Conference Redefining the Self

Redefining the Self:

Biological and Philosophical Perspectives

 

June 23-24, 2014

Université Paris-Sorbonne, Amphitheater Richelieu

17, Place de la Sorbonne 75005 Paris

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Conference website: http://iridia.ulb.ac.be/bersini/Self-NonSelf/

 

Please contact me for audio files of the conference

 

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Hugues BERSINI, IRIDIA institute, Université Libre de Bruxelles, Belgium

What makes a complex system vulnerable (See PDF here)

Needless to say, the immune system is both complex and vulnerable. Why makes a simple system switches to a complex one is: the non-linearity of the interactions, the non-homogeneity of the interaction topology (some biological nodes are much more connected than others) and, above all, the gradual substitution of a linear causality by a circular one (in the presence of many positive and negative feedback loops). This latter reinforces the behavioral autonomy of these systems (as compared with the importance given to external impacts) and gives rise to the most intricate dynamical regimes such as multi-stability, cycles or chaos. Those well-known insights coming from physics and computer sciences allow shedding new lights on these systems vulnerability: the self-organization of a homeostatic/viable regime, the possibility to autonomously getting closer to bifurcation frontiers and the elimination of strategic nodes. The talk will remind those classical physical facts and how, for more than 30 years, they considerably influence how my inspirers (Coutinho, Varela, Stewart) and myself perceive immune functions.

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Irun COHEN, The Weizmann Institute of Science, Israel

Immunology deals with molecules and cells and their interactions; the concepts of self and non-self are not relevant to this scale (See PDF here)

The concepts of self and non-self bear meaning at the scale of social interactions between individuals – whole organisms; the self is how an individual – in the framework of a society – distinguishes himself or herself from other individuals. This distinction arises from cognition, internal awareness, historical narrative, language, communication, emotion, identification, and interpersonal interactions.  A biological human individual includes more resident bacteria and viruses than it includes germline-derived eukaryote cells – children and their mothers and the recipients of allografts also contain non-germline-derived eukaryote cells. The task of the individual’s immune system is to sense and integrate the information needed to apply a dynamic inflammatory response appropriate to the state of the cells, molecules and interactions required to maintain and heal the body in the face of trauma, symbionts, parasites, and any aberrant cells and molecules; these immune decisions are made without recourse to the scale of self-non-self social categories.

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Antonio COUTINHO, Instituto Gulbenkian de Ciência, Portugal

Evolution and Development of Immune Self-Nonself Discrimination: A Layered “Strategy” (See PDF here)

“Ridding” mechanisms of defense against pathogens must be kept from “self” targets. The “oldest solution” may have been the control at induction of the “ridding” response by germ-line-encoded receptors for “very-different-from-self” ligands (Coutinho, 1975); the evolution of feed-forward mechanisms amplifying inflammation involved “hijacking” the “strategy”, by using products of cellular stress responses to activate such receptors; while stress responses also “protect tissues” from damage, it is unclear whether or not a “primitive” “suppressor pathway” exists.

An “adaptive solution” was required by the emergence of immune systems endowed with a large diversity that is generated somatically; while this allowed the efficient “targeting” of older “ridding” mechanisms through V-region reactivity, the degeneracy of V-region-antigen reactions, essential for open-ended “nonself coverage” (Coutinho, 1980), precluded that “self-nonself discrimination” is based on purging self-recognizing TCR/Ig. Self-tolerance could only be compatible with the “completeness” of adaptive immune repertoires through evolution of “dominant” mechanisms derived from “positive self recognition”: the most self-reactive T cells are developmentally selected for a “suppressive pathway”, making it the fail-safe solution (Tolerize one, tolerize them all, Coutinho and Bandeira, 1989). In turn, this imposes that “productive” auto-reactivity is ensured in early development, through the evolutionary selection of self-reactive/multi-reactive V-regions into the germ-line, and of developmental mechanisms that restrict somatic diversification (Holmberg et al. 1984). As first shown by Medawar, organisms are indeed “tolerizable” only in early development, but as later demonstrated by Le Douarin, the mere presence of “self” is not enough, self-tolerance requiring positive selection of dominant mechanisms in the thymus.

