P says if we can find a single blast, then we would know. But it is not possible. But there is no bleeding evidence and ordinarily one would expect to see between 4 and 12 cells. Here there are at least 100 so this really looks like the lymphoma is there. Why else? It could be TB or cryptococcal. We will have to wait for the national TB lab on that. But Dr P doesn't think the TB lab can definitely see it.

Or this scene from a morning meeting in the medical ward in 2007.

The medical officer presents the case of another patient where they are querying lung cancer. His x-ray is displayed. Is it a chronic pulmonary disease like pneumoconiosis or is it a cancer of the lung? Or is it chronic TB? The American medical student and the visiting professor pitch in to push towards cancer. The head of department says first we need to rule out TB. The patient has a history of 24 years in the mines. They agree that they need to rule out TB first, but the x-ray does not provide a clear diagnosis.

Or this one from the oncology ward in 2007.

We are on the Monday ward round. The woman with KS who we brought as a cancer patient to be transferred from the Female Medical Ward is having problems breathing. She had a pleural effusion tapped over the weekend. It was blood tainted, and therefore suggestive of KS. But now she is still having trouble breathing. Now the question is – is this TB or does she need her lungs irradiated. Dr P decides to go for 2 more weeks on TB treatment and see if she responds. If not, then irradiation.

Problems of technical capacity within the system hamper the outcome of public health programmes that are designed to target co-infection. The Isoniazid Prophylactic Therapy (IPT) programme for HIV positive patients began in Botswana in 2001. In a logic that foreshadowed the PrEP programmes for HIV, IPT required screening for active TB among all persons diagnosed with HIV infection, and those not requiring treatment for active disease, receive 6 months of prophylaxis. The IPT programme, therefore, is premised on being able to screen out active disease. However, as we have seen, some patients were on IPT for months before their TB was diagnosed, and some clinicians suspected that this must contribute to a rise of MDRTB.

# Living and dying with co-infection

If co-infection presents challenges to clinical staff and to institutional efforts, for patients, and the relatives who help care for them, existing in a state of unfolding and acute medical complexity is profoundly trying. Physically, any one of these diseases can be miserable and disorientating, much less two or three at once. The same can be said of the pressures of overlapping and intersecting diagnostic and treatment regimes. The bureaucratic and institutional challenges of co-infection mean that patients have multiple appointments and advice to manage, which are incredibly time consuming between long queues at pharmacy lines, on waiting benches for imaging studies or blood taking, for clinic appointments, at bus and taxi ranks, not to mention the expense of travel. Furthermore, it was also existentially overwhelming for people to learn they had all of these problems at once. If there are social models and messages out there for how to 'live positively' with HIV or how to be a 'cancer survivor' there was precious little guidance for those trying to buoy themselves against the bodily insults and psychic uncertainties of co-infection.

Sometimes, this means that a patient with HIV refuses a pap smear, recognising that she is not ready to take on cancer as well if it were to come back positive. Sometimes, it means that a patient fails to come and collect the results from their fine needle aspiration until after some months, when the symptoms of their cancer become so overwhelming that they are now desperate for relief. Sometimes, patients who were co-infected looked at me wistfully and remarked that they wished they just had AIDS, which now seemed so simple and relatively manageable rather than both AIDS and cancer. In late 2006, I visited a young woman in her village home. She had already completed treatment for KS, which had destroyed her knee and she remarked, '… I know if it were the HIV alone, I could take the ARVs, stand up and go and work. But now this cancer has actually crippled me. I can't walk, I can't work.'

Imagine what it feels like to be the parents of this young man.

The parents and aunt (*mmangwane*) of the 29-year-old man with penile cancer and KS, TB and HIV come to talk. They have been waiting since noon and it is now 5.00 p.m. (This is because Dr P first sees all of the patients and then only counsels relatives once all the chemo had been administered and the clinic visits completed). Dr P opens by telling them that the situation is hopeless. 'Your son has two cancers, HIV and TB. It is too much.' They have no questions, though the father is a military officer and speaks excellent English. The father says, 'All we can do is hope. It is in God's hands now.'

 Then again, imagine how relief slowly came to him as against all odds, he recovered from this crisis to become just an HIV patient again (albeit one with scarred lungs and half a penis).