## 1. A Caveat About Theories



A *theory* of development should explain the core phenomena of
growth, cell differentiation, and morphogenesis, which together
transform an egg into a mature organism. However, beyond this rough
consensus uncertainty abounds. Exactly what entities undergo
development, and what are the process' temporal, spatial, and
functional boundaries? These questions are debated in biology and
philosophy (Bonner 1974; Pradeu et al. 2011). Also unsettled are the
nature and significance of scientific theories. Whether a general
theory of development is possible or desirable hinges in part on how
"theory" is defined. Yet there is no philosophical
consensus to fall back on. Furthermore, developmental biology is not a
traditionally theoretical field (in contrast to, say, evolutionary
biology; see the entry on
 developmental biology).
 A recent edited collection, *Towards a Theory of Development*,
reveals a variety of viewpoints and frameworks, ranging from
skepticism about any such theory, to specific proposals influenced by
physics, mathematics, biochemistry, systems biology, and more (Minelli
& Pradeu 2014a). Broadly speaking, however,



> 
> 
> most developmental biologists have not been strongly interested in
> constructing an overarching theory of development and...
> developmental biology has not been a focal topic for philosophers of
> biology. (Burian 2014: xii)
> 
> 
> 



The subject has received little focused attention in biology or
philosophy.



The term "theory", for the purpose of this entry, refers
to broad conceptual frameworks about the nature of the developmental
process as a whole. This is more inclusive and less demanding than
traditional philosophical notions of theory; "big picture"
views offering an overall characterization of and/or basic principles
for understanding development. Epigenesis and preformation are
alternative theories in this sense: two persistent ways of describing
and seeking to explain the development of individual organic form.


## 2. The Problem



The core question underlying the existence of these two competing
philosophical traditions is the extent to which something is formed or
organized from "the beginning" or whether organization and
form arise only over time. Nineteenth-century uses of the term
"evolution" included a sense of unfolding of preexisting
form, a sort of preformationism in contrast to the epigenesis of the
day. Discussions of "evolution" and
"epigenesis" can therefore be misleading in retrospect
since the former term has assumed a meaning closer to the older
meaning of epigenesis (Bowler 1975). Making things even more
complicated, by the late nineteenth century
"preformationism" really was more about various versions
of predetermination or predelineation than preexistence of form as
such. Furthermore some authors saw epigenesis or preformation as
entirely internally directed, while others in each case allowed
responses to the environment. In the background lie debates about the
relative significance of predestination and free will, for persons,
for organic beings, or even for the inorganic. In each case, it is
important to keep in mind what the particular writer was saying and
the arguments presented. Thus, discussions of epigenesis and
preformation often bring in other ancillary questions and are
difficult to separate from their contexts. This entry is an effort to
extract what is centrally at issue and to focus on key contributions
to the discussion.



The terms of debate can in principle apply to the inorganic world;
e.g., solar systems can "evolve" and could develop
epigenetically. Yet they are not thought of as doing so, typically,
and so epigenesis and preformation are primarily applied to the
organic world. Species can evolve or develop more or less gradually,
with more or less form already physically existing or programmed in
from the beginning. Yet typically discussions of epigenesis and
preformation have focused on individual organisms and their
development rather than on species. The emphasis is on different
interpretations of the actual developmental process as it plays out in
time, in individual organisms. Therefore, this entry focuses on
individual organisms and understandings of their development
processes. Even more specifically, this means looking at the
development of their form and to a lesser extent also function.
Epigenesis and preformation offer two competing interpretations of
what is involved, with a range of alternatives in between. The two
approaches draw on different metaphysical and different
epistemological sets of assumptions. We can get at the central issues
by looking most closely at a series of focused episodes.


## 3. Aristotle and Aristotelianism



Aristotle was a keen observer of many things, including embryos.
Looking at chicks, for example, and drawing on his interpretations
developed earlier for the physical sciences, he saw material, final,
formal, and efficient causes at work in the generation of individual
organisms. The early egg was not formed; it did not already contain a
little chick (or whatever the species). Instead, an individual animal
only gradually acquired a heart that began beating; likewise for the
other parts that make it a chick. The material may be there from the
beginning, but the formal cause only gradually plays out along with
the efficient cause of embryonic development.



Thus, Aristotle could fit his observations of embryos into his larger
theoretical interpretations of the world. In sexual generation,
individual organisms begin when the fluids from the mother and the
father come together. This combines the essential causes and initiates
the developmental process. The maternal contribution is the material
cause, which resides in the menstrual blood. After "the
discharge is over and most of it has passed off, then what remains
begins to take shape as a fetus" (Aristotle *De Generatione
Animalium* [GA], 1.727b17-18). Yet the menstrual blood, or female
semen, is only that out of which it generates and must be acted upon
by the male semen which is that which generates. Together, consistent
with the essential nature of the species and *telos* (or final
cause) in question, the formal cause and efficient causal process act
to bring a formed individual organism from potential into actual
being. Gradually, over time, an individual organism's form
begins to emerge from the unformed. The male and female parents serve
as the "principles of generation" for each individual
organism (in sexually-generating species).



