LONG ARTICLE

The Work Surfaces of Morphogenesis: The Roleof 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 Vochting

(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). Vochting

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 thisarticle (doi:10.1007/s13752-014-0177-8) contains supplementarymaterial, 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

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 Vochting, 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 ‘‘Gefalle’’ 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). Runnstrom (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–Vochting 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

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;

Briere 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

promises applications in the treatment of cancer, skin

wounds, fractures, and spinal cord injuries. These therapies

ultimately require knowledge of the forces coordinating

and shaping the work surfaces of morphogenesis, whereby

normal, basic form and phylogenetic diversity are gener-

ated, and for which there is empirical evidence that mor-

phogenetic fields indeed play a role.

Acknowledgments I would like to thank Barbara Verrall for helpful

comments on the manuscript, and Luke Tyler for assistance with

proof reading.

References

Aaron RK, Ciombor DM, Simon BJ (2004) Treatment of nonunions

with electric and electromagnetic fields. Clin Orthop Relat Res

419:21–29

Abel R, Macho GA (2011) Ontogenetic changes in the internal and

external morphology of the ilium in modern humans. J Anat

218:324–335

Abu-Issa R, Kirby ML (2008) Patterning of the heart field in the

chick. Dev Biol 319:223–233

Adams DS, Masi A, Levin M (2007) H? pump-dependent changes in

membrane voltage are an early mechanism necessary and

sufficient to induce Xenopus tail regeneration. Development

134:1323–1335

Allman GJ (1864) Report on the present state of our knowledge of the

reproductive system in the Hydroida. Rep Br Assoc Advmt Sci

33:351–426

Arcangeli A, Crociani O, Lastraioli E et al (2009) Targeting ion

channels in cancer: a novel frontier in antineoplastic therapy.

Curr Med Chem 16:66–93

Astigiano S, Damonte P, Fossati S et al (2005) Fate of embryonal

carcinoma cells injected into postimplantation mouse embryos.

Differentiation 73:484–490

Aufderheide KJ, Frankel J, Williams NE (1980) Formation and

positioning of surface-related structures in protozoa. Microbiol

Rev 44:252–302

Ayala FJ (1983) Microevolution and macroevolution. In: Bendall DS

(ed) Evolution from molecules to men. Cambridge University

Press, Cambridge, pp 387–402

Barth LG, Barth LJ (1974) Ionic regulation of embryonic induction

and cell differentiation in Rana pipiens. Dev Biol 39:1–22

Becker RO, Sparado JA (1972) Electrical stimulation of partial limb

regeneration in mammals. Bull NY Acad Med 48:627–641

Behrens HM, Weisenseel MH, Sievers A (1982) Rapid changes in the

pattern of electric current around the root tip of Lepidium sativum

L. following gravistimulation. Plant Physiol 70:1079–1083

Beloussov LV (1997) Life of Alexander G. Gurwitsch and his

relevant contribution to the theory of morphogenetic fields. Int J

Dev Biol 41:771–779

Beloussov LV, Grabovsky VI (2006) Morphomechanics: goals, basic

experiments and models. Int J Dev Biol 50:81–92

Beloussov LV, Volodyaev IV (2013) From molecular machines to

macroscopic fields: an accent to characteristic times. Eur J

Biophys 1:6–15

Bizzarri M, Cucina A, Biava PM et al (2011) Embryonic morpho-

genetic field induces phenotypic reversion in cancer cells. Curr

Pharm Biotechnol 12:243–253

Borgens RB, Rouleau MF, DeLanney LE (1983) A steady efflux of

ionic current predicts hind limb development in the axolotl.

