The Work Surfaces of Morphogenesis: The Role of the Morphogenetic Field

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  • LONG ARTICLE The Work Surfaces of Morphogenesis: The Role of the Morphogenetic Field Sheena E. B. Tyler Received: 14 December 2013 / Accepted: 25 March 2014 � Konrad Lorenz Institute for Evolution and Cognition Research 2014 Abstract How biological form is generated remains one of the most fascinating but elusive challenges for science. Moreover, it is widely documented in contemporary liter- ature that development is tightly coordinated. The idea that such development is governed by a coordinating field of force, the morphogenetic field, and its position in embry- ology research paradigms, is traced in this article. Empir- ical evidences for field phenomena are described, ranging from bioelectromagnetic effects, morphology, transplanta- tion, regeneration, and other data. Applications of medical potential including treatment of cancer, birth defects, and wound healing are highlighted. The article hypothesizes that distinct morphological forms may have distinct field parameters. Experimentally tractable field parameters may thus provide an exciting research program for probing morphogenesis and phylogenetic diversity. Keywords Bauplan � Bioelectromagnetic information � Cancer � Regeneration � Form � Morphogenetic field The mystery of how [form] was all, and is, brought about is still with us– unsolved! —Wardlaw (1970) The Field Concept: Development of an Idea According to D’Arcy Thompson (1942), the analysis of form can be traced back to Sir Christopher Wren, who proposed that the snail shell form could be described mathematically as a logarithmic spiral (Wallis 1659). The inference from this is that mathematical analyses of form may lead to an understanding of the generative agents of such forms (Løvtrup and Løvtrup 1988). During the early 20th century, the idea emerged that these agents may be organized by a coordinating field of force, the morphogenetic field. The developing foundations for a field concept emerged from numerous experimental observations, which remain useful to this day in assessing the forces coming to bear in development. Graded properties of substances in embryos had been under consideration from the days of Trembley working on Hydra in the 18th century (McLachlan 1999). Allman (1864) had coined the term polarity to describe regeneration (reviewed by Wolpert 1986). One of the first to recognize the importance of both polarity and the posi- tion of cells was the German botanist Hermann Vöchting (1877, 1878). His experimental studies mainly on Tarax- acum (dandelion) roots indicated that the upper part of a cut stem always produced buds, and the lower end roots— indicating a tissue polarity—and that the fate of the cells was determined by their position in the stem (reviewed by Sinnott 1960; Wardlaw 1968; Thorpe 2012). Moreover, he inverted a cut root segment, which developed shoots from the (now upper) root pole. However, a segment cut from this in turn led to the growth of shoots from the original shoot pole, indicating that the original polarity had remained (reviewed by Nick and Furuya 1992). Vöchting envisaged this innate polarity to have a cellular basis, resulting from each cell acting as a minute magnet, con- veying signals in one direction (Sachs 1991). Similarly in animal embryos, Hans Driesch (Fig. 1) pro- posed that the fate of cells depends upon their position. Dri- esch (1892a, b) separated blastomeres of echinoderm eggs, discovering that normal whole embryos could be generated Electronic supplementary material The online version of this article (doi:10.1007/s13752-014-0177-8) contains supplementary material, which is available to authorized users. S. E. B. Tyler (&) John Ray Research Field Station, Cheshire, UK e-mail: s.tyler@johnray.org.uk 123 Biol Theory DOI 10.1007/s13752-014-0177-8 http://dx.doi.org/10.1007/s13752-014-0177-8
  • from them. He added the concept of a reference system of fixed coordinates: ‘‘The ‘whole’ may be related to any three axes drawn through the normal undisturbed egg, on the hypothesis that there exists a primary polarity and bilaterality of the germ; the axes which determine this sort of symmetry may…. be taken as co-ordinates’’ (Driesch 1908, p. 80). Second, he envisaged the embryo as a ‘‘harmonious equipotential system’’—equipotential due to the part hav- ing the potency to generate the whole, and harmonious because in forming the whole the parts work together in an integrated way (Willier and Oppenheimer 1974). Third, like Vöchting, Driesch recognized the importance of cell polarity in addition to that of tissue polarity. In his Analytische Theorie der organischen Entwicklung, Driesch (1894) explained the polarity of the egg with reference to the polarized constituents of the cytoplasm. He added that it was not the position itself that determined the fate but the different signals received by the cells according to their positions (Kalthoff 1996). Theodor Boveri observed a polarized distribution of cytoplasmic components, physicochemical parameters, respiratory rate, and rate of cell division in echinoderm eggs. He linked this with what he termed a ‘‘Gefälle’’ or gradient (Boveri 1901, 1910). He described this as a gradual, graded property to signify a differential endow- ment of determinants that daughter cells received from the egg cell (Sander 1996). Runnström (1914) developed this to describe polarity as an expression of a concentration gradient of a specific chemical material whereby the ‘‘expression of the axes is shown in the direction [of con- centration] of the chemical.’’ In Russia, Gurwitsch (1912; Fig. 2) recognized there to be a dynamic coordination of events (Geschehensfeld), in which a supracellular coordinating principle (Kraftfeld) ordered the whole of development by providing a guiding field of force, which he termed ‘‘embryonales Feld.’’ Reiterating Driesch, he proposed that the spatial position and properties of cells could be referenced in relation to a set of mathematically distinguishable coordinates. He also postulated that such fields are comprised from the vector addition of individual cell fields (Gurwitsch 1944). In 1918 Ross Harrison discovered that a disc of cells normally giving rise to a forelimb could form a forelimb when transplanted into another region of the embryo, suggesting that the disc of cells generated a field of organ- forming potential (Harrison 1918). Hans Spemann, a student of Boveri, in experiments isolating embryo regions with hair loops, discovered that only regions containing the dorsal lip of the blastopore continued development. Moreover, he saw this as Boveri’s ‘‘privileged region,’’ a center of differentiation, which he named the organizer (Horder and Weindling 1983). He considered that this was associated with an organization field, a supracellular model with dominant controlling regions in the embryo. This contrasted with the pervading cellular approach of its day. This dorsal organizer region exhibited many of the properties of a morphogenetic field (De Robertis et al. 1991). For instance, if one organizer is divided into several fragments, each will lead to formation of a new body axis after transplantation. The discovery of the organizer stimulated a worldwide research rush to find its chemical basis. However, the organizer concept was to prove contro- versial. Holtfreter (1945) showed that ectoderm can neur- ulate without any specific organizer induction, indicating a certain predetermination. Yet with the passage of time, some authors maintained that the dorsal lip of the Fig. 1 Hans Driesch (reproduced with permission from The Inter- national Journal of Developmental Biology) Fig. 2 Alexander Gurwitsch (from the personal collection of Lev Beloussov, used with permission) S. E. B. Tyler 123
  • blastopore is indeed the ‘‘organization center’’1 for the amphibian embryo (Nieuwkoop 1973, 1977). Meanwhile the gradients observed by Boveri (1901) led Child (1941) in the U.S. to envisage axial pattern devel- oping from a gradient system that provides a ‘‘physiolog- ical coordinate system,’’ to which he attributed metabolic differentials as the primary agents. In Britain, Huxley and De Beer (1934) reviewed a large body of experimental data, which they interpreted in field terms. They added that such fields seem to be graded, and thus appear to be gradient fields. They considered that the gradients might indeed be metabolic, but remained non- committal by calling them activity gradients. Child had reduced the field to be synonymous with the gradient itself. He proposed that ‘‘developmental fields … are gradient systems; the field is constituted by the gradient…. The gradients are the vectors of the field and determine its extent and orderly relations within it’’ (Child 1941, p. 277; my emphasis). However, Weiss (1939, p. 376) commented that Child’s gradients were not the proven causal instru- ments of development, merely that there was a correlation between the physiological and morphological polarity. Thus the gradual historical development of these ideas, emerging from experimental data, led to the morphogenetic field concept becoming the pervasive research paradigm for embryology in the first half of the 20th century. This was embodied in the dominant texts of the day, such as by Weiss (Principles of Development, 1939), and Child (Patterns and Problems in Development, 1941). In Weiss the morphogenetic field became most greatly developed, with 148 pages marshalling supportive experimental evi- dence, and descriptions of eye, limb, ear, and gill fields. He cited, for instance, the meridianal transection of Styela sea urchin eggs (p. 260, p. 291) in which each half produces a normal embryo. He noted that the new poles appearing after the transection were at some distance from the pre- vious ones, and came to be the new centers of a reduced field district, indicating that there was no fixed material point for organizing activity in the egg. Needham (1942) and Waddington (1956) distinguished fields to more properly refer to the ‘‘character of pro- cesses’’ occurring in a region (reiterating Gurwitsch’s Geschehensfeld, rather than just the geographical location of such events). Then, mysteriously, according to Oppenheimer (1966) and Opitz (1985), the field concept gradually disappeared as a paradigm for development in many research circles. In the aftermath to World War II, the German developmental mechanics school—the main founder and driver for experimental embryology, with which field concepts were associated—disintegrated. Particularly in the U.S., genetics was rising to an ascendency, and a new paradigm became established in which the causal basis of form was assumed to reside exclusively in the genes and their products (Morgan 1934), and in which fields were deemed irrelevant (Gilbert et al. 1996). This view in turn influenced experi- mental design. But actually the field concept did not completely disappear in that period. It remained alive and well in several research avenues. First were studies of bioelectric phenomena, in which field explanations seemed to best fit the data. For instance, Lund (1947; Fig. 3) demonstrated that embryo polarity was predicted by polarity of endogenous ion flow. Second, field theory was highly applicable as an explanation for birth defects (Martinez-Frias et al. 1998). Third, it was relevant at least initially in the idea of positional information (PI) proposed by Wolpert (1969). Wolpert revisited the Dri- esch–Vöchting discoveries of polarity being a function of a cell’s position and—as the term Wolpert coined made clear— focused on the importance of information. Wolpert proposed that when cells have their PI uniquely specified with respect to the same set of boundary reference points, this constitutes a field. He incorporated the ideas of Stumpf (1967) in proposing end cells to be respectively a source and sink of a substance, which provide reference points for the assignment of posi- tional values. The direction of the coordinates was the polar- ity, whether direction of transport of a substance or propagation of a wave. Wolpert also emphasized the idea of interpretation, whereby the cell reads out the PI and converts it into an activity. He stated: ‘‘it is positional information which Fig. 3 E.J. Lund (photo courtesy of University of Texas Marine Science Institute) 1 The organizer is in turn thought to be induced by a signal secreted by the Nieuwkoop center, with similar signaling centres discovered in the zebrafish, chick, and sea urchin (reviewed by Vonica and Gumbiner 2007). Inducers released by the organizer have now been identified which encode antagonists of bone morphogenetic protein, Nodal or Wnt growth factors. The field parameters may be characterized by the different expression domains of these growth factors and their antagonists, which create signaling gradients, which in turn are implicated in patterning the early embryo in a combina- torial fashion (Niehrs 2004). The Work Surfaces of Morphogenesis 123