For Aristotle, an individual life begins when the male and female
semen are brought together. This is an external action, which starts
the individual formative process. From that point on, the process is
internal, initially driven by causes internal to the combined fluids.
The process then leads to formation of the individual's type,
since "once a thing has been formed, it must of necessity
grow" (Aristotle GA 1.735a18-19). (See Lennox 2001 for
discussion of Aristotle's predecessors on these points; see Van
Speybroeck et al. 2002; Vinci & Robert 2005; Connell 2016, 2020;
Falcon & Lefebvre 2017; Henry 2017; Hopwood et al. 2018; on
Aristotle's theory of generation and subsequent scientific
development of these ideas.)



An individual organic life requires an internal source of motion, or
"soul", which resides in the material body from the
outset. This soul guides the gradual epigenetic process of
development. This is the Aristotelian and not the Christian soul. Soul
consists of the vegetative (for all organisms), locomotory (for
animals), and rational (for humans). The soul, consisting of one to
three parts depending on the kind of living being, resides in the
combination of male and female semen. The living differs from the dead
because of the action of the soul. Therefore, it is the teleological
drive of the potential that actualizes the individual and its form and
function, epigenetically, gradually, and internally.



Aristotelians followed Aristotle and without much further study of
embryos interpreted the process of generation, including human
development, as gradual and epigenetic. Traditional Catholicism
agreed. St. Augustine and St. Thomas Aquinas both held that
hominization, or the coming into being of the human, occurs only
gradually. Quickening was thought to occur around 40 days, and to be
the point at which the merely animal mix of material fluids was
ensouled. Until 1859, when Pope Pius IX decreed that life begins at
"conception", the Church was epigenetic along with the
Aristotelians (see Maienschein 2003).


## 4. Eighteenth-Century Debates



Shirley Roe's discussion of the eighteenth-century debates is an
excellent examination of the context. Enthusiasm for scientific study
of natural phenomena of all sorts was combined with particular
interest in natural history and changes over time and with newly
available microscopic methods to stimulate interest in development
(Roe 1981). Aristotelian epigenesis still provided the background
assumptions about individual development as the eighteenth century
began, and researchers sought to observe the gradual emergence of form
from non-form. Yet Aristotelian accounts called for the efficacy of
the causes, acting through the process of ensoulment. In effect, this
interpretation of epigenesis depended on a life force within the
organism driving its emergence of form. Those who accepted epigenesis
also accepted a form of vitalism (see Detlefsen 2006, Zammito 2018 for
more on early modern vitalism debates).



Matter in motion, by itself, would not seem to have the capacity to
produce these results. How could unformed matter become formed? How
could the emerging form acquire capacity to function without some
vital force or factor that was not strictly material? This was the
problem for materialists. Those who began with a materialist
metaphysics, assuming that all that can exist is matter in motion,
could not see how gradual epigenetic emergence of form could occur.
The early modern period brought debates between those who started from
metaphysical assumptions of materialism and those who started from
epistemological assumptions that empirical observation should provide
the basis for scientific knowledge.



One popular representation of the alternative, preformationist view
was the homunculus. Whether initially intended seriously or as a way
to capture alternative ideas, the idea of a tiny preformed little
person did capture attention. Nicolaas von Hartsoeker gave us the
image in 1694 of a tiny man in the sperm, which became the starting
point for spermists. Others, ovists, accepted the idea of a preformed
organism--but in the egg rather than sperm. Both views are
preformationism taken quite literally. The form that the individual
adult organism would assume was, physically and materially, preformed
from the earliest stages of development. The subsequent process was
just growth.



Not all preformationists took their preformationism quite so literally
or graphically. But that view did present a competing alternative to
Aristotelian epigenesis by the eighteenth century (see Bowler 1971,
Pinto-Correia 1997). As Iris Fry has argued in her study of origins of
life debates, only with preformation could a materialistic mechanist
be a good Christian in the eighteenth century (Fry 2000: 26, citing
Farley 1977: 29). This debate played out, for example, in the work of
Caspar Friedrich Wolff and Charles Bonnet, both looking at chick
development (Detlefsen 2006). They looked at the same thing and even
fundamentally agreed about what they saw, but their conclusions were
quite different. This story can be seen as a debate about scientific
theory. Wolff was an epigenesist, maintaining that form emerges only
gradually. Bonnet was a preformationist, insisting that form exists
from the beginning of each individual organism and only experiences
growth over time. In addition to these theoretical and epistemological
issues, there is also a story about metaphysics. The eighteenth
century brought debates between metaphysical materialists who were
forced into preformationism, and epistemological epigenesists who
observed form emerging only gradually and who were willing to accept
vitalism as the only apparent causal explanation for the emergence of
form from the not-formed (Roe 1981; Maienschein 2000; Nicoglou &
Wolfe 2018 [and references therein]; Wolfe 2021).


