Away with words: commentary on the Atlan–Cohen essay `Immune information, self-organization and meaning'

Rodney E. Langman and Melvin Cohn

Conceptual Immunology Group, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA

Correspondence to: R. E. Langman


    Abstract
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 Abstract
 Can the immune system...
 Noise and music
 Meaning in numbers
 Facing the self-non-self problem...
 The punch line
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 The meaning of numbers
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 One example of a...
 Autoimmunity: many meanings or...
 A way with words
 Immunological theory: what is...
 References
 
Drawing on metaphors from linguistics and information theory, Atlan and Cohen challenge us to take a very different view of the immune system, one that engages in constant chatter among the constituents and allows the immune system to arrive at a decision about what to, and not to, destroy. Our commentary responds to this challenge and points out many logical biological flaws in their view. We seem to agree that specificity is important, and that there is some kind of somatic selection process at work to distinguish self from non-self. Our analysis of models depends on the basis of how self and non-self are separated. There are only two possibilities, time or space; and space-based models are all but ruled out. There are two major kinds of time-based model, one based on the time taken for an organism to develop from embryo to adult, the other based on the time taken for a cell to differentiate from one state to another. With so many ambiguities in the metaphors and so little attention to mechanism, the Atlan and Cohen challenge is, we suspect, based on time measured in cell differentiation units. They also make the common mistake of assuming repertoires that are transcendental in size (>1010), making it impossible to have a functional immune system in animals smaller than a rabbit—a feature that does not instil confidence in the biological relevance of such models.


    Can the immune system identify self on a moment to moment basis?
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 Autoimmunity: many meanings or...
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The notion that self can be determined from moment to moment is claimed by Atlan and Cohen (1) to set their position apart from all others. Not only do they see their idea as unique, but they also assert that other models, including our own, are wrong and inadequate. Therefore, it is of value to examine the claims of Atlan and Cohen in detail.

Atlan and Cohen believe that the immune system can best be understood in terms of information theory as the basis for revealing its putative self-organization and ultimately its meaning. This view is to be contrasted with those, like ourselves, who take an evolutionary and function approach to construct a theory that can be reduced to a mechanism. They begin with the poetically stated postulate that, `...the immune system does make sense out of the bombardment of molecular structures that constantly rain down on the body'. This leads them to pose the question, `How does the immune system create information and meaning from this input?'. They conclude that `the ongoing integration of germline and somatic information in one's body is the essence of self'. Using the metaphors of linguistics they find that `the immune self, like a conversation, is a flowing process that adjusts its responses to the requirements of a particular moment'.

Self is viewed by them as ever-changing and, therefore, must be constantly tracked as such by the immune system. The idea that self is ever-changing has had a checkered past, reviewed by Silverstein and Rose (2) as well as Miller and Basten (3) who also champion that position. The Lederberg 1959 model (4) implicitly accepted an ever-changing self by substituting the state of cell differentiation for Burnet's developmental time as the determining factor in establishing the self–non-self discrimination. The belief in an ever-changing self has gained support thanks to rationalizations based on non-self marker theories of which one example is the `Danger Model' (5), but more of this later.


    Noise and music
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 Can the immune system...
 Noise and music
 Meaning in numbers
 Facing the self-non-self problem...
 The punch line
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 Autoimmunity: many meanings or...
 A way with words
 Immunological theory: what is...
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Atlan and Cohen find it paradoxical that biology requires new information and that this new information must be derived from old information, resulting in something being lost in the process. In the context of immunity they argue that `to create a new antibody molecule out an existing antibody molecule requires a mutation of the existing antibody gene' resulting in its loss. Referring to a series of papers by Atlan (69), they find two necessary conditions for the creation of information. First, the system must be hierarchical and have a multilevel organization so that information created at one location depletes information at another level and so maintains a balanced flow. Second, the system must show redundancy so that the creation of new information does not obliterate the old. The difference between Shannon's original theory and their new one is that while noise destroyed information for Shannon, it creates information for Atlan and Cohen who postulate that `noise (mutation) is the (blind) creator of new information'.

