2. The Foundationsof the Disciplinary Matrix
2. The foundations of the disciplinary matrix
In the garden of Eden, Adam saw
the animals before he named them;
in the traditional school system,
children name the animals before
seeing them.
— Alfred North Whitehead
2.1. Introduction1
The present chapter aims at the characterisation of our current knowledge and perception
of the immune system, and substantiates the idea that this endeavour can be guided by a
consideration of the historical development of discipline. Inspired by evolutionary
biology, this idea is essentially grounded on other epistemological principles. Any
attempt to understand scientific knowledge is inevitably an (auto)reflexive exercise — the
object at stake is our own immunological knowledge, not the natural immune system.
The main difficulty inherent in this exercise is the maintenance of an appropriate degree of
objectivity: the tendency is to remain closed in our own scientific terms of reference. A
historical retrospective, being intuitively akin to a view from the outside, can potentially
overcome this difficulty.
The next two introductory subsections are methodological, and present both the
conceptual and the empirical tools guiding the historical retrospective presented later. The
affiliation to the ideas of Thomas Kuhn (1970, 1990) is acknowledged from the outset;
they constitute one of the most enlightening and comprehensive insights into the
development of science as a social dynamic process. As this chapter tries to illustrate, this
view can successfully guide the interpretation of progress in Immunology.
1 Part of the content of this chapter has been published in: J. Carneiro (1996). The Burnetian
revolution and the foundations of the disciplinary matrix. Revista da Sociedade Portuguesa de
Immunologia. 2 , 15.
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2. The foundations of the disciplinary matrix
2.1.1. Conceptual Elements for a Kuhnian History of Science.
Kuhn holds that the research in mature sciences is structured by what he called (Kuhn,
1990) the essential tension between tradition and innovation. Thus, progress in physics
or chemistry alternated between periods of cumulative development and episodes of non
cumulative revolutions in which the perception and conception of nature was profoundly
changed. This conception of scientific development involves a coherent set of
interconnected elements that Kuhn developed and supported with several examples in the
essay "The structure of scientific revolutions" (Kuhn, 1970). These elements —
understood as conceptual boxes in which we will try to fit the history of Immunology —
are just outlined here.
Let us start by the notion of ordinary science, that refers to the research grounded
on one or several established examples from the past scientific work — laws, theories,
applications, or experimental techniques. It is the commitment to these examples —
exemplars 2 — that ensures the peculiarity and coherence of a scientific community.
Fig.2 .1- Any trained immunologist will
instantaneously recognise the image on the
left as a thymus. The switch from an
immediate perception of a 2D dot-plot to an
immediate perception of a lymphoid organ,
was carried out during the training period as a
student. Together with this expertise, the
student immunologist acquires the implicit
conviction that a lymphoid organ can be
appropriately described by the relative
distribution of surface markers in its
suspension of cells.
2 In first edition of "The Structure of the Scientific Revolutions", Kuhn used the term paradigm.
However, this term was rather ambiguous in that essay. In a more recent elaboration (Kuhn, 1990), he
coined several terms like exemplar and disciplinary matrix to avoid some of those original ambiguities.
The later terminology has been adopted here.
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2. The foundations of the disciplinary matrix
Exemplars provide the community with otherwise inexistent common rules, and
determine the focus and scope of its research activity (see an illustration in fig.2.1).
Ordinary research is an exhaustive elaboration, consolidation and enlargement of its
exemplars, involving three major categories of problems: the determination of the
significant facts, the agreement of facts and theory, and the reformulation of theory. The
solution for these problems is anticipated under the light of the exemplars, but requires
the resolution of all sorts of experimental, conceptual, or mathematical puzzles.
According to Kuhn, the challenge of solving these puzzles is the major motivation for
individual scientists, and the fascinating aspect of ordinary science; the ability to come up
with a solution according to the common canons (consistent with the exemplars ) is what
determines the recognition of the individual by the community. A good example of these
puzzles in Immunology was the molecular basis for the generation of antibody diversity,
which was raised upon the elaboration of clonal selection theory. Referred to in
contemporary literature by the emblematic abbreviation of GOD (for generator of
diversity), the solution of this puzzle granted Tonegawa the Nobel prize in 1984.
But ordinary research is just one complementary aspect of scientific development;
the other is revolutionary or extraordinary research associated with scientific discoveries
and the emergence of new theories. Scientific discoveries happen when non predicted
phenomena become the object of scientists attention; they are the demonstration that
nature does not behave as expected. The assimilation of these anomalous facts, which are
inconceivable in the previous theoretical or practical planes, entails a rearrangement of
both intellectual and technical equipment; a rearrangement that is crucial for scientific
progress. Classical examples of such innovative discoveries are the ones of oxygen, of
electric current, X rays, or the electron. The discovery of idiotypy by Oudin is frequently
referred as an example such discoveries in Immunology (Brussard, 1979).
Theoretical revolutions are structurally similar to the discovery and assimilation
of an anomaly, but have a wider scope; they require the awareness, most frequently by a
small fraction of the community, that a traditional set of exemplars is no longer useful,
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2. The foundations of the disciplinary matrix
i.e. that ordinary science is no longer able to consistently generate and solve its puzzles.
During revolutionary episodes, the set of exemplars shared by the community changes
progressively, as scientists commit to the revolutionary exemplars. Under the light of the
new exemplars, old problems are re-stated or become irrelevant (discarded as non-
scientific), while new problems are generated. A typical case of theoretical revolution —
the advent of Burnet's clonal selection — will be discussed in some detail later.
In an attempt to understand these scientific revolutions, Kuhn argued that the
commitment to new exemplars is analogous to a gestalt switch — the perception of
nature is completely changed. The acquisition of traditional exemplars by student
scientists is associated with an assimilation of the corresponding perception of nature —
for example, the gestalt switch from the perception of "a graphic" to that of "a thymus"
illustrated in fig.2.1. It follows that competing schools — those committed to different
sets of exemplars — have incommensurable ways of conceiving ordinary science: they
differ intrinsically in their perception of observations and experimental results, they are
concerned with only partially overlapping sets of problems, and very frequently the usage
of common words hides incompatible terminologies. Because of this
incommensurability, the ordinary way of solving problems and testing hypothesis by
congruence with nature — the logic of ordinary science founded on exemplars — is no
longer operational. Scientists from competing schools typically try to destroy each others
arguments, using the internal logic inherent to their own exemplars, and giving rise to
long debates in the literature which are nothing than interminable misunderstandings.
Neither of the parties is able to accept or take for granted all the assumptions that the other
needs to validate its perspective, and therefore they can never fully understand each other.
Silverstein (1989) has discussed a classical case of intensive debate between
incommensurable parties in Immunology: the Bordet-Ehrlich dispute on significance of
the sensibilatrice-ambozeptor found in serum normal individuals. Another more recent
example, is the long lasting dispute on the mechanisms of B lymphocyte activation
between the schools of Möller ('the one signal only model') and Cohn ('the two signal
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2. The foundations of the disciplinary matrix
model'), whose research strategies are sharply opposed as pointed out by Sinclair
(1992).
Falling outside the realm of objective scientific logic, the commitment to one or
another set of concurrent exemplars calls into action alternative subjective and social
values. The gradual commitment of a scientific community to new exemplars and their
ultimate dominance is best understood at the social level. The success of "founding"
exemplars will be determined by the persuasive capacity of its early adherents, and the
renewal of the community. Kuhn (1990) coined the term disciplinary matrix to refer to
that assembly of factors, explicit or implicit, that determine the coherence of a scientific
community and the commitment of its members to a coherent set of exemplars.
Heretofore, the term paradigm refers to intersubjective metaphysical or theoretical
principles that are characteristic of a disciplinary matrix.
Closing a circle we are now prepared to restate "the affiliation to the ideas of Kuhn" (in
the introduction to this chapter) as "the commitment to the Kuhnian exemplar of the
history of science".
2.1.2. Empirical Elements for a Structured History of Immunology.
Some previous historical studies on Immunology helped in the acquisition of a very first
picture of the development of the discipline. The excellent essays by Silverstein (1989)
and Moulin (1991) deserve special mention. With this first picture in mind and guided by
the conceptual framework of Kuhn, we plunged into past literature in Immunology.
In order to identify the exemplars — established experimental or theoretical
works — guiding research in immunology, a typical review of literature was performed,
following citations from present into the past. Revolutionary periods correspond to
discontinuities in this citation tree. Literature around those episodes was then the object of
more exhaustive study under several headings: (i) a survey of contemporary articles and
reviews, paying special attention to argumentation — experimental evidence, theoretical
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2. The foundations of the disciplinary matrix
elaboration, and a priori reasoning — and judgements of value used in inter-school
discussions, as well as the evocation of exemplars from other disciplines; (ii) the names
of new journals or the headings of reviews; (iii) the timing and appearance of new text
books; etc. All these strategies allowed a characterisation of the changes in the sets of
problems and puzzles, as well as the identification of the subjective values involved in
the exemplar-paradigm switch.
For example, in order to understand the gradual commitment of the scientific
community to the "Clonal Selection Theory", the Annual Reviews of Medicine, Annual
Reviews of Microbiology, or Annual Reviews of Biochemistry were followed
systematically in the period ranging between 1930-1960. The most persuasive arguments
used by the early defenders — Burnet, Jerne, Medawar and colleagues, Talmage, and
Lederberg — are identified, by definition, as those that caught the attention of the
reviewers of the field. The metaphors and thought experiments of the authors — for
example the dictionary metaphor used by Burnet in his Nobel prize lecture — are
additional source of information about the values involved in the commitment to the new
exemplars.
2.2. A Preview of History of Immunology.
The Basic Structure
The foundation of Immunology as a scientific discipline is commonly attributed to
Pasteur, who seeded the field with the basic postulate that immunity is a defensive
reaction against pathogenic invasions. This postulate — a particular facet of his germ
theory of putrefaction that resulted in successful immunisation protocols — pervades
immunological thinking ever since. The nineteenth century, following Pasteur, was
essentially characterised by an initial descriptive phase in which multiple immunological
phenomena were identified. Metchnikoff described phagocytosis and cellular aspects of
immunity. Behring and Kitasato discovered the existence of antibodies. At the turn of the
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2. The foundations of the disciplinary matrix
century, Ehrlich became a major figure through the development of an entire theory of
humoral immunity that had a decisive influence for the faith of the discipline.
The first half of the twentieth century was characterised by approaches based on
physical chemistry. Research was essentially concerned with the descriptive analysis of
biochemical compounds intervening in acquired immunity and allergy, and the
characterisation of their reactions. The most popular names were chemists like Arrhenius
(Nobel Laureate in Chemistry, 1903), Heidelberger, Svedeberg (Nobel Laureate, 1926),
Haurowitz, Tisselius (Nobel Laureate in Chemistry, 1948), Pauling (Nobel Laureate in
Chemistry, 1954), or physicians like Landsteiner (Nobel Laureate, 1930) whose work
was nevertheless based on chemical approaches. As discussed later (section 2.3),
immunological thinking reflected the perception that the body of an animal, and
subsequently antibody producing cells, were chemical reactors , where the introduction
of an antigen reagent promoted a reaction that had antibody as product. This disciplinary
matrix is referred to here as Immunochemistry of Acquired Immunity.