  • provides the co-ordinated and integrated character of fields’’ (1969, p. 19). As to its physical basis, he proposed possibilities including linking polarity potential with a metabolic gradient (Child 1941); or a respiratory pathway; the transmission of a wave of activity according to the phase-shift model of Goodwin and Cohen (1969); membrane interaction; or the transmission of informational macromolecules between cells—the antecedent of the morphogen. It has since been proposed that PI may occur in com- bination with other morphogens, gene regulatory interac- tions, and downstream factors (e.g., gap, pair-rule, and segment-polarity genes) expressed in spatial patterns more complex than gradients, and whose dynamic effects can be monitored using computational modeling (Jaeger and Reinitz 2006). Positional cues may also be provided by bioelectric phenomena (Levin 2009, 2012). Over the course of time a whole spectrum of variants of the model of PI has been developed. One is a stripped- down version in which field aspects have been jettisoned (PI itself becoming the paradigm). At the other extreme, PI is integrated with information-rich cell surface glycocon- jugates interpreted or decoded by morphogenetic field parameters (Morozova and Shubin 2013). In addition to PI, another form of information storage proposed was the prepattern, which provides a template or scaffold for the subsequent morphology. For instance, the inner regions of mammalian bones consist of a latticework of ossified trabeculae whose orientation corresponds to lines of mechanical compression and tensile stress (Wolff 1870; Fig. 4), enabling femur structure to be optimized to withstand the applied forces (Phillips 2012). However, this pattern is already evident in embryonic bone before mechanical loading (Weiss 1939), indicating that there is a prepattern for fetal trabecular development (Abel and Macho 2011; Reissis and Abel 2012). Genetic prepatterns have been implied from Hox genes, whose spatial expression patterns may provide cells with a combinatorial code contributing to patterning of body axes and other structures such as molluscan shell formation (McGinnis and Krumlauf 1992; Hinman et al. 2003). Morphogenetic field prepattern attributes have been inferred by detecting their bioelectrical signatures. Burr (reviewed by Levin 2012) pioneered a bioelectrical pre- pattern model in his discovery that the ratios of two axial dimensions of cucurbit fruit were predicted by voltage gradients in the embryo (Burr and Sinnott 1944). More recently, an embryonic voltage prepattern mapped sub- sequent cranio-facial morphology (Vandenberg et al. 2011). For the above and other reasons, the morphogenetic field is again becoming an integral paradigm of embryology, with Kalthoff (1996) commenting that any serious model of development should take fields into account. There are three variants of this: (1) Genocentric model: the gene-mediated field. In this model, fields are produced by interaction of genes and gene products within specific bounded domains (Gilbert et al. 1996). This model has resulted firstly from dissatisfaction stemming from both the enor- mous gap between the genotype and phenotype, unbridged even in single-cell morphogenesis (Gordon and Parkinson 2005), with a lack of evidence for how changes in genes, or the interaction of their products, can solely explain morphogenesis (Newman and Linde-Medina 2013). Second, there appeared to be a lack of evidence from the genetics program in explaining large-scale evolutionary change; Gould (1980) denounced gradual allelic substitution as a mode for evolutionary change, and Ayala (1983) recognized the problems of extrapolating microevo- lutionary events to explain macroevolutionary pro- cesses. As Gilbert et al. (1996) commented, ‘‘microevolution concerns only survival of the fittest, not arrival of the fittest…. Population genetics must change if it is not to become irrelevant to evolution.’’ Fig. 4 Trabeculae trajectories within femur (from Wolff 1870, 2010) S. E. B. Tyler 123
  • Gilbert and colleagues propose instead the morpho- genetic field, rather than genes, to be the major unit of ontogeny, whose changes mediate evolutionary change. Third, the existence of gradient fields has been suggested by the temperospatial mapping of regulatory gene products (De Robertis et al. 1991), such as gradients of Wnt and BMP proteins forming coordinates that define organ placement along the body axes (Niehrs 2010). (2) Morphomechanics model The emphasis here is on how the generation of mechanical stresses of tension and pressure lead to specific geometric shapes during morphogenesis. This model has emerged from the finding that several families of developmentally important genes and their transcription rate are directly affected by mechanical means and cell shape, and that mutant genes and environmental perturba- tions (leading to phenocopies) have causal equiva- lence (reviewed by Beloussov and Grabovsky 2006). In this model, the fields are proposed to be patterns of mechanical stresses/tension, pressure, or stress relax- ation, which may have a morphogenetic feedback. For instance, Hox gene activation may be mediated by chromatin deforming forces (Papageorgiou 2006). Morphogen signal transduction leads to production of polar molecules that may bind on the chromosome surface, collectively creating an electric field. This in turn acts on the negatively charged Hox cluster, pulling the Hox genes inside the interchromosome domain where they are accessible to transcription factors. However, mechanical cues alone cannot define precise domains and boundaries during mor- phogenesis. This suggests the existence of prepatterns of mechano-sensitivity which guide the activation of mechano-transduction pathways (Farge 2013). (3) Bioelectromagnetics model In this variant, field attri- butes are invoked by bioelectrical components ranging fromthe subcellular to the more global, whole-organism level, which providemorphogenetic cues via integration with biochemical pathways and gap junctions. Although different in emphasis, it is plausible that the above parameters act together in concerted operation. For instance, in recent years advances in molecular techniques have enabled identification of proteins involved in bio- electric signals, and the genetic networks shaping them within a field context (Levin 2009). Field Definitions Emerging from this historical backdrop, a number of def- initions have been proposed, each with different nuances. 1. Physical–mathematical definitions Goodwin (1985, 1988) defined a morphogenetic field as a spatial domain in which each part has a state determined by the state of neighboring parts so that the whole has a specific relational structure. Inherited particulars act to stabilize solutions of field equations so that particular morphol- ogies are generated. Field equations were employed in this way to describe viscoelastic, mechanical deforma- tory forces mediated by the cytoskeleton in morphoge- netic events such as gastrulation and algal whorl patterning (Goodwin and Trainor 1980, 1985; Oster et al. 1980). Goodwin (2000) envisaged a field as a spatial pattern of forces within which a changing molecular composition (controlled by a genetic pro- gram) exerts its influence. As an example of this, the application of coiling equations has enabled computer modeling of shell forms similar to ones real in nature (Raup 1962). Reiterating Driesch, Frankel (1989, 1992) defined a field as a territory within which developmental decisions are subject to a common set of coordinating influences. Reiterating Gurwitsch and Goodwin, Bel- oussov and Volodyaev (2013) envisaged a field as a system of position-dependent forces, regulated from the upper levels, acting on the developing organism. Another physical definition is provided by Gordon (1999), who suggested that the morphogenetic field is the trajectory of a differentiation wave. 2. Mediating phenotype into genotype Tsikolia (2006) envisaged a morphogenetic or a developmental field to be a discrete area of the embryo, and a mediator between phenotype and genotype. 3. Progenitor of organ structure The morphogenetic field has been defined as a piece of embryonic material constituting a given morphological structure (Davidson 1993), or for well-proportioned formation of organs and the whole embryo (Kalthoff 1996). 4. Clinical definition Clinical geneticists have interpreted malformation in terms of developmental field defects (Martinez-Frias et al. 1998). Multifactorial (polytypic) developmental defects could be accounted for by aberrations in the primary field during the first four weeks of gestation, whereas single (monotypic) malfor- mations may be due to defects later in morphogenesis in progenitor fields, from which final organ structures arise (Opitz 1993). Examples of defects proposed to be due to field perturbations include spina bifida, tracheal agen- esis, hypospadias, laryngeal cleft defects, congenital absence of left pericardium, lung and diaphragm agen- esis, median nasal process defects, and renal and sternal agenesis (Opitz 1985). 5. Referenced to information Wolpert (1977) defined a field as a group of cells, the location and the future fate of which have the specification within the same The Work Surfaces of Morphogenesis 123
  • boundary. Bizzarri et al. (2011) reiterate this, stating that morphogenetic fields represent informational and topological relationships within organisms. Levin (2009) defined fields as ‘‘the sum total of local and long-range patterning signals that impinge upon cells and bear instructive information that orchestrates cell behavior into the maintenance and formation of complex 3-dimensional structures.’’ Levin (2012) considered that basic units additional to cells may be subcellular components (notably in unicellular cili- ates), or a cell group/sheet. One problem with mathematical analyses alone is that forms such as shells and horns deviate more or less from the ideal mathematical model. For example, the molluscan turbinate shell, with all the whorls touching the axis of rotation, is impossible to realize mathematically. This problem is solved by filling out the umbilicus with shell material, thus transforming the axis into a conical core (Løvtrup and Løvtrup 1988). More importantly, mathe- matical analyses of form have brought us no closer to identifying the underlying generative mechanisms (Raff and Kaufmann 1983). However, some of the above defi- nitions are not mutually exclusive and can be used in conjunction. For instance, fields can be envisaged as car- riers of information from both the genotype and cell sur- face informational glycoconjugates, to invoke the physicomechanical forces underlying the morphogenetic events that generate the phenotype. Data in the literature are highly relevant to providing an empirical basis for field phenomena underlying morpho- genetic events. These important findings are indicated below. Evidence for Morphogenetic Fields Field Phenomena Predict and Correlate with Morphogenetic Events Evidence for the embryonic field envisaged by Gurwitsch emerged from his discovery that the orientation of embryonic nuclei enabled subsequent epithelial configura- tions to be predicted; and, in flower development, that overall shape developed with increasing precision, in spite of size variability in its components. This suggested to him that the individual cell divisions were governed by a su- pracellular ordering or integrating factor (Gurwitsch 1910, 1922; Beloussov 1997). Endogenous bioelectric signals are a particularly tractable component of morphogenetic field systems (Levin 2009). Ubiquitously, plants and animals generate various natural electromagnetic field systems prior to morphogenesis, which predict and correlate with growth and patterning events. There is an extensive review literature for this (e.g., Burr 1947; Jaffe 1981; Nuccitelli 1984; Levin 2003; McCaig et al. 2005). Thus only a few findings are highlighted here to give an indication of these data. For instance, in plants, the pattern of endogenous potential differences (PDs) in cucurbit fruits correlate with the development of fruit morphology (Burr and Sinnott 1944). A rapid change in the pattern of endogenous current in Lepidium roots after tilting to a horizontal position pre- cedes the response of the root in bending downwards (Behrens et al. 1982). In the algae Pelvetia and Pithophora, a polar distribution of electric potential corresponds with the cells’ growth polarities and the establishment of the developmental axis (Jaffe 1986). Similarly, in Douglas fir, external polarity potentials conform to the complex morphology of the tree (Fig. 5). An electrical dominance of the tree apex corre- sponds to its growth dominance and points to a fundamental relation between them (Lund 1931; Rosene and Lund 1953). In animals, such fields have been shown to predict the appearance of (and are implicated in) various morphoge- netic events. There are numerous examples. Intracellular Fig. 5 Distribution, orientation, and relative polarities of electro- magnetic fields in wood and cortex of Douglas fir and resulting orientation of polarities in main axis and branches (from Lund 1931; copyright of the American Society of Plant Biologists and reprinted with permission) S. E. B. Tyler 123