J Exp Zool 228:491–503

Borgens RB, Vanable JW Jr, Jaffe LF (1977) Bioelectricity and

regeneration: large currents leave the stumps of regenerating

newt limbs. Proc Natl Acad Sci USA 74:4528–4532

Borgens RB, McGinnis ME, Vanable JW Jr et al (1984) Stump

currents in regenerating salamanders and newts. J Exp Zool

231:249–256

Borgens RB, Blight AR, McGinnis ME (1990) Functional recovery

after spinal cord hemisection in guinea pigs: the effects of

applied electric fields. J Comp Neurol 296:634–653

Borgens RB, Toombs JP, Breur G et al (1999) An imposed oscillating

electrical field improves the recovery of function in neurolog-

ically complete paraplegic dogs. J Neurotrauma 16:639–657

Boveri T (1901) Die Polaritat von Ovocyte, Ei und Larve des

Strongylocentrotus lividus. Zool Jahrb 14:630–653

Boveri T (1910) Die Potenzen der Ascaris-Blastomeren bei abgean-

derter Furchung. Festschrift zur sechzichsten Geburtstag Richard

Hertwig 3:131–214

Briere C, Goodwin BC (1990) Effects of calcium input/output on the

stability of a system for calcium regulated viscoelastic strain

fields. J Math Biol 28:585–593

Brockes JP (1998) Regeneration and cancer. Biochim Biophys Acta

1377:M1–M11

Burr HS (1941) Changes in the field properties of mice with

transplanted tumors. Yale J Biol Med 13:783–788

Burr HS (1947) Field theory in biology. Sci Monogr 64:217–225

Burr HS, Sinnott EW (1944) Electrical correlates of form in cucurbit

fruits. Am J Bot 31:249–253

Chang WH, Chen LT, Sun JS et al (2004) Effect of pulse-burst

electromagnetic field stimulation on osteoblast cell activities.

Bioelectromagnetics 25:457–465

Chiang M, Robinson KR, Vanable JW Jr (1992) Electrical fields in

the vicinity of epithelial wounds in the isolated bovine eye. Exp

Eye Res 54:999–1003

Child CM (1941) Patterns and problems of development. University

of Chicago Press, Chicago

Cone CD (1974) The role of the surface electrical transmembrane

potential in normal and malignant mitogenesis. Ann NY Acad

Sci 238:420–435

Cone CD, Cone CM (1976) Induction of mitosis in mature neurons in

central nervous system by sustained depolarization. Science

192:155–158

De Robertis EM, Morita EA, Cho KWY (1991) Gradient fields and

homeobox genes. Development 112:669–678

Dohmen MRV, Van Der Mey JCA (1977) Local surface differenti-

ations at the vegetal pole of the eggs of Nassarius reticulatus,

Buccinum undatum, and Crepidula fornicata (Gastropoda,

Prosobranchia). Dev Biol 61:104–113

Driesch H (1892a) Entwicklungsmechanische Studien. I. Der Werth

der beiden ersten Furschungszellen in der Echinodermenent-

wicklung. Experimentelle Erzeutung von Theil- und Doppel-

bildungen. Z wiss Zool 53(160–178):183–184

Driesch H (1892b) Entwicklungsmechanische Studien VI. Uber

einige allgemeine Fragen der theoretichen Morphologie. Z wiss

Zool 55:1–62

Driesch H (1894) Analytische Theorie der organischen Entwicklung.

Engelmann, Leipzig

Driesch H (1908) The science and philosophy of the organism, vol 1.

Adam and Charles Black, London

Farge E (2013) Mechano-sensing in embryonic biochemical and

morphologic patterning: evolutionary perspectives in the emer-

gence of primary organisms. Biol Theory 8:232–244

Frankel J (1989) Pattern formation: ciliate studies and models. Oxford

University Press, Oxford

Frankel J (1991) The patterning of ciliates. J Protozool 38:519–525

Frankel J (1992) Positional information in cells and organisms.

Trends Cell Biol 2:256–260

S. E. B. Tyler

123

Frankel J (2008) What do genic mutations tell us about the structural

patterning of a complex single-celled organism? Eukaryot Cell

7:1617–1639

Franklin S, Vondriska TM (2011) Genomes, proteomes, and the

Central Dogma. Circ Cardiovasc Genet 4:576. doi:10.1161/

CIRCGENETICS.110.957795

Fukumoto T, Kema IP, Levin M (2005) Serotonin signaling is a very

early step in patterning of the left-right axis in chick and frog

embryos. Curr Biol 15:794–803

Funk RH, Monsees T, Ozkucur N (2009) Electromagnetic effects—

from cell biology to medicine. Prog Histochem Cytochem

43:177–264

Gilbert SF, Opitz JM, Raff RA (1996) Resynthesizing evolutionary

and developmental biology. Dev Biol 173:357–372

Goodwin BC (1985) The causes of morphogenesis. BioEssays

3:32–36

Goodwin BC (1988) Problems and prospects in morphogenesis.