## 5. Evolution and Embryos: A New Preformationism



In 1859, Darwin focused on embryos and their usefulness for
understanding evolutionary relationships. Ernst Haeckel brought the
study of embryos to popular attention. And histologists and
embryologists, especially in Germany and the United States, used
rapidly improving microscopic techniques to observe far more than had
been possible before. These observations, in the context of
evolutionary interpretations, raised new questions and provoked new
answers. The understanding of both epigenesis and preformation
underwent transformation so that the debates brought new questions
along with the traditional differences.



Darwin pointed to embryology as fundamental for interpreting
historical relationships. In Chapter 13 of the *Origin* he
asked



> 
> 
> How, then, can we explain these several facts in
> embryology,--namely the very general, but not universal
> difference in structure between the embryo and the adult;--of
> parts in the same individual embryo, which ultimately become very
> unlike and serve for diverse purposes, being at this early period of
> growth alike;--of embryos of different species within the same
> class, generally, but not universally, resembling each other;--of
> the structure of the embryo not being closely related to its
> conditions of existence, except when the embryo becomes at any period
> of life active and has to provide for itself;--of the embryo
> apparently having sometimes a higher organisation than the mature
> animal, into which it is developed. (1859: 442-443)
> 
> 
> 



But we know that this was a rhetorical question, and sure enough he
concluded that



> 
> 
> I believe that all these facts can be explained, as follows, on the
> view of descent with modification. (1859: 443)
> 
> 
> 



And that furthermore,



> 
> 
> the leading facts in embryology, which are second in importance to
> none in natural history, are explained on the principle of slight
> modifications not appearing, in the many descendants from some one
> ancient progenitor, at a very early period in the life of each, though
> perhaps caused at the earliest, and being inherited at a corresponding
> not early period. Embryology rises greatly in interest, when we thus
> look at the embryo as a picture, more or less obscured, of the common
> parent-form of each great class of animals. (Darwin 1859: 450)
> 
> 
> 



Haeckel saw ontogeny as the brief and rapid recapitulation of
phylogeny and saw each individual's development as following the
sequence of, and indeed caused by, the evolutionary history of that
individual organism's species. In his highly popular books,
widely translated and widely read, Haeckel offered pictures of
comparative embryology. See, he seemed to suggest, the human form
emerges following the evolutionary development and adaptations of its
ancestors. Form comes from form of the ancestors, and it unfolds
following pre-scripted stages (Haeckel 1866).



Darwin was not an embryologist, and he did not contribute to our
understanding of embryogenesis as such. Nor did Haeckel, really. But
while Darwin's use of the embryo in supporting evolutionary
theory and in helping to interpret evolutionary relationships was
consistent with various versions of either epigenetic or
preformationist development, Haeckel's view was decidedly
preformationist. Here, then, was a preformationist interpretation
based not on additional embryological observations but on adherence to
Haeckel's own metaphysical view--monistic
materialism--and to his desire to provide evidence for evolution.
The Haeckelian approach reflected the context in which those studying
cells and embryos worked at the end of the nineteenth century.


## 6. Late Nineteenth-Century Debates: Weismann and Hertwig



In 1899, American biologist William Morton Wheeler suggested that
there are just two different kinds of thinkers. Some see change and
process, while others see stability. Heraclitus, Aristotle,
physiology, and epigenesis characterize one way of looking at the
world, while Parmenides, Plato, morphology, and preformationism
characterizes another. These are, Wheeler felt, stable and persistent
classes, with just the nature and details of their differences
changing over time. Yet by the end of the nineteenth century, he
argued, neither a strict preformationist nor a strict epigeneticist
should prevail. Rather he called for a middle ground, for:



> 
> 
> The pronounced "epigenecist" of to-day who postulates
> little or no pre-determination in the germ must gird himself to
> perform Herculean labors in explaining how the complex heterogeneity
> of the adult organism can arise from chemical enzymes, while the
> pronounced "preformationist" of to-day is bound to
> elucidate the elaborate morphological structure which he insists must
> be present in the germ.
> 
> 
> 



Furthermore, it is not to philosophy but to science that we must look
to resolve the relative contributions of each, for "Both
tendencies will find their correctives in investigation"
(Wheeler 1899: 284).