Since the fifties the discipline has been overwhelmingly dominated by approaches
based on molecular and cellular biology. Research is typically focused on the analysis of
genes, mechanisms of gene expression, molecular structures, cell signals, and cell
differentiation pathways. All the immunological phenomenology is subordinated and
reduced to these observables. Consecrate figures, without being exhaustive, are Burnet
(Nobel Laureate, 1960), Medawar (Nobel Laureate, 1960), Jerne (Nobel Laureate,
1984), Edelman (Nobel Laureate, 1972), Mitchison, Nossal, Tonegawa (Nobel Laureate,
1986), Cohn, Zinkernagel (Nobel Laureate, 1996), etc. Immunological thinking reflects a
very particular perception of reality: molecules are typically treated as if they would carry
information, they are signals that cells process in order to chose alternative programs of
differentiation which are stored in their genome; immunising antigen is the main signal
processed by lymphocytes which are able to make molecular "self nonself
discrimination". Immunopathologies arise from altered genetic programs, altered signal
transduction, or are caused by antigens. This disciplinary matrix is traditionally referred
to as Immunobiology by opposition to Immunochemistry. However, since alternative
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2. The foundations of the disciplinary matrix
"Immunobiologies" exist that are focused on other levels of biological organisation, the
term is equivocal. Therefore, this disciplinary matrix, that has Burnet's Clonal Selection
Theory by main exemplar, is called here Burnetism.
Since the seventies, several research programs are built on exemplars that imply a
break with Burnetism. Not fully coherent with each other, these programs share many
common aspects. They are motivated by the conviction that Burnetism has accumulated
too many anomalies and is no longer able to solve its problems, and that progress in
Immunology requires a major theoretical development that copes with the progress in
other fields of Biology. They are concerned with the immune system qua system. Self-
organisation, internal structure, emergent behaviour, and ontogenesis are the main issues
of research and discussion. The antigen has lost the key status of the cause of all immune
phenomena; physiology and pathology are perceived as internal dynamic states of the
immune system. The nervous system and ecosystems are used in heuristic analogies, and
theoretical discussion is strongly marked by cognitive sciences. The main figures are
Jerne, Vaz, Coutinho, Kearney, Urbain, Avrameas, Cohen. Outsiders from related fields
of Biology associate to this projects, notably Varela.
The structure and scope of these three ways of doing ordinary science and the
corresponding perceptions of reality are discussed in the following sections. The switch
from Immunochemistry to Burnetism — a true scientific revolution that pervaded the
entire community — was paid special attention.
2.3. Immunochemistry of Acquired Immunity
Immunochemistry literature was essentially analytical and devoid of any attempts to draw
synthetic pictures. Both text books and review articles went through exhaustive lists of
reports on the physical chemical properties of antigens, toxins, haptens, or antibodies.
The present retrospective required criteria for the selection of a few issues, that impinge,
in one way or another, in the transition from the Immunochemist to the Burnetist
disciplinary matrix. The text is closely guided by the writings of the immunochemist
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2. The foundations of the disciplinary matrix
"guardians of the temple" , and is therefore representative of the immunological thinking
and construction of scientific objects in those periods. Fig.2.2 presents a chronology of
the main exemplars in Immunochemistry.
Landsteiner (1912)Immunogenic Azotioproteins
Haurowitz (1967)Could Spring Harbor Simposium on Antibodies
1920
1930
1940
1950
1910
1960
Ehrlich (1900)Side chain theory of antibody formation
Pauling (1940)Template theory
Breinl & Haurowitz (1930)Template theory
Burnet & Fenner (1949) Felton(1949)Immunological Paralysis
Chase(1946)Antigen induced desensitisation
Mudd (1932)Templatetheory
Svedeberg (1939)Sedimentation coeficients andMW of Antibodies
Tiselius & Kabat (1939)Antibodies and globulins
Behring & Kitasato(1890)Serologic reaction
Medawar (1946)Acquired immunity to homograft
Heidelberger 19??)Quantitative studies onprecipitin reaction
A Chronology for the Immunochemistry of Acquired Immunity
Fig.2 .2- A chronology of the main exemplars in the disciplinary matrix of the Immunochemistry
of antibody formation.
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2. The foundations of the disciplinary matrix
2.3.1. The Physical-Chemical Nature of Antibodies
Antibodies were originally characterised by their appearance in the serum of animals after
immunisation and detection by serologic reactions (Behring & Kitasato, 1890). The
immediate concern of the community was the chemical analysis of the seric compounds
carrying antibody functions.
The very first achievements were the establishment that serologic reactions were
specific for the eliciting antigen. In this stage, the work of Landsteiner in the twenties
was most relevant, and his strategy of probing antibody specificity against chemically
modified proteins became one of the main exemplars of Immunochemistry (Heidelberger,
1932; Haurowitz, 1953; Bibel, 1988). Additional characterisation of antibodies was
performed by their functional susceptibility to hydrolytic reactions, enzymatic activity,
heat lability, etc.; treatments that were correlated with candidate biochemical
compositions. Precipitin and flocculation reactions were the object of quantitative studies
with special attention being paid to basic principles of physical chemistry —
stoichiometry, applicability of mass action laws, effects of insolubilisation, etc. The
works, consecrate in the thirties, were those of Arrhenius (1907), Heidelberger &
Kendall (refs. in (Heidelberger, 1932; Heidelberger, 1938)), and Marrack (1934).
The invention of ultracentrifugation (Svedberg, 1939) and electrophoresis
(Tiselius & Kabat, 1939) represented a major break through in the purification of
antibodies, that would remain otherwise based on fractional precipitation recipes. Serum
fractions, with clear sedimentation or migration coefficients, could be subjected to finer
biochemical analysis and antibody functional assays. Hence, Svedeberg's group
established the sedimentation coefficients of antibodies, and reported the first estimations
of their molecular weight. Tiselius & Kabat (1939) separated electrophoretically the
antibodies from other compounds reporting that they migrated between the β- and γ-
globulin fractions, or in the later fraction.
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2. The foundations of the disciplinary matrix
Overall, by the late thirties, compelling evidence had accumulated for the protein
nature of antibodies, and refractory claims on "protein free fractions" were regarded
with suspicion, recalling that the assays for detecting antibody function were much more
sensitive that those for detection of proteins (Heidelberger, 1938; Bordet, 1939). The
main concern shifted progressively from the nature of antibody to its origin and
formation, that was still terra incognita.
2.3.2. The chemistry of antibody formation.
Antibody as modified serum globulin.
In the very first volume of the Annual Reviews in Biochemistry from 1932,
Heidelberger stated that "most workers in this field [Immunochemistry] now hold the
view that antibodies are modified serum globulins". It might be useful, to trace further
back the origins of this view, that pervaded the literature until late fifties.
The first widely accepted theory for antibody formation had been Ehrlich's side
chain theory (Ehrlich, 1900), that held that antibodies were preformed nutrient receptors
in the cell surface that would be secreted into the blood by "over compensation" of their
consumption by specific reaction with antigen. Ehrlich's theory was discredited by
Landsteiner's demonstration of the antigenicity of diverse modified proteins, since it had
become "difficult to assume that the animal body should have preformed receptors for all
these artefacts of the chemical laboratory" (Haurowitz, 1950). A new view prevailed,
that subordinated the specificity and diversity of antibodies to the eliciting antigen. Thus,
antigen itself was the cause of the specificity antibody molecule. Essentially two
concurrent hypothesis existed to explain this specific modification. The first, proposed by
Buchner (ref. in Heidelberger (1938)), held that antigen itself or antigen products would
incorporate the antibody. Evidence — the comparative analysis of antigen and antibody
compositions, and the disproportion of antibodies elicited by antigen — was in the
majority against this hypothesis (Heidelberger, 1938; Bordet, 1939). The theory that
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2. The foundations of the disciplinary matrix
finally gained the consensus of the immunochemists was the "more reasonable" proposal
by Breinl & Haurowitz (1930) and later by Mudd (1932), that held that:
The synthesis of normal globulins may occur in such a way that the spatial
configuration of the cellular protoplasm impresses upon the globulin the
spatial3, chemical, and species-specific properties characteristic for the
animal in question. Penetration of injected antigen or its partial
degradation products to the sites of synthesis could disturb the spatial
relations which normally exist and distort them. This distortion might
reasonably occur in a manner characteristic of the foreign material, so that
any new globulin synthesised in this distorted manner would bear a certain
spatial relation to the antigen. Hence if the new globulin molecules would
again encounter the antigen in the circulation, or in vitro, interaction might
be possible.
—Heidelberger (1938)
Note that, although this template theory had no direct experimental support, at the
time it provided a reasonable mechanism for antibody formation, it accounted for the
existence of normal circulating globulins and its physico-chemical similarity with
antibody, and postulated that the specificity in the reaction with antigens was due to a
precise re-ordering or re-arrangement of the aminoacid residues that rendered the two
molecules complementary. The elucidation of the obscure aspects of the theory
represented all sorts of seductive Kuhnian puzzles — in both theoretical and
experimental grounds — that the community of immunochemists would try to solve in
the following years.
The most popular, and for a long time regarded as the most sound refinement of
the template theory, was due to Pauling (1940). Based on his authoritative knowledge on
bonding and molecular structure — Pauling introduced quantum mechanics into
chemistry and later discovered the alpha helix structure of proteins — he proposed a
mechanism of antibody formation (fig.2.3) that as he emphasised could account for a
variety of empirical observations such as "the heterogeneity of immune sera", "the
3 In this and in the following quotations, the original emphasis by the authors is indicated by non
italic characters, while our emphasis is indicated by underlined characters.
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2. The foundations of the disciplinary matrix
bivalence of antibodies and multivalency of antigens", "the antibody-antigen molecular
ratio in precipitates", and "antigenic power". In Pauling's theory there was no particular
reference to cells.
Fig.2 .3- "Antibodies differ from normal serum globulin only in the way in which the
two end parts of the globulin polypeptide chain are coiled, these parts, as a result of their
amino-acid composition and order, having accessible a very great many configurations with
nearly the same stability; under the influence of the antigen molecule they assume
configurations complementary to surface regions of the antigen." — The figure and
the legend are from Pauling (1940) .
Concerning the connection of theory and experimental observations the
polypeptide chains and the conformational adaptation of antibodies and normal serum
globulins were under the spot light. The aminoacid composition of antibody and normal
globulin was identical, and they were serologically indistinguishable (Raffel, 1954).
Although sequencing of an entire antibody molecule was not feasible, the report by Porter
(1950) on the sequence identity of segments of both normal globulins and antibody, was
in perfect agreement with the expectation that they were the same polypeptide chain
(Haurowitz & Crampton, 1950). Attempts were made to mimic in vitro the formation of
antibody under antigen template, by denaturing and renaturing globulins or antibodies in
the presence of antigens. The results were suggestive but not conclusive. Typically, an
antibody would lose reactivity to eliciting antigen and acquire reactivity to other antigens,
but without specificity.
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2. The foundations of the disciplinary matrix
The long persistence of immunity became a major line of research. Hence, the
first report on the half-life of antibody molecules in the serum by Schoenheimer et al.
(1942), who estimated its value as 2 weeks, required a continuous supply of fresh
antibodies. According to the consensus template theories, long lasting immunity was
interpreted by the persistence of antigen molecules in antibody-producing cells. The
hypothesis was exhaustively investigated using labelled or coloured antigens —
polysaccharide antigens were shown to persist for long periods (Heidelberger et al.,
1950), while protein antigens were more rapidly eliminated — the results remaining
controversial and puzzling (Haurowitz, 1953).
From this controversy emerged an alternative conception of antibody production,
that started to shift the focus of research from molecules to cells: antigenic stimulus
would lead to a permanent change in globulin-producing cells (Dixon et al., 1952;
Haurowitz, 1953; Raffel, 1956). The "adaptive enzyme system" of Burnet & Fenner
(1949), that we will discuss in some detail later, was included in this general class of
theories by the literature of that time (Haurowitz, 1953). These hypothesis were
investigated, namely by transfer of antibody producing tissues from immunised to
unmanipulated animals, but again, no definitive conclusion could be drawn (Haurowitz,
1953). The most consistent finding was that the second animal would only produce
antibodies if the eliciting antigen was a live microorganism, that could very well be
transferred with the tissues.
