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J. Biol. Chem., Vol. 279, Issue 9, 7361-7369, February 27, 2004
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Biochemistry and the Sciences of Recognition
From the Neurosciences Institute and the Scripps Research Institute, San Diego, California 92121
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INTRODUCTION |
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TOP
INTRODUCTION
Antigen Recognition and...An account of the slow emergence of scientific insight is not in any straightforward way a reliable reflection of a life course. I do not intend here to be explicitly autobiographical but want nevertheless to reflect on whether there is a pattern that has unconsciously guided my scientific work. I believe there is one, if I neglect some noisy interludes. Like Moliere's Monsieur Jourdain, who was astonished to realize that he had been speaking prose all his life, I have come to realize that even when my scientific interests turned to very high levels of organization (organismal, even mental) I had been following the rules of biochemistry. These rules are not just those of organic chemistry itself but also of that chemistry as it emerged under the constraints of genetics and evolution. So although the precision is lent by the syntax of organic chemistry, the semantics or significance of biochemical processes is embedded within the astonishingly rich complexity of cells, organs, and organisms interacting across many layers of organization.
There is a theme that weaves through these layers, which in retrospect I see has shaped my interest. It is the Darwinian approach of population thinking (1), based on the notion that species, categories, and even molecular interactions in living systems arise by selection acting over time on populations consisting of large numbers of variants. The idea that variation is not noise but is rather the substrate for the emergence of biological form and function provides an underlying theme that is central to and defining of what I have called the sciences of recognition. These include evolution itself, embryology (particularly morphogenesis), immunology, and the neurobiology of complex brains. In all these arenas, recognition at molecular, cellular, and organismal levels occurs through selective processes. In each case, the substrate is biochemical although the higher order rules are governed by variation and selection.
I propose to tell a few anecdotes from my early experiences, particularly those that led to molecular immunology. I recount them to point out that scientists can have blind spots and occasionally forget the lesson that one must consider all the levels of organization that emerge from selective events.
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Antigen Recognition and Molecular Immunology |
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In 1958, I was fascinated by the specificity of antigen recognition by antibodies. At the same time I was frustrated as a chemist by the heterogeneity of the
-globulin fractions containing these antibodies (2). Free boundary electrophoresis by Arne Tiselius and Elvin Kabat (3) revealed a stark contrast between the distribution of net charge of these proteins as compared with that of other serum proteins. I was driven by the hope of resolving this heterogeneity and had the dream, naïve as it was at the time, that by doing the primary structure of antibody molecules, the basis of their specificity would be revealed. In 1959, after cleaving disulfide bonds in so-called 7 S -globulins, I decided to examine their behavior by analytical centrifugation. (From now on I will refer to these molecules as immunoglobulins, the modern term.) I was both startled and elated to find that the molecules dissociated into subunits after reduction and alkylation in a denaturing solvent (4). This provided grounds for my first hope: that one of the polypeptide chains might be small enough to work out its amino acid sequence. At that time, Sanger (5) had completed the sequencing of insulin (molecular weight, 6000), and Stein and Moore (6) were sequencing ribonuclease, which had a molecular weight of about 13,700. My hopes were certainly naïve for the 7 S immunoglobulin had a molecular weight of 150,000. In any event, the problem of heterogeneity remained to be solved. In the early 1960s, two ideas that were derived from my medical experience proved critical. The first was that perhaps the proteins found in large amounts in the serum of patients with the cancer of plasma cells called multiple myeloma might in fact be pure immunoglobulins. Unlike immunoglobulins from normal persons, they were each homogeneous and each differed from the others in net charge. It was easy to show that these myeloma proteins could be cleaved into polypeptide chains of the same size as that of their supposed normal counterparts.
In some patients with myeloma, the urine contains a smaller protein that is also homogeneous but with a remarkable property. When heated, the urine becomes cloudy in much the same fashion as urine containing albumen. However, on continued heating the urine becomes clear. This so-called Bence Jones protein was the second protein discovered after Liebig first described albumen. Given my hypothesis about myelomas, the thought arose that perhaps Bence Jones protein was one of the chains of the myeloma protein that spilled into the urine because of its relatively low molecular weight (about 22,000). If this were the case, the dream of sequencing an immunoglobulin might be realized.