Wheeler was stimulated by recent late nineteenth-century debates,
themselves provoked by a flood of new discoveries. August Weismann and
Oscar Hertwig provided particularly strong and contrasting positions.
Weismann had begun from an epigenetic viewpoint and initially rejected
the idea that individual form emerges through the unfolding, or
evolution, of pre-existent form in the inherited germ. But by the time
his *Das Keimplasm* appeared in 1892 (translated into English
in 1893), Weismann had changed his mind. As Weismann wrote:



> 
> 
> My doubts as to the validity of Darwin's theory were for a long
> time not confined to this point alone: the assumption of the existence
> of preformed constituents of all parts of the body seemed to me far
> too easy a solution of the difficult, besides entailing an
> impossibility in the shape of an absolutely inconceivable aggregation
> of primary constituents. I therefore endeavoured to see if it were not
> possible to imagine that the germ-plasm, though of complex structure,
> was not composed of such an immense number of particles, and that its
> further complication arose subsequently in the course of development.
> In other words, what I sought was a substance from which the whole
> organism might arise by epigenesis, and not by evolution. After
> repeated attempts in which I more than once imagined myself
> successful, but all of which broke down when further tested by facts.
> I finally became convinced that an epigenetic development is an
> impossibility. Moreover, I found an actual proof of the reality of
> evolution, which ... is so simple that I can scarcely understand
> how it was possible that it should have escaped my notice so long.
> (Weismann 1892 [1893: xiii-xiv])
> 
> 
> 



His "proof" provided an account of how, within the context
of cell theory and given that the entire body begins in one fertilized
cell, all the diverse body parts can become so diversely
differentiated. The key is in the special material of the germ cells,
Weismann decided. Within these cells lies all the determinants
necessary to direct development. Inheritance, that is, causes
development and differentiation.



Weismann's theory postulated the existence of several levels of
hypothetical units. By the 1890s, it was agreed that individuals begin
as cells, those cells contain nuclei, and that nuclei contain
chromosomes. The chromosomes are the material of heredity, Weismann
postulated, and they consist of a string of determinants, correlated
with characters in the organism. Each determinant consisted of a
number of material particles called biophores, inherited from both
parents. These biophores compete with each other and some prevail,
which then determines the character of the determinant, which in turn
determines the character of the organism. During each cell division,
the original whole chromosomal material is divided up, so that the
effect is like a mosaic. Each cell becomes the right type just because
of the action of the determinants distributed to it. As Weismann put
it,



> 
> 
> Ontogeny, or the development of the individual, depends therefore on a
> series of gradual qualitative changes in the nuclear substance of the
> egg-cell.
> 
> 
> 



Cells are self-differentiating



> 
> 
> that is to say, the fate of the cells is determined by forces situated
> within them, and not by external influences. (Weismann 1892 [1893: 32,
> 134])
> 
> 
> 



Conditions external to the cell itself cannot guide development, but
rather the causes lie within. And cell differentiations that make up
complex organisms are predetermined. Frederick Churchill's
magnificent biography of Weismann discusses these ideas in depth
(Churchill 2015).



Oscar Hertwig disagreed. He felt that Weismann made too many
assumptions and actually provided no real explanation of development
and differentiation at all. In his work of 1894, *Praformation
oder Epigenese*, Hertwig complained that Weismann's
theory:



> 
> 
> merely transfers to an invisible region the solution of a problem that
> we are trying to solve, at least partially, by investigation of
> visible characters; and in the invisible region it is impossible to
> apply the methods of science. So, by its very nature, it is barren to
> investigation, as there is no means by which investigation may be put
> to the proof. In this respect it is like its predecessor, the theory
> of preformation of the eighteenth century. (Hertwig 1894 [1900:
> 140])
> 
> 
> 



In contrast to Weismann's preformationism, Hertwig pointed to
the interactions of cells and to the differences among cells for the
source of differentiation. Complexity is not built in from the
beginning, but emerges over time, dynamically, and interactively. A
cytologist himself, Hertwig saw the intricate structures already part
of the unfertilized egg, and the changes that occur with
fertilization. The egg is not a completely unstructured blob, but
rather a complex of different materials that can respond to influences
both within the egg and from the external environment. Cells behave
like small organisms, and it is the interactions of these separate
organisms that makes the whole. As Hertwig put it:



> 
> 
> I shall explain the gradual, progressive organization of the whole
> organism as due to the influences upon each other of these numerous
> elementary organisms in each stage of the development. I cannot regard
> the development of any creature as a mosaic work. I hold that all the
> parts develop in connection with each other, the development of each
> part always being dependent upon the development of the whole.
> 
> 
> 



Furthermore,



> 
> 
> during the course of development, there are forces external to the
> cells that bid them assume the individual characters appropriate to
> their individual relations to the whole; the determining forces are
> not within the cells, as the doctrine of determinants supposed.
> (Hertwig 1894 [1900: 105-106, 138])
> 
> 
> 



Hertwig and Weismann continued to argue, as did others, both about the
metaphysical nature of the organism as well as about the
epistemological demands for gaining knowledge about it, with no
generally accepted way to resolve the issues. Given the information at
hand, it seemed that Wheeler was right. There were just two different
types of people, drawing on two different sets of values and emphases.
Both relied on assumptions, and only new evidence could move the
discussion forward.