The extension of this creative noise to the generation of a random immune recognition repertoire is straightforward, but it leads Atlan and Cohen to new difficulties—how to pluck from the vast amount of noise the little bit of new information that is useful. They accept as their noise level the oft-repeated calculation of the numbers of different amino acid sequences in Ig combining sites of between 1010 and 1015 only to find that `the chance realization of a large sample of the potential repertoire must produce an unmanageable and inefficient surplus'. They term this the primordial repertoire and note that `from the primordial repertoire, an actual repertoire has to be generated that is reduced in size and focused in a way that augments the frequencies of the more useful clones'. They envisage a repertoire that has a `hierarchy of dominant specificities'. To generate this repertoire they invoke clonal selection as the mechanism responsible for this `reduction in initial redundancy', via the `selective activation of particular clones...to provide a dynamic ordering of the receptor repertoire that reflects the actual antigenic experience of the individual'. Atlan and Cohen observe, `first noise, then music'.


    Meaning in numbers
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 Autoimmunity: many meanings or...
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This class of argument linking a vast and random virtual repertoire to a small selected actual repertoire is not new. Since 1980 we have been complaining about what we termed the `numbers racket' (1014). Put simply, a low-end estimated repertoire of 1010 specificities that is unstructured with respect to the antigenic experience of the individual (i.e. random) can only be structured (i.e. selected) by antigen one specificity at a time. This means that 1010 specificities would have to be picked over before an `actual' repertoire is extracted. In practical terms, this is an absurdity. For example, the mouse, which has only 108 or so B cells, will have to sample the potential repertoire of 1010 specificities, 102 times (assuming no overlaps) to find a given specificity. Assuming a best case scenario in which the entire B cell population is turned over twice per day, it would take >50 days to screen the primordial repertoire for a given specificity. Then, every time that a new antigen (epitope) is encountered, and a new specificity has to be found, another >50 days would be required. Given that it takes a matter of 5–10 days for a typical pathogen to kill the host, neither the potential nor the actual repertoires could possibly be protective under these idealized scenarios. A repertoire that is not protective (i.e. not functional) is not evolutionarily selectable.


    Facing the self–non-self problem or the `creation of meaning'
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 Autoimmunity: many meanings or...
 A way with words
 Immunological theory: what is...
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Having failed to solve the repertoire problem, Atlan and Cohen now turn to the problem of the self–non-self discrimination by looking to a linguistic metaphor in order to find `the meaning of the message'. They observe that the meaning `is never intrinsic to the message'. Rather, it `is the relationship between the message and some reference point outside the information borne by the message'. They ask `what reference points external to the antigen can serve the immune system to endow the antigen with meaning?'.

They begin their answer by considering Burnet's 1959 proposal (15). With a certain poetic license we can accept Atlan and Cohen's interpretation of Burnet—that `the essence of immune meaning was held to be the product of the lymphocyte's history of being born into a context of self antigens'. Alas, they note, the immune system is more complicated than Burnet had imagined and his view is simply not good enough any more.

What, then, are these complications that must be solved? Atlan and Cohen find the challenges of natural autoimmunity and positive selection to be paramount. They are confounded by the fact, as reported by Avrameas (16), that `the immune repertoires of healthy individuals are filled with lymphocytes whose receptors can perceive self epitopes'. Moreover, as Cohen has noted on several occasions (1719), `infectious invaders, which must be rejected by the system, often express epitopes identical to, or cross-reactive with self-epitopes of the host'. In other words, the first stumbling block for Atlan and Cohen is that, `self is not antigenically unique and self purging is not complete'. This leads them to the second stumbling block, i.e. that `autoreactivity of a type is essential to the creation of the repertoire'. Here they are referring, not to natural autoimmunity, but to the phenomenon of positive selection that occurs during T cell development. Taken together these two complications lead Atlan and Cohen to conclude that `the problem of meaning is not solved by Burnetian-type deletion alone'.