What about specificity? There was no evidence that myeloma proteins were synthesized as a result of immunization by specific antigens. It was much more likely that the process of neoplasia occurred in a single plasma cell, causing it to overproduce a myeloma protein. This was consistent with the idea (not at all popular at the time) that each myeloma was a single member of a vast preexisting population of immunoglobulin antibodies. These notions were consistent with the proposals of Niels Jerne (7) and Macfarlane Burnet (8) that the immune response was a selectional, not an instructional, process. That is, the various immunoglobulins were synthesized prior to antigen exposure and made up a repertoire of variant proteins; immunization by an antigen stimulated division of those cells with immunoglobulins that happened to bind that antigen and thus make more antibodies (Burnet's process of clonal selection). The most popular theory at the time was, by contrast, an instructional one, the clearest expression of which was that of Linus Pauling (9). The single long chain of the antibody was assumed to fold around the immunizing antigen, providing a complementary fit which after dissociation of the antigen could then bind molecules of similar shape by weak forces. This theory by a great chemist was straightforward and widely accepted but later turned out to be incorrect.
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Learning from Theorists |
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And now, two anecdotes. The first considers events that followed the demonstration with my student, Joseph Gally (10), that the light chains of myeloma proteins and Bence Jones proteins were identical. With M. Poulik, we were able to show that each myeloma protein, when reduced and alkylated and subjected to starch gel electrophoresis, had a unique migration pattern (11). Bence Jones protein obtained from a patient's urine exactly matched the mobility of the light chain from the serum myeloma protein of the same patient. Subsequent experiments on antibodies against defined chemical groups called haptens, purified by B. Benacerraf, revealed light chain patterns that differed for each specificity (12). Within short order we were able to show that the light chains from the different antibodies differed in amino acid composition.
Some months after these discoveries, I was invited to speak in San Francisco at a Kaiser Foundation symposium. I decided that I would show how our findings corroborated selectional rather than instructional theories of antibody formation. When I arrived I saw that the first speaker on the day of my lecture was Linus Pauling, who planned to talk about his instructional theory. I arranged in haste to have a mutual friend set up a dinner with Pauling the night before. Most of the evening was spent on Pauling's concern with nuclear containment and all I could get across was one statement: "Sir, we have found that antibodies are composed of multiple polypeptide chains and those of different specificities have different amino acid compositions." Pauling carried on serenely with no rejoinder. This left me in a bit of a quandary concerning how I would present my conclusions the next day.
I decided to stick closely to the facts. Pauling launched forth in his characteristically brilliant style. When he got to a diagram of the antibody molecule folding around the antigen he said: "This is a diagram of one of the polypeptide chains of the antibody molecule." I realized that he had instantly grasped what I had said at dinner the night before. When I finished presenting my contrary evidence (without polemical confrontation) I returned to my seat. I found a note on the seat. It said: "Edelman, send reprints. Pauling."
Before I deconstruct these events, I want to recount a second anecdote about my encounter with another great scientist. This was Macfarlane Burnet, whose selectional theory, the theory of clonal selection (8), turned out to be correct. While Gally and I were pursuing our work on myelomas, convinced that selectionist ideas were correct, we received a visit by Burnet in our small basement laboratory. He asked: "What are you doing?" I replied, "We are working on the chemistry of antibodies and hope to work out their detailed structure. Like you, we are selectionists."
He replied, "You are wasting your time. Chemistry only makes things more complicated. I don't even call them antibodies. The term recognizers is good enough." I replied, "But Sir, if we don't do the chemistry to show how many variants there are in the antibody repertoire, we won't know if the theory is sound." He said, "Mathematics can make things even worse. Don't worry, young man, my theory is correct."
Well, it turned out that it was correct. Reflecting on the gifts and contributions of Pauling, the chemist, and Burnet, the biologist, I could see hints of blind spots that sooner or later we must all confront. Pauling looked only at the chemical level. He ignored the fact that the body did not produce antibodies to its own antigens, a fact difficult to account for simply by instructional folding. This cellular phenomenon of immune tolerance was a key element in Burnet's thinking. For his part, Burnet was insufficiently respectful of the biochemical rules, the syntax that would ultimately reveal in detail the origins of antibody diversity and specificity.