  • voltage gradients within insect ovaries drive maternal substances such as protein and RNA from the follicle to the egg, influencing oocyte polarity (Woodruff and Telfer 1973, 1980). Fertilized eggs drive a current around them- selves orientated from animal to vegetal pole, which in turn predicts the primary embryonic axis. PDs across the embryo midline are required for cranial and tail develop- ment; and an outward flow of ionic current predicts the location of head and limb formation (Borgens et al. 1983; Robinson 1989). Medial–lateral and rostral–caudal voltage gradient patterns correlate with the form of the amphibian neurula (Fig. 6). The electric fields result from a system of localized membrane ion channels and pumps. These generate a network of endogenous ion flows, fields, and voltage gra- dients that provides a signaling system, slower than that of action potentials, and providing instructive information ranging from the subcellular to whole embryo level (reviewed by Levin 2012). For instance, voltage patterns may form coordinates that provide morphogenetic cues (Shi and Borgens 1995). Membrane potentials are involved in the control of mitosis, oogenesis, cell migration and orientation through the embryo, coordination of morpho- genesis, cell proliferation, programmed cell death (Cone 1974; Lang et al. 2005), and the differentiation of stem cells (Sundelacruz et al. 2008) and other cell types (Barth and Barth 1974; Lang et al. 2005). In such studies, electric signals have now become mechanistically integrated with biochemical pathways, activating downstream morphogenetic cascades, via (1) the localization of transcription targets, (2) redistribution of surface membrane charged receptors, (3) conformational changes in membrane proteins, (4) electrophoresis of morphogens, and (5) modulation of voltage-sensitive small molecule and ion transporters (reviewed by Levin 2009). For instance, proton pumps produce gradients that region- alize gene expression and morphogenesis in craniofacial patterning of Xenopus laevis embryos (Vandenberg et al. 2011; Fig. 7); and a battery of cells across the frog embryo produces an electrophoretic force driving serotonin through conductive long-range gap junctions, which influences left- right patterning (Fukumoto et al. 2005). Individual cells act as a complex hydrogel, containing distinct microdomains with nano-scale electric field parameters (Tyner et al. 2007), and generating a variety of voltage characteristics (Martens et al. 2004). These may encode for and transmit large amounts of developmental information (Wallace 2007; reviewed by Funk et al. 2009). The cytoskeleton (both actin filaments and microtu- bules) and even DNA conduct electricity [with actin of similar conduction velocity as in nerves (20 m/s)] and are associated with the anchoring of voltage-sensitive mem- brane receptors and channels. Thus, in addition to gradients Fig. 6 Internal voltage gradient patterns correlate with the form of the amphibian neurula (artist’s reconstruction, from Shi and Borgens 1995; used with permission from John Wiley and Sons) Fig. 7 Endogenous Vmembrane patterns during neurulation (using voltage-reporting dyes), which precede shape changes and gene expression domains of the developing face. For example, hyperpo- larization marks future stomodeum (long black arrows), first pharyngeal fold (black and white arrows), eye field (short black arrow), region lateral to neural folds (short white arrows) and neural tube (long white arrows). (From Vandenberg et al. 2011; used with permission from John Wiley and Sons) The Work Surfaces of Morphogenesis 123
  • of morphogens transduced by receptors into signaling cascades, continuous electrical signaling from the extra- cellular matrix, transduced by voltage-gated mechanisms, may be conducted along cytoskeletal elements and even DNA (McCaig et al. 2009). Moreover, the dynamic changes of ion concentration during embryonic development are tightly regulated. For instance, Ca2?-mediated muscle-assembly instructions are integrated into multiple signaling networks during muscle development (Ochi and Westerfield 2007), by as yet unknown mechanisms, but which may involve subcellular domains with their own Ca2? signaling signatures (Jaim- ovich and Carrasco 2002; Webb and Millar 2011). Morphological Evidence A visible marker of a morphogenetic field may be provided by the global pattern of surface architecture on Crepidula mollusc eggs (Tyler et al. 1998; Fig. 8a). This linear array of ridges (first observed vegetally by Dohmen and van der Mey 1977), is organized with reference to the animal– vegetal (a–v) axis, and to the successive cleavage quartets. Thus the surface architecture may be a morphological marker for a field system which organizes the a–v axis and the cleavage pattern. As cleavage progresses, the surface architecture increases in complexity, correlating with the underlying microtubule and mitotic spindle pattern. This association is maintained during dynamic changes in the microtubule network (Tyler and Kimber 2006). The cell spindles, asters, and global microtubule network are orientated to one another almost as a single unit unimpeded by cell bound- aries, appearing to be temporospatially coordinated throughout the whole embryo (Fig. 8b; see also File S1 in Online Resource 1).2 This reiterates the observation that embryogenesis displays a sophisticated level of intercel- lular cytoskeletal coordination (Tucker 1981). Thus the surface architecture-microtubule association may have a common causality residing in a field system. A similar pattern is also evident in plants. In regener- ating vascular strands of Coleus hybridus, an intercellular lignified band pattern sweeps across groups of cells, which correlates with a cytoplasmic streaming pattern preceding it, indicating a developmental link between them (Sinnott and Bloch 1944; see Fig. S2 in Online Resource 2). Field systems are also evident among single-celled organisms, both eukaryotes and prokaryotes (Harold 1995). Within ciliate protozoa, the number and position of organelles in relation to numbers of ciliary rows seems to be integrated, and patterned in relation to the cell as a whole. This provides evidence of an inductive field thought to define the geometrical placement of the organelles (Nanney 1966; Aufderheide et al. 1980). The field may be characterized by longitudinal and circumferential axes, which map out a field of PI, notable in being continuous between mother and daughter cells (Frankel 1989, 1991, 1992, 2008). The field may also be based on a prepattern, scaffolding, or structural memory, enabling an observed precise Fig. 8 Morphological evidence for a field system in Crepidula mollusc embryos. A Development of embryo surface as revealed by FITC—GSL-1 lectin-staining at 16-cell formation, showing ridges of surface architecture pattern. Arrows indicate pattern continuity between cells. B Microtubule topography, revealed by FITC-anti-a tubulin antibody labeling, showing spindles, asters, intercellular junctions (arrowed), and global microtubule network orientated with reference to one another at 12-cell stage Bars A 25 lm. B 50 lm (from Tyler and Kimber 2006) 2 File S1 in Online Resource 1 is a higher resolution of the Z-series from Tyler and Kimber (2006) web material at http://www.ijdb.ehu. es/data/05/052007st/S4.mov. The file shows morphological evidence for a field system in Crepidula mollusc eggs. It is a confocal imaging Z-series of microtubules stained with FITC-anti-a tubulin antibody. All optical sections of 5 lm interval; 16-cell stage leading to 20-cell formation. Progressing through the Z-series reveals interconnection of microtu- bular network and orientation of spindles and asters with reference to one another throughout the whole embryo; 72 sections. S. E. B. Tyler 123 http://www.ijdb.ehu.es/data/05/052007st/S4.mov http://www.ijdb.ehu.es/data/05/052007st/S4.mov
  • coordination of morphogenetic processes at levels ranging from assembly of cell components to remodeling of elab- orate surface patterns (Jerka-Dziadosz and Beisson 1990). Rod-shaped bacterial cell division provides clear evi- dence for a molecular field morphology supplying spatial information, according to Harold (2005). Division requires construction of a septum to bisect the rod precisely in the middle, specified by a set of proteins oscillating in a field between the cell poles. The septum is placed at the centre of the field, where the proteins are at their lowest con- centration. These proteins may be moving within some sort of framework (Shih et al. 2003). Transplantation Experiments Further empirical evidence came when newt neurula discs’ cells generated limb formation at locations of their trans- plantation (Harrison 1918). Even half of a disc could generate a complete limb at the transplantation site, and if undetermined tissue was grafted into the discs they became organized into the limb. Hence the so-called limb field was recognized to have a regulative ability. Genetic Parameters In vertebrate embryos, gradient fields have been visualized at the level of individual regulatory molecules (De Robertis et al. 1991). There is a correlation between gradients of expression of homeodomain proteins and the behavior of fields defined by classic transplantation experiments, but with no direct evidence causally linking the two. According to De Robertis and colleagues, the morphogenetic fields defined by the experimental embryology of Harrison, Huxley, de Beer, and the like have a molecular substratum that can be probed visually with antibody markers. Regeneration Huxley and De Beer (1934, p. 278), focusing particularly on evidence from regeneration experiments, concluded that morphogenesis cannot be rationally interpreted without postulating the existence of fields. For instance, the flat- worm Planaria, when cut transversely into two pieces, grows a tail from the hind end of the front piece, and a head from the anterior end of the rear piece. But if the transverse cut is made further back, the cells in the previous experi- ment (which had belonged to the hind piece, and prolif- erated to form a head) now belonged to the front piece and formed a tail. They surmised that either a head or a tail could not be generated from identical tissue containing localized determinants, but rather provided evidence for a field system. Yet further evidence for a role of field systems is pro- vided by regenerating systems such as limbs, which drive strong endogenous electromagnetic fields (EFs) around them. Following vertebrate limb amputation, an injury current provides spatial cues for cells migrating into the limb (Becker and Sparado 1972). In earthworm segment regeneration, each segment has a specific electric potential. Segments are added by regeneration until the total endog- enous field potential is that of a normal full-sized worm (Kurtz and Shrank 1955). Changes in orientation and magnitude of PDs correlate with regeneration events in Phaseolus, Coleus, and Bryophyllum (reviewed by Rosene and Lund 1953). The direction of cell division in wound regeneration may be orientated towards the wound edge by wound-induced EFs (Chiang et al. 1992). The Effect of Applied Fields If a morphogenetic field system with electromagnetic parameters does indeed exist, then voltages imposed within the physiological range might affect development in a manner predictable by the applied voltage orientation. This is indeed the case, leading to a range of effects (reviewed by Levin 2003). For example, applied electric fields in plants lead to reversal of orientation of polarity, with the electric potentials corresponding to the morphological polarity, although other agents also disrupt this potential (Rehm 1938; Thomas 1939). In animals, a variety of embryonic cells (e.g., neural crest cells) realign themselves or migrate within an applied field (Nuccitelli 1988). In Obelia, an applied EF caused a reversal of the normal polarity of morphology, i.e., a hydranth appeared at the basal end; and a stolon at the apical end (Lund 1921). In planarian worms, a head–tail dipole, which persisted in cut segments, was reversed by an applied field. Anode-orientated fragments developed a head structure in the tail end, or two heads (Marsh and Beams 1957). Volt- ages imposed during morphogenetic stages such as neuru- lation lead to developmental defects (Metcalf and Borgens 1994). Small, DC electric fields orientate cell division in cultured corneal epithelial cells, with the mitotic spindle aligned to the field vector, associated with a coordinated flow towards the cleavage furrow of cortical cytoplasm, preformed actin filaments and actin-binding proteins, and surface receptors (Zhao et al. 1999a). Physiological EFs induce asymmetric distribution of surface receptors (Poo and Robinson 1977; Zhao et al. 1999b) and cortical F-actin, both being implicated in spindle alignment during mitosis. The application of an external shunt inhibits regenera- tion events (Borgens et al. 1977, 1984). Moreover, an applied field can induce regeneration even in normally non- regenerating systems, such as the regeneration of children’s freshly amputated fingertips (Becker and Sparado 1972). The Work Surfaces of Morphogenesis 123