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Gérard EBERL, Institut Pasteur, France

Immunity and the Microbe-Host Superorganism (See PDF here)

The immune system is commonly perceived as an army of organs, tissues, cells, and molecules that protect from disease by eliminating pathogens. However, as in human society, a clear definition of good and evil might be difficult to achieve. Not only do we live in contact with a multitude of microbes, but we also live with billions of symbionts that span all the shades from mutualists to potential killers. Together, we compose a superorganism that is capable of optimal living. In that context, the immune system is not a killer, but rather a force that shapes homeostasis within the superorganism.

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Anna FRAMMARTINO WILKS, Department of Philosophy, Acadia University, Wolfville, Canada

Know Thyself: Lesson for immunology (See PDF here)

This paper examines current accounts (Varela et al 1988, Atlan and Cohen 1989, Stuart 1994, Cohen 2000) of the nature and function of the immune system as analogous to human cognition (Jerne 1974). These accounts reject the tenet that an antigen begins where the self ends – arguing that, from the perspective of the immune system, there are no absolute boundaries between self and not-self. The reason is that the immune system is not able to interact with something completely heterogeneous with itself, i.e., genuinely foreign to it, since any absolutely foreign substance could not enter the immune system’s cognitive framework, that is, could not be perceived or detected by it. This claim, I suggest, is consonant with the core precept of Kantian epistemology: the cognitive subject can only know objects conditioned by the forms and structures of its own cognitive apparatus. What this entails is that we cannot at all know or perceive things as they are in themselves, unconditioned by our cognitive structures – as these things would be absolutely foreign to us, and thus undetectable by our cognitive radars. For Kant, an object cannot be cognized by a subject unless that object is, in certain fundamental respects, incorporated in the subject. This implies the rejection of the absolute distinction between the cognizing subject (self) and the cognized object (not-self), (Tauber 2009). This is not simply because the identity of the self varies in degrees, and thus cannot be determinately distinguished from the not-self (Hume 1738, Parfit 1989, Pradeu and Carosella 2006), but also because certain features of the self must be manifested in the not-self, since they are necessary conditions for the cognition of the not-self. This paper demonstrates the usefulness of this Kantian epistemological principle for expounding the cognition view of immunology.

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Uri HERSHBERG, Department of Microbiology and Immunology, Drexel University, Philadelphia, USA

What do we mean when we say cognitive? Different cognitive paradigms of immunity imply different definitions of self (See PDF here)

One of the issues of defining self in a multi-cellular organism is that it is a multitude. It has been suggested that the immune system can cope with this ambiguity because it is cognitive. However, what this characterization signifies differs by the theory we adopt. I will contrast the cognitive paradigms of Irun Cohen and Francisco Varela to show that the adaptive capacity of the cognitive immune system implies there is no immutable definition of self. The heart of my argument lies in each theory’s starting point. Varela defines cognition from the top down as the means by which second order autopoetic machines including the body and the immune system create closure and define their identity relative to the world. This closure, like the cell membrane, is well defined through the coupling interaction of individual and environment. Thus, the method of defining the self limits the immune system’s adaptive capacity. By contrast, Cohen’s model starts from the idea that immune cognition is a bottom-up phenomenon that is the emergent result of many small cell-to-cell interactions. Thus, the focus of Cohen’s cognitive paradigm is how many small interactions lead to emergent behavior, learning or understanding. Self is, therefore, malleable and impermanent. Combining both models, I will suggest that in all cognitive systems including the immune system (1) the role of the environment is not merely to define action but, in addition, to define the parameters of the cognitive system itself and thus the types of action that can occur; (2) the closure of cognitive systems is never complete, and thus we should see, at all stages of the immune system’s existence, reactions to the environment embodying different levels of closure involving new learning and new adaptive responses.

