Emerging sciences and new conceptions of disease; or, beyond the monogenomic differentiated cell lineage
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- Dupré, J. Euro Jnl Phil Sci (2011) 1: 119. doi:10.1007/s13194-010-0008-0
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This paper will begin with some very broad and general considerations about the kind of biological entities we are. This exercise is motivated by the belief that the view of what we—multicellular eukaryotic organisms—are that is widely assumed by biologists, medical scientists and the general public, is an extremely limited one. It cannot be assumed a priori that a more sophisticated view will make a major difference to the science or practice of medicine, and there are areas of medicine to which it is probably largely irrelevant. However, in this case there are important implications for medicine, or so I shall argue. In particular, it enables us to appreciate fully the potential medical significance of some of the most exciting contemporary advances in general biology, in such fields as epigenetics, metagenomics, and systems biology; and part of this significance is that these advances have raised serious doubts about how we should understand the biological individuals that medicine is generally assumed to aim to treat.
1 The monogenomic differentiated cell lineage
The subtitle I have added to my official title is not pretty. The phrase “Monogenomic Differentiated Cell Lineage” does refer, however, to a very important idea, and indeed a standard scientific view of ourselves. We are, of course, multicellular organisms. One of the things, we assume, that make the many cells of which we are composed parts of us, is that they form a lineage: our bodies are composed of multiple cells all originating from one single cell formed in the act of conception through the fusion of two gametes. This lineage structure provides more than merely historical connections between our constitutive cells. It also provides them with unique characteristics, notable among which is the unique (except, briefly, for monozygotic twins) sequence of nucleotides in their genomes. And, finally, it is the highly consistent and structured differentiation of these cell lineages, human as well as countless others, that provides the remarkable array of wonderfully structured organisms that have understandably fascinated and obsessed generations of biologists.
The Monogenomic Differentiated Cell Lineage (MDCL) is a powerful image of a vast number of forms of life because it provides a rich explanatory framework. It’s true, and something I have been much concerned to emphasise in recent years, that there is a vastly greater number of monogenomic cell lineages that are not differentiated, namely the countless single-celled bacteria, archaea, and protists. But given that the present topic is medicine, and given also the centrality of ourselves and creatures somewhat like ourselves in so much of biological theory, the MDCL is an appropriate focus for this paper. It is at the core of a highly developed and sophisticated approach to the question why all these life forms exist, in evolutionary theory; understanding the replication and differentiation of cells within MDCLs is the central project of contemporary developmental biology. MDCLs, then, are an important and influential idea.
Why do I use this clumsy term? What’s wrong with ‘multicellular organism’ or, since these are evidently what we are most interested in, just ‘organism’. In recent work Maureen O’Malley and I have questioned the assumption that organisms just are MDCLs or, in the case of simpler life forms, just cell lineages (O’Malley and Dupré 2007; Dupré and O’Malley 2007, 2009). In particular we have stressed the fact that MDCLs typically depend for their successful differentiation and survival on reciprocal interactions with a highly diverse set of symbiotic microbes. In our own case, complex microbial communities cover the entire area of our boundaries with the world outside. They swarm on our skin and in all our body cavities (oral, nasal, genital, etc.) and trillions occupy the length of our digestive tract.
This still does not show that there is anything wrong with the MDCL concept. What it does indicate, however, is that the MDCL is an abstraction from a more complex reality. Again there is nothing wrong with this; in fact this is plausibly the inevitable character of biological concepts. Living things are complexly intertwined and interconnected in multiple ways, and studying them requires identifying parts of this interconnected whole that have some kind of independent coherence. Consider, for instance, a cellular process such as the Krebs cycle. This is an essential component of the processes by which cells derive energy from carbohydrates and other energy sources and its elucidation was rightly seen as a major achievement in the understanding of how cells work. Not only did it illuminate a particular metabolic pathway, but it also served as a paradigm of the biochemical analysis of living processes. But no one imagined that the Krebs cycle was the sort of thing that could in theory exist independently of its cellular context. One reason for this is that it is in constant interaction with other metabolic pathways that provide its essential chemical resources and to which it contributes its own products. The particular series of reactions distinguished as the Krebs cycle are sustained by this dynamic interaction with a variety of simultaneous and interlocking processes.