  • Yet further evidence is provided from the ability of simple bioelectrical signals to trigger orchestrated complex morphogenesis and differentiation (including construction of skeletal bone, muscle, epidermis, vasculature, and spinal cord), whereby artificial induction of H? flux is sufficient to induce complete Xenopus tail regeneration (Adams et al. 2007). Other Parameters Various other physical parameters have been ascribed with field characteristics (reviewed by Levin 2012). These include differential adhesion (haptotactic) fields operating in the extracellular matrix (Murray and Oster 1984; Lord and Sanders 1992); osmotic fields (O’Shea 1988); and viscoelastic tension fields (Lakirev and Belousov 1986; Brière and Goodwin 1990). Application of the Field Model to Research Strategies Medical Applications Organisms continue to maintain their distinct morphology throughout life, and regenerate damaged or lost tissues, sometimes prolifically (e.g., the salamander can regenerate eyes, limbs, heart, skull, and brain regions). Field influ- ences have been implicated in the mechanisms underlying regeneration. Thus knowledge of the basis of such fields may be vital in the development of regenerative procedures to correct degenerative and aging diseases, cancer, and in wound healing; examples follow. Cancer Cancer may represent an escape from a morphogenetic field (Waddington 1935; Needham 1936), in which tumors form when cells stop obeying normal 3-D body patterning cues, with the field having a normalizing influence (Lee and Vas- ioukhin 2008; Levin 2012). In this view, disruption of the field can be teratogenic. Transplanted tumors led to detection of changes in bioelectric field parameters (Burr 1941). Con- versely, neoplastic cells ranging from germ cell, melanoma, breast and liver tumors when introduced into embryonic tissue reverse the malignancy: the embryonic tissue is considered to generate a normalizing morphogenetic field that reprograms the tumor cells (reviewed by Bizzarri et al. 2011). The somatic mutation theory, whereby neoplasia is explained as resulting from the accumulation of mutations, does not explain this ability of tumor cells to revert to normal. Thus, according to the tissue organization field theory (Sonnenschein and Soto 1999, 2000, 2008), there is potential for carcinogenesis to be reversible when cancer cells are exposed to strong morphogenetic fields that provide nor- malizing patterning cues (Astigiano et al. 2005, Bizzarri et al. 2011). Such cues can be found within embryonic microenvironments, where metastatic tumor cells have been reprogrammed (Hendrix et al. 2007). Proteins extracted from embryos based in such fields have produced promising therapeutic results (Potter 2007). Because cancer is also associated with ion channel disruption, this is a promising target for drug therapies (Arcangeli et al. 2009). Since the most highly regenerative animals have the lowest cancer incidence, a better knowledge and applica- tion of patterning pathways involved in regeneration might also preserve cells within a normal patterning plan and prevent neoplasia (Brockes 1998). Wound Healing and Regeneration Human skin wounds generate an endogenous EF, the so- called injury current, which guides keratinocyte migration toward the wounded region, and its magnitude correlates with the organization of the healing epidermis (Nuccitelli et al. 2011). This activity is mediated by polarized activation of multiple signaling pathways that include PI3 kinases/ Pten, membrane growth factor receptors, and integrins (Zhao 2009; see Fig. S3 in Online Resource 2). The importance of such natural electric phenomena in wound healing has led to promising and effective clinical applica- tion of electromagnetic fields and EF interventions (reviewed by Nuccitelli 2003; Ramadan et al. 2008; Levin 2009) in the acceleration of bone formation in osteoporosis treatment and healing of non-union fractures (Pilla 2002; Aaron et al. 2004; Chang et al. 2004), and stimulus of epi- thelial (e.g., eye cornea) wound healing (Zhao et al. 1999a). Electrical stimulation has led to enhanced closure of wounds including pressure ulcers, arterial ulcers, diabetic ulcers, and venous stasis ulcers for chronic wounds resistant to other standard treatments, although the mechanisms by which the fields improve healing are not known, hindering tissue engineering strategies (Messerli and Graham 2011). Pro- gress has been made in applied EF-mediated spinal cord neuronal regeneration in non-human trials (Cone and Cone 1976; Borgens et al. 1990, 1999). Human clinical trials are in progress (Shapiro et al. 2005; Shapiro 2012), with promising results using oscillating field stimulation. In these examples, the electric field may have a master- regulator property, triggering complex, orchestrated pat- terning cascades in the host. The structure need not be directly bioengineered (complex bioassembly being as yet beyond our grasp) rather, such stimuli may activate downstream morphogenetic programs already in place, as may occur in tail regeneration mediated by bioelectric stimulation (Pai et al. 2012). S. E. B. Tyler 123
  • Moreover, in addition to a cell focus in intervention strategies, the anatomical context seems to be required to facilitate the correct developmental program. For instance, transcription factors can induce eye development from progenitor cells, but only within the host, rather than in vitro (Viczian et al. 2009). The Form Question Revisited The above-described medical applications indicate that deciphering and learning to control shape is thus arguably the fundamental problem of biology and medicine (Levin 2012). A research program is proposed that focuses on a search for the developmental signatures underlying distinct morphological forms (Tyler submitted MS), in which field theory may be of relevance. The premise that all necessary information is contained in gene sequences (from which there is a unidirectional, linear flow), is giving way to a new synthesis emphasizing biological networks within hierarchical tiers, with multidi- rectional information moving both within and between the tiers (Franklin and Vondriska 2011; see Fig. S4 in Online Resource 2). Such networks have been demonstrated, for instance, in cardiac development (Lage et al. 2010). Thus type-specific comparative biology of such systems is likely to reveal key informational units of development. Numerous studies indicate that body shape has a com- plex genetic basis, with many different genes contributing to overall differences in body shape (reviewed by Reid and Peichel 2010). Moreover, the identification of such genes may be insufficient to understand the emergence of three- dimensional form (Schwartz 2013). However, discontinu- ities between a number of forms are clearly demarcated by hybridization and other data. In turn this makes the search for underlying generative bases, including distinctive field characteristics, more open to investigation, because the comparative biology is conducted at the right level (rather than, say, merely between species that are all members of a common basic type). These forms are well canalized and robust, with no deviations from them. So, for instance, hybridization is possible throughout the parrot family (Psittacidae), which exhibits a wide range of divergent forms including disparate skull patterns. How- ever, in contrast, no hybridization is evident between members of Psittacidae and outgroups. This indicates that the diversity of form throughout the Psittacidae is repre- sented by variation within a basic parrot type, in which the morphogenetic machinery is compatible, as indicated by successful hybridization. A testable hypothesis is that, if a type can be identified empirically, there should be evidence of a shared morpho- genetic program, which may include field parameters, i.e., distinguishable from disparate types. This indeed seems to be the case. Phylogenetic peculiarities in limb, eye, cardiac field signaling centers, and gene expression patterns are indicated in a separate article (Tyler submitted MS). For instance, there are dramatic differences in the development of the heart from the heart fields in the chick compared with mammals (Abu-Issa and Kirby 2008). There are yet further examples of such data. The expression pattern of Dpp during leg development is divergent among cricket, grasshopper, and Drosophila, and this pattern may correlate with diversity of leg morphology (Niwa et al. 2000). There are notable differences in eye field transcription factors expression and function in eye development between species (reviewed by Graw 2010), indicating that as in the limb field, eye field specification involves the recruitment of disparate mecha- nisms across the phyla. Thus, further exploration of comparative signaling and expression patterns is an avenue likely to be promising. There may be exciting type-specific aspects of a range of phenomena, ranging from the subcellular, such as micro- domain voltage characteristics, to the supracellular, opti- cally tractable morphological and bioelectromagnetic markers (using, for instance, voltage-reporter dyes, com- bined with molecular and genetic tools) for which field systems may play a role. Conclusion Three contemporary models of the morphogenetic field thus emerge. In spite of Waddington’s recognition of fields as a character of processes rather than just location, the location model continues to be a popular view, viz., the temporospatial theater of operation for genes and gene products. However, the location model is problematic in that sometimes certain field boundaries are not precise, nor do they correlate easily with gene expression or fate maps. The second model envisages a field as a pattern of forces, such as mechanical or bioelectromagnetic; in the third, it is a pattern of instructive signals. Whilst all three models have their merits and validity, the model employed influ- ences research strategies and what one is seeking to find. In essence, is the morphogenetic field a region, of gene and signaling influence; or a motive force that physically shapes morphogenesis; or a combination of these? Morphogenesis is a multistep process, with each stage needing careful coordination (Schock and Perrimon 2002). A frequent discovery is that just the right molecules seem to be in just the right place at the right time (e.g., Thomas and Kiehart 1994). The result is that, by as yet undiscov- ered means of such coordination in time and space, tissue morphogenesis is directed with such perfection (Settleman 2001). Experimentally and morphologically tractable field aspects provide a way forward in probing this. This in turn The Work Surfaces of Morphogenesis 123
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Mol Biol Cell 10: 1259–1276 The Work Surfaces of Morphogenesis 123 http://dx.doi.org/10.1101/cshperspect.a004325 The Work Surfaces of Morphogenesis: The Role of the Morphogenetic Field Abstract The Field Concept: Development of an Idea Field Definitions Evidence for Morphogenetic Fields Field Phenomena Predict and Correlate with Morphogenetic Events Morphological Evidence Transplantation Experiments Genetic Parameters Regeneration The Effect of Applied Fields Other Parameters Application of the Field Model to Research Strategies Medical Applications Cancer Wound Healing and Regeneration The Form Question Revisited Conclusion Acknowledgments References
