Introduction: Knowledge is survival—The mission of the immune system and its stochastic simulations

Abstract

In this introduction the timeliness and interest of dedicating an issue of Autoimmunity to mostly “discrete” models is motivated by highlighting number of circumstances, observations encounters, that all have favored the rise of a family of agent based simulations of the Immune System. Franco Celada was among the first experimentalists to accept the challenge of interdisciplinarity and create a computational Immune System. He thinks that discrete models are especially useful in handling hypotheses: initiating them, representing their consequences, and revealing their plusses and minuses. He is sure that “looking at” the immune machinery as a cognitive system is useful both to the intuitive understanding and the creative development of models.

Keywords::

• immune system
• cognition
• prediction

Multiorgan evolution

Combustion engines are initially simple and completely mechanic. Just apply a flint spark, and they are up and running until the fuel is consumed. But cars in their evolution have grown to become multiorgan/multisystem complexes, and one of the organs, which happens to be digital, not mechanical, serves as the coordinator.

To control requires understanding, to understand one must acquire complexity. When the complex brain/mind is the object of research, also the methods need to be refined, to multiply and to be combined. The surprising nuclear magnetic resonance (NMR) images of “localized thought” have shattered the disciplinary lines and forced acceptance of an interdisciplinary participation. Such agreement is still far from emerging for most other fields, despite the strength of the motive: the unrelenting growth of complexity. The next discipline online that will serve as a benchmark for the contribution of the exact sciences, and even of philosophy, has to be immunology.

Cognition

Mathematics underpins all of biology, and is applied everyday for measurements, analysis and statistics. As for immunology there is something more unfolding. This is powered by a “new way of looking at the Immune System and its modus operandi. What had been considered the quintessential effector begins to look like a cognitive system; its mission is still to mount responses to foreign invaders, but not before having gathered and confirmed information about their origin: traits, number, speed and potential danger. When it finally moves, its action resembles more a decision than a series of inevitable consequences. Before expanding on this subject, I note that the existence of a recognizable survival-oriented logic at all stages and levels of the response generates a particular model—friendliness, especially toward the discrete, agent-based models, where the programing of each agent is like constructing the brain of a little robot.

Load of regulation

The origin of the specific immune system can be traced surprisingly late in evolution (two billion years after life appeared on earth) and may have been prompted by the sudden availability of a particularly flexible class of proteins, which, I surmise, favored the formation of effector circuits and start the new responses with high efficiency. I also surmise that “excessive” efficiency accompanied by self-inflicted damage to the organism was what triggered the enormous growth of multiform regulation that makes the immune system a large, growing, complex, difficult to stimulate, and therefore safer organ.

The immunization track is full of caution signals that cause innumerable hesitations. One of them freezes a B cell that has bound an epitope. The cell is seemingly afraid to proceed in the routine attack, lest the epitope may belong to the self body, instead of the attacker's. In 1986, this situation was brought to the attention of Umberto Eco, an authority in semiotics, the science of human communication. He and his school had been invited by curious immunologists in the hills behind Lucca. The immunologists wanted to know whether immunocytes were semiotic subjects, like the mind is. “A kneecap hit with a rubber hammer produces an efficient kick, but is not interesting.” answered Eco.

“Instead a cell that could respond but chooses to wait until another, independent cell comes by, makes contact, certifies that the epitope is foreign and releases the proper activating molecules, is a piece of a rather sophisticated cognitive system: one that exhibits the behavior of the human mind confronted with ambiguity”. The organizers of that workshop, Eli Sercarz, Avrion Mitchison, Tomio Tada, and I, recorded the discussion in a typewritten booklet now difficult to find [1] and were delighted by Eco's verdict. In my case, the importance of the conclusion has not ceased growing with the passing of years and decades.

More than one way to skin a cat

The Autoimmunity special issue on modeling reflects the recent progress of discrete simulations of the immune system. The latter are represented by six articles (C, D, E, F, G, H), while only one is a classic “continuous” effort (B), but it should be noted that the simulations utilizing the simulator of the immune system (IMMSIM)-C vehicle (G, H) may be classified as purely discrete, while the rest reach different compromises or mixtures between composing differential equations and relaying on programed agents, and “purity of style” is not the gold standard in this discipline. I am glad to quote Philip Seiden to whom this special issue is dedicated and from whom I learned the little mathematics I will ever know, telling me that a modeler's ideal and strength is to be able to use both tools in the same program. And, I remember him showing pieces of codes with jumps and annotations like a post-dodecaphonic composer's. My mind formed the image of a tennis player, using interchangeably his backhand and forehand, depending on the position of the ball … and where he planned to send it.