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The Dénouement: Domains and Somatic Variation |
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The analysis of these rules was to emerge largely from the work of our laboratory and that of Rodney Porter (13, 14) in the mid-1960s. Porter had cleaved the antibody molecule by the protease, papain, yielding one fragment with antigen binding properties and another fragment with other physicochemical characteristics. This early work nicely complemented our studies of chain structure and allowed the formulation of a model consisting of two light chains and two heavy chains. Following upon Hilschmann's demonstration (15) that light chains were composed of variable and constant regions, both laboratories began work to establish the complete amino acid sequence of a myeloma protein, work completed in our laboratory in 1969 (16, 17). The resulting picture was quite beautiful, providing a basis for the assignment of function and for analyses of the origin of antibody diversity. It was also the first demonstration of domain structure in a large protein.
From the mid-1960s on, there was an explosion of theoretical work, which would eventually show that antibody variation at the antigen binding site was largely a somatic process involving somatic mutation and recombination of DNA in antibody-forming cells and their precursors. This was eventually confirmed by the studies of Tonegawa (18), which revealed these processes in fact to be the origin of diversity. Immunology was revealed as a science of recognition having special mechanisms of somatic selection that themselves had evolved by natural selection.
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Cell-Cell Recognition and Morphogenesis |
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By 1970, I concluded that the work in immunology had "scratched my itch" and I decided to move on to developmental biology. I was particularly intrigued with the daunting puzzle of morphogenesis. What kind of recognition does this require at the molecular level? In the classic period of embryology, this question could not have been asked with any reasonable expectation of an answer. Instead, there was the now discredited ontogenetic law of Haeckel (ontogeny recapitulates phylogeny) and the rather more correct view of von Baer which stated that, although early stage embryos of different species resembled each other, as development progressed each species expressed its own idiosyncratic morphological pattern. Later on the German biologists His and Roux (19, 20) concentrated on the mechanics of development, the so-called "enwicklungsmechanik." This emphasis is important to this day. However, it did not deal with the equally important problem of how shape is inherited, a central concern of evolutionists and geneticists. How can the genetics (the one-dimensional genetic code) be linked to epigenetic processes to specify a three-dimensional animal in the fourth dimension of time?
Brilliant work had been done by Spemann (21) on embryonic induction, showing that signals from the so-called organizer could set up the embryonic axis. Work by Holtfreter (22) showed that dissociated cells from the different germ layers would sort out to re-form these layers. Despite these and other remarkable achievements of the embryologists, a global explanation of how the genetics and the mechanics worked together to yield form was lacking.
Even during this early work, it was clear that form arose from some combination of the primary processes of development: cell division, cell migration, cell death, cell adhesion, and embryonic induction. It seemed to me in the mid-1970s that cell adhesion was a central candidate process in establishing and maintaining animal form. However, to link it to genetics required that it be mediated by specific protein molecules and not, as the then prevailing view had it, by weak forces at the cell membrane (23). I was stimulated to reach this conclusion by the description of mice that showed abnormal morphogenesis of the cerebellar cortex as a result of point mutations (24).
Given my immunological experience, it was not surprising that I attempted to raise antibodies that, when present in cell cultures, would prevent cell-cell adhesion. My colleagues and I decided to use retinae from embryonic chicks as a source of cells, on the assumption that we would need large numbers of cells. It turned out, in fact, that we used up thousands of fertilized eggs. This effort, which began in earnest in 1974, finally yielded a specific antibody, allowing us to isolate the neural cell adhesion molecule (NCAM), the first cell-cell adhesion molecule to be purified and characterized (25, 26). NCAM is a most unusual intrinsic membrane protein that is expressed at a very early stage of vertebrate development. It is later expressed on all neural tissues and some other tissues in specific patterns that, when perturbed by antibodies, result in distortions of form during embryonic development. At about the same time, we began to isolate CAMS that, unlike NCAM, required calcium for their cell-cell binding activity (27). These calcium-dependent CAMS were also studied extensively by Takeichi and co-workers (28) who named them cadherins.