This finally brings us to the real problem with the MDCL, that it is liable to be understood as just such an independent entity, and indeed it is often treated as what the organism essentially is. Philosophers will be familiar with the idea promoted—or perhaps just assumed—by Saul Kripke that the essence of an individual human is the origination from a particular zygote, or fertilised egg (Kripke 1980). This is a paradigm case in the revival of essentialism over the last 40 years. But similar assumptions can be found in more biologically sophisticated thinkers than Kripke. Particularly salient here is the gene-centred view of evolution famously promoted by Richard Dawkins1 (1976). In this picture evolution is fundamentally a succession of genomes passing down through evolutionary time. The cell provides the context in which the genomes can function to guide the development of organisms, and the environment determines which organisms, and hence which guiding genomes, will thrive and multiply. The function of MDCLs in this picture is to determine the trajectories of a different kind of cell lineage, the sequence of successful zygotes that carry evolving lineages into the future. The monogenomic character of the MDCL is essential for it to play this evolutionary role.
Even this abstraction has its uses. To its credit are a widely admired tradition of modelling in population genetics and a rigorous analysis of such evolutionary processes as kin selection. It does have some very serious limitations, however, not least the tendency to reinforce the idea of the MDCL as the fundamental—real, true—account of the multicellular organism. Since, as I shall argue later, the MDCL really is an inferior or even inadequate conception of the medical individual, the tendency to essentialise it, thus making it unavoidable even for purposes to which it is ill-suited, must be robustly resisted. In the attempt to weaken the hold of this picture let me offer a quite different perspective on evolution.
For over three billion years of evolutionary history, 80% of the history of life, there was nothing but microbes. This is a self-evidently important point to bear in mind for assessing general views of evolution; we would do well to avoid general theories that depend on properties that microbes do not possess. Microbes do not evolve as MDCLs. They have often been thought of, however, as MCLs, or clones, monogenomic but undifferentiated cell lineages. As a matter of fact they do not solely evolve this way, but engage in frequent transfers of genetic material across lineages, a realisation that is transforming a great deal of evolutionary thinking. But this will not be my main concern today. I want rather to emphasise the importance of the background of these aeons of microbial evolution for understanding the emergence of multicellular organisms. Contrary to what seems sometimes to be assumed, multicellular organisms did not just separate themselves from the microbial background and begin to evolve their own transcendent multicellular lifestyles. Rather, they have evolved as deeply embedded components of the complex microbial consortia that long precede them.
The earliest multicellular organisms may perhaps be seen as little more than homes for microbial consortia. Sponges, some of the earliest multicellular organisms to evolve, are hosts to populations of microbes that may make up over half their weight. Some species host photosynthetic bacteria, which provide them with energy, but in most cases the nature of the interaction is poorly understood (Webster and Blackall 2009). However it is known that these microbial populations are often very consistent in their constitutions and this is despite the daily passage through them of thousands of litre of sea water, itself teaming with bacteria. The stable bacterial populations are presumably actively maintained by the system as a whole. Or consider the tube worms that live around hot vents in the deep ocean, and subsist on products generated by resident microbes that subsist entirely on the metabolism of sulphides. Even these, I should stress, are fully developed MDCLs. The structure of the MDCL is, however, somewhat less likely to obscure awareness of the reciprocal relation between MDCL and microbial symbionts than is the case for more immediately impressive organisms.
2 MDCLs and their symbiotic partners
My point in this paper is not primarily to consider issues in deep evolutionary history. However, the recollection that MDCLs evolved against an ancient and entrenched background of microbial life should help us to appreciate that even today they exist typically in intricate and obligate relationships with vast numbers of microbial symbionts. It is easy to underestimate the importance of the fact that microbes are almost all invisible. Imagine for a moment that the world was suffused with a lurid green light the intensity of which was proportional to the prevalence of micro-organisms. Bare soil would glow brightly, registering the billions of microbes in every cubic centimetre, as would damp surfaces—streambeds and suchlike—with their inevitable coverings of microbial biofilms. Other less hospitable inert surfaces would probably display only a much lighter dusting of transient cells. Water would tend to show a diffuse and variable glow from the many planktonic bacteria dispersed throughout. But of particular importance would be the strong light suffusing all or almost all macroorganisms (or macrobes), whether plants or animals. Leaves, for instance, are homes to diverse communities of microbes, changing with diurnal, seasonal, and occasional fluctuations in the physical environment (Hirano and Upper 2000). Similarly the skin of animals, including our own, swarms with diverse and rapidly changing communities of microbes—about one trillion on a typical human skin. Still invisible, for obvious reasons, would be the much larger communities occupying the digestive tract. This vision might reduce the temptation to see macrobes as having diverged from, and somehow left behind, their microbial ancestors: everywhere macrobes are deeply and inextricably associated with microbial life. It might also problematise the even more widespread assumption that microbes are primarily dangerous things that constantly threaten our well-being. I shall say more about that in a moment.
