Development 110, 1-18 (1990) Review Article Printed in Great Britain © The Company of Biologists Limited 1990 'Generic' physical mechanisms of morphogenesis and pattern formation STUART A. NEWMAN1 and WAYNE D. COMPER2 ^Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York 10595, USA 2Department of Biochemistry, Monash University, Clayton, Victoria 3168, Australia Summary The role of 'generic' physical mechanisms in morpho- phogenetic and patterning effects are the inevitable genesis and pattern formation of tissues is considered. outcome of recognized physical properties of tissues, and Generic mechanisms are defined as those physical pro- that generic physical mechanisms that act on these cesses that are broadly applicable to living and non- properties are complementary to, and interdependent living systems, such as adhesion, surface tension and with genetic mechanisms. We also suggest that major gravitational effects, viscosity, phase separation, con- morphological reorganizations in phylogenetic lineages vection and reaction-diffusion coupling. They are con- may arise by the action of generic physical mechanisms trasted with 'genetic' mechanisms, a term reserved for on developing embryos. Subsequent evolution of genetic highly evolved, machine-like, biomolecular processes. mechanisms could stabilize and refine developmental Generic mechanisms acting upon living tissues are outcomes originally guided by generic effects. capable of giving rise to morphogenetic rearrangements of cytoplasmic, tissue and extracellular matrix com- ponents, sometimes leading to 'microfingers', and to Key words: pattern formation, morphogenesis, genetic chemical waves or stripes. We suggest that many mor- mechanism, generic physical mechanism. Introduction diffusion (Crick, 1970) and interfacial tension (Stein- berg, 1978; Heintzelman et al. 1978), participate in Developing, regenerating, healing and neoplastic tis- important ways in morphogenesis and pattern forma- sues undergo changes in form and cellular composition tion. In contrast to molecular machines, which are by mechanisms that are poorly understood. While all mainly suited to bringing about precise outcomes in contemporary approaches assume that tissue morpho- spatially localized tissue regions, some of these general genesis and position-dependent cell differentiation physical effects may act globally, so as to influence (pattern formation) are caused ultimately by the inter- tissue shape and composition over relatively long dis- play of physicochemical behaviors of macromolecules, tances. such behaviors fall into at least two distinguishable Because both highly evolved biomolecular processes categories. Certain developmental processes depend on (conveniently referred to as 'genetic') and more broadly highly organized interactions between specific macro- applicable ('generic') physical processes can each con- molecules, and can be appropriately characterized as tribute to any given developmental episode, investi- 'molecular machines'. The existence of each such gators need to take both categories of phenomenon into machine presupposes the coevolution of several biologi- account. But research on generic morphogenetic and cal macromolecules, leading to the coordination of their patterning processes is a rapidly expanding area of physicochemical properties in the service of a particular physical chemistry that is unfamiliar to most develop- function. Examples include cytoplasmic 'motors' that mental biologists. This has restricted the influx of a affect the shape and motility of individual cells (Vale, number of fruitful concepts into developmental biology 1987), and gene promoter elements sensitive to com- and impeded the use of several informative cell-free plexes of spatially distributed DNA-binding proteins experimental models of morphogenesis. (Stanojevid et al 1989; Goto et al. 1989). In what follows we will attempt to redress this But there is also evidence that physical forces and deficiency by presenting a typology of generic physical dynamical processes that are not the products of the mechanisms relevant to animal tissue behavior. These evolved coordination of macromolecular properties, mechanisms include familiar physical effects such as but are organizing principles of nonliving as well as gravity, viscous flow, phase separation and adhesion. living systems, such as gravity (Ancel and Vintem- But they also include such exotic processes as Maran- berger, 1948; Malacinski, 1984), adhesion (Steinberg, goni effects, convective fingering and chemical concen- 1978; McClay and Ettensohn, 1987; Armstrong, 1989), tration waves. Previous applications of some of these S. A. Newman and W. D. Comper mechanisms to development will be reviewed, and cellular matrices, under this assumption, would have additional examples will be given of developmental less of the character of 'molecular machines' than most processes that may profitably be analyzed in terms of intracellular macromolecular assemblages, and would such mechanisms. therefore be more typical loci for the physical processes In our discussion, the morphogenetic properties of we have termed 'generic'. individual cells - e.g. their extensibility, contractility and motility - are treated as given; they are assumed to arise from the physical chemistry of highly evolved Examples of Generic Processes intracellular proteins such as tubulin, actin, myosin and kinesin, in the presence of sources of metabolic energy The mechanical properties of materials are con- and appropriate cofactors. In this sense they are 'gen- veniently described in terms of their responses to etic'. Similarly, the ability of cells to undergo differen- stresses, which are forces applied to bodies of matter. A tiation in response to microenvironmental signals, and change in the dimensions of a body produced by a stress to produce and secrete specific macromolecules, is is called a strain. Shear stresses act tangentially to planes assumed. Secreted macromolecules will be considered within the material and cause continguous parts of the here only insofar as they can potentially play the role of body to slide past one another. In solids, shear stresses dynamical components in some of the generic physical are opposed by bonds between adjacent subunits and by processes that we will describe. And whereas eggs and elastic restoring forces, whereas liquids begin to flow as multicellular embryos have the ability to produce trans- soon as a shear stress is applied. The capacity of a liquid cellular ion currents and endogenous electrical fields to flow is due to the ability of the liquid's molecules or that reflect morphogenetic polarity, growth and regen- other subunits to readily changetheir relative positions. eration (Jaffe, 1981; Nucitelli, 1984), it is not clear that The physical state of a living tissue, can span the range bioelectricity as a generic phenomenon has a role in from liquid (blood) to solid (bone). But it is only in developing systems, apart from its association with intermediate state, semisolid tissues tljat developmen- transport and utilization of specific ions. We will there- tally significant, short-term morphogenetic effects can fore tentatively group these phenomena with other take place. Typical tissues exhibit both-elastic proper- active chemical processes, and refer the reader to the ties, which permit them to resume their shape when a reviews cited above for further details. shear stress is removed, and viscous properties, in Our main purpose is to familiarize developmental which rearrangement of internal components (cells or biologists with the range of generic physical mechan- extracellular matrix materials) permits shape change in isms that can participate in biological morphogenesis response to shear stress. (Phillips and Steinberg, 1978; and pattern formation, and to indicate possible re- Steinberg and Poole, 1982).- lationships between these processes and the highly Viscoelastic fluids can be compressible or noncom- specific molecular interactions that also mediate devel- pressible; that is, their volume will decrease or remain opmental events and are responsible for the precision of unchanged under compressive stresses, which are forces their outcomes. In particular, we suggest that many directed normal to planes within the material. How- morphogenetic processes may have first arisen in evol- ever, tissues are generally noncompressible because of ution by the action of generic physical mechanisms on their high water content. Even when local reductions of cells and tissues, and that particularly favorable results extracellular space occur, as in mesenchymal tissues were later stabilized and made more dependable by the undergoing condensation (Thorogood and Hinchliffe, superimposition of more evolved genetically deter- 1975), retention of water will ensure that the overall mined mechanisms. In this perspective, the de novo tissue volume is conserved. origin of developmental mechanisms becomes less Like other fluid systems, tissues are subject to the problematic: contemporary molecular mechanisms ubiquitous effects of gravity and adhesion. Either of could have evolved as reinforcements for less precise these forces can effect shape change, but the degree of generic physical determinants, the conditions for which deformation will depend on the mechanical properties may or may not currently prevail. And while the of the particular tissue (its relative elasticity and vis- possible generic origins of certain morphogenetic