As is usually the case in such periods of discovery, there was an explosion of work on the differential binding of these CAMS, their location at different sites during development, their down-regulation during cell movement, and their effects on cell division. A key emphasis in my laboratory was on structure and binding. Early on, we found that NCAM had an unusual negatively charged sugar, polysialic acid, which changed in amount and form during development (29). We were also able to show that NCAM binding was homophilic; NCAM on one cell bound NCAM on an apposing cell. High amounts of polysialic acid tended to weaken this binding during cell migration, which, in some locations, was also favored by down-regulation of the CAM at the cell surface.
All of this work was extremely rewarding. However, none of it conveyed the shock I received when Bruce Cunningham and our colleagues analyzed the cDNA and cloned the gene for NCAM (30). When referred back to amino acid sequence, the data indicated that the molecule was made up of domains that were strongly homologous to immunoglobulin domains. This work also revealed the basis for the three spliced forms of the protein. Although to this day the exact assignment of homophilic domain interactions has not been resolved, the binding mode involves complementarity between immunoglobulin-like domains. Confronting the sequence relation between NCAM and immunoglobulin, I could not help recalling T. S. Eliot's line in his "Four Quartets"—"In my end is my beginning."
Adaptive immunity mediated by immunoglobulins is seen only in vertebrate species. The demonstration of molecules homologous to NCAM in invertebrates suggested that immunoglobulins and NCAM were likely to be descendents of a common evolutionary precursor (31, 32). However, unlike antibodies, NCAM did not operate by expressing variable regions in its combining site. Instead, cell-cell recognition operated by place-dependent differential expression of NCAM along with that of other CAMs. By now, over 100 CAMs have been found. Clearly, many different recognition states could be realized by such differential expression without the need to account for morphogenetic patterns by invoking millions of variants of prespecified binding proteins.
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Topobiology |
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This picture is consistent with the notion that cellular dynamics during development operates to give shape by altering interactions among local collectives of cells. These interactions occur epigenetically and not according to a protein code. Of course, differential gene expression is intimately involved. It is now known, for example, that CAM binding sends signals to the cell nucleus and that signaling molecules involved in induction (for example, sonic hedgehog and NF-
B), can affect CAM expression (33). A most exciting discovery was made by Nusslein-Volhard and Wieschaus (34) of genes in Drosophila in which local expression is correlated with morphological patterns. These developmental regulatory genes are found in many species, and in later studies (35) we found that a number of CAM genes were targets of the products of, for example, Hox and Pax genes that belong to this class of regulatory DNA sequences. It appears that local cell interaction via morphoregulatory molecules such as CAMs and cell substrate adhesion molecules or SAMs alters the mechanochemistry of local cell collectives, collaborating with cell division or cell death to change the shape of these collectives. At the same time, modulation of CAM cell surface expression allows or prevents cell migration. The whole process depends strictly on local signals that are exchanged within and across collectives (36). Borders between collectives are determined by changes in the combinations of CAMs on adjoining cells. To underscore the place-dependent features of these local interactions, I coined the term "topobiology" (37).
Given this picture, how may we place developmental biology within the group of disciplines I have called the sciences of recognition? Clearly all cell-cell recognition is local and dynamic and depends on a series of gene expression events, which are in turn switched on or off depending on the epigenetic history of particular cell collectives. This does not, however, yet account for the overall shape of the developing animal. Inasmuch as there is no prespecified cell-cell binding code in the genome that establishes the position of each cell in an organ or organism, what accounts for final shape and function?
The answer is natural selection, the process we might call the mother of all the sciences of recognition. Natural selection provides the essential link between entwicklungsmechanik and genetic inheritance (37). Genetic change can modify the complex suite of interactions among the primary processes of development including the time and place of expression of the morphoregulatory molecules themselves. Thus, although recognition during development is entirely local through the action of such molecules, global form is achieved by natural selection on those developmental sequences that enhance fitness of the organism.
In considering development, one is struck again by the biochemical interactions across many levels of organization. I had the good fortune to learn how to think about such interactions from my several encounters with Pauling and Burnet. Both did not hesitate to embark on theoretical excursions that led to important insights in their respective fields. From Pauling's example, I learned that biochemical rules must be seen in higher level contexts, both cellular and organismal; and from Burnet, I learned that even a correct theory needs to be fleshed out at the level of chemical mechanism, the syntax provided by biochemistry.