Taking to the bench

Three of the contributions of the issue document the innovative attitude toward modeling that allows to decrease or to eliminate the distance or the difference between observation and simulation (e.g., introducing real epitopes on virtual carriers) (C) using computational simulation to model, reproducing the architecture of body tissues or adding the dimension of time on state chart maps, with the aim of generalizing their application to all systems capable of “reactive animation” (D), or experimenting on local parameters of virus–cell interaction down to simulating the growth and replacement activity in in vitro plaque tests (E). The latter article is also an example of style merging, as, starting with traditional differential equations, broadening this approach by introducing agent-based modeling to test cell–virus interactions. It will be interesting to verify the results of this increased truth in the virtual.

Time capsule

Midway in the roster of this issue, I included at the last minute the article (F) authored by Jeff Stewart, Cordelia Valhadji, and Philip Seiden, on modeling the isotype switch that occurs during the antibody response. It is 10 years old, the last paper written by Philip in Princeton, on a theme dear to Marin Weigert, immunologist and patron of modelers. The manuscript, in one single copy, was lost and forgotten, then emerged in Summer 2010, after I had decided to dedicate this special issue to Seiden. I am thrilled to be able to publish it: Philip's hand and mind are there. I hope reading the article will dampen the nostalgia.

Paradigm

The last group of articles is the result of a group effort that began several years ago; it was conducted by “wet lab researchers” and modelers, and focused on “heterologous immunity.” Heterologous immunity is the situation that materialized when cross-reactive, rather than homologous, antigens stimulate the organism at different stages of its life.

In one of the papers (F), Selin et al., the proposers of this paradigm summarize the background, the facts, and the tenets of a view that is central in our concepts of infectious disease and of vaccination. Let it suffice to mention that the cross-reacting recognition is statistically the most probable and the most charged of momentous consequences on survival, stability, and renewal of immunological memory.

Interdisciplinary

Two articles in this section report on the modeling work achieved through collaboration between the UMASS Viro-Immunologists and the NYU modelers. One is a review of the numerous “interventions” of the modelers on experimental results and their interpretation of experimental results (G), the other (H) is the continuation of a systematic study published last year in Vaccine. We like to show and discuss the latter results because the method of in machina experimenting marks a difference with the previous studies illustrated in (G): instead of mimicking in the model a result obtained in vivo and seeing what it takes to bring it about, and hence offer hypotheses about the phenomenon, we have studied a phenomenon in the model (the effect of increasing antigenic distance on memory) using the power of systematic variations of parameters and repetitions of tests, and then discussed the outcome with the experimental scientists, to determine similarities and differences between the data which were so differently acquired. There were two immediate and not mutually exclusive results from this interdisciplinary exercise: to upgrade the simulator and to issue a prediction.

Prediction, art, and science

Modeling based on agents is not a deterministic exercise. It represents what happens if the hypothesis endowed in the making of the agent and the chosen parameters are implemented. It has to be confronted with the real biology, but carries the weight of the past record of the particular model, and its adherence to the present and evolving scientific vision. This weight, rather than its apparent novelty, is the value of the prediction. An added value is the possibility or ability to apply it to biologically related fields.

When our virtual cross-reacting memory cells thwarted specific new responses, we realized that our findings were compatible with and, therefore, validated by the phenomenon described decades ago as “antigenic sin” [2]. But we also caught the link with the body of knowledge that has coagulated over the years around aging of the immune system. We saw that the model of cross-reaction offers a mechanism for some of the consensus facts of aging: the increasing rigidity and overpowering dominance of memory [3–5], which is also favored by the declining output of the bone marrow and the thymus [6,7].

The importance of linking aging and memory that constitutes another interdisciplinary opening for immunologists is also stressed by a more general consideration, i.e. the social awareness that life on this planet has shifted gears, and senescence has occupied a large chunk of individual life times, and will continue to increase its relative fraction. The immune system is certainly among the factors that caused life elongation, but it also bears some traits, like the memory threat, that could cause a crisis, and a collapse of quantity and quality of human life.

Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.