To emphasise the fundamental importance of the relations between MDCLs and microbial symbionts, Maureen O’Malley and myself have argued that the organism, understood as the functional entity that interacts with the rest of the biotic and abiotic environment, is not the MDCL, but a symbiotic whole (Dupré and O’Malley 2009). A particularly significant implication of this is that it draws a wedge between the elements that make up genetically cohesive evolutionary lineages (microorganisms and MDCLs) and the organisms that interact with the environment and which are, therefore, also the primary units of selection.2 Again, cell lineage looks less fundamental to the distinguishing of biological things than is generally supposed. That, however, is a matter for another time.
For my present purposes a slightly different point about the picture I have been sketching is crucial. Microbes do not just live on human skin, for instance, because it is a convenient living space. Or anyhow, if they do so, it is made a convenient living space because the human MDCL requires that it be occupied by appropriate microbes. Although the benefits that humans derive from their relationship to microbes is better understood for the case of gut bacteria than for those on the skin, information on the latter is beginning to emerge. For example it appears that bacteria produce a substance that plays a vital role in suppressing inflammation following injury (Lai et al. 2009). More generally, it seems that many skin diseases involve some kind of disorder of the microbial skin communities. This ties in with the broader hypothesis that the microbial communities that occupy pretty much the entire interface between the MDCL and the outside world should be seen, among other things, as an essential part of the immune system, as deciding, in effect, which microbes are allowed to settle in the broader system and which are a threat to it.3 It is worth recalling that it has been traditional to consider the human organism as a tube, and therefore to maintain that the digestive tract is on the outside of the organism. On this view gut bacteria are, like skin bacteria, populating the outside of the organism. As I have indicated that for most purposes I take the symbiotic microbes to be part of the organism they occupy, I must clearly take a somewhat different view: either the surface of the tube extends a little further than previously thought or, perhaps better, the inside of the digestive tract is in fact part of the organism. It doesn’t really matter which; the traditional view is at least useful in pointing to continuities between gut and other symbiotic microbes in the human system.
For the case of gut bacteria, at any rate, the interdependence of microbes and MDCL is increasingly widely recognised on the basis of a rapidly growing body of evidence. The role in digestion has long been appreciated, but increasing interest has focused on contributions to the immune system and to development. Studies of animal models confirm that symbiotic microbes regulate the expression of many genes during development (Rawls et al. 2004). The point I particularly want to stress, and which is illustrated in both these cases, is that the boundary between the MDCL and the outside world is a complex symbiotic space and that adaptive responses to the outside environment by either the MDCL or the entire system, is routinely mediated by the behaviour of this symbiotic space.
This last point makes a connection with the other major development in biology generally and human biology in particular that I want to emphasise, epigenetics. Epigenetics is an elusive concept, defined in more or less subtly different ways by different biologists. Etymologically it appears to originate in the contrast between preformationist theories of inheritance, in which development was the pure unfolding of a pre-existent pattern, and epigenesist theories, in which the elements of an organism were accreted one by one throughout the developmental process. Contemporary usages are generally traced to C. H. Waddington, and especially his metaphor of the epigenetic landscape. This metaphor compares the increasingly determinate fate of cells in development to the topography of a ball rolling down a complex landscape. Ridges separating valleys represent degrees to which the fate of a cell lineage has been determined one way or another; the existence of such separate valleys emphasises the existence of distinct possible developmental pathways. This, finally, leads to the narrower contemporary usage, in which epigenetics studies modifications to the genetic material but, crucially, not to the DNA sequence, which influence the expression of genes. That is to say, epigenetics is now understood as embodying a theoretical understanding of how the fate of cell lineages within an MDCL is determined.