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  • LONG ARTICLE The Work Surfaces of Morphogenesis: The Role of the Morphogenetic Field Sheena E. B. Tyler Received: 14 December 2013 / Accepted: 25 March 2014 � Konrad Lorenz Institute for Evolution and Cognition Research 2014 Abstract How biological form is generated remains one of the most fascinating but elusive challenges for science. Moreover, it is widely documented in contemporary liter- ature that development is tightly coordinated. The idea that such development is governed by a coordinating field of force, the morphogenetic field, and its position in embry- ology research paradigms, is traced in this article. Empir- ical evidences for field phenomena are described, ranging from bioelectromagnetic effects, morphology, transplanta- tion, regeneration, and other data. Applications of medical potential including treatment of cancer, birth defects, and wound healing are highlighted. The article hypothesizes that distinct morphological forms may have distinct field parameters. Experimentally tractable field parameters may thus provide an exciting research program for probing morphogenesis and phylogenetic diversity. Keywords Bauplan � Bioelectromagnetic information � Cancer � Regeneration � Form � Morphogenetic field The mystery of how [form] was all, and is, brought about is still with us– unsolved! —Wardlaw (1970) The Field Concept: Development of an Idea According to D’Arcy Thompson (1942), the analysis of form can be traced back to Sir Christopher Wren, who proposed that the snail shell form could be described mathematically as a logarithmic spiral (Wallis 1659). The inference from this is that mathematical analyses of form may lead to an understanding of the generative agents of such forms (Løvtrup and Løvtrup 1988). During the early 20th century, the idea emerged that these agents may be organized by a coordinating field of force, the morphogenetic field. The developing foundations for a field concept emerged from numerous experimental observations, which remain useful to this day in assessing the forces coming to bear in development. Graded properties of substances in embryos had been under consideration from the days of Trembley working on Hydra in the 18th century (McLachlan 1999). Allman (1864) had coined the term polarity to describe regeneration (reviewed by Wolpert 1986). One of the first to recognize the importance of both polarity and the posi- tion of cells was the German botanist Hermann Vöchting (1877, 1878). His experimental studies mainly on Tarax- acum (dandelion) roots indicated that the upper part of a cut stem always produced buds, and the lower end roots— indicating a tissue polarity—and that the fate of the cells was determined by their position in the stem (reviewed by Sinnott 1960; Wardlaw 1968; Thorpe 2012). Moreover, he inverted a cut root segment, which developed shoots from the (now upper) root pole. However, a segment cut from this in turn led to the growth of shoots from the original shoot pole, indicating that the original polarity had remained (reviewed by Nick and Furuya 1992). Vöchting envisaged this innate polarity to have a cellular basis, resulting from each cell acting as a minute magnet, con- veying signals in one direction (Sachs 1991). Similarly in animal embryos, Hans Driesch (Fig. 1) pro- posed that the fate of cells depends upon their position. Dri- esch (1892a, b) separated blastomeres of echinoderm eggs, discovering that normal whole embryos could be generated Electronic supplementary material The online version of this article (doi:10.1007/s13752-014-0177-8) contains supplementary material, which is available to authorized users. S. E. B. Tyler (&) John Ray Research Field Station, Cheshire, UK e-mail: s.tyler@johnray.org.uk 123 Biol Theory DOI 10.1007/s13752-014-0177-8 http://dx.doi.org/10.1007/s13752-014-0177-8
  • from them. He added the concept of a reference system of fixed coordinates: ‘‘The ‘whole’ may be related to any three axes drawn through the normal undisturbed egg, on the hypothesis that there exists a primary polarity and bilaterality of the germ; the axes which determine this sort of symmetry may…. be taken as co-ordinates’’ (Driesch 1908, p. 80). Second, he envisaged the embryo as a ‘‘harmonious equipotential system’’—equipotential due to the part hav- ing the potency to generate the whole, and harmonious because in forming the whole the parts work together in an integrated way (Willier and Oppenheimer 1974). Third, like Vöchting, Driesch recognized the importance of cell polarity in addition to that of tissue polarity. In his Analytische Theorie der organischen Entwicklung, Driesch (1894) explained the polarity of the egg with reference to the polarized constituents of the cytoplasm. He added that it was not the position itself that determined the fate but the different signals received by the cells according to their positions (Kalthoff 1996). Theodor Boveri observed a polarized distribution of cytoplasmic components, physicochemical parameters, respiratory rate, and rate of cell division in echinoderm eggs. He linked this with what he termed a ‘‘Gefälle’’ or gradient (Boveri 1901, 1910). He described this as a gradual, graded property to signify a differential endow- ment of determinants that daughter cells received from the egg cell (Sander 1996). Runnström (1914) developed this to describe polarity as an expression of a concentration gradient of a specific chemical material whereby the ‘‘expression of the axes is shown in the direction [of con- centration] of the chemical.’’ In Russia, Gurwitsch (1912; Fig. 2) recognized there to be a dynamic coordination of events (Geschehensfeld), in which a supracellular coordinating principle (Kraftfeld) ordered the whole of development by providing a guiding field of force, which he termed ‘‘embryonales Feld.’’ Reiterating Driesch, he proposed that the spatial position and properties of cells could be referenced in relation to a set of mathematically distinguishable coordinates. He also postulated that such fields are comprised from the vector addition of individual cell fields (Gurwitsch 1944). In 1918 Ross Harrison discovered that a disc of cells normally giving rise to a forelimb could form a forelimb when transplanted into another region of the embryo, suggesting that the disc of cells generated a field of organ- forming potential (Harrison 1918). Hans Spemann, a student of Boveri, in experiments isolating embryo regions with hair loops, discovered that only regions containing the dorsal lip of the blastopore continued development. Moreover, he saw this as Boveri’s ‘‘privileged region,’’ a center of differentiation, which he named the organizer (Horder and Weindling 1983). He considered that this was associated with an organization field, a supracellular model with dominant controlling regions in the embryo. This contrasted with the pervading cellular approach of its day. This dorsal organizer region exhibited many of the properties of a morphogenetic field (De Robertis et al. 1991). For instance, if one organizer is divided into several fragments, each will lead to formation of a new body axis after transplantation. The discovery of the organizer stimulated a worldwide research rush to find its chemical basis. However, the organizer concept was to prove contro- versial. Holtfreter (1945) showed that ectoderm can neur- ulate without any specific organizer induction, indicating a certain predetermination. Yet with the passage of time, some authors maintained that the dorsal lip of the Fig. 1 Hans Driesch (reproduced with permission from The Inter- national Journal of Developmental Biology) Fig. 2 Alexander Gurwitsch (from the personal collection of Lev Beloussov, used with permission) S. E. B. Tyler 123
  • blastopore is indeed the ‘‘organization center’’1 for the amphibian embryo (Nieuwkoop 1973, 1977). Meanwhile the gradients observed by Boveri (1901) led Child (1941) in the U.S. to envisage axial pattern devel- oping from a gradient system that provides a ‘‘physiolog- ical coordinate system,’’ to which he attributed metabolic differentials as the primary agents. In Britain, Huxley and De Beer (1934) reviewed a large body of experimental data, which they interpreted in field terms. They added that such fields seem to be graded, and thus appear to be gradient fields. They considered that the gradients might indeed be metabolic, but remained non- committal by calling them activity gradients. Child had reduced the field to be synonymous with the gradient itself. He proposed that ‘‘developmental fields … are gradient systems; the field is constituted by the gradient…. The gradients are the vectors of the field and determine its extent and orderly relations within it’’ (Child 1941, p. 277; my emphasis). However, Weiss (1939, p. 376) commented that Child’s gradients were not the proven causal instru- ments of development, merely that there was a correlation between the physiological and morphological polarity. Thus the gradual historical development of these ideas, emerging from experimental data, led to the morphogenetic field concept becoming the pervasive research paradigm for embryology in the first half of the 20th century. This was embodied in the dominant texts of the day, such as by Weiss (Principles of Development, 1939), and Child (Patterns and Problems in Development, 1941). In Weiss the morphogenetic field became most greatly developed, with 148 pages marshalling supportive experimental evi- dence, and descriptions of eye, limb, ear, and gill fields. He cited, for instance, the meridianal transection of Styela sea urchin eggs (p. 260, p. 291) in which each half produces a normal embryo. He noted that the new poles appearing after the transection were at some distance from the pre- vious ones, and came to be the new centers of a reduced field district, indicating that there was no fixed material point for organizing activity in the egg. Needham (1942) and Waddington (1956) distinguished fields to more properly refer to the ‘‘character of pro- cesses’’ occurring in a region (reiterating Gurwitsch’s Geschehensfeld, rather than just the geographical location of such events). Then, mysteriously, according to Oppenheimer (1966) and Opitz (1985), the field concept gradually disappeared as a paradigm for development in many research circles. In the aftermath to World War II, the German developmental mechanics school—the main founder and driver for experimental embryology, with which field concepts were associated—disintegrated. Particularly in the U.S., genetics was rising to an ascendency, and a new paradigm became established in which the causal basis of form was assumed to reside exclusively in the genes and their products (Morgan 1934), and in which fields were deemed irrelevant (Gilbert et al. 1996). This view in turn influenced experi- mental design. But actually the field concept did not completely disappear in that period. It remained alive and well in several research avenues. First were studies of bioelectric phenomena, in which field explanations seemed to best fit the data. For instance, Lund (1947; Fig. 3) demonstrated that embryo polarity was predicted by polarity of endogenous ion flow. Second, field theory was highly applicable as an explanation for birth defects (Martinez-Frias et al. 1998). Third, it was relevant at least initially in the idea of positional information (PI) proposed by Wolpert (1969). Wolpert revisited the Dri- esch–Vöchting discoveries of polarity being a function of a cell’s position and—as the term Wolpert coined made clear— focused on the importance of information. Wolpert proposed that when cells have their PI uniquely specified with respect to the same set of boundary reference points, this constitutes a field. He incorporated the ideas of Stumpf (1967) in proposing end cells to be respectively a source and sink of a substance, which provide reference points for the assignment of posi- tional values. The direction of the coordinates was the polar- ity, whether direction of transport of a substance or propagation of a wave. Wolpert also emphasized the idea of interpretation, whereby the cell reads out the PI and converts it into an activity. He stated: ‘‘it is positional information which Fig. 3 E.J. Lund (photo courtesy of University of Texas Marine Science Institute) 1 The organizer is in turn thought to be induced by a signal secreted by the Nieuwkoop center, with similar signaling centres discovered in the zebrafish, chick, and sea urchin (reviewed by Vonica and Gumbiner 2007). Inducers released by the organizer have now been identified which encode antagonists of bone morphogenetic protein, Nodal or Wnt growth factors. The field parameters may be characterized by the different expression domains of these growth factors and their antagonists, which create signaling gradients, which in turn are implicated in patterning the early embryo in a combina- torial fashion (Niehrs 2004). The Work Surfaces of Morphogenesis 123