Experientia 44:633–637

Goodwin BC (2000) The life of form. Emergent patterns of

morphological transformation. Acad Sci Paris, Sci de la vie/

Life Sci 323:15–21

Goodwin BC, Cohen MH (1969) A phase-shift model for the spatial

and temporal organization of developing systems. J Theor Biol

25:49–107

Goodwin BC, Trainor LEH (1980) A field description of the cleavage

process in morphogenesis. J Theor Biol 85:757–770

Goodwin BC, Trainor LEH (1985) Tip and whorl morphogenesis in

Acetabularia by calcium-regulated strain fields. J Theor Biol

117:79–105

Gordon R (1999) The hierarchical genome and differentiation waves,

vol 1. World Scientific Publishing, London

Gordon R, Parkinson J (2005) Potential roles for diatomists in

nanotechnology. J Nanosci Nanotechnol 5:35–40

Gould SJ (1980) Is a new general theory of evolution emerging?

Paleobiology 6:119–130

Graw J (2010) Eye development. Curr Top Dev Biol 90:343–387

Gurwitsch AG (1910) Uber Determinierung, Normierung und Zufall

in der Ontogenese. Arch Entw Mech 30:133–193

Gurwitsch AG (1912) Die Vererbung als Verwirklichungsvorgang.

Biol Zbl 22:458–486

Gurwitsch AG (1922) Uber den Begriff des embryonalen Feldes.

Arch Entw Mech 51:388–415

Gurwitsch AG (1944) A biological field theory. Sovietskaye Nauka,

Moscow

Harold FM (1995) From morphogenes to morphogenesis. Microbi-

ology 141:2765–2778

Harold FM (2005) Molecules into cells: specifying spatial architec-

ture. Microbiol Mol Biol Rev 69:544–564

Harrison RG (1918) Experiments on the development of the forelimb

of Amblystoma, a self-differentiating equipotential system. J Exp

Zool 25:413–461

Hendrix MJ, Seftor EA, Seftor RE et al (2007) Reprogramming

metastatic tumour cells with embryonic microenvironments. Nat

Rev Cancer 7:246–255

Hinman VF, O’Brien EK, Richards GS et al (2003) Expression of

anterior Hox genes during larval development of the gastropod

Haliotis asinina. Evol Dev 5:508–521

Holtfreter J (1945) Neuralization and epidermization of gastrula

ectoderm. J Exp Zool 98:161–209

Horder TJ, Weindling PJ (1983) In: Horder TJ, Witkowski JA, Wylie

CC (eds) A history of embryology. Cambridge University Press,

Cambridge, pp 183–242

Huxley J, De Beer GR (1934) The elements of experimental

embryology. Cambridge University Press, Cambridge

Jaeger J, Reinitz J (2006) On the dynamic nature of positional

information. BioEssays 28:1102–1111

Jaffe L (1981) The role of ionic currents in establishing develop-

mental pattern. Philos Trans R Soc Lond B 295:553–566

Jaffe LF (1986) Calcium and morphogenetic fields. Ciba Found Symp

122:271–288

Jaimovich E, Carrasco MA (2002) IP3 dependent Ca2? signals in

muscle cells are involved in regulation of gene expression. Biol

Res 35:195–202

Jerka-Dziadosz M, Beisson J (1990) Genetic approaches to ciliate

pattern formation: from self-assembly to morphogenesis. Trends

Genet 6:41–45

Kalthoff K (1996) Analysis of biological development. McGraw-Hill,

New York

Kurtz I, Shrank AR (1955) Bioelectrical properties of intact and

regenerating earthworms Eisenia fetida. Physiol Zool 28:322–330

Lage K, Mollgard K, Greenway S et al (2010) Dissecting spatiotem-

poral protein networks driving human heart development and

related disorders. Mol Syst Biol 6:381. doi:10.1038/msb.2010.36

Lakirev AV, Belousov LV (1986) Computer modeling of gastrulation

and neurulation in amphibian embryos based on mechanical

tension fields. Ontogenez 17(6):636–647

Lang F, Foller M, Lang KS et al (2005) Ion channels in cell

proliferation and apoptotic cell death. J Membr Biol 205:

