the enactive paradigm 33 years later - Constructivist Foundations

Biology of Cognition

The Enactive Paradigm 33 Years Later Nelson M. Vaz

(Vaz & Varela 1978) and Coutinho (Vaz, Martinez & Coutinho 1984; Coutinho et al. 1984) in a period in which I still had not realized major differences between Varela’s and Maturana’s approaches. Today, I would not subscribe to those concepts. Actually, I did not participate in writing the 1988 paper (Varela et al. 1988). Varela quotes this 1988 paper without including my name as an author and my name is not included in the acknowledgements of this paper (see Varela 1991).

The Enactive Paradigm 33 Years Later Response to Alfred Tauber Nelson M. Vaz • Univ. Federal de Minas Gerais • nvaz/at/icb.ufmg.br together with Gustavo C. Ramos & Archimedes B. de Castro Jr.

> Upshot • According to the biology of cognition and language (Maturana’s ap-

proach), the immune system is not a cognitive system and the defining of a cognitive paradigm is not what we understand as a Maturanian approach to immunology. The true cognitive actions in immunology are performed by immunologists acting as observers, not by body organs or systems. Stimuli and responses are not adequate concepts in the description of systems. As a closed network of cellular/molecular interactions, the immune system yields patterns of activity, as is transparent in robust conserved profiles of reactivity of natural immunoglobulins, as investigated by Nóbrega et al. and Cohen et al., which offer the opportunity to unravel its natural, spontaneous activity. Dietary materials, products of the commensal microbiome, are the most abundant and common elements continuously incorporated into the network activity and, thus, also represent an important avenue of investigation.

At the outset, a word of warning on terminology. Cognitivism is that perspective emphasizing symbolization, representationalism, and the computer as a metaphor for a cognitive system. Connectionism (emergence) emphasizes behavioral/configurational emergence in parallel distributed networks, and this formal model is inspired by the neural system as a metaphor for a cognitive system. Varela presented himself as a defender (actually the founder) of a third, distinct cognitive approach, called “enactive,” as made clear by Randall Whitaker (2001) in his site on autopoiesis and enaction. Also relevant to the present distinction, Whitaker notes: “Although the principles underlying enactive cognitive science clearly derive (at least in part) from autopoietic theory (by way of Varela), there are actually few points of reference to Maturana and Varela’s earlier work.” Thus I feel it is improper to label the approach of the “Paris School” as “cognitivist”: it was really “enactive,” i.e., in line with Varela’s ideas. Maturana’s radical statements are impossible to summarize. Varela’s formalizing and modelling efforts aimed at the expression of biological phenomena in mathemat-

ical terms; Maturana goes in the opposite direction and centers his preoccupations in ethics and languaging. One makes biology a harder science; the other makes it softer. Let me also warn against expressions such as the “Santiago School” of cognition, “Paris School” of immunology, or “VarelaVaz-Coutinho-Cohen continuum” (Tauber 2009), which include quite divergent lines of thought. Cherniak and Tauber (1991) addressed heavy criticism to what they understand as the “Paris School” having “applied Maturana’s theory of autopoiesis to immunology” (my emphasis). However, they actually criticize “identity” and “immune selfhood,” which would never be included in Maturana’s approach to biological problems, which includes autopoietic organization in harmony with several other basic concepts. “Identity” is a comment made by an observer to another observer that may be her/himself. It only makes sense in languaging, i.e., consensual, recursive coordination of actions. Varela understood the emergence of identities as entities in themselves. A third problem, not so important but relevant to the present discussion, refers to my (Vaz) early publications with Varela

