Commentary

Computing an organism
Lee A. Segel*
Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel

he social amoebae of species Dic- stability in a uniform layer of cAMPtyostelium discoideum roam individ- secreting chemotactic cells. It turns out ually through the soil as long as their that more than 20 years earlier a paper by bacterial food is present. The social the celebrated mathematician Marston phase for these cellular slime molds be- Morse (4) mentioned slime molds as an gins when the food supply is exhausted. example of equilibria in nature (the title After some hours, the assemblage of of the paper) that could be qualitatively amoebae aggregate into several large described by what is now known as Morse groups, each of which forms a worm-like theory. Many theoretical papers have been slug that propels itself toward heat and light. This brings the slug to the surface written on various aspects of slime mold of the soil, where it executes a sophisti- behavior in the last three decades. Excated internal ballet that eventually re- amples are major recent studies of agsults in a fruiting body, an elegant stalk, gregation (5) and the regulation of stalkformed by dead cellulose-walled cells, spore proportions (6). Earlier simulation atop of which perches a bag of spores. studies by the authors and their collabThe whole structure is about a millimeter orators treated slug formation and mi high. Now in this issue of PNAS Maree gration (79). The work of Maree and and Hogeweg (1) have provided a com- Hogeweg (1) is a culmination of all this puter simulation of the frog-prince trans- effort in two senses. It deals with the so-called culmination phase of Dictyoformation of slug into fruiting body. Scientists have been intensively study- stelium morphogenesis and it caps years ing D. discoideum for decades, as a model of intensive effort, for the first time system in developmental biology. (Dictyo- offering a theoretical model that can stelium turned up 47,500 entries in a reproduce all of the major features of the Google search.) A tremendous boost to structure formation. A simulation of a developing organism these studies occurred when it was discovered that the initial aggregation is induced must represent the motion of a large numby the pulsatile secretion of a chemoat- ber of interacting cells. Like other matetractant that turned out to be none other rials, cells respect the laws of physics. Each than cAMP, one of a few major second cell is not only driven by external forces messengers in mammalian physiology (2). but also generates internal forces by asDictyostelium has become a hydrogen sembling and disassembling an ephemeral atom paradigm in development, for in- cytoskeleton under the direction of varistead of hundreds of cell types as in hu- ous controlling chemicals. A further complication is that almans, the slime mold though cell shape has only two (princidepends on the resultpal) types, stalk and ant of all of the forces, spore, in a ratio that Maree and Hogeweg have the forces themselves is controlled over a provided a computer depend on the shape. wide range of sizes. Impressive progress has What causes aggresimulation of the been made in coping gation and then slug frog-prince transformation with much of this comformation and moof slug into fruiting body. plexity. An example is tion? How are the afforded by Alt and proportions of difDembos (10) twoferentiated cells controlled? And how is the morphogenetic phase model of cytoplasmic dynamics movement organized so that it provides even a simple version of which reproduces the appropriate geometric structure of such features of cell motility as periodic ruff le formation, protrusion-retraction spore-on-stalk? Evelyn Keller and I used to think that cycles, and centripetal flow. Maree and Hogeweg (1) wisely avoided we wrote the first theoretical paper on Dictyostelium in 1970 (3) when we formu- detailed force calculation in their broadlated and analyzed equations to show how brush dynamic portrait of D. discoideum aggregation might be regarded as an in- culmination. One major step was replac-

ing force balancing by an alternative approximate description wherein a type of potential energy was minimized. To see what this involves, recall that one way to describe how and why a ball rolls down a mountain into a valley is to account for the gravitational forces that cause the descent. Often preferable is the alternative explanation that the ball moves to minimize its height and hence its potential energy. Here, too, an energy can be defined, one that limns in broad strokes the influences that induce cell motion. Two such influences are differential cell adhesion and chemotaxis toward relatively high cAMP concentrations. Promotion of relatively strong cell-cell contacts (which minimize the relevant energy function) tends to yield clumps of like cells. This tendency can be overridden by the propensity of cells to move toward higher cAMP concentrations. (Motion resulting from this propensity is not simple, because it turns out that the cells are exposed to traveling waves of cAMP, with their moving maxima and minima.) The Maree-Hogeweg simulations save computer time by considering only a twoSee companion article on page 3879. *E-mail: [email protected].

