segunda-feira, 3 de outubro de 2011

Francisco Varela and the immunological self

Post por Nelson Vaz
Texto aceito para publicação na próxima edição da revista
Systems Research and Behavioral Sciences

Varela participated in lab seminars, experimental design and analysis of results in Antonio Coutinho's Unité d'Immunobiologie, Institute Pasteur, Paris, from 1986 to 1996. With John Stewart he made  important contributions to the modeling of immune systems in computers and, in his own vein, provided mathematical ways to formalize immunological activity. An extended and personal report of this work was published by Coutinho (2003). During this period (1986-1996) Francisco published about twenty important papers in journals of immunology and book chapters.

My intention in this paper is to briefly describe Francisco Varela’s passage through experimental and theoretical immunology, participating in events to which I happened to be instrumental and by which I was deeply influenced. Herein I emphasize: a) his mostly unrecognized work in building a systemic view of immunological activity in opposition to the standard clonal perspective; b) his primary focus on delineating an immune identity (the immunological self); linked to this I will comment on his disregard for the importance of the human observer and immunological languaging - an aspect that separates Varela from the outlook developed by Humberto Maturana (Vaz, 2011); c) lastly and from my personal perspective, I reflect on Varela’s neglect of the phenomenon  presently called ‘oral tolerance’, which we examined together (Vaz and Varela,1978), and that I consider as one of the fundamental aspects of immunological activity.

Something of the history of immune networks
My first encounter with Francisco Varela took place in Denver, in the late 1970’s. It was decisive for my career in immunology and for my life. I welcome this opportunity to contribute to reflect on his excursion, as a neurobiologist and philosopher, into what was for him an unfamiliar field of lymphocyte activities, as I watched his first steps into this area. To convey his impact on my own thinking, I note that our initial association of about one semester was intense enough to make me abandon the idea of working in the United States and return to my former position in Brazil.

In my experiments, I had literally bumped into a phenomenon presently described as ‘oral tolerance’ which consists of a drastic reduction of antibody (i.e., lymphocyte) responsiveness to proteins previously ingested as food. All animals eat thousands of different proteins and there are also thousands of other proteins produced by the intestinal microbiota. This leads to a picture that simply didn’t fit  - and it still doesn’t - standard immunological understanding. For Varela, unaware of the immense changes this demanded from immunology, ‘oral tolerance’ represented the natural insertion of the organism as a totality in its antigenic environment.

Francisco summarized and simplified his epistemological approach in a conversation with Donna Johnson, published in Co-evolution Quarterly (later The Whole Earth Review) in the Summer of 1976, entitled ‘Observing Natural Systems’. In that paper, he conveys the idea that the identity of systems - their wholeness (Varela’s main interest) - may be perceived when we take account of their organizational ‘closure’: (i.e., when we see that, as compound unities that are circularly or more complicatedly turned into themselves - Varela & Johnson, 1976). With these and other arguments, Francisco introduced me to the notion of networks.

Separately and coincidentally, Niels Jerne, a leading immunologist of the time, had recently published his theory explaining immunological activity as derived from immunological networks that are formed by anti-antibodies (Jerne, 1974a). Jerne’s initiative could have represented a major theoretical breakthrough. Francisco and I wrote to Jerne and produced a paper arguing that his (Jerne’s) paper, although truly significant, was incomplete because it lacked the notion of ‘closure’ (systemic organization), a notion which we felt was essential in the description of any system. Jerne praised our paper, and indeed he, himself had previously claimed that:  “…...we must now accept that the immune system is essentially "closed" or self-sufficient in this  respect” (in its recognitions and activations) (Jerne, 19974b). This statement appeared in Jerne’s internal report as Director of the Basel Institute for Immunology but, to my knowledge, was never published again. Actually, Jerne’s main paper lacks the idea of closure (Jerne, 1974a); he refers to a revolutionary new idea that would change immunology as a whole, but never describes this idea explicitly. It could not be the idea of anti-antibodies that built the immune network (anti-idiotypic antibodies), because these connections could not be all equal. I believe (as did Varela,) that this missing idea was actually the idea of “closure”, or, more simply, the idea of the wholeness of systems.