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Neuroanatomical Recognition and Higher Brain Function |
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From the mid-1970s on, my interest in systems of recognition drew me almost inexorably into studies of higher brain function. This is an arena in which both morphogenesis and intricate biochemical mechanisms of recognition reach their highest expression. Thirty years ago, psychology and neuroscience were just beginning a cautious exchange. The reasons for caution were clear enough: psychology was emerging from the straitjacket of behaviorism, and neuroscience was just beginning to link developmental anatomy, synaptic biochemistry, and systems physiology into what is now a firm bond. One could begin to ask a series of critical questions. What are the bases of perception, of the various kinds of memory, and of learned behavioral responses? How can these be related to specific biochemical events?
It seemed to me that to make sense of the data in these apparently disparate fields one needed a global theory of brain action that was based on the biology of recognition events rather than on abstract computation. Unfortunately, in freeing itself from behaviorism, cognitive psychology was based on a computer model, a machine model of the mind that tended to ignore the evolutionary facts (38). Driven by my experience in embryology, immunology, and population thinking, I felt that the problem of recognition of environmental and bodily changes by the brain was likely to be solved by a selectionist theory, not by one based on logical instruction.
Accordingly, in 1977 (39) and more extensively in 1987 (40), I proposed the theory called neural Darwinism or the theory of neural group selection (TNGS). It assumed that morphogenesis of the brain with its myriad connections was initially constrained by homeotic genes and the like but then was subject to epigenetic events that resulted in enormous individual variation at the finest ramifications of neuroanatomy. The epigenetic rule was: neurons that fire together wire together. The key was not only in the neuroanatomy but also in the dynamics of the system regulated by biochemical and morphological changes at each synapse, changes that altered synaptic efficacy or strength. The question then became: how could these variations be orchestrated to yield adaptive behavior?
To answer this question, the TNGS put forth three tenets. The first tenet was that the primary processes of development, acting epigenetically, lead to enormous local variation in the repertoires of microcircuits made by branching axons and dendrites. The second tenet states that, overlapping this process and after emergence of more or less defined neuroanatomy, changes in synaptic efficacy across populations of synapses occur as a result of experience. This produces additional enormous variation in the functional connectivity of the brain. In this process, signals from various sensory channels and motor areas select neuronal groups that are made up of excitatory and inhibitory neurons linked by such synaptic change into functioning circuits.
The two linked epigenetic stages of developmental selection and experiential selection cannot, by themselves, coordinate brain responses over space and time. According to the third tenet of the theory, this is accomplished by a process called reentry. The maps of the vertebrate brain are connected by vast numbers of reciprocal axonal fibers. Reentry is an ongoing recursive process of signaling across these fibers that binds the distributed maps together to form spatiotemporally correlated circuits. Such circuits are dynamic and change selectively with signals from the body, the world, and the brain itself. Among the most important processes governing which circuits are selected are signals from the value systems of the brain. These systems release various neurotransmitters and neuromodulators from diffuse ascending neural systems and thereby change synaptic thresholds in a distributed fashion. Thus, adaptive behavior arises from selection at individual synapses coordinated by reentry but also under biasing by evolutionarily selected value systems. The picture that emerges is one of enormous variation in the biochemical profiles of the brain; this variation provides the substrate for selection of those dynamic circuits whose activity leads to adaptive behavior (41).
Of all the sciences of recognition, brain science is the most sophisticated and demanding. Much of my activity in recent years has been dedicated to testing the self-consistency of the TNGS and its ability to tie together the disparate body of data ranging from chemistry to consciousness. In my own laboratory, we have been studying the mechanisms of translation of messenger RNA (42), particularly in neurons (43). Certain messages are carried to individual synapses along with ribosomes and are then translated at dendritic spines after being triggered by synaptic activity. This process may in some cases change synaptic strength. Because there is not enough of each specific messenger RNA to be distributed to every dendritic spine, however, this process inevitably produces additional variance in the synaptic population.