The acceptance of this contemporary version of epigenetics still leaves a central question open. Epigenetics could be a theory of the way that initial gene sequence determines the differentiation within a monogenomic cell lineage. Initial gene products, for example, could produce epigenetic changes in chromosomes that caused changes in the subsequent history of that lineage. No doubt this is part of the story. If it were the whole story then, paradoxically perhaps, epigenetics would have turned out to be an explanation of preformationism. But it is not the whole story. In fact one of the fascinating aspects of epigenetics is that it appears that we need to reconcile its roles in two almost opposite processes. On the one hand epigenetics clearly has a fundamental role in the explanation of the consistency of biological form, the ability of MDCLs to produce basically similar MDCLs exhibiting, therefore, essentially the same pattern of cell lineage differentiation. But on the other hand it seems increasingly clear that epigenetic processes also serve to mediate the response of the developing organism to the environment, i.e. to provide different patterns of development in response to different environments.
Perhaps there is nothing deeply paradoxical about these contrasting roles for epigenetics. Complex biological systems arise only from other similar systems. They could not exist of they did not have the ability to generate systems extremely similar to themselves. But the replication of absolutely identical systems starting with a system reasonably well adapted to its environment would, assuming a changing environment, inevitably produce systems that gradually became less and less well adapted. So the conflict between the need to reproduce accurately and the need to track environmental change is an inescapable one. A familiar answer to this problem is, of course, the Darwinian appeal to evolution by natural selection. In its currently orthodox neo-Darwinist version organisms are seen as adaptively tracking their environments by endogenously generating random changes some of which will, with luck, produce adaptive advantages.
But of course this is not the only way that organisms adapt flexibly to their environments, and much adaptation takes place on a far shorter time scale than the Darwinian process just mentioned. Many readers will be familiar with Mary Jane West Eberhard’s (2003) classic work on developmental plasticity as not only a way for individual organisms to adapt to the environment, but even as a crucial driver of evolution. That organisms do exhibit some adaptive plasticity in development is hardly news. The phenomenon is perhaps most familiar in plants, which can adopt quite different forms according to the availability of light, nutrients, and so on. Or, for that matter, the fact that humans growing up in England learn to speak English while those growing up in France learn to speak French is an example of the way that nervous systems not only enable immediate adaptive responses to salient features of the environment (food, predators, mates, etc.) but also make possible the acquisition of different behavioural dispositions or capacities honed by the particular environments they have experienced.
But although the phenomenon of developmental plasticity is not news, epigenetics indicates hitherto unperceived subtleties. A much-discussed example is of the impact of food scarcity on early stages of foetal development. A classic case has been the epigenetic consequences of the Dutch hunger winter of 1944–5, which appears to have had epigenetic effects on foetuses that remain detectable in individuals 60 years later (Heijmans et al. 2008). Although it has been reported that these effects are heritable to subsequent generations, this claim remains controversial (Morgan and Whitelaw 2008). Environmental epigenetics is beginning to explore the ways in which exposure to a variety of toxins can cause developmental changes that may be transgenerationally inherited (Bollati and Baccarelli 2010). And neurogenetics is beginning to explore the ways in which parts of the brain, especially the hippocampus, react with highly dynamic epigenetic changes in response to various environmental conditions (Covic et al. 2010). As I shall discuss in more detail below, a very important set of features of the environment to which epigenetic changes are reactions are states of the complex cellular communities that constitute the boundary between an organism and what is external to it.
What is the central point so far? Although nobody much subscribes officially nowadays to preformationism, it is very easy to maintain central aspects of that philosophy. It is easy to think of the organism as something that has an intrinsic nature that is realised in development and then finds itself in some kind of interaction with the natural environment that surrounds it. No doubt the revival of essentialism in recent years will lend support to such ways of thinking. And even without essentialist prejudices, the phenomena of reproduction, the constant reappearance of strikingly similar forms, will naturally encourage the thought that the form must somehow have been there all along. The neo-Darwinist account of evolution, finally, as composed only of random, internally generated changes, also assumes a fundamentally endogenous view of development.
There are many things wrong with neo-Darwinism, but the point I need to stress here is the error of this treatment of development as endogenous. This is something that has been emphasised by developmental systems theorists, who have insisted for a number of years on the importance of non-genetic aspects of inheritance including the construction of an external niche in which the organism develops (Oyama et al. 2001). What I have said so far is entirely congenial with that framework. What I have particularly wanted to stress is the need for a very close scrutiny of the complex and dynamic interface between an MDCL and its surroundings. And this, finally, brings us to the implications for medicine.
