The Curtain of the Ballet Mercure: The Biological Individual Beyond the

Immune Self

Thomas Pradeu

Paris-Sorbonne University & IUF

Conference Redefining the Self

(Sorbonne, June 23-24, 2014)

Thanks to all the speakers

Thanks to Hugues Bersini, Marc Daëron, Leila Périé, Véronique

Thomas-Vaslin

1. Prelude: various boundaries

Picasso, curtain of the Ballet Mercure (1924)

• Biology and the definition of boundaries.

• (Science-based) ontological revision

• Hull: science-based individuation; living world and the individual .

2. The problem

The delineation problem

• How to delineate biological individuals?

• Phenomenal individuation

• Failures.

Difficult cases• A group or an individual?

Difficult cases• A group or an individual?

• Botryllus schlosseri.

Difficult cases• A group or an individual?

• Botryllus schlosseri.

• Siphonophores, incl. Physalia physalis.

Difficult cases• A group or an individual?

• Botryllus schlosseri.

• Siphonophores, incl. Physalia physalis.

Difficult cases• A group or an individual?

• Botryllus schlosseri.

• Siphonophores, incl. Physalia physalis.

Difficult cases• A group or an individual?

• Botryllus schlosseri.

• Siphonophores, incl. Physalia physalis.

• Clonal plants. Eg. Aspens.

Difficult cases• A group or an individual?

• Botryllus schlosseri.

• Siphonophores, incl. Physalia physalis.

• Clonal plants. Eg. Aspens.

Difficult cases• A group or an individual?

• Botryllus schlosseri.

• Siphonophores, incl. Physalia physalis.

• Clonal plants. Eg. aspens.

• Social insects; bacteria: biofilms; etc.

• (Every individual is a group. Cells within a multicellular organism.)

The delineation problem

• How to delineate biological individuals?

• Phenomenal individuation

• Failures.

• Hull: we must use science.

Alternative boundaries• Dawkins

• Immunology

• Intuition and internalism

• Abandonment of self framework does not force us to abandon the idea of immunology-based delineation.

• Origin-based delineation vs variation-based delineation .

3. Delineation based on the immune self: origin-based delineation

SNS as an answer to the delineation problem

Burnet (1899-1985)

Immunology and the delineation of biological individuals

• Loeb L (1945) The Biological Basis of Individuality.

• Medawar PB (1957) The Uniqueness of the Individual.

• Burnet FM (1969) Self and Notself.

• Hamburger J (1978) Discovering the Individual.

• Gould&Lloyd (1999).

Principles of the self-nonself theory• Principles:

1) the organism does not trigger an immune response against its own constituents

2) the organism triggers an immune response against every foreign entity.

• E.g., grafts

Principles of the self-nonself theory• Principles:

1) the organism does not trigger an immune response against its own constituents

2) the organism triggers an immune response against every foreign entity.

• E.g., grafts

• The immune system preserves the integrity of the organism by rejecting everything which is genetically foreign to it. (Burnet, The Integrity of the Body, 1962).

• 1941: “the whole subject matter of immunology is founded on this intolerance of living matter for foreign matter”.

• (See Moulin (1991), Tauber (1994), Pradeu (2012)).

• The immune system, keeper of a fixed, homogeneous identity.

Endogenicity• The criterion: endogenicity

• Origin-based delineation

• Internalism: closure and self-construction.

• The "higher vertebrate" bias

• "The inside of the mouse"

The self vocabulary is alive and well!

• Tran et al. (2014) Cancer Immunotherapy Based on Mutation-Specific CD4+ T Cells in a Patient with Epithelial Cancer. Science 344, May 9, 2014:

The human immune system has evolved to recognize and eliminate cells expressing foreign, nonself antigens. All malignant tumors harbor nonsynonymous mutations or other genetic alterations, some of which may generate neo-“nonself” epitopes that could potentially trigger an antitumor T cell response.

4. Problems with the delineation based on the

immune self

The principles of the self-nonself framework are

inadequate. (Tauber 1994, Matzinger 1994, 2002, Pradeu 2012, etc.)

Normal autoreactivity and normal autoimmunity

• Normal autoreactivity: selection of lymphocytes in central lymphoid organs and at the periphery.

Tanchot C. et al. (1997) Differential requirements for survival and proliferation of CD8 naive or memory T cells, Science 276, 2057-2062.

• Normal autoimmunity: e.g., phagocytic cells and TRegs. Jeannin, P., Jaillon, S. & Delneste, Y. (2008) Pattern recognition

receptors in the immune response against dying cells. Curr. Opin. Immunol. 20, 530–537.