## 7. Late Nineteenth-Century Debates: Roux and Driesch



Wilhelm Roux adopted much the same approach as Weismann's and
so, at first, did Hans Driesch. Yet their experiments ultimately led
to new approaches and revised interpretations of what was at issue
with epigenesist and preformationist accounts of development
(Maienschein 1991b and Weber 2022). In 1888, Roux published results of
his experiments on frog eggs. Working on the assumption of a mosaic
type preformationism, Roux was persuaded that starting from the very
first cell division, each cell would be different because it was
already predetermined to be different.



Roux proposed an experiment, a simple and elegant experiment on the
face of it. He proposed to take a developing frog egg, after the first
cell division, and to separate the two cells. Finding it impossible to
separate the two cells, however, he simply killed one by inserting a
hot needle. That cell just hung there like a blob of material and no
longer differentiated. The other half organism, or single cell
proceeded to develop, in Roux's interpretation, as it normally
would have developed (Roux 1888). The half became a half, just as it
should if it were already preformed or predetermined as to its fate in
the organism. Roux had, it seemed, confirmed the mosaic
hypothesis.



A few years later, Driesch was working at Naples and had access to sea
urchin eggs. Fortunately, because of Oscar and his brother Richard
Hertwig's study of these eggs, Driesch knew that if he shook the
two cells they would separate completely. Driesch reported agreeing
with Roux and intending to confirm Roux's results. But since the
sea urchin eggs could actually be separated, he felt that his results
would be even more convincing. Imagine his surprise when he looked the
next morning after separating the eggs and found not two half embryos
but two smaller sized urchin larvae. As he noted,



> 
> 
> I must confess that the idea of a free-swimming hemisphere or a half
> gastrula open lengthwise seemed rather extraordinary. I thought the
> formations would probably die.
> 
> 
> 



Not so.



> 
> 
> Instead, the next morning I found in their respective dishes typical,
> actively swimming blastulae of half size. (Driesch 1892 [1964:
> 46])
> 
> 
> 



In later experiments they developed even further, into apparently
perfectly normal pluteus larvae, and even the four cell stage could do
the same.



Driesch concluded with an epigenetic account, but an epigenesis
relying strictly on materialistic factors (at least that was his
initial response; Driesch did turn later to a version of vitalism).
The early embryo retains its totipotency, he concluded. The fertilized
egg clearly has the capacity to become a whole organism and so,
apparently, do the cells after the early cell divisions. Not a mosaic
of cells already predetermined by their inherited determinants in the
nucleus, the early embryonic stages are instead a population of
separate totipotent organisms, each capable of becoming a whole. It is
only the interactions among them under normal conditions that lead to
a complex, organized, integrated differentiated organism.



It might seem that Roux would have had to acknowledge the superiority
of Driesch's approach, since Driesch had actually separated the
cells. But no. Instead Roux countered with an additional hypothesis.
The nucleus retains the capacity to adapt, especially in simpler
organisms. They need the capacity to regenerate when injured, and
therefore the mosaic determination simply has not occurred yet. Each
cell retains a "reserve idioplasm", he argued, and this
provides the necessary backup determination needed to form a whole
organism (see Churchill 1966, 1973).



It seems that Wheeler was right. Roux, Weismann, and others had
decided that development must be guided by predetermined mosaic
differences. Preformation, stability, and predictability stood on one
side, with epigenesis, dynamic process, and change on the other. And,
as Wheeler noted, by 1899 the way forward lay between the extremes of
strict preformation or epigenesis. Wheeler's dissertation
director Charles Otis Whitman agreed. Whitman felt that what biology
needed was a clear statement of the alternative views, and then
movement to a new standpoint examining how much depends on the
organism's developmental response to external conditions drawing
on preformation, rather than on programmed internal unfolding
alone.



Whitman, Edmund Beecher Wilson, and others at the Marine Biological
Laboratory in Woods Hole, Massachusetts, dedicated considerable energy
to discovering the nature of each cell and its internal organization
and relationships, in an attempt to discover the relative
contributions of preformation and epigenetic development to a
materialistic explanation of development. By the early twentieth
century, they had moved toward an understanding that included a
fertilized egg that was to some extent preorganized and
differentiated, including in the nuclear chromosomes, and also a
capacity of the individual organism to respond to changes in its
environment or to self-regulate. This was epigenesis allowing some
minimal predeterminism.


## 8. Regulative Theories of Development



This "epigenesis-first" view of development set the stage
for a strand of theorizing that continued well into the twentieth
century. The main theoretical tension in twentieth- and
twenty-first-century studies of development is not between classic
preformation and epigenesis, but between different views about control
of developmental processes. If genes are the primary source of
control, then organismal development is preformationist in an
important sense: it is genetically determined. But if control is more
distributed or holistic, such that developing organisms are (in some
sense) self-organizing, then the process is regulated in a way
recalling classic theories of epigenesis. Several influential theories
of morphogenesis and pattern formation take the latter view.
Gene-based accounts of development take the former. In this way, the
classic theoretical opposition between preformation and epigenesis is
transformed and carried forward into the twentieth and twenty-first
centuries. In the first half of the twentieth century, theoretical
concepts associated with epigenesis played a significant role in
studies of development. This section surveys the main theoretical
efforts along these lines.