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Philippe KOURILSKY, Collège de France (Chair of Molecular Immunology), France

A Dynamic Theory of Self/Non-self Discrimination (See PDF here)

The issue of self/non-self discrimination has been re-evaluated within the conceptual frame of complex systems. It was further attempted to integrate various elements exposed in several previous theories (particularly the “danger” theory [Matzinger 2002] and the “discontinuity” theory [Pradeu, Jaeger and Vivier 2013]) into a single model. In the latter, cells are pictured as “intelligent”, autonomous automata (as suggested for T cells more than twenty years ago [Grossman and Paul 1992]), and endowed with certain interactive properties. This leads to a self-referred definition of the self.

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Polly MATZINGER, National Institute of Allergy and Infectious Diseases, NIH, USA

Does the Immune System Really Care About Self vs. Non-Self? (No PDF)

Some of the most creative thinking in immunology has revolved around the search for practical definitions of self and non-self. Yet, over the years, this has been an almost impossible task.  Various investigators have suggested definitions as widely diverse as “everything encoded by the genome”; “everything under the skin” (sometimes including structures encoded by commensal genomes, and sometimes excluding the "privileged" sites such as brain, cornea, and testes); or any tissue accessible to lymphocytes. For T cells, the definitions include – the set of peptides found complexed with MHC molecules -Waldmann;  or only those molecules expressed by APCs and thymic epithelium (all other tissues being “ignored”) – Zinkernagel. For B cells, cell surface and soluble molecules, (internal cell molecules assumed not to be “self” and antibodies against intracellular components might serve a housekeeping function to help clear cellular debris) – Cohn; the set of bodily proteins that exist at a concentration above a certain threshold – Mitchison; anything except idiotypes – Jerne; an idiotype-anti-idiotype network that creates a "positive definition of self" – Coutinho; and any molecule that exists at a constant concentration – Grossman and Pradeu.

   The reason that so much energy has gone into defining “self” is that most immunologists were working with the idea that the primary function of the immune system was to distinguish between self and non-self. I abandoned that idea 20 years ago, and have found that it is completely possible to define an immune system based on the idea that its primary function is to discriminate between things that do damage and things that don’t. In fact, using this latter assumption allows for a model of immunity that explains almost all of what the immune system does right, as well as almost all of which it seems to do wrong. It allows for a model explaining how the immune system determines what kind of immune response to mount, a feature not incorporated into most other models of immune response. It allows for useful recognition of “self”, especially for recognition of “stressed” self, which is also not a feature of most other models. Finally, it suggests that control of immunity does not lie within the immune system, but instead with the tissues that the immune system has evolved to protect.

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Margaret McFALL-NGAI, University of Wisconsin-Madison, USA

‘An Inconvenient Truth’: New findings in Symbiosis Challenge the Balkanized Field of Biology (PDF is just too big, please contact me if you are interested)

Recent genomic data have revealed that all life forms visible to the human eye represent a very small portion of the biosphere’s diversity. We inhabit an Earth that has been historically and is now dominated by the microbial world. In addition, the activities of this microbial contingent are required for the health of Earth’s ecosystems and are defining forces for all animals and plants that live therein. Thus, it will be imperative that biologists integrate this new knowledge, yet such integration will be impossible without changes in the basic fabric of the discipline of biology. Notably, beginning in the 1950’s, with the advent of molecular biology, the field became strongly balkanized into a series of sub-disciplines (e.g., microbiology, neurobiology, cell biology, developmental biology). This presentation will consider, in light of these structural and conceptual constraints, possible ways forward for the development of a more integrated field, one that reflects the true nature of the biological world.