Poetic license is sorely stretched when Atlan and Cohen describe our efforts to solve the self–non-self discrimination problem as an attempt to simply `enrich the concept of clonal selection'. While the necessity for two signals was a postulate of the 1970 version or `minimal model' of the self–non-self discrimination (20), what was central to that model is the principle of associative recognition of antigen that linked the two signals. The two signals were put in a precise relationship or context to each other. One signal had to produce a necessary state of irreversible unresponsiveness with respect to self components, the other signal had to produce a protective response to potentially pathogenic non-self agents. There is no mention in any of our papers of a cytokine produced by T cells acting as one of these two signals; rather, we envisage cytokines as regulating the class and the magnitude of the response, not whether a response can occur. In a series of papers (2126), we have gone to some pains to explain the principle of associative recognition of antigen (ARA) and to warn against equating it with just any two signals. As for the complaint by Atlan and Cohen that the ARA theory has not been able to account for natural autoimmunity, where natural autoimmunity of the type they refer to is clearly not lethal, or even severely debilitating, we first have to ask if such an accounting is necessary. The evolutionary selection pressure for a self–non-self discrimination is the necessity to rid the invader without debilitating the host. In this framework, does immunity to effete cells and senescent proteins contradict the theory of associative recognition of antigen? The answer is clearly, NO. Indeed there is a beneficial role for what we have called `housekeeping', which includes antibodies to effete erythrocytes, Ig and other waste products that make up the vast majority of those so-called anti-self antibodies referred to as `natural autoimmunity' by Atlan and Cohen. The mechanism by which the immune system recognizes housekeeping antigens as non-self is a valid question that we will address later.

For Atlan and Cohen to brush off the idiotypic network concept proposed by Jerne by lumping it with the concept of ARA and claiming that the two concepts merely added `diversity and complexity to the organization of the repertoire', leading to `more information, not necessarily meaning' is a little surprising. We have provided detailed arguments explaining why idiotypic networks (2729), including such variations as the `homunculus' of Cohen, are untenable on a priori grounds. These arguments are ignored by Atlan and Cohen who offer instead cabala, such as, `meaning must be created by relating the antigens seen by the receptor repertoire to something else, outside of the repertoire'.

The `danger model' (5) is given more ink, but it suffers the same fate of becoming lost in Atlan and Cohen's convoluted reasoning. Our criticism of the `danger model' includes the point that this model has simply renamed the self–non-self discrimination, the danger–non-danger discrimination (21,2426,30,31). However, Atlan and Cohen comment `even if we were to argue with Langman and Cohn, and accept the novelty of the `danger' idea, the concept is deceptively simple'. We simply dare not hazard a guess at the meaning of this sentence of theirs. Atlan and Cohen go on to dismiss `danger' on the grounds that there have to be different types of danger for the different classes of protective response, in other words, `the system has to diagnose the type of `danger' to be able to deal with it properly'. Nobody has argued that the class of the immune response is determined by the self–non-self, or danger–non-danger discrimination, making this dismissive argument of Atlan and Cohen quaintly irrelevant.


    The punch line
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 Can the immune system...
 Noise and music
 Meaning in numbers
 Facing the self-non-self problem...
 The punch line
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 Back to Burnet
 One example of a...
 Autoimmunity: many meanings or...
 A way with words
 Immunological theory: what is...
 References
 
Finally, we come to the sections entitled `the cognitive creation of meaning' and `the language metaphor'. Here Atlan and Cohen expound the notion of a cognitive paradigm that suggests to them a linguistic metaphor. A language is created by `linking two ontogenetically different classes of molecules in a syntactical fashion'. These two classes are a set of specific antigen-receptors on T and B cells that are `somatically generated' and `a class of molecules responsible for internal information processing...encoded in the individual's germline'. Atlan and Cohen explain that `the antigen is like a noun serving as the subject (or address) of the immune sentence, while the germline signals are like predicates'. Therefore, a `chosen type of immune response is the outcome of concrete connection between antigen subject and germline predicate signals'. They continue, `the transcription of the antigens into processed peptides embedded in a context of germline ancillary signals constitutes the functional language of the immune system'. Despite several careful readings of these sections we remain unsure if the meanings of self and non-self are the germline predicate or whether it is some other property of the immune system that they are concerned with here.

