Immunology is in crisis. Despite advances in the knowledge of molecular mechanisms and therapies made in the past 25 years, the structure of the theory that has guided the discipline since the 1950s is collapsing. Irun Cohen, a leading experimental and theoretical immunologist, is one of the prophets who clearly sees the limits of current dogma and who has the vision to propose new alternatives. Not content with continuing his argument with fellow immunologists alone, he designed his book for a wide readership.Tending Adam's Garden can be roughly divided into two parts. The first half serves as background for Cohen's alternative concept of immune function: a dynamic, self-organizing system devoted to cognition. With this general introduction, Cohen, in the second half, sketches a portrait of the immune system and autoimmunity, emphasizing causation, cognition, and complexity, in an attempt to replace the existing concepts. Beyond the philosophy and polemics, Cohen offers a creative and provocative reading of contemporary immunology, one that may well guide the discipline as it seeks solutions to its paradoxes, and he creates models for restoring its increasingly complex components into a coherent whole. The focus of Cohen's critique is the clonal-selection theory, which was originally proposed by Sir Frank Macfarlane Burnet and is the governing model of immunology. But this theory, which some orthodox textbooks have referred to as a fact, can, in Cohen's words, no longer account for what we have learned about the immune system. The basic precept of the clonal-selection theory -- the specificity of self-antigens and the discrimination between them and foreign antigens -- does not hold. The theory's notion that there exists a one-to-one correspondence between an antigen and its receptor ignores the essential lessons of contemporary immunology: The meaning of a given antigen is governed by the complex interplay of the endogenous and exogenous factors in which it appears. What Cohen calls specificity -- the particular meaning of an antigen (is it self or foreign?) -- is determined not by its intrinsic character, but rather by the context of its presentation. The idea that an antigen is either self or nonself is lax and ultimately inadequate because of the degeneracy (nonfidelity of perception), pleiotropism (the diversity of effects), redundancy, and randomness of immune receptors. Cohen asks, How can the system generate specificity out of the basic non-specificity of its component parts? The answer Cohen offers requires thinking about the immune system in a radically different way. Cohen is one of the principal proponents of a contextual theory of immune function, which asserts that the components of the immune system mutually respond to the antigenic world by forming regulatory networks. Macrophages, T cells, and B cells reinforce and modify their diverse views of the world and thereby forge an intricate network of cytokines, antigen receptors, and antibodies in a self-regulating lattice. Working in parallel, the major cellular components note different features of any target (host or foreign) and, after making their respective observations, report their characteristic findings to the other components. In other words, the immune system responds to its own response. As Niels Jerne argued in the 1970s, it is the pattern of cognition, not some simple on-off switch, that is critical for responsiveness. So, just as the cones of the retina can sense only three colors, so too do three types of immunocytes give rise to a cognitive system that perceives, processes, and acts on information. The seeming defects of the lack of a one-to-one specificity of antigen and receptor is, according to Cohen, the solution to immune behavior. In his scheme, degeneracy and pleiotropism become the essential characteristics of the construction of immune patterns. In short, immune specificity... is not a given, it is a construction. It is a short step from this postulate to the idea that nothing is intrinsically foreign or native: only the context designates the character of an antigen. Cohen's views relate directly to his concept of autoimmunity, which is not an aberration, as taught by the classical CST [clonal-selection theory], but is at the heart of the immune system. For Cohen, the immune system is organized around key self-antigens, the so-called immune homunculus, a schematic signature of the self that serves as the organizational point of immune function. For Cohen, the immune system is constantly sensing these self-antigens and thereby governs the integrity of the organism (an idea first proposed in a different form by Elie Metchnikoff more than a century ago). The foreign is seen with that antigenic lexicon, and reaction occurs when the pattern of sensing self is disturbed. In this scheme, Cohen has retained Jerne's essential theoretical point: the immune system can only know itself, and thus autoimmunity is intrinsic to the behavior of the normal immune system. Autoimmune disease is the disregulated state of this normal surveillance, and Cohen argues that the treatment of autoimmune diseases should be directed at reestablishing the homeostatic balance of autoimmunity. He believes that the clonal-selection theory will ultimately be overturned because its therapeutic approach -- abolishing autoimmune clones -- has failed, and the success of reactivating or balancing autoimmunity will confirm the cognitive concept. Cohen has attempted to undercut the complacency of a discipline that at times seems excessively satisfied with its own achievements and expectations. He challenges the clonal-selection theory but aims even higher: Tending Adam's Garden is an ambitious statement about biology, and like Gerald Edelman's Neural Darwinism: The Theory of Neuronal Group Selection (New York: Basic Books, 1987) or Richard Dawkins's The Selfish Gene (New York: Oxford University Press, 1976), it seeks to establish a new vision, a different way of conceiving the organism. Cohen is fundamentally concerned with our attraction to oversimplified models of life processes that are based on linear mechanical causation. He would have us think instead of the system as a whole -- its informational character and developmental properties and the complex self-organizational dynamics required to explain these characteristics. In this sense, immunology is a particular example of more general complex biologic systems. The ultimate success or failure of Cohen's concepts will depend on many factors beyond his control or prediction, but at the very least he may be satisfied with, and we may be grateful for, the cogency of his argument and the creative insight he has offered into the nature of immunity, the organization of its function, and the promise of therapeutic approaches based on new ways of thinking. He has provoked us to question the basic assumptions of immunology, I believe he has done more, by showing us the shape of its future. Reviewed by Alfred I. Tauber, M.D. Copyright © 2000 Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine is a registered trademark of the MMS.