The paper that Francisco and I wrote together was called ‘Self and non-sense: an organism-centered approach to immunology’ (Vaz and Varela, 1978). It was rejected by the European Journal of Immunology as “too theoretical” (which, of course, it was), and we published it in Medical Hypotheses.

In addition to its network aspect, our paper was also devoted to ‘oral tolerance’, or the differential quality of immune responsiveness to previously ingested proteins. The definition of these phenomena in clearer terms turned out to be a lifelong objective in my own laboratory. It was to be abandoned by Varela in his future association with Coutinho (more on this in the following sections).

During our collaboration in Denver, Francisco visited Gregory Bateson in California. I was aware of Bateson’s importance in epistemological discussions, having recently read his ‘Steps to an Ecology of Mind’ (Bateson, 1972). On the other hand, although I was also aware of Humberto Maturana existence through Francisco’s bibliography, his importance was not emphasized by Francisco and I failed to realize Maturana’s participation in the joint construction of the notions of autopoiesis and closure.
In 1981, I returned to Brazil and Francisco went back to Chile. I was invited to a Congress of Genetics in Viña del Mar. I met Francisco in Santiago on which occasion he introduced me to Maturana. Already in our first conversations, I felt great sympathy for Maturana’s way of seeing.

In 1982, in Campinas SP, Brazil, I organized a Symposium for the Brazilian Society for the Advancement of Science (SBPC), on the biological nature of knowledge. I invited Varela, Maturana and the Portuguese immunologist Antonio Coutinho. The latter seemed to me to be one of the few immunologists who might be interested in the issues Varela and Maturana were raising. I also invited the Brazilian geneticist Oswaldo Frota-Pessoa.

The Symposium organizers lodged us in a nearby farm and we could get to know a little  of each other for a whole day before the symposium - of which, unfortunately, no records remain. On a personal level I would like to mention that Maturana told me then that he preferred to be invited separately from Varela, which reinforced my impression that there were major differences between the approaches adopted by the two of them. The Symposium was fascinating for all of us and, as it turned out, generated important collaborations.

Over the next few years Francisco moved from Chile to Paris while Coutinho moved from Sweden to Paris, and they could continue the conversations they had started in Campinas.  I myself spent about a year at Coutinho’s lab (1986-87). In addition, I also believe I was instrumental in inviting John Stewart, then a geneticist interested in theoretical biology, to Coutinho’s lab. I should perhaps note that Maturana has always remained in Santiago and has never been involved in immunology.

Self and non-sense revisited
Immunologists are mainly concerned with self/nonself discrimination. Our 1978 paper described the immune system as a closed network of interactions, such that whatever fell outside this domain, simply had no sense so far as the immune system was concerned, ‘outside’ was irrelevant. This denied the importance of self/nonself discrimination.  We also claimed that ‘oral tolerance’ resulted from the  assimilation of proteins encountered as food or as products of the gut flora into this network of interactions. Thus, in addition to the attempt to add the notion of organizational closure to Jerne’s (idiotypic) network (Jerne, 1974), we proposed that physiological contacts with potential antigens involved an assimilation into the immune network, rather than a rejection of these materials (Vaz and Varela, 1978). A similar perspective also adopted years later by Parnes, who proposed an ‘incorporation’ instead of an ‘interception’ of antigenic materials (Parnes, 2004). In our way of seeing things, these new materials are ‘incorporated’ into the ‘closed’ network of interactions with constitutes the immune system. Thus, our paper was a two-prong approach  to immunology, dealing with networks and also with ‘oral tolerance’ (Vaz and Varela, 1978).