147–157

Lee M, Vasioukhin V (2008) Cell polarity and cancer–cell and tissue

polarity as a noncanonical tumor suppressor. J Cell Sci

121:1141–1150

Levin M (2003) Bioelectromagnetics in morphogenesis. Bioelectro-

magnetics 24:295–315

Levin M (2009) Bioelectric mechanisms in regeneration: unique

aspects and future perspectives. Semin Cell Dev Biol 20:543–556

Levin M (2012) Molecular bioelectricity in developmental biology:

new tools and recent discoveries. BioEssays 34:205–217

Lord EM, Sanders LC (1992) Roles for the extracellular matrix in

plant development and pollination. Dev Biol 153:16–28

Løvtrup S, Løvtrup M (1988) The morphogenesis of molluscan shells:

a mathematical account using biological parameters. J Morphol

197:53–62

Lund EJ (1921) Experimental control of organic polarity by the

electric current. I. Effects of the electric current on regenerating

internodes of Obelia commissuralis. J Exp Zool 34:470–493

Lund EJ (1931) Electric correlation between living cells in cortex and

wood in the Douglas fir. Plant Physiol 6:631–652

Lund EJ (1947) Bioelectric fields and growth. University of Texas

Press, Austin

Marsh G, Beams HW (1957) Electrical control of morphogenesis in

regenerating Dugesia tigrina. J Cell Comp Physiol 39:191–211

Martens JR, O’Connell K, Tamkun M (2004) Targeting of ion

channels to membrane microdomains: localization of KV

channels to lipid rafts. Trends Pharmacol Sci 25:16–21

Martinez-Frias ML, Frias JL, Opitz JM (1998) Errors of morphogen-

esis and developmental field theory. Am J Med Genet. 76(4):

291–296

McCaig CD, Rajnicek AM, Song B et al (2005) Controlling cell

behavior electrically: current views and future potential. Physiol

Rev 85:943–978

McCaig CD, Song B, Rajnicek AM (2009) Electrical dimensions in

cell science. J Cell Sci 122:4267–4276

McGinnis W, Krumlauf R (1992) Homeobox genes and axial

patterning. Cell 68:283–302

McLachlan JC (1999) The use of models and metaphors in

developmental biology. Endeavour 23:51–55

Messerli MA, Graham DM (2011) Extracellular electrical fields direct

wound healing and regeneration. Biol Bull 221:79–92

Metcalf MEM, Borgens RB (1994) Weak applied voltages interfere

with amphibian morphogenesis and pattern. J Exp Zool

268:322–338

The Work Surfaces of Morphogenesis

123

Morgan TH (1934) Embryology and genetics. Columbia University

Press, New York

Morozova N, Shubin M (2013) The geometry of morphogenesis and

the morphogenetic field concept. In: Capasso V, Gromov M,

Harel-Belan A et al (eds) Pattern formation in morphogenesis:

problems and mathematical issues. Springer, Berlin, pp 255–282

Murray JD, Oster GF (1984) Cell traction models for generating

pattern and form in morphogenesis. J Math Biol 19:265–279

Nanney DL (1966) Cortical integration in Tetrahymena: an exercise

in cytogeometry. J Exp Zool 161:307–318

Needham J (1936) New advances in the chemistry and biology of

organized growth. J Proc R Soc Med 29:1577–1626

Needham J (1942) Biochemistry and morphogenesis. Cambridge

University Press, Cambridge

Newman SA, Linde-Medina M (2013) Physical determinants in the

emergence and inheritance of multicellular form. Biol Theory

8:274–285

Nick P, Furuya M (1992) Induction and fixation of polarity: early

steps in plant morphogenesis. Dev Growth Differ 34:115–125

Niehrs C (2004) Regionally specific induction by the Spemann

Mangold organizer. Nat Rev Genet 5:425–434

Niehrs C (2010) On growth and form: a Cartesian coordinate system

of Wnt and BMP signaling specifies bilaterian body axes.