Has the enactive (“cognitive”) approach resulted in progress since 1978?7 Yes and No. Yes, there was progress because in the 1980s and 1990s Coutinho and co-workers generated massive experimental evidence incompatible with the clonal selection theory. Varela and Stewart’s computer model of the immune system indicated that stability derived from connectivity contradicting self/non-self discrimination (cf. Appendix 1). No, there was no real progress because of the lack of an adequate supporting theory. These data are as strong or as weak as the theory behind them. Experimental facts, by themselves, will not force change in paradigms (Kuhn 1965). Coutinho followed Jerne’s network theory and a patchwork of Varela’s ideas. Jerne’s theory was incomplete because idiotypic connections could not all be equivalent, and an organization should have been defined (Vaz & Varela 1978). Varela’s presence in his laboratory, participating in experimental designs, made him discuss “second-generation immune networks” (Varela, Coutinho & Stewart 1991) and “immuknowledge” (Varela & Coutinho 1991), “metadynamics,” etc., and placed him in contact with complex mathematical notions such as “shape spaces” (Stewart & Varela 1991). The term “immuknowlege,” for example, endows the immune system with cogitive identity and enables it to “enact.” To Maturana, cognition 7 | Taking “Self and non-sense” (Vaz & Varela 1978) as the starting date.

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is an effective action of a living organism in its medium. This action is also a distinction made by a human observer, rather than a comment about an ultimate reality experimentally revealed. I further believe that this vacuum, this necessity of defining an organization, is what led Cohen to his homuncular idea, i.e., a sort of internal hierarchy in the reactions of lymphocytes among themselves and with the body (Cohen 1992; see also Appendix 2). In our way of seeing, the solution is not hierarchical as in Cohen’s homunculus; it involves distinguishing what we do as immunologists as separated from what the immune system does as a component of the organism. Understanding “how do we do what we do” is the province of Maturana, the core of his biology of cognition and language and, most especially, his definition of human languaging (Maturana 2002; Maturana & Poerksen 2004).

A legitimate attack on the wrong target In short, Cherniak and Tauber’s (1991) efficient attack on the “Paris School” is philosophical and legitimate: notions such as “identity” and “selfhood” are profound philosophical issues and I strongly believe that immunology can indeed help to define them. But what they identify as the “Paris School” is Varela’s proposal of “enactive” science, not what the Varela-Vaz-CoutinhoCohen continuum (Tauber 2009), with their different outlooks, could offer. In his present answer, Tauber separates Cohen from this continuum – with which I fully agree – but does not identify our experimental work on “oral tolerance” and our reference to Maturana’s ideas as also separate from the “Paris School,” as I insist should happen.

Some of the history of immunological networks When I met Varela in Denver he was jobless and I invited him to my laboratory, I had just bumped into the phenomenon of so-called “oral tolerance,” a presumed inhibition of immune responsiveness to proteins previously ingested as food, and I was

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deeply overwhelmed by its meaning. Varela, who knew nothing of immunology, was not aware of the impact this finding was having on me. Understood as an inhibition, “oral tolerance” was the exact opposite of immunological memory: it was a kind of specific amnesia directed to an enormous array of proteins, including those in the intestinal microbiome. To Varela, who did not have to deal with the implied contradictions, “oral tolerance” was obviously part of the insertion of the organism into its antigenic medium. The combined effect of bumping into “oral tolerance” and meeting Varela’s cognitive ideas made me temporarily abandon the idea of being a scientist. I gave up my job as department head and returned to Brazil, where I have been ever since. Gradually, I returned to science and “oral tolerance,” which turned out to be not an inhibition, but a robust regulatory mechanism that includes specific antibody formation (Vaz et al. 1996; Verdolin et al. 2001). Seeing “oral tolerance” as assimilation, or insertion of the organism into its antigenic medium, stems from a vision of an autopoietic system that is “closed” in its organization but “open” for incorporating elements of the medium – as Varela saw it (see Vaz & Varela 1978). For Maturana, it is enough to understand that the system maintains an invariant organization. Although self-maintained/self-created, this organization is part of an organism and, among other sub-systems, it helps to build this organism in another domain of description in which effective actions of the organism take place: to know is to live. We cannot properly say that the immune system is “alive,” even though its component cells are alive and the organism to which it belongs is also alive, as long as it maintains its congruence (its adaptation) to its medium.