Sakaguchi, S. (2006) Regulatory T cells: Meden Agan, Immunological Reviews 212, 5-7

Jerne (1974), "Paris school" (Varela, Coutinho, Stewart, etc.),

Irun Cohen, Alfred Tauber.

Immune responses to tumors

• Genetically, tumor patterns belong to the “self”

(however “abnormal” they may be).

• The “altered self”: a tautology. Why other forms of “alterations” do not trigger rejection responses?

Our bacteria, ourselves

• A mammalian organism is made of 90% of bacterial cells, and only 10% of cells bearing its ‘own’ genome. (even 99%-1% from a genetic point of view)

• Estimated 1014 microorganisms in the gut.

• 400-1000 species

• Only a small proportion has been successfully cultured in the lab.

• In the great majority of cases: mutualism; even obligatory symbiosis.

Key functional roles• Digestion

• Development: in many cases, symbiotic bacteria are indispensable for a normal development. In particular, they can activate host’s developmental genes. Hooper (2004), Bacterial contributions to mammalian gut development McFall-Ngai (2002) Unseen forces: The Influence of Bacteria on Animal Development Eberl & Lochner (2009), The development of intestinal lymphoid tissues at the interface of self and microbiota. Pradeu (2011) A Mixed Self: The role of symbiosis in development

• Immunity

Hill&Artis (2010), Intestinal bacteria and the regulation of immune cell homeostasis, ARI.

Even an influence on behavior

Heijtz et al., PNAS (2011)

Also true in insects, plants, squids, etc.

A diversity of internalized passengers

• Microbiota

• Virobiota (Duerkop and Hooper, Resident viruses and their interactions with the immune system, Nat Immunol, 2013)

• “Mycobiota”

At the interface between immunology, microbiology, developmental biology, general

physiology, etc.

Gilbert and Epel (2009)

McFall-Ngai (2002) McFall-Ngai et al. (2013)

Consequence

• Organisms are massively inhabited by “foreign” entities, which are “internalized”.

• It is simply not true that organisms reject foreign entities.

Conclusion of this section

• The two principles of the SNS theory are flawed.

• Origin-based delineation is wrong.

5. Re-defining the self?

• An extended self?

• Problem: loss of explanatory power

• This objective must be conserved (Matzinger, etc.)

• A different explanatory framework.

• An extended organism.

6. A different explanatory framework: the

discontinuity theory

Basic ideas

• The immune system responds to rapid changes.

• Objective: strong unifying power. In particular: innate immunity.

• A variation-based delineation.

7. The extended organism

Delineating the organism

• The immune system offers a principle of individuation as it delineates the organism’s boundaries: it rejects/accepts entities as constituents of the organism. (Principle of inclusion).

• Some entities (both endogenous and exogenous) are accepted, and some entities (both endogenous and exogenous) are rejected.

• In this view, the question of membership (= belonging or not to a given organism) is separated from that of the origin: inside/outside should not be confused with endogenous/exogenous.

• => The immune system ensures the unity of the organism, despite the heterogeneity of its constituents.

A definition of the organism

An organism is a functionally integrated whole, made up of heterogeneous constituents that are locally interconnected by strong biochemical interactions and controlled by systemic immune interactions that repeat constantly at the same medium intensity.

Pradeu (2010), What is an organism? An immunological answer, Hist. Phil. Life Sci., 32: 247-268.

Pradeu (2012) The Limits of the Self: Immunology and Biological Identity. New York: Oxford University Press.

Mutualistic entities and the heterogeneous organism

• Actively tolerated mutualistic entities (bacteria, viruses, etc.) are true constituents of the organism.

Pradeu & Carosella (2006) The self model and the conception of biological identity in immunology. Biology and Philosophy 21(2): 235–52.

Pradeu (2010), What is an organism? An immunological answer, Hist. Phil. Life Sci., 32, 247-268.

McFall-Ngai et al. (2013) Animals in a bacterial world, a new imperative for the life sciences. PNAS

Bosch & McFall-Ngai (2011) Metaorganisms as the new frontier. Zoology 114: 185-190.

8. What kind of boundaries?

Two main ideas here

• Immunology offers a critical contribution to the question of the delineation of biological individuals.

• It contributes to disentangle fuzzy cases.

Disentangling fuzzy cases

• Colonial animals. E.g. Botryllus schlosseri.

The example of Botryllus schlosseri

• Rinkevich (2005), Natural chimerism in colonial urochordates

• De Tomaso A.W. et al. (2005), Isolation and characterization of a protochordate histocompatibility locus, Nature, 438(24): 454-459.

• Nyholm SV et al (2006), fester, a Candidate Allorecognition receptor from a primitive chordate, Immunity 25, 163-173.