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March 27, 2001

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COMMENTARY

Fig. 1. Representation of simulated cell movement. The heavily outlined square of cell A is more likely to switch to be part of cell B (corresponding to a pushing of B by A) if the squares energy is decreased by a combination of factors.

dimensional cross section of the fruiting body. An individual amoeboid cell is represented by a blob formed of about 30 squares. [Early simulations represented a cell by a point, but this appears to be an oversimplification. The connected blob representation is a grandchild of the Potts generalization of the Ising model, fathered by the physicists Glazier and Graner (11).] Each simulated cell has a target volume; deviation from this volume is penalized by an increase in energy. Cells continually check whether a shift of their boundaries will decrease the overall energy. If the decrease is large enough then the new position is accepted. A smaller decrease makes the motion likely but not certain (the simulations are stochastic). Cells thus move in such a way as to increase cAMP concentration in their environment while adhering with different strengths to the various cell types. As it moves, cell A pushes cell B when the boundary of A fluctuates to invade what was previously the territory of cell B (see Fig. 1). As mentioned, simulating energydiminishing boundary fluctuations permits side-stepping the more accurate but dauntingly complex approach via differential equations. But differential equations enter the simulations when the diffusion and reaction of secreted cAMP is accounted for. Here, too, a simplification
1. Maree, A. F. M. & Hogeweg, P. (2001) Proc. Natl. Acad. Sci. USA 98, 38793883. 2. Konijn, T. M., Van de Meene, J. G., Bonner, J. T. & Barkley, D. S. (1968) Proc. Natl. Acad. Sci. USA 58, 11521154. 3. Keller, E. F. & Segel, L. A. (1970) J. Theor. Biol. 26, 399415. 4. Morse, M. (1949) Proc. Am. Philos. Soc. 93, 222225. 5. Van Oss, C., Panfilov, A. V., Hogeweg, P., Siegert, F. & Weijer, C. J. (1996) J. Theor. Biol. 181, 203213.

is madethe true cAMP dynamics is replaced by the FitzHugh-Nagumo caricature of excitability borrowed from neurobiology (14, 15). Can one trust simulations that ignore much biological detail? Certainly the omission of known phenomenology is no a priori reason to scorn a model or simulation. For example, classical Newtonian models, bare of relativistic or quantum effects, are universally accepted to offer the right approach to problems ranging from bacterial swimming to hurricane prediction. The art is to fulfill the dictum attributed to Einstein, simplify as much as possible but no further. The robustness peculiar to biology plays an interesting dual role in the evaluation of relatively simple models. On the one hand, robustness implies that variations in detail are without major significance. Such variations are unlikely to alter the essence of phenomena that are essential for survivalsuch as fruiting body construction in slime molds. On the other hand, this very robustness implies that a model that flawlessly reconstructs much phenomenology might well be seriously wrong in the underlying detail that it assumes. Concerning this second point, however, new developments have indicated that the picture is more subtle and more interesting than has been thought. In
6. Schaap, P., Tang, Y. & Othmer, H. G. (1996) Differentiation 60, 116. 7. Savill, N. J. & Hogeweg, P. (1997) J. Theor. Biol. 184, 229235. 8. Maree, A. F. M., Panfilov, A. V. & Hogeweg, P. (1999) Proc. R. Soc. London Ser. B 266, 1351 1360. 9. Maree, A. F. M., Panfilov, A. V. & Hogeweg, P. (1999) J. Theor. Biol. 199, 297309. 10. Alt, W. & Dembo, M. (1999) Math. Biosci. 156, 207228.

their study of developing segment polarity networks, von Dassow et al. (12) found that their 50-parameter model gene networks were indeed remarkably robust when and only when their original mathematical translation of known interactions between relevant genes was supplemented by two crucial additions. E. Shochat, S. Stemmer, and I (unpublished work) found a similar phenomenon in an unpublished large-scale model of hematopoeietic cell kinetics. In essence, replacing a parameter by a small model (compare ref. 13) very considerably enlarged the range of other parameter choices that could lead to a fit with a number of kinetic results. It appears that a biological model enjoys robustness only if it is correct in certain essential features. Years ago the slime mold biologist Maurice Sussman said to me that the goal of theoretical biologists should be to compute an organism. This has now been done by Maree and Hogeweg (1). The necessity of refining and generalizing the calculations and the importance of linking changing gene expression with cell movement means that this achievement is not the beginning of the end but rather the end of the beginning.
Thanks to J. T. Bonner, P. Hogeweg, and E. F. Keller for helpful comments on an earlier version.
11. Glazier, J. A. & Graner, F. (1993) Phys. Rev. E 47, 21282154. 12. Von Dassow, G., Meir, E., Munro, E. M. & Odell, G. M. (2000) Nature (London) 406, 188 192. 13. Muller, V., Maree, A. F. M. & De Boer, R. J. (2001) Proc. R. Soc. London Ser. B 268, 235242. 14. FitzHugh, R. (1961) Biophys J. 1, 445466. 15. Nagumo, J. S., Arimoto, S. & Yoshizawa, S. (1962) Proc. IRE 50, 20612071.

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