In his subsequent association with immunologists, Varela ceased to stress the relevance of this assimilation of dietary proteins and, curiously enough, was able to maintain a close collaboration with Coutinho, in spite of Coutinho’s explicitly denial  of the concept of closure:

“ I did not agree (and I still do not agree today, despite many discussions with Nelson Vaz) that their (Vaz-Varela) central claim was right. I continue to think that a ‘decision-making behavior’ naturally emerges from the immune system’s development, structure and operation, allowing for the differential treatment of molecular shapes it identifies either as ‘self’ or ‘nonself.’ “ (Coutinho, 2003, p.17).

However, in our paper we explicitly claimed that:

“... the transformations of the cognitive domain of the immune network in an organism’s ontogeny are a combination of its recursivity (its closure) and the fact that it is exposed to random perturbations or fluctuations from the environment (its openness). In other words, it exhibits self-organization, the transformation of environmental noise into adaptive functional order, in a manner similar to many other biological systems such as cells, nervous systems, and animal populations.” (Vaz & Varela, 1978: p 33).

Coutinho confounded the idea of “closure” with solipsism and insisted to ‘put the network back into the body’ although Varela himself is careful in explaining that, although ‘closed’ in its organization, the system is ‘open’ for interactions (see Varela & Johnson, 1976; p 4). I can only ascribe the conciliation of these opposing views to Varela’s great personal talent in establishing associations with other scientists.

Varela and immune networks
The prolongued  association of Varela with frontier research in immunology in Coutinho’s laboratory brought forth truly systemic ideas to the idiotypic network  which were lacking in Jerne’s proposal almost two decades before (Jerne, 1974). Coutinho had been an important collaborator of Jerne at the Basel Institute and produced an impressive array of experimental evidence in favor of the network model both before, during and after the association with Varela. The 1980s coincided with a great deal of both experimental and theoretical interest as to immune networks, leading to the publication of about five thousand papers. This, however, had a negligible impact on  the main questions of immunology and the interest in networks gradually waned and disappeared from sight (Eichmann, 2008).

Varela and Coutinho claimed that this happened because network immunologists were addressing the wrong questions. Virtually all experiments with idiotypes and theoretical discussions of the network focused the regulation of clonal expansions by idiotypic interactions (i.e., the regulation of specific immune responses). However, a stimulus/response framework is not adequate for the description of networks. Systems (networks or compound entities) cannot be ‘stimulated’ nor can they be said to ‘respond’ to anything; this amounts to applying  mechanisms which belong to one theory onto another and this is the main reason why the idiotypic network theory failed to influence immunology significantly. A crucial aspect of this disparity is that specific immune responses (i.e., lymphocyte clonal expansions) may be studied in vitro, and can also be transposed (adoptively transferred) from one organism to another; whereas systemic observations have no such parallels, except, perhaps in computer simulations.

Varela, Coutinho and Stewart made a vigorous and persistent effort to show the supraclonal properties of the immune system that emerge from its network organization, such as natural tolerance and memory, both experimentally and in theory (Stewart, Varela & Coutinho, 1989). They performed landmark experiments on the dynamics of immune networks both in mice and humans, in healthy organisms and autoimmune diseases (Lundqvist et al, 1989; Varela et al, 1991).  Varela claimed, in a somewhat obscure vein, that the really important questions belong  to studies of ‘second generation immune networks’ (Varela and Coutinho, 1991). Varela’s mathematical inclination became a powerful formalizing tool of immune networks, as it had happened also in neurobiology. Mathematical problems, such as discussions of ‘shape space’ (Stewart & Varela, 1991), however, were and still are beyond the understanding of most immunologists and, therefore, had little consequence inside immunology (but see Carneiro & Stewart, 1994).

Although a defender of  ‘enaction’  (),Varela frequently used terms that are central to connectionism, such as the ‘emergence’ of new properties in wholes, terms that were used in a large variety of different fields, ranging from biology, to engineering, to statistics and physics and, most importantly, in cognitive sciences. He also frequently referred to the switch between ‘local’ and ‘global’ properties. He emphasized that:

“the passage from local rules to a new emergent property of the entire system, which cannot be reduced to the quality or performance of single components, is the very heart of network mechanisms. To miss such emergent, global properties (...) is to doom a network view to trivial information (Varela and Coutinho, 1991). 