### 8.1 Organicism, gradients, and fields



Driesch's experiments (see
 Section 7)
 demonstrated regulative development: the developing embryo
compensated for experimental intervention rather than following a
pre-determined plan. To account for this phenomenon without resorting
to vitalism, a new theoretical approach was needed. One such was
organicism, which Donna Haraway (1976) casts as a new Kuhnian paradigm
for embryology in the first half of the twentieth century. Its tenets
included:


1. the organism is a unified whole, with multiple connections between
levels of complexity/organization;
2. development is a goal-directed process, regulated throughout
rather than pre-determined; and
3. organismal shape and structure should be understood in terms of
principles for achieving form.



Lenoir (1982) traces these ideas to Kant's *Critique of
Judgment*, notably reciprocal determination of parts and the whole
organism during the process of development. A more explicit influence
was von Bertalanffy's systems theory of development (1928 [1933,
trans. Woodger]; see the entries on
 levels of organization in biology and
 systems and synthetic biology). Another influence was D'Arcy
Thompson's seminal *On Growth and Form* (1917; see the entry on
 developmental biology).
 A key idea was that organismal form emerges from a self-organizing
system, not the unfolding of a pre-existing program.



Haraway (1976) identifies four main elements of organicism:


1. the goal of explaining organismal form;
2. concepts of symmetry, polarity, and pattern;
3. field-particle duality (analogous to physics); and
4. links to structuralism in philosophy (i.e., a structure as a
self-regulating, complex system involving multiple interacting levels
of organization and spatio-temporal scales).



She examines these elements in the work of the paradigm's
principal architects in twentieth-century developmental biology: Ross
Harrison, Joseph Needham, and Paul Weiss. Organicists sought
mathematical yet autonomously biological laws to account for emergent
order in developmental processes. Although such laws did not
materialize, Haraway argues that metaphors (principally those of
crystals and fields) played significant theoretical roles in their
stead. More abstract theoretical concepts--of polarity,
gradients, and fields--were also used to explain organismal form
in the first half of the twentieth century. For example, Hans Spemann
(1936 [1938]) proposed that



> 
> 
> the body of many, if not all animals, at least in the embryonic state,
> possesses one or several axes with unequal poles along which there
> exists a gradient of some sort. The course of development depends upon
> these gradients to a high degree. (1936 [1938: 318]).
> 
> 
> 



Similarly, Charles Manning Child hypothesized that organismal
development is based on "activity gradients" grounded in
metabolism. Others objected that these concepts are unclear,
metaphysically murky, and unscientifically vitalist (see Gilbert,
Opitz, & Raff 1996).



An important spur to gradient and field theories was the phenomenon of
"the organizer", demonstrated by Hilde Mangold's
experiments transplanting newt tissue. She moved a small piece from
the dorsal lip of a developing *Triton cristatus* embryo into
the early gastrula of another newt species (*Triton
taeniatus*). Donor tissue thus came in contact with
undifferentiated ectoderm of another species. The result: two
conjoined embryos with different body axes. This indicated that dorsal
lip tissue somehow "organized" host cells and tissues into
another embryonic body. Spemann designated the dorsal lip of the
embryo "the organization-center" or
"organizer". But how did this work? The proposed answer
suggested that body axes result from a gradient of some chemical
substance emanating from cells of the organizer. This was the
starting-point for "field theories"; e.g.,



> 
> 
> ...the egg and early embryo consist of fields--gradients or
> differentiation centers in which the specific properties drop off in
> intensity as the distance from the field center increases....
> (Harrison 1969: 258)
> 
> 
> 



In discussions with other members of Cambridge's Theoretical
Biology Club, Joseph Needham sought a theory of the chemical nature of
the "organizer". Building on D'Arcy Thompson's
theories of biological form and insights from biochemistry, he
conceptualized fields as spatial regions of a developing embryo, which
determine for all points within a region a specific quality,
direction, and intensity. The field as a whole exhibits (in)stability
and equilibrium positions. Organismal development is thus defined
as



> 
> 
> a progressive restriction of potencies by determination of the parts
> to pursue fixed fates...this state of affairs can best be
> pictured in the manner of a series of equilibrium states. (Needham
> 1936: 58)
> 
> 
> 



The overall process is to be explained by probabilistic "field
laws" describing a sequence of equilibrium positions for a
field, extending from proteins and fibers to cell shape and organismal
morphology. Although Needham did not flesh out his theoretical ideas
in detail, they show clear parallels with Waddington's view of
development, as well as recent systems approaches (see
 Section 9.1
 and
 section 10.2).



