Pauling’s theory that there is just one kind of antibody protein proved to be wrong. In 1969 Edelman and his colleagues worked out the complete chemical structure of the antibody molecule, providing the important clue to what structures within the molecule are varied to produce millions of different kinds of antibodies needed to protect the body against foreign organisms. For this work he won the Nobel Prize in 1972 along with the late Rodney Porter of England. Their studies confirmed a theory suggested in the 1950s by MacFarlane Burnet and Niels Jerne that all animals are born with a complete repertoire of antibodies and that intruding bacteria select those antibodies that can effectively combat their presence.
Contrary to Pauling’s theory, the presence of the bacteria does not determine the nature of the antibody that is made, but only the amount. A limited number of genes, a few hundred or a few thousand at most, provide, through recombinatory mechanisms, the codes for the many millions of different antibodies. Specialized cells in the blood each produce one of the many kinds of possible antibodies that then become attached to the cell surface. An antibody molecule that happens to fit more or less closely a virus or bacterium floating in the bloodstream will bind itself to the virus or bacterium. This sets off a chain of events that causes the cell to divide and make thousands of copies (clones) of itself and more of the same kind of antibody. Other cells may carry antibody molecules that fit the virus or bacterium in different ways, and these cells, too, will bind to the virus or bacterium and produce clones. The body can only rid itself of a virus or bacterium if there is at least one good enough fit in its antibody repertoire. Usually there are several fits and some of them may overlap.
So the immunological system is not taught what antibodies it has to make to rid the body of a particular virus. The invading virus selects the appropriate antibodies and these will be different in each individual. An unfortunate organism may not have any antibodies in its repertoire that can bind the virus, and this could be fatal. Scientists were generally pleased with this solution to the immunological question because it was consistent with Darwinian principles of selection that have formed the basis of modern biology. Theories of immunology based on a process of learning or instruction were not.
Comparison of those findings on immunology to the theory of evolution suggested to Edelman that the brain too may function as a selective system and that what we call learning is really a form of selection. The theory he worked out is based on three fundamental claims: 1) during the development of the brain in the embryo a highly variable and individual pattern of connections between the brain cells (neurons) is formed; 2) after birth, a pattern of neural connections is fixed in each individual, but certain combinations of connections are selected over others as a result of the stimuli the brain receives through the senses; 3) such selection would occur particularly in groups of brain cells that are connected in sheets, or “maps,” and these maps “speak” to one another back and forth to create categories of things and events.
But is it the case that there is a mechanism that creates such diversity in each brain? In 1963, the Nobel Prize-winning neurologist Roger Sperry proposed that the billions of complicated connections in the brain were each determined by specific chemical markers on each neuron. On this view, particular genes presumably provide a code for each of the markers. Twins with identical genes therefore should have identical, or nearly identical, brains. Learning may not have been preprogrammed in Sperry’s model, but this model seems to imply that what any person could learn was limited by predetermined connections in his or her brain. If Sperry were right, many brain functions would be genetically determined, and to this extent organisms could be limited in their ability to adapt to new environments. Adaptive behavior and flexibility would have to arise by instruction; i.e., by external stimuli creating patterns in the brain, much as programs give instructions to computers. Yet we know that animals can adapt individually to different environments. The human brain has permitted survival in remarkably varied circumstances throughout history. Genetic determinism strains credibility because it makes it difficult to account for the enormous variability of thought and action.
For Edelman, the important question was not, as Sperry had argued, how specific structures in the brain are made according to markers on each neuron, but how, given a particular set of genes, enough variability would be created within the constant overall structure of the brain to account for the adaptability of humans and higher animals in an unpredictable environment. The deeper issue that had to be explored to understand this was the relationship between genes, on the one hand, and, on the other, the form and structure—or “morphology”—of animals. Notwithstanding all the work on the genetic code, biologists still cannot predict the shape of an organism from the information in its genes. If dinosaur genes rather than dinosaur bones had been found we would never have known they were dinosaurs and could not have said what they looked like. Why don’t genes tell us about morphology?