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Anne Marie MOULIN, UMR SPHERE, CNRS/University of Paris 7, France

The Challenges Raised by the Exclusion of the ‘Self’ in the Science of Immunity: A Test of the Relation between Philosophy and Immunology (See PDF here)

The self has been central to the definition of immunology since Burnet’s famous formulation and remains today highly controversial. The reference to the self introduces a philosophical notion, which has appeared to many as flawed and superfluous. Most notably, it has been argued that the reference to the self represented by no means a consistent and fruitful theory, and only offered at best the commodity of a metaphorical language, particularly useful to communicate about immunological knowledge (the picture of the immune system as a fortress of the self, the military imagery and the extensive use of self-defence and war vocabulary). Accordingly, many authors have proposed to excommunicate a cumbersome metaphor borrowed from literature, poetry and psychology and replace it by a thick description of experimental and clinical phenomena, and multiple metabolic pathways, avoiding any teleological perspective. It is interesting to note that the central metaphor of the preservation of the self has also received criticism from the social sciences, mainly anthropology, as favouring the confusion between otherness and a biological threat, fostering discrimination and exclusion of the foreign elements in society.

   But can immunological language, if not theory, avoid referring to the survival of the individual body? While the former dogma of « horror autotoxicus » in Nature is definitely outdated, how can the multiplicity of diverging and converging pathways in the immune system be described without reference to some form of ontology?

Behind the debate around the eviction of the self in immunological parlance and thinking, the real issue is the nature of the relationship between immunology and philosophy, the status and the reality of their exchanges. The author of the presentation will revisit her own former conception of immunology as a language adequate to the expression of numerous physiological and pathological phenomena, with formal and concrete analogies with philosophical visions, and the consequences of the adoption of an agnostic stance by immunologists, at the light of recent investigations on immunity, (e.g., intestinal microbiome, immune tolerance in pregnancy or the role of allergy in the regular doings of the immune system).

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John PERRY, Philosophy Department, Stanford University, USA

The Biological Unity of Apperception (See PDF here)

Philosophers have long agonized about the nature and even the existence of the self.  I will use Kant’s "transcendental conditions" on the self to argue that biology provides the conception of a self that philosophy needs.  I will also try explain how our system of "propositional attitudes" leads to some of the problems philosophers have had with the self.

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Thomas PRADEU, Philosophy Department, Université Paris-Sorbonne & Institut universitaire de France, France

The Curtain of the Ballet Mercure: The Biological Individual Beyond the Immune Self (See PDF here)

In 1924, Picasso painted the Rideau pour le Ballet Mercure – a giant and beautiful theater curtain, which can be seen at the Centre Pompidou in Paris. On this painting, the characters have two different, non-overlapping boundaries: the colors of the characters do not coincide with the outlines of their bodies, as if the colors and the outlines were floating around. In this talk, I want to suggest that, in a similar way, there exist two non-overlapping manners to draw the boundaries of biological individuals, one based on the idea of a “self”, while the other is not.

   Recent reflections in immunology and philosophy of immunology have shown that the self-nonself theory faces many problems, and that living things cannot be understood as self-defining and closed entities (Tauber 1994; Cohen 2002; Matzinger 2002; Pradeu 2012). Research on normal autoreactivity has proved that every organism reacts, and indeed needs to react, to its own constituents. Research on immune tolerance, and in particular on the ubiquity of symbiosis and symbiont-induced development (McFall-Ngai 2002; Eberl 2005; McFall-Ngai et al. 2013), demonstrates that every organism integrates “foreign” material, and even that sometimes this material becomes a crucial component of the organism.

   Biological individuality and the boundaries of living things, therefore, cannot be understood on the basis of the immunological self-nonself framework. But this conclusion, I suggest, does not entail that the project of delineating the boundaries of living things on the basis of the action of the immune system should be abandoned. Biological individuality can indeed be redefined on the basis of current immunology, revealing unexpected, more open and flexible “boundaries” – very much like the floating colors of the characters on Picasso’s curtain.