Disentangling fuzzy cases

• Colonial animals. Eg. Botryllus schlosseri.

• Siphonophores? (To be investigated.)

• Plants, incl. clonal plants (eg. Aspens)

• Social insects? (Cremer&Sixt, 2009, Analogies in the evolution of individual and social immunity).

• Social amoeba?

Boundaries without a 'self'• The very idea of biological boundaries could be

put into question.

• Yet if the IS offers a principle of inclusion, it does play a key role in establishing the boundaries of biological individuals.

• It does so in a dynamic and flexible way.

• Eg. epithelia.

In agreement with intuition?• Humans, mice.

• But: as we saw, failures of intuition.

• The criterion suggested here helps to decide in cases that cannot be decided thanks to our intuitions.

• So, though the view presented here is sometimes consistent with intuition, it is not based on intuition.

Conclusions• Philosophers of biology have focused on evolution when

thinking about the delineation of biological individuals. This approach needs to be complemented by other approaches, in particular an immunological approach.

• Mainstream immunology has offered an origin-based delineation. Though this idea seems vivid, reasonable, and in agreement with some of our most fundamental intuitions about what it means to be "oneself", it is flawed.

• I suggested here (on the basis of DT) a variation-based delineation.

• It can be related to other philosophical views over identity, in particular genidentity.

Picasso, curtain of the Ballet Mercure (1924)

• Intuitive delineations, scientific delineations. There are indeed several scientific delineations.

• They can be in strong disagreement with  intuitive delineation.

• What is particularly difficult: those delineations are distinct but not entirely independent; sometimes, they interact. (Eg. Aphids and symbionts). => An important challenge is to determine where exactly they need to be articulated, and how.

Human identity• What does the vision presented here

(immunological delineation, based on the degree of variation) tell us about our identity?

• It depends on your conception of human identity. It concerns only our biological identity.

• It can impact "biological views" in the philosophical debate over identity. E.g. Olson (1997) remains to a large extent internalist.

Thanks!

Acknowledgements: John Dupré, Gérard Eberl, Jean Gayon, Scott Gilbert, Peter Godfrey-Smith, Alexandre Guay, Richard Lewontin,

Maureen O'Malley, Margaret McFall-Ngai, Anne Marie Moulin, Elliott Sober, Alfred Tauber, and Eric Vivier.

Additional material

Biological genidentity

• What has been said here shows the continuous construction of the organism, with both endogenous and exogenous constituents.

• Revival of genidentity: identity is nothing more than continuity.

(Pradeu T. 2012. The Limits of the Self: Immunology and Biological Identity.)

• Locke (1690) Essay concerning human understanding.

• Anti-substantialism in the sense of Leibniz, in particular (New Essays).

• An “open” genidentity: the organism is the product of local, concentrated, continuous interactions, controlled by the immune system, and the organism is always slightly modified by the progressive integration of external constituents.

• Consistent with John Dupré’s “processual” view of the organism.

• Burnet (The Darwinian approach to immunity, 1965): “there is continued justification to keep thinking about immunology at the theoretical level as well as at the level of experimental detail.”

Important aspects of TDT• Important scope, with in particular the idea that explaining innate

immunity is a priority (in partic. NK, Mϕ)

• Immune responses to tumors

• Tolerance of symbiotic microbes

• Difficulties encountered by the immune system for responding to chronic pathologies

• Related to the concept of “immune surveillance”

• Related to Grossman and Paul

• => The aim is to offer a theory that has a strong unifying power. (Plant immunity, phagocytosis, NK cells, regulatory cells, responses to tumors, etc.)

Tolerogenous immune interactions

• Chu & Mazmanian, Innate immune recognition of the microbiota promotes host-microbial symbiosis. Nat Immunol 14(7), July 2013.

• Garrett WS, Gordon JI, Glimcher LH. Homeostasis and inflammation in the intestine. Cell 140(6), 2010, 859–870.

• Faith et al., The Long-Term Stability of the Human Gut Microbiota. Science 341, 5 2013.

A (key) component of the body

• The gut flora is a true organ.

• O’Hara &Shanahan (2006), The gut flora as a forgotten organ.

• All the organism’s interfaces are concerned: lungs, mouth, sexual organs, etc.

• Xu & Gordon (2003), Honor thy symbionts, PNAS 100:10452-10459.

How is it related with the question of identity and individuality?

• The discontinuity theory helps understanding the constant (controlled) change in an organism, and in particular its capacity to integrate initially environmental entities (in particular microbes).

• In my reflection, it has been a basis to re-think the question of how one should delineate biological individuals.