Development 137:845–857

Nieuwkoop PD (1973) The organization center of the amphibian

embryo: its origin, spatial organization, and morphogenetic

action. Adv Morphogenet 10:1–39

Nieuwkoop PD (1977) Origin and establishment of embryonic polar

axes in amphibian development. Curr Top Dev Biol 11:115–132

Niwa N, Inoue Y, Nozawa A et al (2000) Correlation of diversity of

leg morphology in Gryllus bimaculatus (cricket) with divergence

in DPP expression pattern during leg development. Development

127:4373–4381

Nuccitelli R (1984) The involvement of transcellular ion currents and

electric fields in pattern formation. In: Malacinski GM, Brant SV

(eds) Pattern formation: a primer in developmental biology.

Macmillan, New York, pp 23–46

Nuccitelli R (1988) Physiological electric fields can influence cell

motility, growth and polarity. Adv Cell Biol 2:213–232

Nuccitelli R (2003) A role for endogenous electric fields in wound

healing. Curr Top Dev Biol 58:1–26

Nuccitelli R, Nuccitelli P, Changyi L et al (2011) The electric field near

human skin wounds declines with age and provides a non-invasive

indicator of wound healing. Wound Repair Regen 19:645–655

O’Shea PS (1988) Physical fields and cellular organization: field

dependent mechanisms of morphogenesis. Experientia 44:684–694

Ochi H, Westerfield M (2007) Signaling networks that regulate muscle

development: lessons from zebrafish. Dev Growth Differ 49:1–11

Opitz JM (1985) The developmental field concept. Am J Med Genet

21:1–11

Opitz JM (1993) Blastogenesis and the ‘‘primary field’’ in human

development. Birth Defects Orig Artic Ser 29:3–37

Oppenheimer JM (1966) The growth and development of develop-

mental biology. In: Locke M (ed) Major problems in develop-

mental biology. Academic Press, New York, pp 1–27

Oster GF, Odell G, Alberch P (1980) Mechanics, morphogenesis and

evolution. In: Oster G (ed) Mathematical problems in the life

sciences. American Mathematical Society, Providence, pp 165–255

Pai VP, Aw S, Shomrat T, Lemire JM, Levin M (2012) Transmem-

brane voltage potential controls embryonic eye patterning in

Xenopus laevis. Development 139:313–323

Papageorgiou S (2006) Pulling forces acting on Hox gene clusters

cause expression collinearity. Int J Dev Biol 50:301–308

Phillips A (2012) Structural optimisation: biomechanics of the femur.

Proc ICE—Eng Comput Mech 165:147–154

Pilla AA (2002) Low-intensity electromagnetic and mechanical

modulation of bone growth and repair: are they equivalent?

J Orthop Sci 7(3):420–428

Poo M, Robinson KR (1977) Electrophoresis of concanavalin A

receptors along embryonic muscle cell membrane. Nature

265:602–605

Potter JD (2007) Morphogens, morphostats, microarchitecture and

malignancy. Nat Rev Cancer 7:464–474

Raff RA, Kaufmann TC (1983) Embryos, genes and evolution.

Macmillan, London

Ramadan A, Elsaidy M, Zyada R (2008) Effect of low-intensity direct

current on the healing of chronic wounds: a literature review.