  • provides the co-ordinated and integrated character of fields’’ (1969, p. 19). As to its physical basis, he proposed possibilities including linking polarity potential with a metabolic gradient (Child 1941); or a respiratory pathway; the transmission of a wave of activity according to the phase-shift model of Goodwin and Cohen (1969); membrane interaction; or the transmission of informational macromolecules between cells—the antecedent of the morphogen. It has since been proposed that PI may occur in com- bination with other morphogens, gene regulatory interac- tions, and downstream factors (e.g., gap, pair-rule, and segment-polarity genes) expressed in spatial patterns more complex than gradients, and whose dynamic effects can be monitored using computational modeling (Jaeger and Reinitz 2006). Positional cues may also be provided by bioelectric phenomena (Levin 2009, 2012). Over the course of time a whole spectrum of variants of the model of PI has been developed. One is a stripped- down version in which field aspects have been jettisoned (PI itself becoming the paradigm). At the other extreme, PI is integrated with information-rich cell surface glycocon- jugates interpreted or decoded by morphogenetic field parameters (Morozova and Shubin 2013). In addition to PI, another form of information storage proposed was the prepattern, which provides a template or scaffold for the subsequent morphology. For instance, the inner regions of mammalian bones consist of a latticework of ossified trabeculae whose orientation corresponds to lines of mechanical compression and tensile stress (Wolff 1870; Fig. 4), enabling femur structure to be optimized to withstand the applied forces (Phillips 2012). However, this pattern is already evident in embryonic bone before mechanical loading (Weiss 1939), indicating that there is a prepattern for fetal trabecular development (Abel and Macho 2011; Reissis and Abel 2012). Genetic prepatterns have been implied from Hox genes, whose spatial expression patterns may provide cells with a combinatorial code contributing to patterning of body axes and other structures such as molluscan shell formation (McGinnis and Krumlauf 1992; Hinman et al. 2003). Morphogenetic field prepattern attributes have been inferred by detecting their bioelectrical signatures. Burr (reviewed by Levin 2012) pioneered a bioelectrical pre- pattern model in his discovery that the ratios of two axial dimensions of cucurbit fruit were predicted by voltage gradients in the embryo (Burr and Sinnott 1944). More recently, an embryonic voltage prepattern mapped sub- sequent cranio-facial morphology (Vandenberg et al. 2011). For the above and other reasons, the morphogenetic field is again becoming an integral paradigm of embryology, with Kalthoff (1996) commenting that any serious model of development should take fields into account. There are three variants of this: (1) Genocentric model: the gene-mediated field. In this model, fields are produced by interaction of genes and gene products within specific bounded domains (Gilbert et al. 1996). This model has resulted firstly from dissatisfaction stemming from both the enor- mous gap between the genotype and phenotype, unbridged even in single-cell morphogenesis (Gordon and Parkinson 2005), with a lack of evidence for how changes in genes, or the interaction of their products, can solely explain morphogenesis (Newman and Linde-Medina 2013). Second, there appeared to be a lack of evidence from the genetics program in explaining large-scale evolutionary change; Gould (1980) denounced gradual allelic substitution as a mode for evolutionary change, and Ayala (1983) recognized the problems of extrapolating microevo- lutionary events to explain macroevolutionary pro- cesses. As Gilbert et al. (1996) commented, ‘‘microevolution concerns only survival of the fittest, not arrival of the fittest…. Population genetics must change if it is not to become irrelevant to evolution.’’ Fig. 4 Trabeculae trajectories within femur (from Wolff 1870, 2010) S. E. B. Tyler 123
  • Gilbert and colleagues propose instead the morpho- genetic field, rather than genes, to be the major unit of ontogeny, whose changes mediate evolutionary change. Third, the existence of gradient fields has been suggested by the temperospatial mapping of regulatory gene products (De Robertis et al. 1991), such as gradients of Wnt and BMP proteins forming coordinates that define organ placement along the body axes (Niehrs 2010). (2) Morphomechanics model The emphasis here is on how the generation of mechanical stresses of tension and pressure lead to specific geometric shapes during morphogenesis. This model has emerged from the finding that several families of developmentally important genes and their transcription rate are directly affected by mechanical means and cell shape, and that mutant genes and environmental perturba- tions (leading to phenocopies) have causal equiva- lence (reviewed by Beloussov and Grabovsky 2006). In this model, the fields are proposed to be patterns of mechanical stresses/tension, pressure, or stress relax- ation, which may have a morphogenetic feedback. For instance, Hox gene activation may be mediated by chromatin deforming forces (Papageorgiou 2006). Morphogen signal transduction leads to production of polar molecules that may bind on the chromosome surface, collectively creating an electric field. This in turn acts on the negatively charged Hox cluster, pulling the Hox genes inside the interchromosome domain where they are accessible to transcription factors. However, mechanical cues alone cannot define precise domains and boundaries during mor- phogenesis. This suggests the existence of prepatterns of mechano-sensitivity which guide the activation of mechano-transduction pathways (Farge 2013). (3) Bioelectromagnetics model In this variant, field attri- butes are invoked by bioelectrical components ranging fromthe subcellular to the more global, whole-organism level, which providemorphogenetic cues via integration with biochemical pathways and gap junctions. Although different in emphasis, it is plausible that the above parameters act together in concerted operation. For instance, in recent years advances in molecular techniques have enabled identification of proteins involved in bio- electric signals, and the genetic networks shaping them within a field context (Levin 2009). Field Definitions Emerging from this historical backdrop, a number of def- initions have been proposed, each with different nuances. 1. Physical–mathematical definitions Goodwin (1985, 1988) defined a morphogenetic field as a spatial domain in which each part has a state determined by the state of neighboring parts so that the whole has a specific relational structure. Inherited particulars act to stabilize solutions of field equations so that particular morphol- ogies are generated. Field equations were employed in this way to describe viscoelastic, mechanical deforma- tory forces mediated by the cytoskeleton in morphoge- netic events such as gastrulation and algal whorl patterning (Goodwin and Trainor 1980, 1985; Oster et al. 1980). Goodwin (2000) envisaged a field as a spatial pattern of forces within which a changing molecular composition (controlled by a genetic pro- gram) exerts its influence. As an example of this, the application of coiling equations has enabled computer modeling of shell forms similar to ones real in nature (Raup 1962). Reiterating Driesch, Frankel (1989, 1992) defined a field as a territory within which developmental decisions are subject to a common set of coordinating influences. Reiterating Gurwitsch and Goodwin, Bel- oussov and Volodyaev (2013) envisaged a field as a system of position-dependent forces, regulated from the upper levels, acting on the developing organism. Another physical definition is provided by Gordon (1999), who suggested that the morphogenetic field is the trajectory of a differentiation wave. 2. Mediating phenotype into genotype Tsikolia (2006) envisaged a morphogenetic or a developmental field to be a discrete area of the embryo, and a mediator between phenotype and genotype. 3. Progenitor of organ structure The morphogenetic field has been defined as a piece of embryonic material constituting a given morphological structure (Davidson 1993), or for well-proportioned formation of organs and the whole embryo (Kalthoff 1996). 4. Clinical definition Clinical geneticists have interpreted malformation in terms of developmental field defects (Martinez-Frias et al. 1998). Multifactorial (polytypic) developmental defects could be accounted for by aberrations in the primary field during the first four weeks of gestation, whereas single (monotypic) malfor- mations may be due to defects later in morphogenesis in progenitor fields, from which final organ structures arise (Opitz 1993). Examples of defects proposed to be due to field perturbations include spina bifida, tracheal agen- esis, hypospadias, laryngeal cleft defects, congenital absence of left pericardium, lung and diaphragm agen- esis, median nasal process defects, and renal and sternal agenesis (Opitz 1985). 5. Referenced to information Wolpert (1977) defined a field as a group of cells, the location and the future fate of which have the specification within the same The Work Surfaces of Morphogenesis 123
  • boundary. Bizzarri et al. (2011) reiterate this, stating that morphogenetic fields represent informational and topological relationships within organisms. Levin (2009) defined fields as ‘‘the sum total of local and long-range patterning signals that impinge upon cells and bear instructive information that orchestrates cell behavior into the maintenance and formation of complex 3-dimensional structures.’’ Levin (2012) considered that basic units additional to cells may be subcellular components (notably in unicellular cili- ates), or a cell group/sheet. One problem with mathematical analyses alone is that forms such as shells and horns deviate more or less from the ideal mathematical model. For example, the molluscan turbinate shell, with all the whorls touching the axis of rotation, is impossible to realize mathematically. This problem is solved by filling out the umbilicus with shell material, thus transforming the axis into a conical core (Løvtrup and Løvtrup 1988). More importantly, mathe- matical analyses of form have brought us no closer to identifying the underlying generative mechanisms (Raff and Kaufmann 1983). However, some of the above defi- nitions are not mutually exclusive and can be used in conjunction. For instance, fields can be envisaged as car- riers of information from both the genotype and cell sur- face informational glycoconjugates, to invoke the physicomechanical forces underlying the morphogenetic events that generate the phenotype. Data in the literature are highly relevant to providing an empirical basis for field phenomena underlying morpho- genetic events. These important findings are indicated below. Evidence for Morphogenetic Fields Field Phenomena Predict and Correlate with Morphogenetic Events Evidence for the embryonic field envisaged by Gurwitsch emerged from his discovery that the orientation of embryonic nuclei enabled subsequent epithelial configura- tions to be predicted; and, in flower development, that overall shape developed with increasing precision, in spite of size variability in its components. This suggested to him that the individual cell divisions were governed by a su- pracellular ordering or integrating factor (Gurwitsch 1910, 1922; Beloussov 1997). Endogenous bioelectric signals are a particularly tractable component of morphogenetic field systems (Levin 2009). Ubiquitously, plants and animals generate various natural electromagnetic field systems prior to morphogenesis, which predict and correlate with growth and patterning events. There is an extensive review literature for this (e.g., Burr 1947; Jaffe 1981; Nuccitelli 1984; Levin 2003; McCaig et al. 2005). Thus only a few findings are highlighted here to give an indication of these data. For instance, in plants, the pattern of endogenous potential differences (PDs) in cucurbit fruits correlate with the development of fruit morphology (Burr and Sinnott 1944). A rapid change in the pattern of endogenous current in Lepidium roots after tilting to a horizontal position pre- cedes the response of the root in bending downwards (Behrens et al. 1982). In the algae Pelvetia and Pithophora, a polar distribution of electric potential corresponds with the cells’ growth polarities and the establishment of the developmental axis (Jaffe 1986). Similarly, in Douglas fir, external polarity potentials conform to the complex morphology of the tree (Fig. 5). An electrical dominance of the tree apex corre- sponds to its growth dominance and points to a fundamental relation between them (Lund 1931; Rosene and Lund 1953). In animals, such fields have been shown to predict the appearance of (and are implicated in) various morphoge- netic events. There are numerous examples. Intracellular Fig. 5 Distribution, orientation, and relative polarities of electro- magnetic fields in wood and cortex of Douglas fir and resulting orientation of polarities in main axis and branches (from Lund 1931; copyright of the American Society of Plant Biologists and reprinted with permission) S. E. B. Tyler 123