It is under the title `dangerous teleology' that Atlan and Cohen show how their cognitive paradigm permits the system to generate its own meaning, in contrast with `the self–not-self and `danger' concepts, which attribute the functional organization of the immune system to some end or aim'. It is no good, they argue, to say that these are merely shorthand ways of saying `that `evolution' has naturally selected the immune system to be the way it is because it is the absence of autoimmunity or of danger that has survival value'. Atlan and Cohen think that this `passing the buck will not help; if natural autoimmunity is prevalent, then autoimmunity must be compatible with the supposed `aims' of evolution'. Cautiously we are advised `to keep an open mind' and Aristotle's view that teleology, as `one of the prime causes for the existence of an entity', might be right after all. We remain confident that evolution cannot be goal-oriented on the grounds that mutation precedes selection, rather than selection preceding mutation. Atlan and Cohen seem to again stretch poetic license and argue that prevalent `natural autoimmunity' is all `autoimmunity' that `must be compatible with the supposed `aims' of evolution'. We all agree it is only biodestructive autoimmunity that is a selection pressure.


    The bottom line
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 Meaning in numbers
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 Autoimmunity: many meanings or...
 A way with words
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The self–non-self discrimination is more than a mysterious chant, because, at the end of the day, we need mechanisms not metaphors or descriptive translations into information theory. We need to reveal the mechanism that the immune system uses to decide what to destroy (e.g. a pathogen) and what not to destroy (e.g. the host itself). Words, eloquent, poetic and otherwise, are not understood by the immune system, and melding all forms of self-recognition into one giant muddle and calling it `autoimmunity' is not clarifying. It would be hard to disagree with Atlan and Cohen's conclusion that `autoimmunity is benign so long as autoimmune inflammation has the capacity to turn itself on and turn itself off as the need arises, to kill aberrant cells or to heal, repair and regenerate damaged tissues'. We would all accept that it is the lethal effect of immune reactions, not their binding characteristics, that drives the necessity for a self–non-self discrimination. Only when details of mechanism are discussed are the differences apparent—the cognitive language metaphors of Atlan and Cohen are detached from any hint of mechanism.


    The meaning of numbers
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 Autoimmunity: many meanings or...
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We have proposed (1013) that the `primordial' repertoire referred to by Atlan and Cohen is limited in size and germline encoded. Antigenic selection on the germline results in a repertoire of paratopes of N VLVH, which, by random complementation, yields an antigen-unselected germline-encoded repertoire [(N2 N) VLVH]. Given that N ~ 102, this germline-encoded repertoire is of the order of 104. We have described this repertoire as the Stage I or high copy number (HCN) repertoire because, as a consequence of germline expression, each specificity is present in 102–103 copies per 107 B cells. Of course, today, distinguishing between the antigen-selected and antigen-unselected specificities encoded in the germline is only based on reasonable guesses (8). Under this view, the DNJ (so-called CDR3) region, which contributes almost all of the amino acid sequence diversity, must have another functional role (11,12,14). Quite obviously a set of N VL and N VH gene segments can only contribute N2 VLVH = 104 specificities that comprise the `primordial' repertoire. To arrive at a `primordial' repertoire of 1010–1015 specificities, the DNJ region must contribute the rest. What would the selection pressure for more than a handful of VLVH pairs or for somatic hypermutation, if DNJ variation alone generated >>106 specificities per VLVH pair?

A HCN repertoire of 104 is the substrate for somatic hypermutation, which yields an antigen-unselected low copy number (LCN) repertoire of ~105, each specificity of which is expressed at the level of 1 copy per 107 B cells. This is the initial or virgin repertoire that is functional and responds in a primary encounter with `pathogen'. Any individual who cannot survive a primary encounter is unlikely to worry about a secondary encounter. The HCN and LCN repertoires cooperate synergistically. The HCN repertoire permits a sufficient response in a short enough time but lacks a large enough repertoire of paratopes to protect against the encountered pathogenic world. The LCN repertoire is sufficiently large but its response time is too long. Together they are adequate (12).