2.3.3. Immunology as Immunochemistry
The immunochemist conceptions on the nature and the formation of antibodies, that were
briefly overviewed, were not only the interpretation for acquired immunity, but
influenced the understanding of all other immunologic phenomena, and therefore the
focus of research. The scope and significance of this reductionist subordination of
immunology to chemistry, is illustrated here by the immunochemical account of
biological issues like the role of cells in acquired immunity, immunopathology,
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2. The foundations of the disciplinary matrix
immunologic paralysis, and the transplantation problem. These issues emerged in the
literature during the late stages of the immunochemistry period, and some contributed to a
switch in the disciplinary matrix, and the advent of what is referred to here as Burnetism.
CELLULAR ASPECTS OF IMMUNITY
Around 1950, the significance of cells was restricted their active role in local
inflammation, namely by extracellular and intracellular degradation of microbial
pathogens and immunising material, and to their passive role as a reactor for globulin-
antibody synthesis4.
The early notion, due to Ehrlich's side chain theory, that antibody formation
occurred in any cell in the body had been essentially abandoned, and antibody synthesis
was believed to be restricted to "reticular tissues" (Taliaferro, 1949) . The importance of
the spleen was demonstrated already around 1930, by the impact of splenectomy on
acquired immunity (refs. in Taliaferro (1949)). In the fourties, Ehrich & Harris (refs in
(Taliaferro, 1949; Raffel, 1954) established that antibodies were also produced locally in
the lymph nodes.
The finer analysis of the cell type producing antibody gave rise to several non
mutually exclusive hypotheses, implicating phagocytes (based on the "reasonable"
assumption that the same cell that degraded particulate antigen should produce
antibodies), lymphocytes (Raffel, 1954), plasma cells (Fagraeus, 1948), and appropriate
combinations (Taliaferro, 1949; Raffel, 1954). The issue, however, could not be clarified
by the available technology — histology based on cell morphology; transfers of cells and
assays for hypersensitivity or acquired immunity; correlation between histology and
serum antibodies; etc.— and the multicellular hypothesis remained quite popular (Raffel,
1954).
4 Note that globulin- antibody producing cells were conceived as a chemical reactor that produced
normal globulins in the absence of antigen, and specific antibody in the presence of antigen or upon an
antigenic inprint.
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2. The foundations of the disciplinary matrix
IMMUNOPATHOLOGY
One of the unique characteristics of the immunochemistry period was the
conviction that antibodies specific for body constituent molecules (autoantibodies) could
not exist. The dogma was known as Ehrlich's "horror autotoxicus", although, as pointed
out by Silverstein (1989), the original formulation by Ehrlich was not synonymous of an
absolute inability to produce autoantibodies, but expressed the notion that they were
somehow prevented from reacting with autologous antigens. The truth of the matter is
that autoantibodies were not easily conceivable under "template theories". At the time, it
was believed that in the absence of immunisation, antibody-globulin polipeptide chain
would fold into species-specific normal globulin, not into antibody. The molecular
composition of the body was what "catalised" the folding of the polipeptide chain into
normal globulins; the immunisation required that some other molecules would be
brought into the body or the cell in order to "catalyse" the folding of the polipetide chain
into a different product: the antibody molecule.
A growing interest of the community for pathologies involving antibodies —
allergic hypersensitivity and anaphylaxis — would lead to a pragmatic reconsideration of
the horror autotoxicus dogma. The 1950 review by Grabar (1950) was particularly
significant in this context:
It seems that sufficient indications exist to warrant further investigations into
the possibility of the existence of auto-antibody. It deserves much more
attention, as it would explain numerous pathological states.
—Grabar (1950)
In the fifties, the possible involvement of autoantibody and autoimmunisation was
investigated in many diseases, such as disseminated lupus, rheumatoid arthritis,
thrombopenic purpura, with unknown ethiology but displaying "immunologic aspects"
(Cooke et al., 1955). Animal models of autoimmunisation were also generated, following
the discovery of adjuvants by Freund and colleagues (reviewed in Freund (1947)), that
were used to elicit autoantibodies by injection of autologous, homologous or
heterologous tissue homogenates, extracts, or proteins. The final result of these research
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2. The foundations of the disciplinary matrix
programs is rather well known: in a 1958 review on "Autoimmunity in disease" (!),
Dixon (1958) concluded that horror autotoxicus was definitively "buried" .
The speculative accounts for the pathogenesis of autoimmunity in the literature of
that time are worth closer examination since they reveal the deep influence of
immunochemistry exemplars. Indeed, in a clear analogy with Landsteiner's chemically
modified proteins, autoantibodies were believed to be elicited by some modification of
body proteins into new "foreign" proteins (Grabar, 1950). The main examples under
discussion were therefore drug induced "autoimmunologic disorders", as can be
illustrated by the following account for the pathogenesis of thrombopenic purpura:
Ackroyd (...) subjected a patient with thrombopenic purpura attributable to
Sedormid (...) to exhaustive and critical analysis. (...) From these findings
the author surmises that Sedormid-platelet combination acts as antigen to
produce anti-platelet auto-antibody.
—Cooke et al. (1955)
Some authors, however, were aware that immunochemistry exemplars were failing to
account for autoimmune pathologies. For example, the hypothesis that lupus lesions were
due to allergic sensitisation was regarded by Klemperer et al. (cited in Cooke et
al.(1955)) with scepticism, arguing that it meant "only to explain an obscure structural
alteration by an equally obscure pathogenic mechanism".
IMMUNOLOGIC PARALYSIS
Some instances of induced immunologic unresponsiveness were known from the
beginning of the century (refs. in Chase (1959)), but they were never given special
attention. In the fourties, the issue regained interest following several reports on
unexpected decreases of immunologic response. Chase (1946) reported the inhibition of
experimental drug allergy and anaphylaxis by prior feeding with the sensitising agent.
Felton (Felton & Ottinger, 1942; Felton, 1949) reported on the phenomena of
"immunologic paralysis": mice injected with excessive amounts of pneumococcal
polysaccharide remained specifically unresponsive to immunising doses of this antigen.
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2. The foundations of the disciplinary matrix
Felton's work became one of the main immunochemical exemplars in the fifties (Raffel,
1956; Chase, 1959).
The candidate explanations for "immunologic paralysis" were that excessive
amounts of antigen persisting in the antibody-producing cell inhibited the reaction of
antibody synthesis, or neutralised all the antibody being synthesised (Raffel, 1954).
These hypotheses were founded and consistent with the demonstration by Felton that
polysaccharide remained in cells for long periods. They were, nevertheless,
controversial since, as already mentioned, the persistence of the antigen was evoked by
Heidelberger to explain the long persistence of polysaccharide specific antibodies in the
serum.
THE HOMOTRANSPLANTATION PROBLEM
The emergence of the transplantation problem in the post-war period was more
the consequence of contemporary social context, rather than the result of an elaboration of
immunochemistry exemplars. Medawar, who contributed notably to the field, was
personally motivated by his frustrating attempts to treat patients with extensive burns
during the war (Bibel, 1988). Under the cold-war environment, the medical
consequences of exposure to radiation were being investigated (Byars & Randall, 1953).
Extensive skin lesions and destruction of hematopoietic tissues were anticipated problems
that could potentially be successfully overcome by transplantation (Byars & Randall,
1953). The progress of plastic surgery was such that tissue autografting no longer
represented a problem; the transplantation of skin from the same species — then called
homotransplantation — remained, however, "completely unsatisfactory" (Cooke et al.,
1955).
The reappraisal of homotransplantation as an immunological problem is mainly
due to the work of Medawar, notably upon the demonstration that skin graft survival time
was inversely proportional to the quantity of tissue, and that secondary grafts were
rejected faster than primary grafts, that suggested a phenomena of acquired immunity
(Medawar, 1946a; Medawar, 1946b; and refs. therein).
– 29 –
2. The foundations of the disciplinary matrix
Although Little and his successors Snell and Görer (reviewed by Medawar
(1958)) had already established the genetic basis for the transplantation of tumours, the
solution envisaged for the transplantation problem was oriented to the possibility of
inducing immunologic paralysis. Hence, the issues of transplantation tolerance induction
and immunologic paralysis were always associated and discussed as similar phenomena
in the reviews of the field (Raffel, 1956; Chase, 1959).
2.4. Burnetism
The emergence of Burnetism, between 1949 and 1967, was a critical period in the
history of Immunology, and is the root of its currently dominant disciplinary matrix. As
in other fields of Biology, the focus of attention switched from the chemistry of
molecules to the genetics and molecular biology of cells. A chronology of the main
exemplars of Burnetism and some events directly or indirectly involved in its
consecration are presented in fig. 2.4.
2.4.1. A Change in Immunological Concerns.
The Transplantation Tolerance Trojan Horse
Burnet was a true biologist who felt that the preponderance of immunochemistry and its
enlargement to all questions of biology was illegitimately leading to a "pseudo-
knowledge" (Burnet, 1969; Bibel, 1988; Moulin, 1991). He asserted these positions in
both the 1941 and 1949 versions of "The production of antibodies", where he restated the
problem of antibody production in a "general biological background" (Burnet, 1941;
Burnet & Fenner, 1949).
In 1941 Burnet had been unable to immunise chicken embryos against influenza
virus, and related this finding to the classical epidemiological observations of high
infantile mortality by infectious disease and with the observation that infants after
exposure to tuberculosis or vaccination remain negative for the tuberculin reaction.
– 30 –
2. The foundations of the disciplinary matrix
Burnet & Fenner (1949)Production of antibodies
Jerne (1955) The natural selection theory of antibody formation
Talmage (1957) Allergy and Immunology
Burnet (1957)
A modification of Jerne's theory ... clonal selection.
Billingham, Briant, & Medawar (1953) 'Actively acquired tolerance' to foreign cells
Burnet (1958)The clonal selection theory of acquired Immunity
The Nobel Prize, 1960 , awarded to Burnet and Medawar
1950
1955
1960
1965
Watson & Crick (1953)Genetical implications of the structure of DNA
Could Spring Harbor Simposium on Antibodies is opened by Burnet"The clonal selection theory is accepted withoit reservations by the community"
Burnet (1969)Cellular Immunology
Crick (1958)The biological replication of macromolecules
Lederberg (1959)Genes and antibodies
Burks, Goldstine, &Von Neuman (1946)... logic design of an electronic computing instrument
1945
The first International Phage Symposium
Prague Conference on Antibody"Signs of rapidly increasing interest in the clonal selection ideas"
Cronology for the Emergence of Burnetism
Fig.2 .4- A chronology of the founding exemplars within the Burnetian disciplinary matrix. The arrows
indicate direct influences.
– 31 –
2. The foundations of the disciplinary matrix
If in contemporary literature these observations were rather vaguely interpreted as the
result of a "transient immaturity" of antibody production, Burnet regarded them as
problem requiring a scientific explanation. His genius lay in postulating a theory for
antibody production, that tied together the inability to immunise animals in the early
stages of ontogenesis, and the widely accepted non antigenicity of body components.
Evoking the concept of adaptive enzyme — at that time the interpretation of
enzyme induction by a substrate (see for example Monod (1947)) — Burnet & Fenner
(1949) postulated that during embryogenesis, or in an immediate post-embryonic phase,
the first enzymatic units involved in the production of antibodies would adapt to one or
another of the molecular "self-markers" , becoming thereafter involved in the disposal of
effete and damaged body components. Following the introduction of foreign antigen into
cells carrying these "self-replicating enzymatic systems" , the units would adapt to adsorb
the antigen and the enzymatic system would multiply. Circulating antibodies were
understood as "partial replicas of the intracellular enzymatic system", that would lose
replicating and enzymatic potential, but not the peculiar adsorptive properties. In order to
account for the long persistence of acquired immunity, the hypothesis required that
"when cells carrying the adaptative enzyme multiply, the descendant cells will also carry
the new character".
