A Pioneer Presses Search For 'Other Side of Biology'

When I was a high school student, I came across Erwin Schrödingers What Is Life?. I still remember my exultant reaction—a combination of adolescent pride in feeling able to understand ideas considered beyond a young person’s means, and a genuine intellectual thrill engendered by the problems that Schrödinger addressed. Upon rereading the book, it appears to me that its major value was to provoke interest in a central problem of biology. Schrödinger’s question—What is life? —was mainly, although not exclusively, related to the molecular basis of heredity. The issue has now been resolved, and many of the questions asked in that classic little book have been answered: The molecular basis of heredity rests in the structure of DNA and in the genetic code. This view resolves the ancient and paradoxical problem of preformation, which asserted that a replica of an organism was contained m the sperm or egg. Rather than preformation, with its endless regress, there is a set of rules for translating the structure of the code into proteins that share in forming the phenotype—the aggregate of interactive structures and functions that constitute an organism of a species upon which natural selection acts. This side of biology, once obscure, is now in the light. But the task of understanding biology is still radically incomplete. DNA and the findings of molecular biology alone are not “the answer to life”; there is another side to biology, that of epigenesis. To understand epigenesis, two key questions must be answered: (1) How does the one-dimensional genetic code specify a three-dimensional animal? (the developmental genetic question); and (2) How can the answer to this question help account for relatively large changes in morphology in relatively short evolutionary times? (the evolutionary question). Controlling Units Epigenesis operates by means of place-dependent molecular signaling over many scales of biological organization finally to reach back to DNA. The cell responding to place-dependent mechanochemical schemes and the organism obeying rules of both natural and somatic selection are the controlling units of topobiology, a name I have ap- plied to the study of place-dependent cellular regulation. Topobiology is concerned with that part of developmental biology dedicated to the understanding of animal form and to the related subject of morphologic evolution—how genes can define animal shape, pattern, and phenotypic function in developmental and evolutionary time. Progress in molecular embryology suggests evolution leads to phenotypic changes in morphologic pattern mainly by genetic perturbations of topologically constrained developmental processes. These processes, while complex, follow definitive rules, as can be shown by studies of the expression of cell adhesion and substrate adhesion molecules (CAMs and SAMs). While they lead dynamically to an extraordinary number of morphologic states, the number of these processes and their attendant morphoregulatory molecules is not very large. Instead, these processes are applied repeatedly and create new contexts that lead to nonlinear changes in which the same rules can be interpreted in different fashions. Differences in time and place are at the heart of such topobiological transformations. Topobiological processes show degeneracy in their pathways—several different genetic and epigenetic changes can lead to morphologically and functionally similar results or transformations. As a result of such properties development is self-regulating an nonlinear, as a further consequence, even though it is stochastic, it can yield regularities. Development is nonetheless directional and historical, and as such it is, in general, irreversible. The coordinate functioning of thousands of genes is required for the development of complex animals, and we are now probably not too much closer to a detailed solution to the problems of epigenesis than biologists were in 1945 when Schrödinger wrote What Is Life?. But we may take heart in the fact that, following the appearance of that book, the attempts to transform the problems of heredity and to produce a molecular transformation of the ancient problem of preformation succeeded in a remark- ably short time—no more than a decade and a half. In one sense, topobiology is more challenging because its problems require not only a molecular approach to epigenesis but also the merger of several very large and complex fields, including evolution and ecology. Moreover, genetics itself was very well formulated by Schrödinger’s time—although not molecular, it had a quite robust theory of the gene as a linear entity, providing a basis for continued analysis at the molecular level. We cannot say that this is yet so for development. While topobiological theories are moving in the direction of unification, they hardly have been tested over a long enough period of time and with a sufficiently great variety of examples to afford any degree of confidence. Nonetheless, they can be tested and modified and they do serve to focus attention upon the linkage of the developmental genetic and evolutionary questions at a molecular level. They all share the idea that epigenesis leading to form depends upon a type of place-dependent signaling through many levels of organization. The places that govern the signaling are created in time by the previous signaling events. They are genetically constrained because the morphoregulatory molecules (such as CAMS and SAMS) that are essential to their creation are under the influence of special sets of regulatory and structural genes. They are somatically variant, at least at a fine scale, because they have been generated by dynamic cellular processes. Both natural and somatic selection operate on organisms to effect this variance and constrain it. It appears that somatic variance is important in brain function; whether it has a physiological role in other organ systems remains to be seen. A molecular analysis of this complex historical process of develop- ment is feasible, particularly given the powerful research tools provided by molecular biology and immunology. Such a molecular approach is sensible, however, only if pursued against the larger background provided by an analysis of morphologic evolution. This in turn requires a developmenta; analysis of the origins and limits of morphologic novelty and phenotypic transformation and a genetic analysis of the regulatory loops and special gene products governing primary processes. Both of these efforts must be reconciled with evolutionary ecology—the selection of morphs in habitats in terms of their function and fitness. The complexity of this challenge is enormous—indeed, in the case of the evolution of higher brain functions, it is staggering. Nevertheless, in the dialogue across many disciplines that has been facilitated by the growth of molecular approaches to embryology, some common themes can be discerned. When they are finally linked into a fully coherent theory of morphologic evolution, we will have a biologically satisfactory answer to Schrödinger’s question, and the other side of biology—epigenesis—will finally be in the light. Gerald M. Edelman, the 1972 Nobel laureate in physiology or medicine, is Vincent Astor Professor and director of the Neurosciences Institute at the Rockefeller University in New York City. The foregoing is excerpted from two chapters in his book Topobiology: An Introduction to Molecular Embryology, which was published last month by Basic Books. The excerpt appears here by permission of the author and the publisher. Copyright © 1988, Basic Books Inc.

A Pioneer Presses Search For 'Other Side of Biology'

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