    Back to Burnet
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Burnet (15), by producing a model, should be credited with being one of the first to face the problem of a biodestructive immune response that was at once helpful if directed at pathogens and harmful if directed at essential self components. He insisted that the self–non-self discrimination had to have a solution. His model was erroneous in several ways, but these were corrected by the ARA model, which has been developed and made more precise over some 30 years (20,22,23,32,33).

Burnet (15) arrived at his conclusion that developmental time was the basis for distinguishing self from non-self, as a consequence of an erroneous assumption that he borrowed from Jerne (34), i.e. that the total repertoire was generated `big bang' during a window in developmental time. Once this window closed, the next ontogenic stage of the animal's development rendered all of the antigen-responsive cells tolerizable-only. Any reaction with antigen during this period deleted the cells (these would be the cells with specificities defined by the immune system as anti-self). The animal then developed to a normal adult-like stage where the unreacted cells (defined by default as anti-non-self) differentiated to be inducible-only in the presence of antigen. Given the `big bang' expression of the repertoire, a filtering or clonal deletion of anti-self reactive cells was obligatory. It is the window of diversification that dictated the requirement for a window of tolerizable-only activity during developmental time. Self in this model need only be prior; persistence is not required. As an aside, in 1964 Burnet (35) abandoned this 1959 model that required a window of diversification and in the end left us with no theory of the self–non-self discrimination.


    One example of a mechanism of self–non-self discrimination
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The ARA Model made three clean breaks with all previous formulations (20,22,23,32,36):

(i) It defined an initial state or intermediate cell (i-cell) with no effector function. At this stage a decision is made between i-cells that are anti-self, which are inactivated, and those that are anti-non-self and activated. Immunologists have used terms like `antigen-sensitive or antigen-responsive cells' for i-cells without putting them in the precise context as a decision step.
(ii) It provided a mechanism for activation referred to as ARA, which permits a coherent response to a given antigen. A pathogen is a collection of proteins and proteins are processed to peptides. An effector regulatory cell (e.g. eTh or eTs) interacting with one epitope on the antigen (defined as the unit of elimination by the effector output) signals every i-cell interacting with other epitopes on the antigen (unit of elimination) what its behavior should be. This is how the response is made coherent. In the absence of eTh, the response to that antigen by all i-cells that interact with its component epitopes, is one of inactivation.
(iii) By postulating the steady-state generation of the repertoire throughout life, it made the origin of the distinction between self and non-self a historical process, developmental stage dependent, in that it defined self as `prior and persistent' and non-self as `posterior and transient'. All previous models had defined self as either prior (15,34) or persistent (4), not both.


    Autoimmunity: many meanings or one?
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Atlan and Cohen, like many others before them, run into difficulty when using the term `autoimmunity' to describe many kinds of `self' in the `auto' of autoimmunity, and many kinds of reactivity, from in vitro antibody binding to in vivo death or serious debilitation, in the `immunity' of autoimmunity. We have dealt with these issues repeatedly in the past (26,28,29,32, 37,38). Any immunologist who defines self as anything under the integument, or encoded in the germline, or autogenously generated, invites being misled. The immune system has no way of assaying the origin of the antigen it encounters. It must be the immune system, not the immunologist, which defines self.

We examined the relative merits of using time and space as ways of separating self from non-self (30,31), and concluded that self can only be defined as that which is `prior and persistent,' making non-self that which is `posterior and transient'. To achieve this there is a period during developmental time when self, but not non-self is present, and the immune system is unresponsive due to an insufficiency of eTh. As long as these prior antigens persist, i-cells specific for these antigens (i.e. anti-self i-cells) are deleted as they arise, thereby maintaining the insufficiency of eTh anti-self. During this period the cells of the developing embryo die by apoptosis, which means that they form vesicles that are phagocytosed without releasing their contents. The newly arising immune system does not encounter the cellular contents. The mature animal faces a set of housekeeping antigens, which are derived from cell necrosis, proteins that become effete and cell senescence. These components become targets of the immune system because they are treated as non-self (`posterior and transient') and are ridded.