J Wound Care 17:292–296. Erratum 17(8):367

Raup DM (1962) Computer as aid in describing form in gastropod

shells. Science 138:150–152

Rehm WS (1938) Bud regeneration and electrical polarities in

Phaseolus multiflorus. Plant Physiol 13:81–101

Reid DT, Peichel CL (2010) Perspectives on the genetic architecture

of divergence in body shape in sticklebacks. Integr Comp Biol

50:1057–1066

Reissis D, Abel RL (2012) Development of fetal trabecular micro-

architecture in the humerus and femur. J Anat 220:496–503

Robinson KR (1989) Endogenous and applied electrical currents:

their measurement and application. In: Borgens RB, Robinson

KR, Vanable JW Jr et al (eds) Electric fields in vertebrate repair:

natural and applied voltages in vertebrate regeneration and

healing. Liss, New York, pp 1–25

Rosene HF, Lund EJ (1953) Bioelectric fields and correlation in

plants. In: Loomis WE (ed) Growth and differentiation in plants.

Iowa State College Press, Ames, pp 219–252

Runnstrom J (1914) Analytische Studien uber die Seeigelenentwick-

lung. I W Roux Arch Entw Mech Org 40:526–564

Sachs T (1991) Cell polarity and tissue patterning in plants.

Development Suppl 1:83–93

Sander K (1996) On the causation of animal morphogenesis:

concepts of German-speaking authors from Theodor Schwann

(1839) to Richard Goldschmidt (1927). Int J Dev Biol 40:7–20

Schock F, Perrimon N (2002) Molecular mechanisms of morphogen-

esis. Cell and Dev Biol 18:463–493

Schwartz JH (2013) Emergence of shape. Biol Theory 8:209–210

Settleman J (2001) Rac ‘n Rho: the music that shapes the embryo.

Dev Cell 1:321–331

Shapiro S (2012) A review of oscillating field stimulation to treat

human spinal cord injury. World Neurosurg. doi:10.1016/j.wneu.

2012.11.039

Shapiro S, Borgens R, Pascuzzi R et al (2005) Oscillating field

stimulation for complete spinal cord injury in humans: a phase 1

trial. J Neurosurg Spine 2:3–10

Shi R, Borgens RB (1995) Three-dimensional gradients of voltage

during development of the nervous system as invisible coordi-

nates for the establishment of embryonic pattern. Dev Dyn

202:101–114

Shih YL, Le T, Rothfield L (2003) Division site selection in

Escherichia coli involves dynamic redistribution of Min proteins

within coiled structures that extend between the two cell poles.

Proc Natl Acad Sci USA 100:7865–7870

Sinnott EW (1960) Plant morphogenesis. McGraw-Hill, New York

Sinnott EW, Bloch R (1944) Visible expression of cytoplasmic

pattern in the differentiation of xylem strands. Proc Natl Acad

Sci USA 30:388–392

Sonnenschein C, Soto AM (1999) The society of cells: cancer and

control of cell proliferation. Springer, New York

Sonnenschein C, Soto AM (2000) Somatic mutation theory of

carcinogenesis: why it should be dropped and replaced. Mol

Carcinog 29:205–211

S. E. B. Tyler

123

Sonnenschein C, Soto AM (2008) Theories of carcinogenesis: an

emerging perspective. Semin Cancer Biol 18:372–377

Stumpf HF (1967) Uber den Verlauf eines Schuppenorientierenden

Gefalles bei Galleria mellonella. Wilhelm Roux Arch Entw

Mech Org 158:315–330

Sundelacruz S, Levin M, Kaplan DL (2008) Membrane potential

controls adipogenic and osteogenic differentiation of mesenchy-

mal stem cells. PLoS One 3:e3737

Thomas JB (1939) Electric control of polarity in plants. PhD thesis,

Wageningen University, Wageningen, The Netherlands

Thomas GH, Kiehart DP (1994) Beta spectrin has a restricted tissue

and sub-cellular distribution during Drosophila embryogenesis.

Development 120:2039–2050

Thompson DA (1942) On growth and form. The University Press,

Cambridge

Thorpe TA (2012) History of plant tissue culture. Methods Mol Biol

877:9–27

Tsikolia N (2006) The role and limits of a gradient based explanation

of morphogenesis: a theoretical consideration. Int J Dev Biol

50:333–340

Tucker JB (1981) Cytoskeletal coordination and intercellular signal-

ling during metazoan embryogenesis. J Embryol Exp Morphol

65:1–25

Tyler SEB, Kimber SJ (2006) The dynamic nature of mollusc egg

surface architecture and its relation to the microtubule network.