It is important to note, once again, that the "modified-enzyme" mechanism was
already cellular (although not yet clonal), like many other contemporary "template
theories". At variance with those, however, it provided a coherent synthesis of
previously unrelated observations and principles in immunochemistry, embryology,
physiology, and epidemiology. More than its mechanistic details, this general framework
caught the attention of immunologists. The following prediction of the theory was
particularly consequent.
If in embryonic life expendable cells from a genetically distinct race are
implanted and established, no antibody response should develop against the
foreign cell antigen when the animal takes on independent existence.
—Burnet & Fenner (1949)
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2. The foundations of the disciplinary matrix
Indeed, the group of Medawar turned towards the homotransplantation problem with this
new insight. In an article that became famous, Billingham et al. (1953) reported the
induction of homotransplantation tolerance by intraembryonic injection of cells, and
discussed this finding as an experimental confirmation of the major prediction of Burnet
& Fenner (1949). "The electrifying success of Medawar's group in establishing tolerance
to skin homotransplantation" (Chase, 1959), and its intelligibility under Burnet's
proposal synergised to persuade the community (Raffel, 1956). As matter of fact, Burnet
and Medawar shared the Nobel Prize in Physiology and Medecine 1960 for having
"unveiled a fundamental law governing the development and maintenance of" immunity
"by penetrating analysis of existing data and brilliant deduction, and by painstaking
experimental research" (Gard, 1960).
The general conception of immunity proposed by Burnet became increasingly
popular after 1953, and consequently any convincing mechanism for antibody formation
had to accounted for its main axiom:
The failure of antibody production against autologous cells demands the
postulation of an active ability of the reticulo-endothelial cells to recognise
"self" pattern from "not-self" pattern in organic material taken into their
substance. The first requirement of an adequate theory of antibody
production is to account for this differentiation of function ...
—Burnet & Fenner (1949)
Anyone can recognise this axiom as one of the main exemplars of current immunology,
that acquired the reputation of the science of "self non-self discrimination" (Klein, 1982).
Note, however, that this axiom is both historically and conceptually distinct from the
principles of clonal selection, that are addressed in next sections.
2.4.2 Towards Selective Antibody Formation
Burnet himself (1967) acknowledges Jerne as the "only begetter" for the origin and
development of the clonal selection principles. In 1955 Jerne (1955) proposed a
revolutionary solution to the problem of antibody formation, based on antigen selected
– 33 –
2. The foundations of the disciplinary matrix
amplification of circulating antibody variants; this mechanism not only satisfied the axiom
postulated by Burnet, but "made the self-marker ideas (...) look clumsy and artificial"
(Burnet, 1967).
The core of the "natural selection theory of antibody formation" as formulated by
Jerne himself:
The role of the antigen is neither that of a template nor that of an enzyme
modifier. The antigen is solely a selective carrier of spontaneously
circulating antibody to a system of cells which can reproduce antibody.
Globulin molecules are continuously being synthesised in an enormous
variety of different configurations.(...) The introduction of an antigen into
the blood or into the lymph leads to the selective attachment to the antigen
surface of those globulin molecules which happen to have a complementary
configuration.
—Jerne (1955)
The natural selection theory was so revolutionary and far-reaching in its consequences
that its origins and nature are worth closer examination.
Jerne joined Delbruck's phage group in 1955, where he studied antibodies
specific for bacteriophages, apparently because "immunology was not then an 'in'
subject" (Jerne, 1966). It was in this special environment that Jerne's ideas flourished.
His observations that avidity of antibodies seemed to increase during the course of an
immunisation (both in the case of antitoxin or anti-T4 antibodies) had "Darwinian
overtones", and encouraged the elaboration of the natural selection theory of antibody
formation.
Jerne (1966) recalled that during many preliminary discussions with his peers, the
theory had great difficulties in being accepted. For example, Pauling, with whom
Delbrück arranged a meeting, understood the selective principles being exposed, and
rejected them "probably within five seconds". Watson rejected the mechanism of
antibody reproduction by a succinct and unambiguous: "it stinks!". Despite all these
"blows" the article was written and published. The very same difficulties might be
reflected in absence of any mention to the article in any Annual Reviews until 1957.
– 34 –
2. The foundations of the disciplinary matrix
For different reasons, both traditional immunochemists and the founding fathers
of molecular biology found unacceptable features in Jerne's theory; as a whole, however,
the proposal of applying Darwinian principles to immunity had something intriguingly
seductive and revolutionary. Under the dominant "template theories" the external antigen
was the source of antibody complementarity and specificity. Antibody diversity was
therefore derived from antigenic diversity, and acquired immunity required no genetic
mechanism. In Jerne's proposal, the diversity of antibody variants preceded specificity;
specificity arose from the selection of antibodies variants that were already
complementary for the antigen. The generation of antibody variants and their selection by
antigen, was in the same conceptual framework of the post-mutational selection of
bacterial variants established by Luria and Delbrück. Jerne was seeding Immunology
with the founding principles of molecular biology, that would be consolidated after the
establishment of the central dogma , and pervaded the whole of biology.
2.4.3 The Clonal Selection Theory of Acquired Immunity
Talmage (1957) compared the antibody formation model of Burnet & Fenner with that of
Jerne, arguing that the natural selection theory gives a "simpler and more definitive
explanation for the absence of auto-antibodies". Talmage also pointed out the logical
similarity between Jerne's ideas and the side chain theory of Ehrlich, and suggested that it
would be more appropriate if the "multiplying unit in the antibody response is the cell
itself". It might be relevant to recall here that Talmage belonged to the cellular school of
"template theories" (Dixon et al., 1952).
The appropriate refinement of the natural selection theory would be carried by
Burnet, who placed the selective principles on a cellular and clonal basis within his
general scheme of immunity. Burnet (1957) published the outline of this clonal selection
hypothesis in the Australian Journal of Science. Apparently this obscure journal was
chosen to ensure priority, but to minimise the impact on Burnet's reputation in case of a
failure of the revolutionary selection principles. The fully developed hypothesis was only
– 35 –
2. The foundations of the disciplinary matrix
presented next year, in the Abraham Flexner Lectures in Vanderbilt University (Burnet,
1958). The major postulate of the clonal selection hypothesis was that:
Each type of [gamma globulin molecule] is the product of a clone of
mesenchymal cells, and it is the essence of the hypothesis that each cell
automatically has available on its surface representatives reactive sites
equivalent to those of the globulin they produce.
—Burnet (1957)
Antigen entering in blood or tissue fluids, would attach to the surface of lymphocytes
carrying complementary reactive sites, and activate them to settle in appropriate tissues,
and undergo local proliferation. Their progeny should include forms capable of
spontaneously producing soluble antibodies, and forms maintaining functions identical to
their parental cells. The net result should be both a change in the serum population of
gamma globulin molecules such that those reacting with antigen should be in excess (i.e.
antibody response), and an increase in the number of circulating lymphocytes of the
expanded clones that could ensure a rapid and extensive response to a subsequent entry
of the same antigen (i.e. a secondary immune response).
It is worth emphasising that the original clonal selection theory was placed in the
realm of the ontogenesis of the individual animal. Both the generation of antibody
diversity and the elimination of lymphocytes reacting with body determinants was
postulated to take place, once and for all, during embryogenesis; the actual repertoire of
lymphocyte clones was therefore conceived as settled for the life time of the animal.
The theory requires at some stage in early embryonic development a genetic
process for (...) 'randomisation' of the coding responsible for part of the
specification of gamma globulin molecules (...). At this stage, (...) any
clones of cells which carry reactive sites corresponding to body determinants
will be eliminated.
—Burnet (1957)
The outline of the clonal selection theory is illustrated in fig. 2.5.
– 36 –
2. The foundations of the disciplinary matrix
... ...... ...
G.O.D.
1 2 3 4 111 112 623 1245 n
1 2 3 4 111 112 623 1245 n... ...... ...
Ag A
Ag B
Stem Cell
Antigen Independent D
ifferentiation
Ear
ly S
tage
s of
Ont
ogen
y (B
urne
t)
111 111 111 111 1245 1245 1245 1245
Ig 1245Ig 111
111 111 1245 1245
Antigen D
ependent Differentiation
Fig.2 .5- Illustration of Clonal Selection Theory. In the original proposal by Burnet, both the
generation of diversity (GOD) and the elimination of cells recognising autologous antigens (A)
were assumed to occur in the early stages of the ontogeny of the animal. Lederberg proposed a
switch from the standpoint of the individual organism to the standpoint of the individual
lymphocytes.
– 37 –
2. The foundations of the disciplinary matrix
2.4.4. The Early Elaboration of Clonal Selection
Lederberg (1959), who had been a guest in Burnet's laboratory two years before,
published a formulation of the clonal selection hypothesis in 9 postulates. The aim was to
give it a sound foundation on the "genetic doctrines developed in studies of microbial
populations". One important new feature was the switch from the realm of ontogenesis of
the animal as a whole, to the realm of the differentiation of individual antibody-forming
cells. For example, the absence of antibodies against body components, previously
interpreted as resulting from the elimination of corresponding cells during
embryogenesis, was now interpreted as a lifelong process (see also fig.2.5):
A6. The immature antibody-forming cell is hypersensitive to an antigen-
antibody combination: it will be suppressed if it encounters the homologous
antigen at this time.
—Lederberg (1959)
Note that this subordination of the biology of the animal to the biology of individual cells,
although not due to Burnet himself, represents one of the major reductionist features of
what is called here Burnetism. Lederberg clearly identified as the most questionable
proposal his hypothesis that genetic diversity was due to hypermutability by random
assembly of the DNA of globulin gene during certain stages of cellular proliferation.
From 1957 to 1967 the clonal selection theory was, directly or indirectly,
consolidated by several lines of research (Burnet, 1967).
Edelman (1959) and Porter (1959) characterised the basic structure of antibodies.
Edelman & Gally (1962) demonstrated that Bence-Jones proteins were light chains
chemically identical to those in myeloma globulins from the same patients. Following this
lead, Hilschman & Craig (1965) "electrified the immunological community" with the
report that Bence-Jones proteins, and thus antibody light chains, had a diverse N-terminal
and an invariant C-terminus. Specificity and antibody folding was ascribed to aminoacid
sequence by several methods of denaturing and reconstituting antibodies (reviewed in
Freedman & Sela (1966)), supporting the first postulate of Lederberg (1959).
– 38 –
2. The foundations of the disciplinary matrix
The specificity of antibodies produced by single cells generated considerable
debate and controversy as can be seen by the inconclusive review by Nossal & Mäkëla
(1962). The clarification of the issue required studies on single cells, using several
techniques like immunofluorescence, autoradiography, bacterial immobilisation,
agglutination, and chaining, bacteriophage neutralisation test. When closing the 1967
Symposium, following the report by Makëla (1967), Jerne (1967) concluded that the one
cell—one antibody rule applied to heavy and light chains and probably also to the
antibody combining site.
As often happens in research, before the one cell-one antibody controversy was
solved, the studies on single cells gave fundamental information on the nature of antibody
forming cells, on stages of lymphocyte differentiation, on the proportion of antibody
producing cells, etc. Plasma cells were definitively identified as the antibody producers.
A non negligible role would be played from then on by the haemolytic plaque forming
cell assay (Jerne & Nordin, 1963). The development of in vitro cell cultures, in vivo
isotope labelling , transfer of cells into irradiated recipients, and mitotic inhibitors allowed
the establishment of the pathway precursor lymphocyte - (antigen) target lymphocyte -
proliferating lymphocyte - plasma cell or memory lymphocyte. (see Papermaster, 1967;
and refs. therein).
The genetic basis for the diversity of antibodies was a matter of speculative
debate, and the concurrent hypotheses ranged from the hypermutable genes and point
mutations during evolution of multiple genes, to translational control of antibody
synthesis, errors introduced in DNA repair, or somatic recombination of multiple
antibody genes (for the main references at that time see (Smithies, 1967); for a general
understanding of the state of affairs in this period see Crick (1967)). The solution for the
generator of diversity, a key feature of clonal selection theory that granted it the
abbreviation of GOD, became progressively one of the major puzzles of Burnetism.