Where do we go from here? As we have explained elsewhere, our approach allows a new understanding of immune physiology and also of immune pathology based on the expansion of lymphocyte populations with a sub-optimal degree of diversity (oligoclonal expansions) (Vaz et al. 2003; 2006; Pordeus et al. 2009). The same approach explains anti-infectious

vaccination by the expansion of clonal diversity, rather than by enhancing immunological memory, and this suggests new avenues of research. Inflammatory activity can finally be reunited with immunological activity as aspects of biological development (Ramos 2011a). A few recent findings in the literature already suggest that classic autoimmune diseases are not primarily autoimmune, but rather derive from developmental defects (Liston 2008) or require the combined effects of several factors (Cadwell et al. 2010). Attempts to break immunological tolerance, such as the injection of tolerated proteins into tolerant organisms trigger anti-inflammatory phenomena (Ramos et al. 2008) that can affect phenomena ranging from Graft versus Host (GvH) reactions, to granuloma formation, to the healing of skin wounds (Costa et al. 2011). All these approaches derive from a new global understanding of immunological activity, rather than by enumerating cellular and molecular components underlying its performance. In the biology of cognition and language (Maturana 2002; Maturana & Poerksen 2004), immunological phenomena have correlates in patterns of clonal diversity rather than in the activation or regulation of individual clones. What takes place in one domain of descriptions cannot be reduced to another (“simpler”) domain of descriptions. The search for correlates of protection, or correlates of disease, should be replaced with a search for patterns or sets of elements that act together, as shown in immunoglobulin blots (Nóbrega’s) or microarrays (Cohen’s). As Mpodozis and Maturana have insisted, systems only change systemically. Probably that is why “tolerated” antigens injected into a “tolerant” organism have such strong effects (Costa et al. 2011). “Oral tolerance” is an excellent example of how the organism interacts with myriad of different epitopes and yet remains the same, assimilating by coherence rather than “tolerating” for convenience. “Tolerance” is closely related to protection (i.e., maintenance, remaining the same), which what is expected of an immune system. It is also a demonstration that the “self ” cannot be defined in molecular terms. It may seem acceptable to interpret “tolerance” as “assimilation” or “incorporation” (Parnes 2004).


The Enactive Paradigm33 Years Later Nelson M. Vaz

But assimilation into what? Here, what is missing is the definition of the invariant, conservative organization of the immune system (Vaz et al. 2003; 2006; Pordeus et al. 2009).

Appendix 1: On Coutinho/ Varela/Stewart In the 1980–90s, Coutinho and coworkers produced a tremendous amount of experimental evidence in support of the network theory, evidence that cannot be explained by clonal concepts. I have selected just one of their publications per year in that decade to show this: minute amounts of IgM would trigger the production of many more immunogloblulins with the same specificity (Forni et al. 1980); suppression of a recurrent idiotype resulted in profound alterations of the whole B cell compartment (Bernabé et al. 1981); pretreatment of newborn mice with idiotypes also triggered changes in T cells (Holmberg, Ivars & Coutinho 1983); idiotypic determinants of natural IgM antibodies resemble self MHC determinants (Holmberg et al. 1984); there is a high frequency of natural autoantibodies in normal newborn mice (Dighiero et al. 1985); the high idiotypic connectivity of “natural” newborn antibodies is not found in adult mitogen-reactive B cell repertoires (Holmberg et al. 1986); autonomous activation of B and T lymphocytes also takes place in antigen-free mice (Pereira et al. 1986); (Ir-gene) low-responders could be turned into high-responders by manipulation of the developing immune system using antibodies’ (Martinez et al. 1987); the “natural” autoreactive B cell activation in the spleen of normal mice is Tcell dependent (Huetz et al. 1988); transplantation tolerance correlates with high levels of T and B lymphocyte activity (Bandeira et al. 1989). None of this can be explained by the expansion of isolated clones of lymphocytes, but Jerne’s theory lacked the concepts to