Int J Dev Biol 50:405–412

Tyler SEB, Butler RD, Kimber SJ (1998) Morphological evidence for

a morphogenetic field in gastropod mollusc eggs. Int J Dev Biol

42:79–85

Tyner KM, Kopelman R, Philbert MA (2007) ‘‘Nanosized voltmeter’’

enables cellular-wide electric field mapping. Biophys J 93:

1163–1174

Vandenberg LN, Morrie RD, Adams DS (2011) V-ATPase-dependent

ectodermal voltage and pH regionalization are required for

craniofacial morphogenesis. Dev Dyn 240:1889–1904

Viczian AS, Solessio EC, Lyou Y et al (2009) Generation of

functional eyes from pluripotent cells. PLoS Biol 7:e1000174

Vochting H (1877) Ueber Theilbarkeit im Pflanzenreich und die

Wirkung innerer und ausserer Krafte auf Organbildung an

Pflanzentheilen. Arch gesamte Physiol Mensch Tiere 15:153–190

Vochting H (1878) Uber Organbildung im Pflanzenreich. Cohen,

Bonn

Vonica A, Gumbiner BM (2007) The Xenopus Nieuwkoop center and

Spemann-Mangold organizer share molecular components and a

requirement for maternal Wnt activity. Dev Biol 312:90–102

Waddington CH (1935) Cancer and the theory of organisers. Nature

135:606–608

Waddington CH (1956) Principles of embryology. Allen and Unwin,

London

Wallace R (2007) Neural membrane microdomains as computational

systems: toward molecular modelling in the study of neural

disease. Biosystems 87:20–30

Wallis J (1659) Tractatus duo, priore de Cycloide. Oxford

Wardlaw CW (1968) Morphogenesis in plants. Methuen, London

Wardlaw CW (1970) Cellular differentiation in plants and other

essays. Manchester University Press, Manchester

Webb SE, Millar AL (2011) Visualization of Ca2? signaling during

embryonic skeletal muscle formation in vertebrates. Cold Spring

Harb Perspect Biol 3(2). doi: 10.1101/cshperspect.a004325

Weiss PA (1939) Principles of development: a text in experimental

embryology. Holt, New York

Willier BH, Oppenheimer JM (1974) Foundations of experimental

embryology. Hafner Press, New York

Wolff J (1870) Uber die innere Architectur der Knochen und ihre

Bedeutung fur die Frage vom Knochenwachsthum. Virchows

Arch Pathol Anat Physiol 50:389–450. Translated and abridged

by Heller MO, Taylor WR, Aslanidis N et al. In: Wolff J (2010)

On the inner architecture of bones and its importance for bone

growth. Clin Orthop Relat Res 468:1056–1065

Wolpert L (1969) Positional information and the spatial pattern of

cellular differentiation. J Theor Biol 25:1–47

Wolpert L (1977) The development of pattern and form in animals.

Carolina Biological, Burlington

Wolpert L (1986) Gradients, position and pattern: a history. In: Horder

TJ, Witkowski JA, Wylie CC (eds) A history of embryology.

Cambridge University Press, Cambridge, pp 347–361

Woodruff RI, Telfer WH (1973) Electrical properties of ovarian cells

linked by intercellular bridges. Ann NY Acad Sci 238:408–419

Woodruff RI, Telfer WH (1980) Electrophoresis of proteins in

intercellular bridges. Nature 286:84–86

Zhao M (2009) Electrical fields in wound healing—an overriding

signal that directs cell migration. Semin Cell Dev Biol 20:

674–682

Zhao M, Forrester JV, McCaig CD (1999a) A small physiological field

orients cell division. Proc Natl Acad Sci USA 96:4942–4946

Zhao M, Dick A, Forrester JV et al (1999b) Electric field-directed cell

motility involves up-regulated expression and asymmetric

redistribution of the epidermal growth factor receptors and is

enhanced by fibronectin and laminin. Mol Biol Cell 10:

1259–1276

The Work Surfaces of Morphogenesis

123