4 Medical implications of going beyond the MDCL
I could begin by noting that of course medicine should care about how its primary object—the human body—is to be understood. However, this is more than just a philosophical matter. Many of the most interesting developments in our understanding of disease and disease aetiology are emerging in the context of a growing awareness of the complexity of the boundary between the organism and its external environment.
Consider the human microbiome project, what might be considered the remaining 99% of the human genome project after the completion of the sequence of the human MDCL (see http://nihroadmap.nih.gov/hmp/). One explicit aim of this project is the discovery of correlations between human health and characteristics of, or changes in, the human microbiota. And some such correlations are already being explored in detail.
The intestinal bacterium Enterococcus faecalis has a dichotomous metabolism: under normal circumstances it has a respiratory metabolism, but when not provided with exogenous haematin it reverts to a fermentative metabolism that generates potentially harmful superoxide (Allen et al. 2008). Further exploration of the consequences of this change revealed substantial changes in gene expression in the colonic mucosa, the internal lining of the intestine. These changes affect inflammation, apoptosis (or cell death) and cell-cycle regulation (Allen et al. 2008) and there is a natural suggestion that these phenomena may be implicated in colon cancers. But crucially, this is not a case of invasion by hostile alien organisms, but a potentially pathological behaviour of organisms that are a normal, and generally desirable part of the overall system.
That colon cancer or inflammatory bowel disease might be linked to conditions of the gut bacteria may not seem so surprising, though the fact that this appears to work through modulation of gene expression in the ‘human’ gut cells might be more unexpected. But this is by no means the limit of the implications of gut microbiota for health. Currently research is ongoing on a suspected link between microbiota and breast cancer (http://www.rush.edu/rumc/page-1262026413817.html), a hypothesis that was suggested, interestingly enough, almost 40 years ago (Hill et al. 1971). If this seems surprising, one should reflect on the very familiar suggestion that many cancers and indeed most of the most serious non-infectious diseases are strongly linked to aspects of the diet. If the excessive consumption of the wrong kinds of fat or the inadequate ingestion of fruit and vegetables are indeed, as we are increasingly told, the major determinants of disease, then the suggestion that that influence might be transmitted by the population of microbes in our digestive tract would hardly be shocking. Put together with the observation that the gut microbiota can modulate the expression of genes within the human MDCL it becomes at least plausible that this may be a fundamental site at which disease or health is determined throughout the body. But again I must emphasise disease or health. The suggestion is that a functional, indeed essential, part of the system can malfunction and cause illness. The fact that pathological effects are prima facie distant from the parts that are causing the malfunction is indicative of the depth of involvement of the latter, the microbiota, in the overall system.
Consider the question how we should best allocate cancer to one of the various branches of contemporary biomedical science. Prima facie, one might think, it was a cytological disorder. Observations of the close similarity between stem cells and cancer cells (both involve cell lineages the fate of which is not yet fully aligned with the orderly development of the MDCL) fit within this disciplinary domain. For a long time, on the other hand, we have been told that cancer is turning out to be a genetic disease. Many genes have been identified as being implicated in the aetiology of cancers and there is certainly no question but that there is a genetic aspect to all or most cancers.
Cancer-causing genes are generally genes supposed to be involved in the suppression of tumours that have been damaged by mutations, deletions, insertions, and so on. However the failure of a gene to be transcribed may also have epigenetic causes as may also up-regulation of gene expression. So epigenetics is very likely to be a parallel possible cause of cancer, and may well be a more important one than gross genetic damage; certainly a great deal of current research on cancer aetiology is focused on epigenetic issues.
It is also a very familiar fact that much cancer is environmentally induced, by toxins such as tobacco smoke or asbestos. This could be mediated through genetic changes (mutation, etc.) or through epigenetic effects. As mentioned above, one active area of research in epigenetics concerns the epigenetic response to toxins, and it is very plausible that this will start to provide some mechanistic substance to epidemiological work on the carcinogenic properties of toxins. Saturated fats and other dietary elements currently seen as unhealthy may not, perhaps, be properly classified as toxins, but their impact directly on human microbiota and indirectly thereby on epigenetic features of cells in the human MDCL may turn out to be an important pathway from environment to cancer. I don’t, of course, propose to advocate one approach to the study of cancer as of preeminent importance. The point is rather to note the complex interactions between environment, symbionts, genetics and epigenetics that are likely to be implicated in the misregulation of cell replication.