pull together all this evidence in a coherent framework. After Varela’s interventions, Coutinho’s laboratory published several important theoretical papers and further experimental evidence, such as: 1 | measuring the serum concentrations of four natural IgM antibodies, two of which showed idiotypic complementarity in in vitro assays, the injection of nanograms of these idiotypes triggered long-lasting changes in other idiotypes (Lundqvist et al. 1989); 2 | idiotypes in normal human sera and in patients with autoimmune diseases had different patterns of fluctuation (Varela et al. 1991); 3 | treatment by infusion with high doses of intravenous immunoglobulins (IVIg) was correlated with regaining normal patterns of idiotypic connectivity (Dietrich et al. 1993). A most relevant development was the introduction of “global” methods of analysis of antibody repertoires using a modified immunoblot (Nóbrega et al. 1993). This was also directed at the analysis of “spontaneous” lymphocyte activation, but had the additional merit of looking into immunoglobulin populations instead of analyzing “specific” clonal reactions. The “profiles” of reactivity generated by these “global” methods, subsequently much expanded by Cohen and co-workers (Madi et al. 2011), are “snapshots” of network dynamics that open up the possibility of observing a large sector of the immune system instead of clones that react with a defined antigen.

Appendix 2: On Cohen

tity that processes information from body tissues and the external medium, computes what is best for inflammation control in each organ, and decides which cells should be activated, etc. This is classic cognitivism: the connectionist side emerges as a systemic (collective) action of otherwise isolated cells. For Maturana, the distinction of a system is something made by a human observer that draws the limits of an entity, sees the invariance of its organization, and identifies it as a member of a class of systems. In this sense, Cohen’s homunculus derives from the organization of immune systems and would display the same patterns in every organism. Computing the inflammatory status of tissues and organs lacks a parallel in Maturana because it depends of the computer metaphor of living networks. However, computers follow their programs, whereas living systems follows their internal dynamics, which depend on what a structure allows at each particular moment. The analysis of invariant patterns of reactivity in natural immunoglobulins, inaugurated by Avrameas, expanded by Nóbrega (Nóbrega et al. 1993), and highly refined by Cohen and co-workers (Madi et al. 2011), is highly suggestive of an invariant organization, which, although genetically based (Vasconcellos et al. 1998), is determined epigenetically at each moment. If lymphocytes and immunoglobulins are ceaselessly changing, the maintenance of invariant profiles of reactivity is a strong argument for an invariant organization, which is also assembled in “antigen-free” organisms.

Computer models of the network

The description of maintenance as permanence/constancy of immune reactions with sets of autologous proteins (Cohen’s homunculus) emphasizes the need to define an organization (a “class identity”) for the immune system (Cohen 1992). But this requires a proper definition of terms such as (variable) “structure” and (invariant) “organization.” Cohen’s choice hides this otherwise major advance by using a patchwork of representationist terms, such as homuncular notions, and connectionist terms, such as “information” and “emergence.” He also sees the immune system as a cognitive en-

The possibility to analyze and interpret “global” data, however, depends on the kind of questions being asked. These methods are as good as the theory behind them. Working in Coutinho’s laboratory, Stewart and Varela produced quite a few papers on simulations of network behavior, mainly based on reactions in a set of newborn and adult non-immunized mice monoclonal globulins. They proposed mechanisms of “tolerance” based on internal connectivity and showed that autoimmune diseases are associated with changed patterns of connectivity.


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This was an advance toward “systemic” definitions; however, without a more encompassing biological theory, it remains incomplete. Varela saw the immune system as a cognitive system and aimed to define its “identity.” However, the interference of human observers and human languaging in constructing immunological realities was never mentioned. Subsequent efforts led by Stewart (Stewart & Coutinho 2004; Rohde & Stewart 2008) invoked Maturana’s ideas but also failed to mention human observers and their languaging. Received: 17 June 2011 Accepted: 24 June 2011

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