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John STEWART, CRED, Université de Technologie de Compiègne, France

Putting the immunological self in biological context (See PDF here)

In immunology, there is currently a welcome resurgence of interest in the themes of the “self” (self versus non-self, or self versus non-sense). It may therefore be timely to ask what may properly be meant by the term "self", at the interface between philosophy and natural science. A major reference here is that of von Uexküll, and the “world of the tick”. The question arises as to whether this “lived world” – which is “brought about” or enacted by the organism – is merely an anthropomorphic projection by observing scientists; or whether the organism itself actually has any experience of itself and its world. This leads to consideration of a “psychological self”, and "animal consciousness" – a notorious "Hard Problem". Phenomenologically, this corresponds to the co-emergence of a "self" and a corresponding "lived world" which are radically inseparable. Biologically, this would seem to bear some relation with a Central Nervous System (which is not to say that “the mind is in the head”). Arguably, another key point is the role of proprioception, without which the self/world distinction cannot be scaffolded. With this background briefly sketched out, I propose to raise the following questions in immunology: – is the "self/non-self" distinction in immunology simply an anthropomorphic projection by the observing scientists; or is there a genuine sense in which the immune system itself establishes this sort of distinction as such ? – is there anything like an “immune world”, corresponding to the "lived world" enacted by an organism as an inseparable counterpoint to the "self"? – does the distinction between a “Central” and a “Peripheral” immune system bear any relation to that between a Central and Peripheral Nervous system? – is there anything corresponding to "proprioception"?

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Bartlomiej SWIATCZAK, Department of History of Science, University of Science and Technology of China, China

On the therapeutic implications of the self/nonself discrimination model (See PDF here)

The Hippocratic idea that a physician’s role is to assist healing powers of nature lied at the heart of research on antimicrobial therapy in the first half of the 20th century. Indeed, early immunologists tried to design treatment methods that would facilitate or imitate action of the immune system in clearing infection. Thus, fundamental ideas concerning the immune system function influenced design of anti-infective interventions. One immunological concept that influenced the course of research on antimicrobial therapy was the idea of self/nonself discrimination. Macfarlane Burnet insisted that this idea can be already found in the Paul Ehrlich’s research on immune mechanisms that prevent reaction to one’s own blood cells and in his principle of “horror autotoxicus”. By presupposing that the immune system reacts only to foreign material and never to self-antigens, this principle motivated quest for "Therapia sterilisans magna" (massive sterilizing therapeutic) or “internal disinfectant” that is an agent that would behave like an antitoxin, binding specifically to microbes to kill them and eliminate them. It also reinforced the rationale for the use of sulfa drugs and antibiotics. Overall, the binary view of the immune system function favored antimicrobial therapies that lead to sterilization of the host. The view of the immune system as a killer of nonself strangers should be contrasted with an alternative one, according to which the system is concerned with counterbalancing changes in the chemical and microbial environment to ensure integrity of bodily tissues. This view paved the way to ecologically-based treatment strategies including probiotics and phage therapy. The advocates of this approach include Felix d’Herelle, Theobald Smith and Hans Zinsser but its origin can be traced to Metchnikoff who believed that the harmony disrupted by intestinal microbes could be restored by administration of “antagonistic microbes” in the form of lactic acid bacteria.

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Alfred TAUBER, Center for Philosophy and History of Science, Boston University, USA

Ecologies of Selfhood (See PDF here)

When immune reactions are conceived in terms of normal physiology and open exchange with the environment, where borders dividing host and foreign are elusive and changing, host defense is only part of the immune system’s functions, which actually comprise two basic tasks: protection, i.e., to preserve host integrity, and maintenance of organismic identity. And thus if the spectrum of immunity is enlarged, differentiating low reactive ‘autoimmune’ reactions from activated immune responses against the ‘other’ is only a matter of degree.  Simply, all immunity is ‘autoimmunity,’ and the pathologic state of immunity directed at normal constituents of the organism is a particular case of dis-regulation, which appropriately is designated, autoimmune.  Other uses of ‘autoimmunity’ and its congeners function as the semantic remnants of Burnet’s original self/nonself theory and should be replaced.  A new nomenclature is proposed, concinnity, which more accurately designates the physiology of the animal’s ordinary housekeeping economy mediated by the immune system than ‘autoimmunity’ when used to describe such normal functions.