Pathological epigenetic effects are surely not the only medically significant feature of human symbiotic microbial communities. One fascinating thought is that the microbiota are active at various timescales in maintaining a stable and sustainable relationship between the organism as a whole and the biotic environment, in part by recruiting organisms or genetic material from the environment. One striking example of this has been the recruitment by Japanese human microbiota of genes from generally marine microbes, which facilitate more efficient metabolism of raw fish (Hehemann et al. 2010). This is an example of microbes mediating a rapid evolutionary response to an environmental pressure. Rapid generation times, high mutation rates, and lateral gene transfer are several convincing reasons why we should expect the microbiota to be the part of the whole human system best able to respond rapidly (and evolutionarily, i.e. heritably) to environmental changes. The possibility of recruitment of new types of cell to the system is another potentially powerful such mechanism. This, as opposed to the rather dubious programme pursued as Darwinian medicine, is arguably the really interesting area for evolutionary medicine. This idea has been developed in recent work by Pierre-Olivier Méthot (2010).
A fascinating and related topic for further study, but one which seems hardly yet to have been broached in the scientific literature, is the potential role of viruses in mediating even more rapid such responses. Here again cancer research provides remarkable if tantalising insights. A lot of recent research has suggested an important role for viruses in the aetiology of cancer, for example high incidences of human papilloma virus have been found in lung tumours (Klein et al. 2009). However, there is also quite promising research on a virus known as the Seneca Valley Virus-001 that appears to have considerable potential for selective destruction of tumour cells, and is currently being investigated as a possible therapy for cancers of the lung (Venkataraman et al. 2008). It is at any rate an intriguing possibility that viruses may have far more diverse roles in biological systems than merely the pathological, parasitic ones with which we are most familiar.
Returning to the parallel consideration for cellular microbes, consideration of the inclusive organism that comprises all of the cells that together are required for successful and sustainable functioning should make one worry about the extent to which it is still assumed that microbes are invariably the enemies of health; or as the point appears in typical advertisements for cleaning products, the only good bacterium is a dead one. This idea has been aptly referred to as the Pasteurian Paradigm. It is in fact difficult to find serious questioning of this perspective outside the realm of alternative and not always evidence-based medical practices; and of course no one should question that some very dangerous micro-organisms are responsible for some very nasty diseases. One serious discussion explicitly questioning the ‘Pasteurian Paradigm’ focuses, interestingly enough, not on medicine, but on craft cheese making with unpasteurised milk (Paxson 2008). This paper is mostly concerned with the ethnography of small-scale cheese-making, but it clearly raises the thought that food products properly made from local microbes might have beneficial effects in facilitating adjustment between organism and environment. (It should be stressed that this is not a naïve microbophilia: makers of unpasteurised cheese take great pains to ensure the access by only welcome microbes to their products.)
Consideration of this relation between organism and microbial environment raises the whole question of immunology. The major tradition in immunology has unsurprisingly begun with the concept of the MDCL, and has seen its major problem as explaining how the organism identifies alien cells—pretty much any genomically different cell—and eliminates them. This perspective clearly has a problem in understanding the relation of the MDCL to symbiotic microbes but, recalling the idea that the human (or other vertebrate) body is a tube, and the inside of the digestive tract is therefore on the outside, the solution is not too difficult: it is simply a matter of maintaining the boundary and making sure alien (i.e. microbial) material remains on the outside. Important recent work by Thomas Pradeu (forthcoming), however, shows how much research in immunology supports a rather different picture, in which the immune system consists of a continuous and dynamic process of monitoring all the cells in the system, and neutralising and disposing of whatever biological objects fail to pass rigorous quality control tests. This perspective reminds us that the immune system doesn’t merely target alien material, but is also busy disposing of dead and diseased material from the human MDCL. Much more interestingly, it presents the relation between the MDCL and what I would describe as other parts of the human system (symbiotic microbes) as an active process of maintaining an appropriate equilibrium at the organisms’s boundaries, while constantly monitoring and responding to the presence of potentially harmful cell-types.
This alternative perspective on the immune system is an important ingredient in the view of the organism that goes beyond the MDCL. On the MDCL conception, the organism is a set of relevantly homogeneous cells warding off attacks by other, hostile, cell lineages. The extended conception looks at the functioning of the system in relation to what is outside it, and observes that a proper account of functioning requires inclusion of much more than the MDCL. The immunological perspective adds another criterion for distinguishing what is and what is not a part of the system, namely by analysing a process through which the system itself determines what biological entities are and are not welcome constituents of the whole.