Working in the US, Paul Weiss also elaborated field and gradient
concepts to sketch a theory of development that anticipated key ideas
of systems biology today (see the entry on
 systems and synthetic biology).
 His mature theory ("molecular ecology") posited an array
of molecular species in a cell, distributed, arranged, grouped in ways
determined by their sterically-mediated interactions and physical
environment (1968). Steric interactions are based on molecules'
shape and charge; biochemical features such as bonding and repulsion.
Weiss theorized that these molecular interactions are organized by
higher-level fields so as to produce patterns of cell differentiation,
growth, and morphogenesis according to the principle of "gradual
determination". There is no pre-existing "seat" of
embryonic organization in the egg or early embryo--instead,
organization emerges in the process itself, through a physiological
gradient. Weiss's theory was based on extensive research on limb
regeneration, neural development, grafting, and cell culture. A
regenerated amphibian limb, for example, shows the correct orientation
and organization of parts, even if derived from different cell types
in another body part. How do the new parts acquire a "sense of
direction" yielding correct morphological organization?
Weiss's answer is that some physiological gradient in the body,
tells the cells "where they are and what to do".



Weiss theorized this idea in terms of fields:



> 
> 
> factors which cause the originally indefinite course of the individual
> parts of a germ to become definite and specific, and, furthermore,
> cause this to occur in compliance with a typical pattern. (1939:
> 290)
> 
> 
> 



A field is organized from center to periphery, with a focal point of
maximal intensity and gradual decrease from this center. This
organization entails a "physiological gradient": a robust
distribution of (molecular) properties, which vary along the three
spatial dimensions and along one or more axes (polarity). Its causal
activity is holistic, determining cell behavior, which in turn
produces growth, differentiation, and morphogenesis. Haraway (1976),
Keller (2002), and Vecchi and Hernandez (2014) examine the
complex and uneven history of gradient and field concepts in
developmental biology. Haraway, as discussed above, is concerned
primarily with these concepts as metaphors structuring the organicist
paradigm via the work of Harrison, Needham, and Weiss. Evelyn Fox
Keller considers these concepts as part of the (so far largely
unsuccessful) tradition of mathematicizing biology to understand
development. Davide Vecchi and Isaac Hernandez elaborate on
Keller's view, arguing that the concept of "morphogenetic
field" was supplanted by Wolpert's concept of
"positional information", part of the
mid-twentieth-century theoretical shift from organicist ideas to
genetic control of development (see
 Section 8.3).


### 8.2 Turing's reaction-diffusion model



Eschewing genetics, Turing's theory of morphogenesis (1952)
sought to explain how patterns first emerge in an early embryo. His
answer was a simple model consisting of two reaction-diffusion
equations, representing chemical "morphogens" *X*
and *Y* diffusing through a tissue
at rates determined by constants \(D\_x\) and \(D\_y,\) coupled to
chemical reactions with effects represented by functions *f*
and *g*:

 

\[\begin{align} X\_t &= f(X,Y) + D\_x\nabla^2X \\ Y\_t &= g(X,Y) + D\_y\nabla^2Y \end{align}\]


(These equations follow Keller's 2002 presentation, which is
more streamlined than Turing's original.) One morphogen is an
activator, the other an inhibitor. Both are made and destroyed at
constant rates. Initially, the tissue is homogeneous, lacking any
spatial organization. Crucially, for stable patterns to emerge
*X* and *Y* must diffuse at different rates, the
inhibitor having the larger diffusion coefficient. Under these
parameter values, random fluctuations in the system lead to
instability resulting in pattern-formation. That is, from an initially
stable, homogeneous system of cells/tissue, interaction between two
diffusing chemicals (morphogens) leads to emergence of a stable
chemical pattern. Turing assumes that steady-state chemical patterns
determine patterns at the cell/tissue level (through mechanisms wholly
unspecified). Given that assumption, the model accounts for pattern
formation in a group of cells or a tissue.



Turing's model of morphogenesis has several striking features.
First, it is based on physics and chemistry rather than biology:
reaction-diffusion equations incorporating Fourier series and the law
of mass action. Reaction-diffusion equations are a class of non-linear
partial differential equations. (Hodgkin and Huxley's model of
neural propagation is also of this class--at the time, one of the
few applications of these equations to biology; see the entry on
 mechanisms in science.)
 Turing's use of these equations to model the transition from
homogeneity to spatial patterning is rather counterintuitive, as
diffusion is a characteristically homogenizing process. So his model
was a theoretical advance, extending the insight that
reaction-diffusion equations can model transitions and "waves of
advance" (e.g., in neurons) to morphogenesis (Berestycki 2013).
Second, the model is strikingly abstract--"...a
simplification and an idealization, and consequently a
falsification" (Turing 1952: 37). Yet it has many biological
applications. Turing (1952) explored mainly simple cases of chemical
diffusion through a tissue of fixed size. But he also applied the
model to chemical waves on spheres to represent gastrulation. That
more complex case, with three interacting morphogens, can produce
traveling waves and out-of-phase oscillations. Turing also applied his
model to plant development, specifically phyllotaxis (arrangement of
leaves on a stem; see S. B. Cooper & van Leeuwen 2013). Subsequent
generalizations of Turing's equations have been used to model a
wide variety of developmental phenomena, including fish pigmentation
patterns, human mesenchymal cell differentiation, butterfly wing
patterns, mouse hair follicles/coat color patterns, limb and tooth
development, and bacterial colony growth dynamics (Meinhardt 1982,
Murray 1989). However, its explanatory role is controversial,
primarily because it is hard to show that Turing's model
describes how development actually proceeds in real organisms.