  • voltage gradients within insect ovaries drive maternal substances such as protein and RNA from the follicle to the egg, influencing oocyte polarity (Woodruff and Telfer 1973, 1980). Fertilized eggs drive a current around them- selves orientated from animal to vegetal pole, which in turn predicts the primary embryonic axis. PDs across the embryo midline are required for cranial and tail develop- ment; and an outward flow of ionic current predicts the location of head and limb formation (Borgens et al. 1983; Robinson 1989). Medial–lateral and rostral–caudal voltage gradient patterns correlate with the form of the amphibian neurula (Fig. 6). The electric fields result from a system of localized membrane ion channels and pumps. These generate a network of endogenous ion flows, fields, and voltage gra- dients that provides a signaling system, slower than that of action potentials, and providing instructive information ranging from the subcellular to whole embryo level (reviewed by Levin 2012). For instance, voltage patterns may form coordinates that provide morphogenetic cues (Shi and Borgens 1995). Membrane potentials are involved in the control of mitosis, oogenesis, cell migration and orientation through the embryo, coordination of morpho- genesis, cell proliferation, programmed cell death (Cone 1974; Lang et al. 2005), and the differentiation of stem cells (Sundelacruz et al. 2008) and other cell types (Barth and Barth 1974; Lang et al. 2005). In such studies, electric signals have now become mechanistically integrated with biochemical pathways, activating downstream morphogenetic cascades, via (1) the localization of transcription targets, (2) redistribution of surface membrane charged receptors, (3) conformational changes in membrane proteins, (4) electrophoresis of morphogens, and (5) modulation of voltage-sensitive small molecule and ion transporters (reviewed by Levin 2009). For instance, proton pumps produce gradients that region- alize gene expression and morphogenesis in craniofacial patterning of Xenopus laevis embryos (Vandenberg et al. 2011; Fig. 7); and a battery of cells across the frog embryo produces an electrophoretic force driving serotonin through conductive long-range gap junctions, which influences left- right patterning (Fukumoto et al. 2005). Individual cells act as a complex hydrogel, containing distinct microdomains with nano-scale electric field parameters (Tyner et al. 2007), and generating a variety of voltage characteristics (Martens et al. 2004). These may encode for and transmit large amounts of developmental information (Wallace 2007; reviewed by Funk et al. 2009). The cytoskeleton (both actin filaments and microtu- bules) and even DNA conduct electricity [with actin of similar conduction velocity as in nerves (20 m/s)] and are associated with the anchoring of voltage-sensitive mem- brane receptors and channels. Thus, in addition to gradients Fig. 6 Internal voltage gradient patterns correlate with the form of the amphibian neurula (artist’s reconstruction, from Shi and Borgens 1995; used with permission from John Wiley and Sons) Fig. 7 Endogenous Vmembrane patterns during neurulation (using voltage-reporting dyes), which precede shape changes and gene expression domains of the developing face. For example, hyperpo- larization marks future stomodeum (long black arrows), first pharyngeal fold (black and white arrows), eye field (short black arrow), region lateral to neural folds (short white arrows) and neural tube (long white arrows). (From Vandenberg et al. 2011; used with permission from John Wiley and Sons) The Work Surfaces of Morphogenesis 123
  • of morphogens transduced by receptors into signaling cascades, continuous electrical signaling from the extra- cellular matrix, transduced by voltage-gated mechanisms, may be conducted along cytoskeletal elements and even DNA (McCaig et al. 2009). Moreover, the dynamic changes of ion concentration during embryonic development are tightly regulated. For instance, Ca2?-mediated muscle-assembly instructions are integrated into multiple signaling networks during muscle development (Ochi and Westerfield 2007), by as yet unknown mechanisms, but which may involve subcellular domains with their own Ca2? signaling signatures (Jaim- ovich and Carrasco 2002; Webb and Millar 2011). Morphological Evidence A visible marker of a morphogenetic field may be provided by the global pattern of surface architecture on Crepidula mollusc eggs (Tyler et al. 1998; Fig. 8a). This linear array of ridges (first observed vegetally by Dohmen and van der Mey 1977), is organized with reference to the animal– vegetal (a–v) axis, and to the successive cleavage quartets. Thus the surface architecture may be a morphological marker for a field system which organizes the a–v axis and the cleavage pattern. As cleavage progresses, the surface architecture increases in complexity, correlating with the underlying microtubule and mitotic spindle pattern. This association is maintained during dynamic changes in the microtubule network (Tyler and Kimber 2006). The cell spindles, asters, and global microtubule network are orientated to one another almost as a single unit unimpeded by cell bound- aries, appearing to be temporospatially coordinated throughout the whole embryo (Fig. 8b; see also File S1 in Online Resource 1).2 This reiterates the observation that embryogenesis displays a sophisticated level of intercel- lular cytoskeletal coordination (Tucker 1981). Thus the surface architecture-microtubule association may have a common causality residing in a field system. A similar pattern is also evident in plants. In regener- ating vascular strands of Coleus hybridus, an intercellular lignified band pattern sweeps across groups of cells, which correlates with a cytoplasmic streaming pattern preceding it, indicating a developmental link between them (Sinnott and Bloch 1944; see Fig. S2 in Online Resource 2). Field systems are also evident among single-celled organisms, both eukaryotes and prokaryotes (Harold 1995). Within ciliate protozoa, the number and position of organelles in relation to numbers of ciliary rows seems to be integrated, and patterned in relation to the cell as a whole. This provides evidence of an inductive field thought to define the geometrical placement of the organelles (Nanney 1966; Aufderheide et al. 1980). The field may be characterized by longitudinal and circumferential axes, which map out a field of PI, notable in being continuous between mother and daughter cells (Frankel 1989, 1991, 1992, 2008). The field may also be based on a prepattern, scaffolding, or structural memory, enabling an observed precise Fig. 8 Morphological evidence for a field system in Crepidula mollusc embryos. A Development of embryo surface as revealed by FITC—GSL-1 lectin-staining at 16-cell formation, showing ridges of surface architecture pattern. Arrows indicate pattern continuity between cells. B Microtubule topography, revealed by FITC-anti-a tubulin antibody labeling, showing spindles, asters, intercellular junctions (arrowed), and global microtubule network orientated with reference to one another at 12-cell stage Bars A 25 lm. B 50 lm (from Tyler and Kimber 2006) 2 File S1 in Online Resource 1 is a higher resolution of the Z-series from Tyler and Kimber (2006) web material at http://www.ijdb.ehu. es/data/05/052007st/S4.mov. The file shows morphological evidence for a field system in Crepidula mollusc eggs. It is a confocal imaging Z-series of microtubules stained with FITC-anti-a tubulin antibody. All optical sections of 5 lm interval; 16-cell stage leading to 20-cell formation. Progressing through the Z-series reveals interconnection of microtu- bular network and orientation of spindles and asters with reference to one another throughout the whole embryo; 72 sections. S. E. B. Tyler 123 http://www.ijdb.ehu.es/data/05/052007st/S4.mov http://www.ijdb.ehu.es/data/05/052007st/S4.mov
  • coordination of morphogenetic processes at levels ranging from assembly of cell components to remodeling of elab- orate surface patterns (Jerka-Dziadosz and Beisson 1990). Rod-shaped bacterial cell division provides clear evi- dence for a molecular field morphology supplying spatial information, according to Harold (2005). Division requires construction of a septum to bisect the rod precisely in the middle, specified by a set of proteins oscillating in a field between the cell poles. The septum is placed at the centre of the field, where the proteins are at their lowest con- centration. These proteins may be moving within some sort of framework (Shih et al. 2003). Transplantation Experiments Further empirical evidence came when newt neurula discs’ cells generated limb formation at locations of their trans- plantation (Harrison 1918). Even half of a disc could generate a complete limb at the transplantation site, and if undetermined tissue was grafted into the discs they became organized into the limb. Hence the so-called limb field was recognized to have a regulative ability. Genetic Parameters In vertebrate embryos, gradient fields have been visualized at the level of individual regulatory molecules (De Robertis et al. 1991). There is a correlation between gradients of expression of homeodomain proteins and the behavior of fields defined by classic transplantation experiments, but with no direct evidence causally linking the two. According to De Robertis and colleagues, the morphogenetic fields defined by the experimental embryology of Harrison, Huxley, de Beer, and the like have a molecular substratum that can be probed visually with antibody markers. Regeneration Huxley and De Beer (1934, p. 278), focusing particularly on evidence from regeneration experiments, concluded that morphogenesis cannot be rationally interpreted without postulating the existence of fields. For instance, the flat- worm Planaria, when cut transversely into two pieces, grows a tail from the hind end of the front piece, and a head from the anterior end of the rear piece. But if the transverse cut is made further back, the cells in the previous experi- ment (which had belonged to the hind piece, and prolif- erated to form a head) now belonged to the front piece and formed a tail. They surmised that either a head or a tail could not be generated from identical tissue containing localized determinants, but rather provided evidence for a field system. Yet further evidence for a role of field systems is pro- vided by regenerating systems such as limbs, which drive strong endogenous electromagnetic fields (EFs) around them. Following vertebrate limb amputation, an injury current provides spatial cues for cells migrating into the limb (Becker and Sparado 1972). In earthworm segment regeneration, each segment has a specific electric potential. Segments are added by regeneration until the total endog- enous field potential is that of a normal full-sized worm (Kurtz and Shrank 1955). Changes in orientation and magnitude of PDs correlate with regeneration events in Phaseolus, Coleus, and Bryophyllum (reviewed by Rosene and Lund 1953). The direction of cell division in wound regeneration may be orientated towards the wound edge by wound-induced EFs (Chiang et al. 1992). The Effect of Applied Fields If a morphogenetic field system with electromagnetic parameters does indeed exist, then voltages imposed within the physiological range might affect development in a manner predictable by the applied voltage orientation. This is indeed the case, leading to a range of effects (reviewed by Levin 2003). For example, applied electric fields in plants lead to reversal of orientation of polarity, with the electric potentials corresponding to the morphological polarity, although other agents also disrupt this potential (Rehm 1938; Thomas 1939). In animals, a variety of embryonic cells (e.g., neural crest cells) realign themselves or migrate within an applied field (Nuccitelli 1988). In Obelia, an applied EF caused a reversal of the normal polarity of morphology, i.e., a hydranth appeared at the basal end; and a stolon at the apical end (Lund 1921). In planarian worms, a head–tail dipole, which persisted in cut segments, was reversed by an applied field. Anode-orientated fragments developed a head structure in the tail end, or two heads (Marsh and Beams 1957). Volt- ages imposed during morphogenetic stages such as neuru- lation lead to developmental defects (Metcalf and Borgens 1994). Small, DC electric fields orientate cell division in cultured corneal epithelial cells, with the mitotic spindle aligned to the field vector, associated with a coordinated flow towards the cleavage furrow of cortical cytoplasm, preformed actin filaments and actin-binding proteins, and surface receptors (Zhao et al. 1999a). Physiological EFs induce asymmetric distribution of surface receptors (Poo and Robinson 1977; Zhao et al. 1999b) and cortical F-actin, both being implicated in spindle alignment during mitosis. The application of an external shunt inhibits regenera- tion events (Borgens et al. 1977, 1984). Moreover, an applied field can induce regeneration even in normally non- regenerating systems, such as the regeneration of children’s freshly amputated fingertips (Becker and Sparado 1972). The Work Surfaces of Morphogenesis 123