In a new twist Atlan and Cohen find `autoreactivity of a type is essential to the creation of the repertoire'. They note that `thymic T cells will not survive...unless they have been positively selected...to recognize self-epitopes', making it `clear that some degree of self-recognition is a prerequisite for thymic T-cell development'.

Is positive selection in the thymus an example of the violation of the necessity to make a self–non-self discrimination? The literature contains repeated statements that the MHC-encoded restricting elements (R) are special when considering the self–non-self discrimination because the immune system must recognize self-R in order to carry out restricted cell-mediated T cell functions. The recognition of self-R is then viewed as a violation of the necessity to make a self–non-self discrimination. This muddled use of `self' in describing the allele of R expressed uniquely on special thymic epithelial cells ignores the fact that this `self-R' is functioning in a signaling interaction referred to as restrictive recognition of antigen (its normal physiological role). In this context it is not functioning as a self component. However, this same R must also function as a normal self component with respect to the biodestructive immune reactions and deliver Signal[1] via the TCR to an iT cell leading to its inactivation.


    A way with words
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While we are seeking to analyze the immune system in evolutionary, cellular and molecular terms, Atlan and Cohen feel that metaphorical descriptions give us an insight and guidance missed by this approach. They, like many immunologists (e.g. 2,3,5), feel that the assumption of a static self must be wrong, citing such intuitive arguments as self must change during pubescence and aging, or foreign fetuses are not rejected by the mother, or lactating females do not become autoimmune to milk, etc. These arguments are of limited value as we have no clear cut example of a self component to which the postpubescent individual is tolerant and the prepubescent individual is responsive. The maternal–fetal relationship remains special and enigmatic, even in light of the surprising recent finding that the fetus is not rejected by the mother because of an inhibitory enzymic activity present in the placenta preventing T cell responsiveness (39).


    Immunological theory: what is it that has to be explained?
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First, it is so obvious we can consider it a law, that any biodestructive defense mechanism must specifically distinguish self from non-self. Whatever other properties one might choose to assign to the immune system, it does function as a biodestructive defense mechanism and the defense mechanism itself must make a self–non-self discrimination.

Second, there is the F1 experiment, which demonstrates that the AB offspring of AA and BB parents does not self-destruct even though the AA and BB parents would reject tissue grafts from each other, and importantly tissue grafts from the AB hybrid. This illustrates the principle of a somatically selected self–non-self discrimination where the somatic history of an individual determines the antigens that are tolerated from those that are not. The alternate form of self–non-self discrimination is via germline selection and the elimination of individuals.

The questions seem clear.

(i) Does the immune system make a germline or somatically selected self–non-self discrimination? (As an aside, if the repertoire of immune specificities is generated somatically, then the self–non-self discrimination must be made somatically. A germline selected self–non-self discrimination can only operate on a repertoire of immune specificities that is germline encoded.)
(ii) If the self–non-self distinction is made by a somatic selection process, is the separation of self and non-self made on the basis of time or space?
(iii) If the self–non-self distinction is made by a time-based separation, is time measured in terms of the life of a cell or the life of the organism?

Our answers to these questions are less important than the need to face them. We searched the Atlan and Cohen paper for answers, and found conflicting answers, including the possibility that both germline and somatic factors are needed to make the self–non-self discrimination, and the only hint of how time is used comes from the notion of an ongoing set of decisions, which could only be made via mechanisms that measure time in terms of the life of a cell. Our interpretations may, of course, be wrong, but the first thing to get straight is what questions we all think need answering.


    Acknowledgments
 
This work was supported in part by NIH grant RR07716


    Notes
 
Transmitting editor: B. Bloom

Received 5 December 1998, accepted 18 February 1999.


    References
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 Meaning in numbers
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 Autoimmunity: many meanings or...
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 Immunological theory: what is...
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