The general scheme of differentiation dependent antigen responsiveness proposed
by Lederberg (1959), was taken by Mitchison (1964) to interpret low and high zone
induction of immunologic paralysis. The classical immunochemical explanation of
– 39 –
2. The foundations of the disciplinary matrix
paralysis by the accumulation of antigen in the responding cell was briefly discussed and
refuted; Felton's paralysis — that had been, as pointed out before, a major exemplar of
immunochemistry — was mentioned but discarded as probably no longer relevant. In the
new disciplinary matrix, the work by Mitchison became the new exemplar for antigen
mediated tolerance (see for example Nossal et al. (1967)).
In this period, there was a quite popular hypothesis on antibody formation, that
attributed a fundamental role to macrophage (Fishman & Adler, 1967; Gottlieb et al.
1967). It held that the macrophage would phagocyte the antigen and transfer specific
RNA to plasma cells, that would use it to produce the antibody proteins. Respecting the
central dogma, this hypothesis retained nevertheless some classical features, notably the
understanding of the antibody producing cell as a mere chemical reactor.
2.4.5. Fashionable Metaphors and Sources of Inspiration.
Information, IO-machines, and computers.
From 1955 to 1967 there is a considerable change in the language of immunologists, that
reveals much of the contemporary scientific fashion. Notions from cybernetics,
information theory, and computer science started to be commonly used, and inevitably
inspired immunological thinking. The influence of information theory was not peculiar to
Immunology; it represents one of the major tenets of molecular biology. The central
dogma (Crick, 1970) postulated that information — sequential code — passed
unidirectionally from nucleic acids to proteins.
Lederberg (1959) refers to the classical "template theories" as the "instructionist
theories" explaining that "antigen conveyed the instructions" for the synthesis of
complementary antibody, in a clear violation of the central dogma. The selective theory is
contrasted by the fact that "the information required to synthesise a given antibody is
already inherent in the organism". The new language and ideas are also evident in Jerne's
"Immunological speculations" from 1960, that start with the following citations:
– 40 –
2. The foundations of the disciplinary matrix
I shall always regard the differentiation between self and not-self as crucial
to all immunological theory. F.M.Burnet
Or, aucune machine n'est capable de choix, sauf selon des crìteres précis
prédéterminés et inscrits dans son programme. E.Delavenay
—Jerne (1960)
Also Burnet, in his Nobel Lecture, discussed the essence of clonal selection theory under
the heading of "Immunological Information" . Following the then "popular convention of
discussing coding" , he illustrates the mechanism of "differentiation between self and not-
self" by a dictionary metaphor (inspired by Jerne's "Immunological speculations") in
which a computer plays the role of the generator of diversity.
One can easily recognise here the foundations of the metaphoric conceptualisation
of cells as IO-machines with a DNA-encoded program of cell differentiation and gene
expression, that process information inherent to molecular signals. Note that these new
metaphors imply a profound revolution in the perception of reality. Haurowitz (1967),
unable to adopt this perception of reality, was still comparing template theories and
selective theories in the classical terms of physico-chemical reactions.
2.4.6 Consecration of Burnetism
In the 1967 Cold Spring Harbour Symposium on "Antibodies" the majority of the
participants were committed to the clonal selection principle. Burnet (1967) and Jerne
(1967) made respectively the opening and closing sessions, in a clear recognition of their
contribution to the recent face-lifting of Immunology. Only Haurowitz (1967), in a
typical Kuhnian resistance, tried to convince the audience that most of the experimental
observations supporting clonal selection, could still be accommodated by a refinement of
his classical "template theory" of antibody formation.
Confirming another aspect of the Kuhnian views on scientific activity, in 1969
Burnet published the first text book providing a general interpretation of immune
phenomenology under the clonal selection principles — Cellular Immunology (Burnet,
– 41 –
2. The foundations of the disciplinary matrix
1969). The following extract of the Preface of the book summarises clearly the reasons
for the dominance of Burnetism over the classical immunochemistry.
It was a point of view that seemed to be in accord with the way biology was
developing, and even in a rather crude early form provided a better frame
for the facts of immunity than any variant of the dominant instructive theory.
It was not enthusiastically received and has been 'disproved' on several
occasions. But it is the only theoretical approach to immunology which has
been able to adapt itself successfully to the accelerating flood of new
techniques and new facts coming from experimental immunology.
—Burnet (1969)
In 1970 a new journal was created — Cellular Immunology — to account for "the
remarkable growth in the scope and volume of significant contributions to the cellular
aspects of the immune response" (Lawrence, 1970).
2.4.7 Immunology as Burnetism
The core of current perceptions of immunity — genetic generation of diversity, antigen
driven immune responses, self nonself discrimination by induction of cellular-tolerance to
body components — was already fully developed during the one and a half decades that
were just reviewed. Proceeding with an examination of how this basic set of exemplars
of Burnetism has been elaborated and enlarged in the last 30 years is clearly outside the
scope and limits of this historical retrospective. Some discoveries entailed some structural
readjustments of the basic set of exemplars — the establishment of the two independent
B- and T- lymphocyte systems, and their co-operation for antibody formation, the
discovery of MHC restriction, the characterisation of somatic mutation and affinity
maturation. Other sets of observations, discoveries in stricto senso, were not truly
accommodated by elaboration of Burnetism and remain anomalous. Dominant or
infectious tolerance, idiotypic interactions, and natural autoreactivity, are the basic
– 42 –
2. The foundations of the disciplinary matrix
examples of such anomalies. The scientific innovations entailed by these anomalies are
the essence of Jerneism, and are discussed in section 2.5.
An historical outline of the accounts for the mechanism of tolerance to body
antigens and its relation to autoimmune pathologies, illustrates how the refinement of
Burnetism proceded without major changes of its key postulates. The issue is
particularly relevant in the context of the contrast between Burnetism and Jerneism.
CELLULAR-TOLERANCE AND AUTOIMMUNE PATHOLOGIES
The intriguing puzzle represented by the mechanism of tolerance to body
components, changed progressively from neonatal deletion of "forbidden clones" in the
original proposal of Burnet in 1957, to deletion in early phases of lymphocyte
differentiation as suggested by Lederberg, to Mitchison's "low zone tolerance" in the
seventies, to central deletion in the eighties (Kappler et. al., 1987; MacDonald et al.,
1988; von Boehmer et al., 1989), which has been "complemented" with several hill
defined mechanisms of peripheral inactivation or deletion of clones, like clonal abortion
(Nossal & Pike, 1975), clonal anergy (Pike et al., 1983; Rammensee et al., 1989;
Schwartz et al., 1989; Webb & Sprent, 1990), clonal exhaustion (Webb et al., 1990;
Moskophidis et al., 1993; Rocha et al., 1995), etc. The target of tolerance induction
changed from B-lymphocytes to T-lymphocytes, upon the discovery of their synergy for
immune responses (Claman et al., 1966; Cooper & Good, 1966; Mitchell & Miller,
1968), the carrier effect (Mitchison et al., 1970; Mitchison, 1971), and MHC restriction
(Katz et al., 1973; Rosenthal & Shevach, 1973; Zinkernagel, 1974; Bevan, 1977;
Zinkernagel et al., 1978). It became common sense that it is sufficient to tolerise helper
lymphocytes. This is a major qualitative postulate that made it possible to disregard as
major scientific problems the otherwise paradoxical findings that natural autoreactive
antibodies exist (as discussed below) and that autoreactive B-lymphocytes arise during
somatic mutations.
– 43 –
2. The foundations of the disciplinary matrix
Overall, the mechanism(s) of tolerance remains central to immunological thinking
and its status in the theoretical context remains exactly the same. In a nutshell, the whole
phenomenon of tolerance is reduced to its cellular levels of description . The main idea of
underlying tolerance is that individual cells bearing autoreactivity are potentially harmful,
and therefore must be, and normally are, prevented from being activated. Any means are
good as long as the end is the same: cellular-tolerance, the cellular IO-machinery is
rendered non operational. Even the regulation of potentially malignant autoreactivity, that
imposed itself as a consistent empirical fact, is still seen as one of the many candidate
mechanisms by which otherwise malignant autoreactive cells are "shut down".
The conceptual and practical consequences of this simple and reductive postulate
are multiple. Autoimmune pathologies must involve by definition the activation of
autoreactive cells. A brief overview of the fashionable accounts for their etiology during
the last fifty years illustrates the argument. In the sixties, the popular explanation for
autoimmunity was the accidental exposure of organ specific antigens that had been
secluded from the unknown mechanism of induction of cell-tolerance. The demonstration
of circulating levels of candidate target antigens during autoimmune pathologies
supported this interpretation. However, upon the demonstration that target antigens could
be found in the circulation of healthy individuals, it became obvious that the explanation
was not general (Torrigiani et al., 1969). The relatively low concentration of the target
antigen in circulation in normal individuals as compared to patients, contributed to
establish Mitchison's "low zone tolerance" as the candidate explanation for cell-tolerance
to the body antigens (Torrigiani et al., 1969). In the same period, B-T co-operation and
the carrier effect became accepted facts, and entailed new perspectives about the etiology
of autoimmune diseases. Since the popular explanations were that self-tolerance involved
essentially T-lymphocytes, autoimmunity arose by any conceivable mechanism that
provided an alternative carrier to autologous antibody determinants (Weigle, 1971;
Allison, 1971): antibody crossreactivity between somatic and microbial antigens,
microbial adjuvants overcoming the need of T lymphocytes, the classical drug induced
autoimmunity, etc.. Presently, the list of mechanisms for the etiology of autoimmunity
– 44 –
2. The foundations of the disciplinary matrix
maintains the very same items, and is supplemented by the failure of signalling
transduction or signal processing mechanisms with a probable genetic basis. Thus,
currently, the most popular animal models of autoimmunity are mutant strains — NOD
(Wicker et al., 1995), lpr (Singer et al., 1994; Nagata & Suda, 1995), etc. In the IO-
machine metaphor of the cell this amount to saying that autoimmunity results from either
altered inputs or altered processing of the normal Inputs.
In the context of these views on individual cell-tolerance and pathogenic
autoreactivity it is unavoidable that the therapy of autoimmune diseases is essentially
based on immunosuppressive agents like cyclosporin, corticoids, FK506, etc.
2.5. Jerneism
A significant number of research programs in Immunology are presently constructed
upon a common set of exemplars that remain anomalous and paradoxical in the context of
Burnetism. The commitment to these exemplars reflects a perception of reality, which is
different from traditional one. Jerneism refers to this revolutionary way of doing
Immunology. As in other fields of Biology, the focus of attention switches from the
molecular biology of cells to the organisation of biological systems. The main exemplar
is the idiotypic network hypothesis of Jerne (1974), that contained already many of the
basic ideas that have been subsequently developed by different groups. It is worth
emphasising that Jerneism is not a disciplinary matrix in stricto senso. Although it has
many features of a potential scientific revolution, notably being based on non ortodox
exemplars, so far it has failed to persuade the entire community. A chronology of some
of its exemplars are presented in fig. 2.6.
– 45 –
2. The foundations of the disciplinary matrix
Jerne (1960)"Immunological spcculations"
Jerne (1974) "Towards a network theory of antibody formation"
Oudin & Cazenave(1971)Antibodies with different spceificites share common idiotypes
1965
1970
1975
1980
Cronology of Jerneism
1960
Lindenman(1973) Speculations on idiotypes and homobodies
Hart et al. (1972)Idiotype suppression by antiidiotypic antibody administration
Gershon & Kondo (1970)Suppressor cells and infectious tolerance
Kunkel et al (1963)Oudin & Michel (1963) Antibodies idiotypes
Mitchison (1969)Helper cells and carrier eff'ect
Claman et al (1966)Synergism of thymus-marrow cells in antibody production
Mitchel & Miller(1968)T and B cell subsets
Richter (1975); Hoffman (1975) The first mathematical models of immune networks
Fig.2 .5- A chronology of the founding exemplars of Jerneism.