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Davide VECCHI, Department of Philosophy, Universidad de Santiago, Chile

Towards an heteroplastic view of biological individuality and the self (See PDF here)

In this talk I would like to highlight the essential tension between two antithetical metaphysics of biology and conceptions of biological individuality. The homeostatic view emphasises the influence of internal causes in development and evolution (West-Eberhard 2003), the stability of the internal environment and the organisational closure (Mossio et al. 2010) of biological individuals. The homeostatic view highlights three features of biological individuals: firstly, their autonomy as causal agents; secondly, their spatial boundedness and particulate nature (i.e. corporeal atomism, cf. Tauber 2012); thirdly, their detachment from the external environment. This view arguably formed during modernity (Gilbert et al. 2012), a period that also saw the emergence of the Western notion of political individual: as people possess natural rights (e.g. freedom of thought and emotion, freedom to pursue tastes, cf. Mill 1859) intrinsically and not relationally (i.e. as members of social groups), so biological individuals possess biological characteristics (e.g. metabolic and reproductive autonomy) intrinsically and not relationally (i.e. as members of bio-aggregates). In my opinion the homeostatic view permeates and dominates all facets of biological thinking, including the conception of the self. However, I will argue that this dominance is unwarranted in the light of various theoretical (e.g. Kitano 2006, McFall-Ngai 2013) and experimental developments in the life sciences (e.g. Gilbert et al. 2010, Hsiao et al. 2013). I will propose that a “post-modern” alternative exists. The heteroplastic view, traditionally popular in microbiology (Sonea et al. 2001, McInerney et al. 2011), emphasises the interpenetration between living system and environment, the ontogenetic and phylogenetic negotiability of their relationship, the embeddedness of biological individuals in complex biotic networks and the continuous dynamic fine-tuning of their internal ecologies. But, is the heteroplastic conception of biological individuality and the self coherent? The aim of this presentation is to help answering this question.

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Eric VIVIER, Centre d’Immunologie de Marseille-Luminy, France (in collaboration with Sébastien Jaeger and Thomas Pradeu)

The Discontinuity Theory (See PDF here)

Immunology – though deeply experimental in everyday practice – is also a theoretical discipline. Recent advances in the understanding of innate immunity, how it is triggered and how it shares features that have previously been uniquely ascribed to the adaptive immune system, can contribute to the refinement of the theoretical framework of immunology. In particular, natural killer cells and macrophages are activated by transient modifications, but adapt to long-lasting modifications that occur in the surrounding tissue environment. This process facilitates the maintenance of self-tolerance while permitting efficient immune responses. In this talk we extend this idea to other components of the immune system and we propose some general principles that lay the foundations for a unifying theory of immunity — the discontinuity theory. According to this theoretical framework, effector immune responses (namely, activated responses that lead to the potential elimination of the target antigen) are induced by an antigenic discontinuity; that is, by the sudden modification of molecular motifs with which immune cells interact.

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Round tables:

  • The Self Metaphor and Its Alternatives. Chair: Leïla Périé. Participants: G. Eberl, P. Matzinger, A-M. Moulin, A. Tauber. (See PDF here)

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  • Complex Systems and the Self. Chair: Véronique Thomas-Vaslin. Participants: H. Bersini, I. Cohen, A. Coutinho, P. Kourilsky. (See PDF here).

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Organizing committee:

  • Hugues Bersini (IRIDIA, Université Libre de Bruxelles, Belgium)
  • Marc Daëron (Institut Pasteur, CIML & ITMO IHP, France)
  • Leïla Périé (National Cancer Institute & Utrecht University, Netherlands)
  • Thomas Pradeu (Université Paris-Sorbonne, France)
  • Véronique Thomas-Vaslin (CNRS & Université Pierre et Marie Curie, France)

 

This conference was organized thanks to the financial support of:

 Université Paris-Sorbonne; Ecole doctorale “Concepts et langages”; Université Libre de Bruxelles; SND; IHPST; ITMO Immuno-Hémato-Pneumologie de l'Aviesan; Labex TransImmunom; Réseau ImmunoComplexiT (Réseau National des Systèmes Complexes); and the Institut universitaire de France (IUF).

 

 

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(From Bartlomiej SWIATCZAK's talk)

 

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