At The Neurosciences Institute, my colleagues and I have been simulating the activity of neuronal populations in supercomputers, and to test the integrative activity ranging from molecules to behavior, we have even constructed brain-based devices (44) that operate according to the principles of the TNGS. Our physiological efforts are focused on the use of magnetoencephalography (MEG) to show that reentry occurs across distributed regions of the human brain when a subject becomes conscious of an object (45). This neural correlate of consciousness is consistent with the supposition of the TNGS that, during evolution of the vertebrate brain, reciprocal connections developed between more posterior regions of the cerebral cortex carrying out perceptual categorization and the more anterior regions involved in memory influenced by value systems. According to the theory, reentry across these connections and those to the thalamus allowed enormously heightened discriminations among different signals to arise from the dynamic activity of the thalamocortical system of a brain so equipped. The phenomenal experiences entailed by these neural activities are these discriminations, the so-called qualia discussed by philosophers. By being able flexibly to plan their responses, animals possessing these abilities would have an adaptive advantage over those unable to make such discriminations (46).
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Selection upon Selection and the Sciences of Recognition |
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The long trail from antibodies to conscious brain events has reinforced my conviction that evolution, immunology, embryology, and neurobiology are all sciences of recognition whose mechanics follow selectional principles. Natural selection is, of course, the governing process, selecting the biochemical mechanisms of those systems that are able to deal with individual recognition events in somatic time.
All selectional systems follow three principles. There must be a generator of diversity, a polling process across the diverse repertoires that ensue, and a means of differential amplification of the selected variants. However, each selectional system employs a different set of mechanisms. In evolution we see mutation, competition, and differential reproduction. In immunology, we have somatic mutation and recombination, antigenic modification and circulation, and clonal expansion of selected lymphocytes. In development, we have variation in local collectives with epigenetic selection of primary processes resulting in form that is subject to natural selection. In neurobiology we add to these morphogenetic principles the polar properties of neurons firing together and wiring together to create an enormous network of functional connectivity within an overall anatomy. This anatomy is characteristic of a species but necessarily shows enormous individual variation. Within this network, synaptic strengths are selected in a value-dependent fashion by behavior. Synchronization of these selective events occurs via the process of reentry, which acts in time periods of milliseconds.
In all cases, although the syntactic rules are given by the biochemistry, the operation of these rules is constrained by the behavior of the higher order organization they help to create. Achieving a deeper understanding of these systems, a project that I like to call completing Darwin's program, will continue to rest on further exploration of the details of their biochemical interactions.
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Understanding: The Ultimate Recognition |
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In reflecting on the tale just told, I realize that I have left out much and that what appears to be a pattern in retrospect was not all that apparent in prospect. I have not mentioned all the colleagues that made it possible to realize the insights I have mentioned here. Claude Bernard, the doyen of homeostasis, once said: "Art is I, Science is We." We begin our research as artists but must combine our efforts in a community. In the long reach of scientific truth that we pursue together, we end as a paragraph. That is as it should be.
After 50 years in research, it may be of some use if I make a few remarks about change and organizational style. I have the impression that when I began my work, a central driving force of biochemical research was, above all, the desire to understand. In the enormous technological explosion that has occurred in the last decade that desire is still there but it seems to be muted. We live now in an age of quick publication, fashionable journals, multi-author papers, and the predominance of rather bureaucratic or risk-free criteria for the awarding of grants. We seem to be living in a period dominated by data collecting, a period of molecular natural history.
What has emerged from this effort is a picture of enormous biochemical complexity (47), one only dimly foretold in previous times. On reflection, this is perhaps not surprising, given the fact that not all evolution occurs by natural selection and the fact that correlative variation can occur during selection. The more we see, the more the creatures of our effort seem to grow hair. I suspect that it will take some time before we develop a theory that will allow us to understand the intricate parallel biochemical networks in the eukaryotic cell. As is obvious from my account, I believe that, in this enterprise, thinking is the most important and challenging part of the biochemist's task. Taking this position involves a risk that many large organizations of science are not willing to support. I would hope that some measures are put in place to support scientific monasteries, institutes that are small (less than 50 scientists), freely funded to avoid burdening the young with grant bureaucracy, and diverse across specialties but not too diverse (48). In founding The Neurosciences Institute, I have tried to realize these conditions. The diversity that would be created if there were more such organizations, each arranged around a different focus, might help to encourage young scientists to transform the present mass of data into a general picture that will ultimately relate biological complexity to evolution in a satisfying way. Understanding—the ultimate recognition—remains the name of the game.
Address correspondence to: edelman{at}nsi.edu.
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