2.5.1 The Seeds of an Idea ?
In his "Immunological speculations", Jerne (1960) proposed an "immunological
terminology", in order to clarify conceptual discussions. The interaction between the
complementary regions in antibody and antigen molecules was called parataxis. The
binding sites in the antigen and the antibody were respectively the epitope and the
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2. The foundations of the disciplinary matrix
paratope ; antibody molecules would carry two identical paratopes and, being themselves
antigenic, a set of characteristic epitopes. Epitopes carried by the molecules of a given
individual animal were called the idiotopes. After a few other definitions that time has
lost, Jerne proceeded to an examination of the question "are paratopes epitopes?", well
aware of its conceptual significance. His inflexible logic lead him to conclude that
symmetry in parataxis would bring into existence reactions amongst antibodies of the
same individual — idiotypic interactions and networks in 1960! . Recognising the
conceptual challenge, he made a pragmatic retreat:
To avoid these conceptual difficulties, the assumption is made that
paratopes and epitopes represent two different classes of stereospecific
regions. A paratope is not potentially immunogenic. Paratopes are not
epitopes but anti-epitopes; keys are keys, and locks are locks.
—Jerne (1960)
In the next decade, the concept of idiotypic networks evolved from a repulsive conceptual
difficulty to a major conceptual break through. A few events contributed to this switch,
and are discussed in next section. Curiously enough, the network hypothesis (Jerne,
1974) maintained this original assumption that "parataxis" was asymmetric.
2.5.2 The Melting Pot of the Network Hypothesis
THE ANTIGENICITY OF INDIVIDUAL ANTIBODY MOLECULES:
ALLOTYPY AND IDIOTYPY
Oudin is one of the first hand references in idiotypic networks (Jerne, 1974;
Brussard, 1979; Kearney, 1993). In 1953, he was injecting antigen-antibody complexes
to rabbits, in order to generate large amounts of antibody specific for the antigen. Against
this expectation, Oudin found not only antibodies against the antigen but also against the
immunoglobulin of the animal that was source of the first antibody. This "exploration of
the unexpected" (Brussard, 1979) was the basis for the concept of allotypes, i.e.
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genetically determined antigenic determinants from immunoglobulin molecules that vary
between groups of the same species.
The relevance of the question whether or not individual antigenic determinants
existed in each antibody molecule was strongly reinforced by antibody allotypy. The
issue intrigued the community, and remained controversial (reviewed by Kunkel et
al.(1963)). Kunkel et al. (1963) and again Oudin & Michel (1963) reported on the
specific antigenicity of individual antibodies, respectively in humans or rabbits. Oudin
(1966) called idiotypic to this antigenicity that was peculiar "firstly to antibodies against
one given antigen, and secondly to the individual or perhaps to one group of individuals,
within which the idiotypic specificities of the antibodies is not the same as it is in the
other individual groups".
The characterisation of idiotypy of antibodies originated many research programs,
namely that of Kellus & Gell (1968) that are systematically associated to the discovery of
idiotypy. Experimental research was essentially based on immunoadsorption,
immunoelectrophoresis and the Ouchterlony (1948, 1968) analysis of antibody
crossreactivities, that redeployed as a major experimental exemplar.
In this context, several findings came to be very important, notably the
suppression of idiotypic specificities in adult mice by administration of anti-idiotypic
antibodies (Hart et al., 1972), and the observation that immunisation generated both
antigen-specific and antigen-non specific antibodies that shared the same idiotypes (Oudin
& Cazenave, 1971). The two later observations were essentially unexpected and defied
any possible explanation under Clonal Selection Theory. Jerne built upon these anomalies
of the dominant theory to elaborate the network hypothesis.
THE ERA OF SUPPRESSION!
Gershon & Kondo (1970, 1971) surprised the immunological community in 1970
with a report that the B lymphocyte responses against erythrocytes could be specifically
inhibited by co-operation with T-lymphocytes. At that time, regulatory circuits were quite
fashionable in Biology. Following the lead of Gershon, regulatory suppression became
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2. The foundations of the disciplinary matrix
quite popular, and was the candidate interpretation of many other experimental systems,
notably allotype or idiotype suppression, genetic inability to respond to particular
antigens, or low-zone tolerance. The following extract of the preface for the Proceedings
of a Conference on The Immune System, Genes, Receptors and Signals illustrates rather
well the spirit of the community in 1974:
It is the era of suppression! This meeting saw a common acceptance of a
new paradigm that the outcome of immune cellular interactions was due to
competition between synergistic and suppressive T-cells.
—Sercarz et al. (1974)
The suppressor cell was considered metaphorically as the new "conductor of the
immunological orchestra", replacing GOD in main subject of immunological discussions
(Sercarz et al., 1974).
Note that negative regulation has more fundamental implications for
immunological theory, than the discovery of helper cells. The synergy between T and B
lymphocytes for the production of antibodies was rather immediately accommodated in
the scaffold of the Clonal Selection Theory, with no reformulation of its major rules.
Namely, the immune response would still increase with the size of the (cor)responding
clones; and the elimination of cells or precursors (cor)responding to the body
determinants would always eliminate the possibility of autoimmune responses. The two
signal model of lymphocyte activation of Cohn and Langman (for a good retrospective
see (Cohn, 1994)) is an explicit elaboration on this basic idea.
The situation changes dramatically with the introduction of suppressor cells.
Regulatory circuits can potentially be included in Clonal Selection Theory, by regarding
each cluster of antigen responding cells — helper, suppressor, and B lymphocytes — as
absolutely independent units of selection. However, the conceptual difficulties and
pitfalls are many, and stem from the fact that the simple direct relation between the
antigenic stimulus and acquisition of immunity, that was so seductive in Clonal Selection
Theory, is lost. On the one hand, the increase in the size of the (cor)responding
suppressor clone leads to a decrease in the immune response; and on the other hand, the
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2. The foundations of the disciplinary matrix
elimination of suppressor clones or precursors (cor)responding to body determinants can
paradoxically potentiate an autoimmune response. The paradoxical and counter intuitive
nature of suppression in a Burnetist context is probably the reason why its "guardians of
the temple", Cohn and Langman, have always regarded with scepticism the role of
suppression in "self nonself discrimination" (Cohn, 1986; Langman, 1987).
Jerne was well aware that specific suppression was an anomaly from a Burnetist
perspective. The network hypothesis was not a simple refinement of Clonal Selection
Theory, but represented a revolutionary conception of the Immune System in which
specific suppression had a major role.
SYSTEM THEORY AND SELF-ORGANISATION
In the late sixties, large, dynamic and complex systems, in which many identical
units interact with each other, became the object of scientific interest. These systems were
often social or biological, and the main paradigm was the nervous system, with 1010
neurones. The regain of interest in system theory — for which von Bertalanffy (1928,
1952) had provided the basis already in 1928 — was entailed by the recent developments
of cybernetics, and also by the possibility to treat problems of such dimension due to the
advent of computers.
In was in this context that Von Föerster (1962) developed the concept of a self-
organised system, as an independent system governed by internal rules that is able to
adapt to changes in its environment. Self-organisation was illustrated and guided research
programs in several fields of biology. The work of Weiss in embryology was particularly
significant, and his demonstration that single cell suspensions from chick-embryos in
advanced stages of differentiation could reconstitute complete organs became a major
exemplar (Weiss & Taylor, 1960).
In the early seventies the notion of self-organised system bursted from every
corner of Biology. Eigen (1971) was talking about self-organised matter; Maturana and
Varela (1980) were developing the concept of autopoiesis ; etc. The idiotypic network
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2. The foundations of the disciplinary matrix
theory of Jerne, and the concern with the "eigen-behaviour" of the immune system, were
well integrated in this general intellectual movement.
2.5.3 Towards a Network Theory.
The Eigen-Behaviour of the Immune System
In the early seventies, Jerne had developed the conviction that the Clonal Selection
Theory was no longer able to cope with the pace of accumulation of experimental
observations, and that Immunology needed a major theoretical development. He
sustained this conviction in the closing session of a colloquium on "The Genetics of
Immunoglobulins and of the Immune Response":
I think there is now a need for a novel and fundamental idea that may give
a new look to immunological theory, similar to the impact the idea of
selection had on theoretical developments in the period 1950-1970.
—Jerne (1974)
Upon a consideration of the potential diversity of the repertoire of antibodies and
lymphocyte receptors, Jerne came to the basic conclusion that,
Formally, the immune system is an enormous and complex network of
paratopes that recognize sets of idiotopes, and idiotopes that are recognized
by sets of paratopes. (...) this network interwines cells and molecules.5
—Jerne (1974)
Jerne addressed the potential responses of lymphocytes to signals involving the paratopes
(either repressive or activatory) or the idiotopes (repressive) in their receptors,
maintaining, as mentioned before, the asymmetry in the idiotypic-paratopic interaction.
He proceed to express the popular conviction that "the essence of the immune system is
the repression of its lymphocytes", reviewing its experimental support. So far the
5 The last sentence deserves emphasis because Jerne has been unfairly accused of being concerned
only with circulating antibody, neglecting lymphocytes in general, and T lymphocytes in particular.
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2. The foundations of the disciplinary matrix
proposal was not very different from some of its contemporaries, notably Lindenman's
speculations on idiotypic interactions and regulation (Lindenmann, 1973), or Gershon's
attribution of a major functional significance to suppression (Gershon, 1974).
However, Jerne proceeded into major discontinuity with Burnetism. Based on the
estimation of the concentrations of individual paratopes and idiotopes in circulation, Jerne
reached the conclusion that the network that could be conceptually outlined has
unavoidable functional existence even in the absence of immunising antigen.
The immune system, even in the absence of antigens that do not belong to
the system, must display a eigen-behaviour mainly resulting from paratope-
idiotope interaction within the system. By its eigen-behaviour the immune
system achieves a dynamic steady state as its elements interact between
themselves, and as some elements decay and new ones emerge.
—Jerne (1974)
Jerne explicited the meaning of eigen-behaviour (fig.2.8) and further demonstrated that
the network hypothesis offered simple "alternatives to current explanations" for several
unrelated phenomena, and allowed an interpretation for findings that the consensus
theory could not account for — the dynamics and regulation of the immune response,
low-zone tolerance, the inhibition of response to antigen by administration of specific
IgG antibody (then called "7S inhibition"), the antigen-competition phenomenon, the
Weigle phenomenon, the Oudin-Cazenave phenomenon, the non-specific component of
the response, and anamnestic responses or immunologic memory.
The article was concluded with a discussion of the "striking phenotypic" analogy
between the immune and the nervous systems. This conclusion not only revealed his
sources of inspiration, but opened immunological thinking to many paradigms from
cognitive sciences — representationalism, internal images, autopoiesis, etc.
Two aspects in the proposal of Jerne were fundamentally revolutionary and
innovative. They are distinct but closely related, and pointing them out here might help in
the understanding the subsequent history of the Immune Network Hypothesis. The first
aspect is that the properties of the immune system, the immunological phenomena, cannot
be reduced to the description of isolated molecules, cells, or clones; they involve
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2. The foundations of the disciplinary matrix
organisational properties of a dynamic network of molecules and cells. The second aspect
is the notion that the immune system has an eigen-behaviour, an internal structure and
dynamics that is not subordinated to external immunisation. In the context of this eigen-
behaviour, the antigen is not the cause of every immunological phenomena; its new
status is that of a perturbation that can potentially entail a change from one eigen-state to
another eigen-state, from one internal state to another internal state.