Another term introduced by Varela was ‘metadynamics’ (Varela et al., 1988). The immune system has to cope not only with a high turnover rate of lymphocytes (in the mouse, up to 25% per day (Freitas, Rocha & Coutinho, 1986)), “but there is also a constant renewal of the very structure of the immune network via the recruitment of newly-formed lymphocytes into activity” (Varela and Coutinho, 1991).

The amount of information available on specific immune responses, accumulated since  the origins of immunology, is overwhelming and impossible to ignore. This is the standard way of studying immunology. In the early 1990s, Varela and Coutinho proposed a division of the immune system into two systems: a central immune system (CIS) corresponding to Jerne’s idiotypic network (i.e. to a systemic description); and a peripheral immune system (PIS) responsible for lymphocyte clonal expansions in specific immune responses, as traditionally studied in immunology - actually, a separation between ‘local’ and ‘global’ events. Perhaps this division was only made to call the attention of the immunological community to systemic aspects of immunological activity (i.e. to the CIS). Actually, there is only one immune system, but clearly there are two distinct ways of seeing and defining its activities.  But, as was generally the case in Varela’s approach to cognition, the human observer and its way of seeing remains occult. This is in sharp contrast with Maturana’s attitude, which always tries to make explicit the observer and his actions in human languaging (Maturana, 2002; Maturana & Poerksen, 2004).

Varela’s collaboration with Coutinho’s group lasted for ten years and resulted in twenty publications between 1986 and 1995. After that, Varela’s interest in immunology then gradually waned. There were several reasons: his work in neurobiology, which he had never left was boosted by new techniques of brain imaging; his health was beginning to fail; but primarily the particular outlook in immunology “brought us into what seemed to be a deadlock, a feeling also shared by John Stewart” (Coutinho, 2003).

If we take this deadlock as real, it is something shared by the whole field of immunology that has lingered for the last 25 years. I have recently quoted one chosen reference per year from Coutinho’s lab between 1980-1990 as examples of the massive amount of experimental evidence they produced, entirely incompatible with clonal selection concepts (Vaz, 2011). As examples of problems that only now are being seriously considered, but were already tackled by Varela, Coutinho and Stewart, we can mention: a) dynamics and fine structure of immune networks; b) maturational changes in immune networks; c) therapeutic effects of high-dose intravenous immunoglobulins (IVIg); d) inclusion of T lymphocytes in immune networks; d) pathogenesis by fragmentation of immune networks; etc.

Several years after Varela’s demise, Stewart and Coutinho published a new perspective on  the immune system based on what they consider to be the concept of autopoiesis (Stewart and Coutinho, 2004). I have recently insisted that, due to their familiarity with Varela’s (enactive) ideas  and their lack of contact with Maturana, these attempts are far from representing the main trust of Biology of Cognition and Language as proposed by Maturana (Maturana, 2002; Maturana & Poerksen, 2004).

Overall, Varela’s contribution is marked by his aim of defining the organization of an immune self as an identity for the immune system (Varela, 1979; Varela, 1991; Varela, 1995; Varela and Coutinho, 1991; Varela Thompson & Rosch, 1995).

Modern immunology
In spite of its enormous importance and technological sophistication, to call contempoorary Immunology ‘modern’ might be to stretch a point. Its main theory - Clonal Selection (Burnet, 1959) - has not changed its central tenets in half a century. In spite of the fact that it is still praised (Hodgkin, 2008), it is indeed surprising that it has not been supplanted by a new theory. Such a new theory will not emerge without incorporating a host of new knowledge : knowledge gained through genomics, molecular and developmental and evolutionary biology, but, mainly, from a radically new understanding of systems in general, and of biological systems in particular – a meaning quite different from the many meanings of the term systems biology (Kirschner, 2005).