  • Yet further evidence is provided from the ability of simple bioelectrical signals to trigger orchestrated complex morphogenesis and differentiation (including construction of skeletal bone, muscle, epidermis, vasculature, and spinal cord), whereby artificial induction of H? flux is sufficient to induce complete Xenopus tail regeneration (Adams et al. 2007). Other Parameters Various other physical parameters have been ascribed with field characteristics (reviewed by Levin 2012). These include differential adhesion (haptotactic) fields operating in the extracellular matrix (Murray and Oster 1984; Lord and Sanders 1992); osmotic fields (O’Shea 1988); and viscoelastic tension fields (Lakirev and Belousov 1986; Brière and Goodwin 1990). Application of the Field Model to Research Strategies Medical Applications Organisms continue to maintain their distinct morphology throughout life, and regenerate damaged or lost tissues, sometimes prolifically (e.g., the salamander can regenerate eyes, limbs, heart, skull, and brain regions). Field influ- ences have been implicated in the mechanisms underlying regeneration. Thus knowledge of the basis of such fields may be vital in the development of regenerative procedures to correct degenerative and aging diseases, cancer, and in wound healing; examples follow. Cancer Cancer may represent an escape from a morphogenetic field (Waddington 1935; Needham 1936), in which tumors form when cells stop obeying normal 3-D body patterning cues, with the field having a normalizing influence (Lee and Vas- ioukhin 2008; Levin 2012). In this view, disruption of the field can be teratogenic. Transplanted tumors led to detection of changes in bioelectric field parameters (Burr 1941). Con- versely, neoplastic cells ranging from germ cell, melanoma, breast and liver tumors when introduced into embryonic tissue reverse the malignancy: the embryonic tissue is considered to generate a normalizing morphogenetic field that reprograms the tumor cells (reviewed by Bizzarri et al. 2011). The somatic mutation theory, whereby neoplasia is explained as resulting from the accumulation of mutations, does not explain this ability of tumor cells to revert to normal. Thus, according to the tissue organization field theory (Sonnenschein and Soto 1999, 2000, 2008), there is potential for carcinogenesis to be reversible when cancer cells are exposed to strong morphogenetic fields that provide nor- malizing patterning cues (Astigiano et al. 2005, Bizzarri et al. 2011). Such cues can be found within embryonic microenvironments, where metastatic tumor cells have been reprogrammed (Hendrix et al. 2007). Proteins extracted from embryos based in such fields have produced promising therapeutic results (Potter 2007). Because cancer is also associated with ion channel disruption, this is a promising target for drug therapies (Arcangeli et al. 2009). Since the most highly regenerative animals have the lowest cancer incidence, a better knowledge and applica- tion of patterning pathways involved in regeneration might also preserve cells within a normal patterning plan and prevent neoplasia (Brockes 1998). Wound Healing and Regeneration Human skin wounds generate an endogenous EF, the so- called injury current, which guides keratinocyte migration toward the wounded region, and its magnitude correlates with the organization of the healing epidermis (Nuccitelli et al. 2011). This activity is mediated by polarized activation of multiple signaling pathways that include PI3 kinases/ Pten, membrane growth factor receptors, and integrins (Zhao 2009; see Fig. S3 in Online Resource 2). The importance of such natural electric phenomena in wound healing has led to promising and effective clinical applica- tion of electromagnetic fields and EF interventions (reviewed by Nuccitelli 2003; Ramadan et al. 2008; Levin 2009) in the acceleration of bone formation in osteoporosis treatment and healing of non-union fractures (Pilla 2002; Aaron et al. 2004; Chang et al. 2004), and stimulus of epi- thelial (e.g., eye cornea) wound healing (Zhao et al. 1999a). Electrical stimulation has led to enhanced closure of wounds including pressure ulcers, arterial ulcers, diabetic ulcers, and venous stasis ulcers for chronic wounds resistant to other standard treatments, although the mechanisms by which the fields improve healing are not known, hindering tissue engineering strategies (Messerli and Graham 2011). Pro- gress has been made in applied EF-mediated spinal cord neuronal regeneration in non-human trials (Cone and Cone 1976; Borgens et al. 1990, 1999). Human clinical trials are in progress (Shapiro et al. 2005; Shapiro 2012), with promising results using oscillating field stimulation. In these examples, the electric field may have a master- regulator property, triggering complex, orchestrated pat- terning cascades in the host. The structure need not be directly bioengineered (complex bioassembly being as yet beyond our grasp) rather, such stimuli may activate downstream morphogenetic programs already in place, as may occur in tail regeneration mediated by bioelectric stimulation (Pai et al. 2012). S. E. B. Tyler 123
  • Moreover, in addition to a cell focus in intervention strategies, the anatomical context seems to be required to facilitate the correct developmental program. For instance, transcription factors can induce eye development from progenitor cells, but only within the host, rather than in vitro (Viczian et al. 2009). The Form Question Revisited The above-described medical applications indicate that deciphering and learning to control shape is thus arguably the fundamental problem of biology and medicine (Levin 2012). A research program is proposed that focuses on a search for the developmental signatures underlying distinct morphological forms (Tyler submitted MS), in which field theory may be of relevance. The premise that all necessary information is contained in gene sequences (from which there is a unidirectional, linear flow), is giving way to a new synthesis emphasizing biological networks within hierarchical tiers, with multidi- rectional information moving both within and between the tiers (Franklin and Vondriska 2011; see Fig. S4 in Online Resource 2). Such networks have been demonstrated, for instance, in cardiac development (Lage et al. 2010). Thus type-specific comparative biology of such systems is likely to reveal key informational units of development. Numerous studies indicate that body shape has a com- plex genetic basis, with many different genes contributing to overall differences in body shape (reviewed by Reid and Peichel 2010). Moreover, the identification of such genes may be insufficient to understand the emergence of three- dimensional form (Schwartz 2013). However, discontinu- ities between a number of forms are clearly demarcated by hybridization and other data. In turn this makes the search for underlying generative bases, including distinctive field characteristics, more open to investigation, because the comparative biology is conducted at the right level (rather than, say, merely between species that are all members of a common basic type). These forms are well canalized and robust, with no deviations from them. So, for instance, hybridization is possible throughout the parrot family (Psittacidae), which exhibits a wide range of divergent forms including disparate skull patterns. How- ever, in contrast, no hybridization is evident between members of Psittacidae and outgroups. This indicates that the diversity of form throughout the Psittacidae is repre- sented by variation within a basic parrot type, in which the morphogenetic machinery is compatible, as indicated by successful hybridization. A testable hypothesis is that, if a type can be identified empirically, there should be evidence of a shared morpho- genetic program, which may include field parameters, i.e., distinguishable from disparate types. This indeed seems to be the case. Phylogenetic peculiarities in limb, eye, cardiac field signaling centers, and gene expression patterns are indicated in a separate article (Tyler submitted MS). For instance, there are dramatic differences in the development of the heart from the heart fields in the chick compared with mammals (Abu-Issa and Kirby 2008). There are yet further examples of such data. The expression pattern of Dpp during leg development is divergent among cricket, grasshopper, and Drosophila, and this pattern may correlate with diversity of leg morphology (Niwa et al. 2000). There are notable differences in eye field transcription factors expression and function in eye development between species (reviewed by Graw 2010), indicating that as in the limb field, eye field specification involves the recruitment of disparate mecha- nisms across the phyla. Thus, further exploration of comparative signaling and expression patterns is an avenue likely to be promising. There may be exciting type-specific aspects of a range of phenomena, ranging from the subcellular, such as micro- domain voltage characteristics, to the supracellular, opti- cally tractable morphological and bioelectromagnetic markers (using, for instance, voltage-reporter dyes, com- bined with molecular and genetic tools) for which field systems may play a role. Conclusion Three contemporary models of the morphogenetic field thus emerge. In spite of Waddington’s recognition of fields as a character of processes rather than just location, the location model continues to be a popular view, viz., the temporospatial theater of operation for genes and gene products. However, the location model is problematic in that sometimes certain field boundaries are not precise, nor do they correlate easily with gene expression or fate maps. The second model envisages a field as a pattern of forces, such as mechanical or bioelectromagnetic; in the third, it is a pattern of instructive signals. Whilst all three models have their merits and validity, the model employed influ- ences research strategies and what one is seeking to find. In essence, is the morphogenetic field a region, of gene and signaling influence; or a motive force that physically shapes morphogenesis; or a combination of these? Morphogenesis is a multistep process, with each stage needing careful coordination (Schock and Perrimon 2002). A frequent discovery is that just the right molecules seem to be in just the right place at the right time (e.g., Thomas and Kiehart 1994). The result is that, by as yet undiscov- ered means of such coordination in time and space, tissue morphogenesis is directed with such perfection (Settleman 2001). Experimentally and morphologically tractable field aspects provide a way forward in probing this. This in turn The Work Surfaces of Morphogenesis 123
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Mol Biol Cell 10: 1259–1276 The Work Surfaces of Morphogenesis 123 http://dx.doi.org/10.1101/cshperspect.a004325 The Work Surfaces of Morphogenesis: The Role of the Morphogenetic Field Abstract The Field Concept: Development of an Idea Field Definitions Evidence for Morphogenetic Fields Field Phenomena Predict and Correlate with Morphogenetic Events Morphological Evidence Transplantation Experiments Genetic Parameters Regeneration The Effect of Applied Fields Other Parameters Application of the Field Model to Research Strategies Medical Applications Cancer Wound Healing and Regeneration The Form Question Revisited Conclusion Acknowledgments References
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