Fig . 2 .8 - "The eigen-behaviour of the immune system. The immune system contains a
set p1 of combining sites (paratopes) on immunoglobulin molecules and on cell receptors
which recognize a given epitope (E) of an antigen. This recognizing set includes the
potentially responding lymphocytes. The molecules of set p1 also display a set i1 of
idiotopes. Apart from recognizing the foreign epitope, the set p1 like wise recognizes a
set i2 of idiotopes which thus constitutes, within the immune system, a kind of internal
image of the foreign epitope. This set i2 occurs in molecular association with a set p2 of
paratopes. Likewise, the i1 is recognized within the immune system, by a set of p3 of
paratopes which represent anti-idiotypic antibodies. Beside the recognizing set p1i1 there
is a parallel set pxi1 of immunoglobulins and cell receptors which display idiotopes of
the set i1 in molecular association with combining sites that do not fit the foreign
epitope. As a first approximation, the arrows indicate a stimulatory effect when idiotopes
are recognized by paratopes on cell receptors and a suppressive effect when paratopes
recognize idiotopes on cell receptors. Successive groups of ever larger sets encompass the
entire network of the immune system" — The illustration and the legend are
from Jerne (1974) .
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2. The foundations of the disciplinary matrix
2.5.4 A parenthesis.
Idiotypic Network as an Elaboration of Burnetism.
Jerne argued that the network hypothesis was not a refusal of clonal selection, but was a
comprehensive view of the immune system in which the selection of clones was
reinterpreted and integrated in the wide context of an idiotypic network. The reaction of
the immunological community was clearly the opposite. Note that one of the heuristic
values of the Clonal Selection Theory was that, for the purposes of immunisation, the
entire immune system could be reduced to the isolated cells or clones (cor)responding to
the antigen. Most of the research programs exploring the potential of idiotypic
interactions and suppression, applied the symptomatically the very same reductionist
principle — concerned with responses, vaccination, memory, or tolerance to immunising
antigen, both theoretical or experimental research studied how individual antigens
triggered and animated the (cor)responding regulatory network. This pragmatic attitude
was also reflected in the examples that Jerne used to illustrate and promote the idiotypic
networks.
In this specific context, local networks, regulating specific immune responses,
substituted single lymphocyte clones in the traditional scaffolding of Burnetism. Those
research programs are therefore outside what we call Jerneism; and their discussion has
no place here unless a brief comment. The conceptual paradoxes and difficulties
undermining any Burnetist perception of regulatory networks have already been
mentioned. The truth of the matter is that those difficulties were never overcome by
appropriate elaboration of the Clonal Selection Theory that accommodated networks, and
the interplay between theory and experimentation remained overwhelmingly unfruitful.
Nevertheless, these studies had the consequence which was the accumulation of several
consistent observations which remain problematic or paradoxical for Burnetism. In this
context, the existence of antibody and lymphocyte autoreactivity in normal healthy
individuals is particularly relevant as we will discuss below.
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2. The foundations of the disciplinary matrix
2.5.5 Eigen-Behaviour and Cognitive Properties of the Immune System.
The concept of eigen-behaviour of the immune system and its analogy with the nervous
system — the core of what is called here Jerneism — inspires many research programs.
The experimental and theoretical approaches are systematically discussed in the respective
literature as requiring a discontinuity with the traditional views of Burnetism. The titles of
several view point and reviews articles are rather illustrative of this feature — "Self and
Nonsense" (Vaz & Varela, 1978), "From horror autotoxicus to gnothi seauton"
(Avrameas, 1991), "The Cognitive Paradigm Challenges the Clonal Selection Principle"
(Cohen, 1992b). This revolutionary immunological thinking is hopefully reflected in the
following discussion of a few theoretical and experimental exemplars shared in Jerneism.
THE COGNITIVE IMMUNE SYSTEM: SELF OR NONSENSE
Strong in his ideas on system theory, self-organisation and cognitive science,
Varela became interested in Immunology in the late seventies. Hence, Vaz & Varela
(1978) presented an elaboration of the idiotypic network hypothesis within the general
framework of autopoiesis (Maturana & Varela, 1980). The proposal situated the eigen-
behaviour on the main stream of research on idiotypic networks. Moreover, it was
probably the very first article that discussed Immunology in the context of serious
paradigms from cognitive science. The advantages and difficulties in such enterprise were
identified, notably those involving the interplay between the cognitive domains of the
immune system and that of the immunologist observer.
Several aspects of the theoretical framework were particularly innovative and
would rapidly reveal both theoretical and experimental consequences. The first was a
conception of the organisation of the immune system that was almost a logical inversion
of the "self nonself discrimination" axiom.
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2. The foundations of the disciplinary matrix
We must replace the notion of the lymphoid system as a collection of
unconnected lymphocyte clones carrying receptors directed outwards —
towards unpredictable encounters, with the notion of a network of
interacting lymphocytes where the receptors are directed inward, making
the activities of the whole lymphoid system curl and close onto itself.
—Vaz & Varela (1978)
The second aspect of the theory was the postulate that direct correlations exist between
the network structure and the immune function.
The higher the number of influences converging upon a node, the higher
must be its immunologic inertia, in the sense that the larger portions of the
network will be disturbed when the node is disturbed.
—Vaz & Varela (1978)
The conceptual shift is not trivial and must be emphasised. A suppressor cell intervening
in regulatory circuits as proposed by the Gershon school, was intrinsically suppressive,
i.e. it could be isolated as such and it displayed identified surface markers (for a
significant example see (Jandinski et al., 1976)). According to the Vaz & Varela (1978)
proposal, a suppressor cell is only be defined by its status in the network organisation
and corresponding to any cell "which resists displacements in the organisation of the
network which can be necessary for the production of intense immune responses" . In the
parlance that we introduced in chapter 1, a suppressor cannot be isolated as such, it is a
relational object.
Finally, they proposed a reasonable explanation for the disproportionate impact of
the genetic background and the manipulations in early ontogenesis on the composition
and function of the immune system; these findings, not easily accounted for by
contemporary immunological theories, were interpreted by the extreme sensitivity of self-
organised systems, with recursive eigen-states, to initial conditions or perturbations.
IDIOTYPIC NETWORKS:
GENETICS, ONTOGENESIS , DYNAMICS, AND CONNECTIVITY
As already referred, the Idiotypic Network Hypothesis inspired many experiments
based on idiotype-directed manipulations (reviewed by Kearney (1993)). Although,
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2. The foundations of the disciplinary matrix
many of these were designed to analyse specific immune responses, and not the eigen-
behaviour of the immune system, they became nevertheless exemplars of Jerneism. Only
the most classical findings are listed here without any pretension to be complete.
Several studies revealed that the antibody responses to certain haptens are
characterised by strain specific idiotype dominance (Blomberg et al., 1972; Lieberman et
al., 1974; Hansburg et al., 1977; Crews et al., 1981). The chronic elimination of
idiotypic response or dominance by administration of small amounts of complementary
anti-idiotypic antibodies in neonatal periods was reported (Augustin & Cosenza, 1976;
Strayer & Köhler, 1976), and extended to several other systems (reviewed by Kearney &
Vakil (1986)).
From the follow up of idiotypes and anti-idiotype titers in multiple immunisation
protocols and autoimmune pathologies the picture emerged that these complementary
antibodies tend to circulate in reciprocal concentrations (Kelsoe & Cerny, 1979; Bona,
1982; Rodkey & Adler, 1983), as easily predicted by the network hypothesis. Lundqvist
et al. (1989) studied the dynamics of natural serum antibodies in mice reporting erratic
fluctuations of the titers of idiotype and anti-idiotypes, that were extremely sensitive to
the administration of minimal amounts of their counterparts.
Holmberg et al. (1984) and Vakil & Kearney (1986) independently reported on
the high internal connectivity in the neonatal B lymphocyte from the spleen and foetal
liver. These neonatal antibodies revealed also a considerable degree of multireactivity
reacting against panels of autologous antigens (Dighiero et al., 1985).
IMMUNOLOGIC ACTIVITY IN NON-IMMUNISED ANIMALS
Already since the late sixties animals were raised without intestinal microflora —
"germ free" — and fed chemically defined ultrafiltered diet — "antigen free". These were
originally designed to investigate nutritional, biochemical, and metabolic effects of the
interactions between the host and the microflora (Reddy, 1971), but it became soon
obvious that they represented a good model to study the impact of background
immunisation on the immune system (reviewed in (Wostmann et al., 1971)). In this
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2. The foundations of the disciplinary matrix
period, the basic observables were the serum titers of γ-globulins by
immunoelectrophoresis, the size and morphology of spleen, lymph nodes and Peyer's
patches, the frequency of PFCs, and the blood leukocyte counts. In general, the immune
system of germ free and antigen free animals was regarded as "small and relatively
inactive but functionally intact" as expected by the Clonal Selection Theory (Pollard &
Nordin, 1971); the issue was essentially disregarded as a relevant field of research.
In late seventies and in the eighties, the activity in germ free and antigen free
animals regained obvious interest under the light of the hypothesis of an autonomous
immune network. Several groups (Kashimoto et al., 1978; Hooijkaas et al., 1984;
Pereira et al., 1986) confirmed the previous serologic observations, namely that while the
levels of IgM were essentially the same in conventional, germ free or antigen free, the
titers of IgG were considerably reduced with the decrease in the antigen load.
Comparable observations were extended to the lymphocyte compartments, namely
antigen free animals were then shown to be essentially devoid of germinal centers and
lymph nodes, but had frequencies of "naturally" activated B and T lymphocytes non
significantly reduced as compared to those found in germ free or conventional animals
(Pereira et al., 1986).
The theoretical implications of these new findings were driven notably by
Coutinho and colleagues (Pereira et al., 1986; Huetz et al., 1988; Coutinho, 1989; Varela
& Coutinho, 1991), who emphasised their incompatibility with the traditional Burnetist
view that lymphocyte activation requires external immunisation, and their consistency
with the autonomous, self-centered, immune network. Pereira et al. (1986) interpreted
the assembled observations as suggestive that "cells involved in the autonomous activity
represent a compartment of the immune system basically distinct from the antigen-
dependent one" (one can recognise here the seminal ideas of what would mature into the
Central and Peripheral Immune System).
The different facts emerging in early seventies and in late eighties from essentially
the same crude observations, represents a typical illustration of the critical role that the
commitment to exemplars plays in the establishment the significant facts.
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AUTOIMMUNITY IN PHYSIOLOGY AND DISEASE
The conception of physiological autoreactivity is one of the hallmarks of
Jerneism. Historically, it emerged from the convergence of several lines of research,
namely the investigation of the presence of autoantibodies in normal healthy
individuals, the research on spontaneous and experimental autoimmune pathologies and
its putative regulation by suppressor cells or anti-idiotypic antibodies.
Although the presence of autoantibodies in healthy individuals was reported
several times since the beginning of the century (reviewed by Grabar (1983) and Mackay
(1983)), the issue only regained interest with the works of Avrameas and colleagues in
the early eighties (Gilbert et al., 1982; Dighiero et al., 1983; Dighiero et al., 1985), who
established that the existence of autoantibodies in healthy individuals was the rule rather
than the exception. The contrast between this finding and the Burnetist theory was
immediately emphasised, notably by Grabar (1983) (who revived his old postulate of
physiologic role for autoantibodies), Mackay (1983) , and Cohen & Cooke (1986).
As already mentioned, in the seventies Gershon's suppressive circuits and
dominant tolerance became a major exemplar for experimental research and manipulation
of autoimmune pathologies. Cohen & Wekerle (1974) were already addressing the
questions like "do T lymphocytes with specificity for self antigens exist in healthy
individuals?", what is their relation to autoreactive effectors in organ specific autoimmune
diseases?, and "how is self-recognition controlled?". The popularity and success of these
empirical research programs is rather patent in the emergence in reviews and text books
of "a failure in regulatory circuits" as a candidate mechanism for the etiology of
autoimmune diseases (for example in (Nossal, 1983) or (Roitt, 1980) ).