5 Metaphysical aside
I have advocated a view of the human organism that includes an extended set of elements that are together required for proper functioning and sustainability of the whole. Though I have suggested that immunological considerations may provide some convergent criteria for deciding what is and what is not a part of the organism, I do not want to suggest that such decisions reflect unequivocal matters of fact that science will eventually resolve one way or another. On the contrary, my view is that drawing boundaries round biological objects is to an important extent a matter of human decision driven by particular human goals, practical or theoretical. I propose a ‘promiscuous individualism’ parallel to the promiscuous realism I have advocated for many years with reference to natural kinds. That is to say, there are various ways of drawing such boundaries, reflecting real biologically salient aspects of the multiply interconnected systems that make up the biological world.
So I have not wanted to say that the MDCL is an erroneous conception. It is arguably an inevitable conception for pursuing certain kinds of evolutionary question. The mistake is to think that it involves a discovery of what the organism really is, and must therefore be the right conception for all purposes. Against this, I have suggested that a more inclusive, functional and polygenomic, understanding of the organism is better suited to many or most medical purposes; in this context commitment to the fundamental importance of the MDCL does more harm than good. It is an interesting thought that within this broader perspective various important processes such as metabolism, development, and immunology, will not necessarily provide the same answers to questions about the boundaries of the organism. I don’t see that this should be a cause for concern. Indeed, appreciation of a degree of arbitrariness in any boundary between ourselves and our biological environment should help us to move away from the isolated, antagonistic view of our relation to our biological environment, towards a more nuanced one which, while recognising that nature is full of threats, also appreciates the deep interconnectedness of ourselves and our environment.
This interconnectedness is historical as well as functional. One common idea is that after billions of years in which only simple primitive organisms were evolving, something new and better appeared, and the primitive precursors remained either as lowly chemical operatives disposing of waste, or as hostile predators, bent on turning us into further waste for their chemical maw. But we have not transcended our ancestors, but rather have evolved as fully interdependent enhancements of the pre-existing biological systems. Eventually, it may be expected, this insight will have a profound effect on our view of health and disease.
Research in many areas of biology is changing our basic understanding of living processes. Epigenetics has undermined earlier deterministic ideas about the action of genes; microbial ecology and metagenomics are demonstrating the massive interconnectedness of the diverse elements of functional biological systems; systems biology is offering a few glimpses of ways that we might eventually learn to analyse these terrifyingly complex systems. And there are many other advances that I have not considered in this brief discussion. It is self-evident that medicine must attempt to come to grips with these new insights into the nature of the biological.
But more specifically, the diseases of the wealthy nations—cancer, heart disease, diabetes, etc.—seem increasingly to require this broader perspective as we try to understand the relations between the environmental, cytological, genetic and epigenetic perspectives on these maladies. And the infectious diseases that continue to plague poor countries, may well return to afflict the wealthy as the policy of massive and indiscriminate microbicide is gradually being defeated by the resilience of the microbes themselves. It may be hoped, though perhaps it is still little more than a hope, that a better understanding of the relation between the human MDCL and the microbes together with which it constitutes the functional human system, may provide us with new ways of responding to the catastrophic imbalances of the system that can result from the wrong microbes in the wrong place. There are, at any rate, massive challenges and opportunities for medicine in emerging biological science.
There is a further problem here in the tendency to reduce the cell to the genome. For present purposes I shall treat Dawkins view (charitably) as acknowledging the whole cell as the minimum unit of reproduction.
In terms of Hull’s well-known distinction between replicators and interactors, we are saying that an interactor typically contains many different kinds of replicators. However I am sceptical of the ultimate viability of this distinction. From the developmental systems perspective that I advocate the whole interactor replicates itself, but it does so, in part, by virtue of the replication of many other replicators (which are also at their own scales interactors) of diverse kinds.
Researchers concerned with the incidence of serious fungal infections of the skin that affect amphibians have found that application of a bacterium with fungicidal capacities to the skin can be an effective treatment (Harris et al. 2009). Comparable therapeutic uses of microbes in human medicine are at least an interesting possibility.
This paper has benefitted from comments from Sabina Leonelli, Pierre-Olivier Méthot, Staffan Müller-Wille, and Maureen O’Malley. I also gratefully acknowledge funding from the Economic and Social Research Council (UK). The research in this paper was part of the programme of the ESRC Centre for Genomics in Society (Egenis)