Something analogous is the case in evolutionary biology, instanced for example in meetings discussing the general nature of the field, such as the “Altenberg-16” of 2008  (published as ‘The Extended Synthesis’ Pigliucci & Müller, 2010; see also Mazur, 2009; Fodor & Piatelli-Palmarini, 2010). Not all biologists agree that a reform in evolutionary theory is necessary and, similarly, most immunologists seem to be happy with Clonal Selection principles as the cornerstone of their theoretical needs. Thus, the situation faced by Varela in the 1980-90s still prevails basically unaltered.

The central problem in immunology, like those in most complex areas of endeavor is that systems (compound unities) cannot be controlled in a linear-causal manner, because by definition systems follow their own internal rules of operation; instructive interventions are impossible. This raises the critical question of how should we act in  fields and contexts that are intrinsically uncontrollable?  The immune system displays activities which are undoubtedly spontaneous; how can we understand such dynamics? Indeed, what are the novel insights that might arise for a new understanding of its complexity?

It is, therefore, truly surpring to realize that challenging problems contemporary immunologists are presently facing were already tackled by Coutinho, Varela and Stewart in the 1980-90s. This anticipation was a result of the fruitful association between Coutinho immuno-competence  and Varela’s formalizing abilities and outlook in cognitive sciences. Also, the collaboration of Stewart cannot be minimized, especially in the painstaking construction of computer simulations of immunological activity (Stewart & Varela, 1989; 1990; Varela, Coutinho & Stewart, 1991; 1992; Detours et al., 1994; Calenbuhr et al.,1995).

Differently from Varela and Coutinho’s, our own laboratory persisted investigating ‘oral tolerance’ and, eventually, demonstrated that it is not, after all, an inhibition of specific immune responsiveness. No form of tolerance is absolute and ‘partially tolerant’ animals  are still able to form specific antibodies to the ‘tolerated’ antigen; and when the ingested (‘tolerizing’) dose of antigen is small, this formation can be quite high. However, in animals in which the exposure to the antigen was initiated by a mucosal route,  the responsiveness is not  progressive ( i.e. it cannot simply be boosted by further exposure to the antigen with or without adjuvants). Therefore, ‘oral tolerance’ is actually a robust stabilization of levels of specific responsiveness to previously ingested materials  (Verdolin et al., 2001). This is an important change in perspective because the same thing happens with  the responsiveness to body components in ‘natural tolerance’. The issue is not whether the organism may or may not form auto-reactive lymphocytes and antibodies; these elements are irrevocably present in healthy organisms. The issue is that ‘autoimmune’ activities are stabilized at low levels and are never progressive under normal conditions (Pordeus et al., 2009). Thus, the study of ‘oral tolerance”’, as well as the study of ‘closure’, lead to systemic aspects of immunological activity.

The insertion of the immune system into the organism (its embodiment) is essential to our understanding, in that it is organisms that are the actual entities that effectively do things; it is as a result of all its components collaborating (interacting) that leads to the self-maintenance and activities of the organism (i.e. its living and cognitive activities). Although usually seen as performing ‘defensive’ actions, the development and operation of immune systems may rather be seen as a part of the construction of the vertebrate organism. In a wider picture, there is a reciprocity  between the organism’s structure and its actions. New structures give rise to the possibility of new actions and these new actions in turn may lead to the transgenerational conservation of new structures. Indeed it is possible to say that a better understanding of the nature of immunological activity will spontaneously follow from its insertion within the organism as a whole.

Immunologists seem unable to abandon the stimulus-sponse/regulation framework to which they have remained committed since the very beginning of the field of immunology. As an important component of the experimental findings and theoretical proposals  arising at Coutinhos’s laboratory in the decade 1986-1996, Varela’s contribution in designing a systemic view of immunological activity was groundbreaking, unprecedented and invaluable. Unfortunately, it has fallen back into the conceptual blindspot of traditional immunology which, because of the same kind of blindness, has rejected Jerne’s network theory (Jerne, 1974). Jerne’s idiotypic network theory was  the only significant move toward a systemic description of immunological activity, and Coutinho and collaborators provided abundant experimental support of its tenants. The difficulty here, however, is not scientific, but rather conceptual; it will not be solved by more experiments but rather by an extended discussions of the issues at stake.

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