In the framework of Jerneism, physiological autoreactivity described in healthy
individuals is understood precisely as the natural way by which pathologic autoimmunity
is avoided (Cohen & Cooke, 1986; Huetz et al., 1988). Pathology is understood as a
deviation from healthy physiology, and not the result of some external germ or cause.
The theoretical implications are obvious, but even more significant, are the consequences
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2. The foundations of the disciplinary matrix
in terms of clinical application. On the one hand, the understanding of the onset of
disease requires, as a major prerequisite, the adequate characterisation of the healthy
physiology, which is another way of saying the eigen-behaviour. On the other hand,
again in contrast with classical immunosupression, the therapeutic strategies envisaged
are based on an appropriate stimulation of the immune system in order to re-enforce and
restore the healthy state (Rossi et al., 1989).
HETEROGENEITY OF THE COGNITIVE PARADIGMS:
A PSEUDO-DISCIPLINARY MATRIX
The assembly of experimental exemplars just mentioned, represents a common
basis for several research programs, which also share the nervous system metaphor and
the inspiration from cognitive science. However, it is important to note that these research
programs are not fully homogeneous in terms of the paradigms from cognitive science.
Representationalism is rather patent and explicitly assumed in the perception of the
immune system by Cohen (1992b) — the immune system has a primitive representation
of foreign microorganism in the genome, while the immunological homunculus is
nothing else than a representation of the dominant antigens in the body (Cohen, 1992a).
Many authors follow this very same line of thought, which is characteristic of
mathematical studies on the memory capacity of the immune networks (reviewed in next
Chapter).
Varela and colleagues are systematically in a different register. The operation of
the autopoietic immune network brings forth its own cognitive domain and categories; it
does not store or represent any information already present in the antigenic world. This
contrast between autopoietic cognition and representation is explicitly developed, notably,
in the final section of Varela et al. (1988) — "Enacting vs. Representing" .
The heterogeneity in the cognitive paradigms imported into Immunology reflects
an actual heterogeneity in contemporary cognitive science itself.
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2. The foundations of the disciplinary matrix
2.5.6 The Central and Peripheral Immune Systems.
In late eighties Coutinho and colleagues (Huetz et al., 1988; Coutinho, 1989) attempted a
synthesis of many experimental observations on the autonomy and ontogenesis of the
immune network, that was guided by several studies on mathematical models. The result
of this synthesis was the concept that the immune system is organised as Central and
Peripheral Immune Systems, that embody complementary sets of lymphocytes.
We consider a central immune system (CIS), composed of activated
lymphocytes expressing a repertoire characterised by high levels of
connectivity both with V-regions in the same set, and with other somatic
structures (autoreactivity). This organisation results in typical dynamics
which are very different from immune response dynamics and ensure
recursivity in the continuous selection of newly arising clonal reactivities,
which are connected and autoreactive. The majority of the lymphocytes in a
normal individual, however, integrate the peripheral immune system (PIS),
composed of resting cells which find no productive complementarities in the
internal environment, and, therefore, embody a repertoire which is devoid of
V-region connectivity and autoreactivity. Lack of network organisation in
this set, however, allows it to perform clonal immune responses, elicited
obviously by molecular patterns absent from the internal environment.
—Huetz et al.(1988)
This hypothesis is particularly interesting for its pragmatism — it provides a
comprehensive synthesis of otherwise incommensurable Burnetian and network
descriptions of immune phenomena (Coutinho, 1989; Varela & Coutinho, 1991). On the
one hand, the Central Immune System accommodates most of the phenomenology that
was referred to above — autonomous activity in non immunised animals, preimmune
selection of the lymphocyte repertoires, physiological autoreactivity, and dominant
tolerance — on which the Clonal Selection Theory or its later elaborations do not
pronounce. On the other hand, it not only allows a rather useful accommodation of many
exemplars of Burnetism, but it explains why these research programs seem to be so
productive in the description of immune responses and memory. The essence of the
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2. The foundations of the disciplinary matrix
Peripheral Immune System, conceptualised as a set of disconnected resting lymphocytes,
can indeed be captured by the Clonal Selection Theory. Thus, once the Central and
Peripheral dualism is ensured, each peripheral disconnected cell or its clone can be
operationally treated as independent of the rest of the immune system. Note, however,
that its conceptual status has changed considerably — previously it was a cell produced in
order to respond to an antigenic stimulus, whereas it is now a cell that does not engage in
interactions with the Central Immune System, and therefore can respond independently to
eventual antigenic stimuli.
As already mentioned, the literature embodying Jerneism is typically built around
the argument that it provides a better alternative for the interpretation of the
phenomenological dualism that is traditionally discussed in terms of Burnet's axiom of
"self nonself discrimination". Unfortunately, these alternative interpretations are typically
too qualitative, descriptive and vague to support a solid research program. The
organisational dualism between Central and Peripheral Immune Systems is a good
exception since it provides an explicit and concrete account for a phenomenological
dualism, that is based in the direct mapping between network structure and
immunological function.
In the original proposals there was no hint on how the distinction between Central
and Peripheral Immune Systems could come about, i.e. how the immune network
restricts its domain of operation to a fraction of the potential repertoire. The problem was
identified clearly and its solution remains a major theoretical problem.
2.6. Recapitulating ...
The aim of this chapter was the characterisation of our current knowledge and perception
of the immune system. Although limited and not exhaustive, this brief historical outline
of well-established theories, of a few decisive observations, and of the overall
perceptions of immune phenomena is enough to confirm that progress in Immunology
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has not been a continuous accumulation of discoveries. Hence, three ways of organising
immunological thinking and practice were identified — Immunochemistry, Burnetism,
and Jerneism (some aspects are compared in Table 2.1). These three forms of carrying
out science, are not only founded on alternative exemplars, but embody incommensurable
perceptions of reality. Some major switches in the significant facts were already illustrate
(notably by the status of Gershon's paralysis and by the immunologic activity in antigen-
free animals). A consideration of the perception and scientific relevance of normal or
natural serum immunoglobulins will further illustrate the extent of their
incommensurability.
Table 2.1
Disciplinary
Matrix
Immunochemistry
(1900-1960)
Burnetism
(1960-...)
Jerneism
(1970-...)
Level
of
Description
Physical Chemistry
of
Immune Reactions
Molecular biology
of
Molecules and Cells
Organisation of
Molecule and Cell
Populations
Conception of the
Behaviour of
Immune System
Heteronomous
Antigen driven
(Antigen as reagent)
Heteronomous
Antigen driven
(Antigen as cell signal)
Autonomous
Organism centered
Operational
Metaphors
Body or Cells as
Chemical Reactors
Cells as IO-Machines
(Computer)
Self-Organisation
(Brain, Ecosystem)
As discussed previously, normal (or natural) serum (immuno)globulins had a
major experimental and theoretical status in the Immunochemistry matrix — they were
easily revealed and quantified by the analytical methods; they shared with antibody all the
observable physical chemical properties, with the exception of the reactivity to antigen;
and they were believed to be the product of a continuous reaction that antigen, as an
additional reagent, could drive towards the production of specific antibody. Internal to
immunological theory and models, with a different status from that of antibodies elicited
by immunisation, normal (immuno)globulins were one of the most relevant
immunological facts. In the Burnetist matrix, normal or natural serum immunoglobulins
became an irrelevant observation not internal to the theory — by definition they have to
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2. The foundations of the disciplinary matrix
result from contingent environmental immunisations. The finding that the serum levels of
IgM are essentially independent of the antigenic load must be, and therefore has been,
regarded as irrelevant. No one with a Burnetist common sense would spend time
analysing (normal or) natural serum immunoglobulins, expected as they are to have the
same nature and origin as any other antibody, and to have a purely contingent
repertoire.However, (normal or) natural serum immunoglobulins are a fundamental
immunologic fact in Jerneism, where they are back in the core of theory. They constitute
the idiotypic network, they reflect and participate in the self-organisation of the immune
system. The structure of their interactions, the repertoire they embody and their
population dynamics are amongst the most relevant properties of the immune system.
When an Immunologist looks at a band in a gel electrophoresis or an ELISA
titration of natural serum immunoglobulins, what he perceives is strictly dependent on the
Immunological matrix he was trained in. An Immunochemist used to see a species
specific globulin continuously synthesised by globulin-antibody producers; a Burnetist
sees a miscellaneous collection of antibodies resulting from contingent environmental
immunisations, and a Jerneist sees a stable network of interacting immunoglobulins
embodied in a self-organising immune system. They are simply not seeing the same
things! The same conclusion would be reached if a similar exercise was made with any
other observation or concept.
Currently, Burnetism and Jerneism mark the tone of the scientific discussion of
both theorical models and experimental observations. The two incommensurable
perceptions they embody are only rarelly made explicit in literature, that remains in this
regard ambiguous and equivocal. According to Kuhn the coexistence of
incommensurable paradigms is a symptom of periods of crisis in a discipline, and this
crisis is currently acknowledged by both traditional burnetian and innovative jernean.
literature. The historical retrospective allows us to trace the origins of this crises to the
accumulation of anomalies in the dominant burnetian matrix. These were the basis of
jerneism and are now the cumulative product of its research. The other side of the coin is
that jernean research, being concerned with levels of description which are not addressed
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2. The foundations of the disciplinary matrix
by traditional empirical methods, has difficulties in establishing a proper relation between
theory and experimentation, and consequently in convincing a sceptical scientific
community. Whether or not a scientific revolution will emerge from this crises is
something that obviously will only be known a posteriori.
Concluding this historical exercice, some aspects that characterised the emergence
of Burnetism and may be generic for other scientific revolution, can be stressed. Firstly,
the consolidation of Burnetism involved some special situations in which the interplay
between theory and experimentation was fully operational and fruitful, the best example
being the synergy between Burnet and Medawar. Secondly, the newly developed theory
provided a solution for major problems or puzzles steming from the previous disciplinary
matrix, namely the allotransplantation problem and the production of antibodies, but
reformulated them in completely different terms. Thirdly, the alterations in immunological
thinking and practice followed the wider developments in Biology, represented by the
emergence of information theory and of molecular biology.
2.7. Final Remarks.
The emergence of three different perceptions of the immune system along the history of
Immunology was the object of this chapter. Hopefully, the reader has acquired the notion
that current immunological thinking is determined by two incommensurable conceptions
of immunity that were referred here as Burnetism and Jerneism. The former is the
traditional disciplinary matrix. It is rooted in the Clonal Selection Theory of Burnet.
During the last four decades it has accumulated many anomalies in the Kuhnian sense,
notably the established finding that a physiologic (in the sense of nonpathologic)
autoreactivity exists. Jerneism is precisely built upon the major anomalies of Burnetism.
Its classic exemplar is the Idiotypic Network Hypothesis of Jerne, that restated the most
solid propositions of Clonal Selection Theory — notably the one cell-one receptor axiom,
and the generation of diversity —, and accommodated them in the context of the internal
– 65 –
2. The foundations of the disciplinary matrix
organisation of the immune system. The most recent theoretical elaboration on this
exemplar is the working hypothesis that the immune system is organised into a Central
and a Peripheral subsystems; a hypothesis that stems from the recent history of
Immunology as a radically simple but comprehensive view. The postulate of an
organisational dualism allows a comprehensive restatement of the main exemplars of
both Burnetism and Jerneism in a common framework, and in so doing creates a major
problem — How can the ontogenesis of an immune network give rise to an
organisational dualism? The present thesis is precisely an elaboration on the Central and
Peripheral Immune Systems, with special attention being paid to the nature of this
dualism.
– 66 –
2. The foundations of the disciplinary matrix
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