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PERSPECTIVES IN BIOLOGY AND MEDICINE Volume 26 · Number 4 ¦ Summer 1983 THE FORCE OF THE PACEMAKER CONCEPT IN THEORIES OF AGGREGATION IN CELLULAR SUME MOLD EVELYN FOX KELLER* A given problem may attract a scientist for any number of reasons. In turn, those reasons, or interests, influence the manner in which he or she deals with the problem. It is appropriate, therefore, that I begin this review with a description of my own initial interest in the problem of slime mold aggregation. That interest began over 10 years ago, when, working as a mathematical biologist, I had become preoccupied by what might be regarded as the fundamental question of developmental biology—namely, the origin of structure, or the origin of difference in an initially undifferentiated system. AU cells of a complex organism derive from the same initial cell and presumably, therefore, have the same genetic material. What, then, determines the differential expression of a given genetic complement in cells that take on widely varying structural and functional characteristics ? Just at this time, I discovered an old, and at the time little known, paper by Alan Turing [I]. Turing demonstrated that a hypothetical system of interacting chemicals, reacting and diffusing through space, could generate a regular spatial structure which, he speculated, could provide a basis for subsequent morphogenetic development. What was appealing about this view was that it offered away out ofthe infinite regress into which thinking about the development of biological Paper presented atthe American Mathematics Society meetings, Amherst, Massachusetts, October 17, 1981, and to be published in their proceedings, Fundamenta Scientiae, vol. 3, no. 2. . * Department of Mathematics and Center for Humanities, Northeastern University, Boston, Massachusetts 02115.© 1983 by The University of Chicago. All rights reserved. 0031-5982/83/2604-0345$01.00 Perspectives in Biology and Medicine, 26, 4 · Summer 1983 j 515 structure so often falls. That is, it did not presuppose the existence of a prior pattern, or difference, out of which the observed structure could form. Instead, it offered a mechanism for self-organization in which structure could emerge spontaneously from homogeneity. Thinking like a mathematician and not like a biologist, I found it seemed natural to look for a system that would lend itself to such an analysis, that is, that might provide a demonstrable instance of such self-organizing principles. At this time I met Lee Segel, who introduced me to the problem ofaggregation in the cellular slime moldDictyostelium discoideum. Dictyostelium has the remarkable property of existing alternatively as single cells or as a multicellular organism. As long as there is enough food around, the single cells are self-sufficient, growing and dividing by binary fission. But, when starved, these cells undergo internal changes that lead to their aggregation into clumps which, as they grow bigger, topple over and crawl offas slugs. Under appropriate conditions of light, humidity, and pH, the slug stops, erects a stalk, and differentiates into stalk and spore cells; the spores subsequently germinate into single-celled amoebae. The onset of aggregation is the first visible step in the process that eventually leads to the cellular differentiation observed in the multicellular organism. Prior to aggregation, no difference among cells is apparent. But once it occurs, aggregation itself induces a differential environment which could presumably be the basis of subsequent differentiation . The question is, What triggers the aggregation? It was already known that the individual cells produce an acrasin (identified as cyclic AMP) to which they are chemotactically sensitive as well as an acrasinase that degrades the acrasin. Following in the spirit of Turing, Segel and I examined the spatial stability of a homogeneous field of undifferentiated cells interacting through the production and degradation of, and Chemotaxis to, acrasin. We showed that the conditions for instability, for the onset of aggregation, would be met by an increase of individual cellular production of acrasin and/or chemotactic sensitivity, without prior differentiation. That these changes actually take place was independently corroborated by experiment [2]. Unfortunately, because our analysis was linear, we could only comment on the onset ofinstability. Furthermore, the model itselfwas highly oversimplified. In particular (and this proved to be a fatal flaw), we ignored the fact that the aggregation process is...


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