The answer to this question, according to Edelman’s findings, lies in early embryonic development. As an embryo develops, cells divide, move from place to place, and ultimately become specialized. A cell’s fate, whether it becomes a liver cell or a nerve cell, depends on where it happens to be at the moment that specialization begins, as well as where it has been. Cell shapes and movements will inevitably vary in each individual, making it impossible to predict exactly where a particular cell will be at a given time. Therefore the genetic mechanisms that determine what a cell will become must somehow be sensitive to its location at a particular time. If each cell’s specialization were completely predetermined by genes, even one misplaced cell could create havoc and the organism’s subsequent development would follow an abnormal course. A supporting beam placed between two walls that arrived just moments too late would be of no use once the walls had collapsed.
How does a pattern emerge in the embryo from early activity of the cells? Biological systems are not built from preformed parts. Instead cells are cemented together in the embryo and the individual cells or groups of cells are then shaped into structures that serve more complex functions. In determining the shape, it is the signals across the boundaries of such structures that count. How this works may be suggested by an analogy.
Imagine an architect given the task of shaping a brick wall into the façade of a building, with windows, ornaments, and a main door. One way our imaginary architect may proceed is to indicate where the holes for the windows would be drilled by drawing the borders on the brick wall. The holes drilled and the window frames added, he might then add indications for the shutter hinges on the window frames. In general, shaping a relatively uniform collection of interconnected material units, such as bricks, into a well-differentiated structure requires determining the boundaries of the structures that have to be carved into the units or added to them. And those boundaries can only be determined once all the bricks (or other material subunits) are delivered or are in place. One brick might be substituted for another without changing the pattern. Above all, the boundaries will determine the function of the bricks, such as supporting a window or a door.
As tissue grows in the embryo, borders are formed demarcating the different functional parts of the organism; but obviously there is no architect. The borders are established between different groups of cells by different intercellular cements or glues, known as cell adhesion molecules or CAMs. Three kinds of CAMs were discovered by Edelman and his colleagues in the late 1970s; and more have since been found. Two of the CAMs appear on the surfaces of cells very early in embryonic development. One is called L-CAM because it was first discovered in the liver, and the other N-CAM since it was originally found in association with nerves. L-CAMs on the cell surface will only stick to other L-CAMs on the cell surface and the same is true of N-CAMs; L-CAMs and N-CAMs will not stick to each other. For these primary CAMs, cells can adhere to each other only when they have the same kind of CAMs on their surfaces.
The structure of the cell adhesion molecules themselves is determined by particular genes. And in early development of the embryo other genes regulate when the CAMs are produced. However, the exact amount and “stickiness” of the CAMs (which vary continuously as the embryo develops) depend on where the cells carrying them are and where they have moved, and the individual cell’s position is not under direct genetic control. Therefore the arrangement of groups of cells that are linked together by one kind of CAM will vary even in genetically identical individuals. These groups of cells send signals that turn CAM genes on and off, as well as turning on and off the action of genes that specify cell specialization. The entire sequence by which differentiation occurs is therefore determined not directly by genes but indirectly by the combined action of genes and signals from cell groups that activate genes, and is therefore called epigenetic.
Cells linked together in collectives by L-CAMs form borders with other cells linked together in other collectives by N-CAMs. The borders result because the two kinds of molecules do not stick to each other. Edelman and his colleagues have shown that cells on one side of the border will subsequently change into more specialized cells of one kind, and those on the other side of the border will become specialized cells of another kind. Throughout embryonic development, borders are formed between cells that are linked together with different CAMs, and following border formation the cells specialize. As the cells differentiate further, new CAM borders are formed before new changes are introduced by signals from the cell groups to the genes that activate both CAMs and the genes that specify cell specialization. Depending on the past history of the two cell groups, signals exchanged at the border between collections of N-CAM and L-CAM cells will determine the subsequent formation of very different kinds of cells on each side of the border. (Recently a chemical signal that activates CAM production has been identified.)
The function of the border between cell groups with different CAMs thus depends on the context—the surrounding cells, and the past history of the cells. In general, moreover, the rules governing CAM response are similar both for the neurons of the brain and for other body structures. Because the borders of cell collectives depend on dynamics of movement, there will be individual variations that are not determined just by genes and whose diversity will ensure that different brains would have different structures. Yet the general patterns formed and the broadly similar sequences of embryonic development would account for the fact that the individual brains of members of a species resemble one another.