Keller (2002) discusses this issue, as well as major features of
Turing's model. One key problem (noted by Waddington at the
time) is that "pure homogeneity" as a starting point for
development is unrealistic; the egg or early embryo is never a
"blank slate" as Turing assumed. She argues that
Turing's was a premature attempt at mathematical biology, noting
as well the challenge it posed to prevalent ideas about causality:
organismal form as emergent, self-organizing; holistic, arising from
the system rather than driven by genes. Vecchi and Hernandez
(2014) build on Keller's view, diagnosing "a clash of
causal ideologies" in the different possible interpretations of
initiating cause in Turing's model. They are more optimistic
about its biological relevance and influence. Scientists continue to
apply and reflect on Turing's model of morphogenesis (e.g.,
Kondo & Miura 2010). As the latter scholars note, Francis
Crick's source-sink model of embryonic development (1970) can be
considered the simplest form of a reaction-diffusion model, with the
reaction term removed. However, Crick's model is mechanistically
simpler, with morphogenesis controlled by a single morphogen diffusing
along a line of cells:



> 
> 
> At one end of a line of cells one postulates a source--a cell
> that produces a chemical (which I shall call a morphogen) and
> maintains it at a constant level. At the other end the extreme cell
> acts as a sink: that is, it destroys the molecule, holding the
> concentration at that point to a fixed low level. The morphogen can
> diffuse from one cell to another along a line of cells. (Crick 1970:
> 420)
> 
> 
> 



Unlike Turing's more holistic model, in which patterns emerge
from initial random instability due to interaction of multiple
morphogens, Crick's model grounds morphogenesis in simple
chemical diffusion. Agutter, Malone, and Wheatley (2000) and Vecchi
and Hernandez (2014) argue that Crick's model lacks
explanatory power. However, Minelli (2009) suggests an updated
source-sink model, informed by advances in molecular and cell
biology.


### 8.3 Positional information



More influential for mainstream developmental biology was the concept
of positional information. Though originally a contribution to
regulative theories of development, the concept soon transformed to
support theories of genetic control. This epitomizes the shift in
biological thought that followed breakthroughs on DNA structure,
protein coding, and other phenomena of molecular genetics (see the entry on
 molecular genetics).
 Lewis Wolpert (1969) introduced the concept of positional information
to solve (like Turing)



> 
> 
> the problem of assigning specific states to an ensemble of identical
> cells, whose initial states are relatively similar, such that the
> resulting ensemble of states forms a well-defined spatial pattern.
> (1969: 4)
> 
> 
> 



Wolpert's answer was that each cell in a developing system has a
unique value reflecting its position in that system, encoded by the
spatial gradient of a diffusible molecule across the system.
Specification of a cell's position in the system is relative to
one or more points in the system: the source(s) of the diffusible
molecule or cell property. Cells that share the same set of points
relative to which their position is specified make up a field. Wolpert
used this model to explain a range of experimental results and
observations of development in various species (as well as the toy
"French flag" example). In 1969, Wolpert saw the next task
as discovering and articulating rules (and underlying mechanisms) for
specification of positional information and polarity, the nature of
points and boundaries, and "new meaning to classical concepts
such as induction, dominance and field" (1969: 1).



Wolpert's theoretical approach differed from predecessors in its
relation to genetic information. Positional information was proposed
as a "universal mechanism" for "translation of
genetic information into spatial patterns of differentiation"
(Wolpert 1969: 1). The concept was designed to integrate gene-based
and organicist approaches to development. Cells
"interpret" changes in their positional information, so as
to change the pattern of gene activation in a cell. Changing patterns
of gene expression drive cell differentiation in a developing
organism. This in turn effects spatial distribution of cell forces
(e.g., contraction, motility, cell-cell contact), which drives
organism-level morphogenesis. However, by 1975, Wolpert's
thinking about development had undergone a conceptual shift (Keller
2002). Between 1971 and 1975, Wolpert's ideas were
"geneticized", after which he accepted the idea of a
genetic program for development and the embryo as
"computable" from an egg. In this way, the idea of a
morphogen gradient establishing positional information for cells was
put under genetic control (see
 Section 9).



Wolpert and Lewis (1975) proposed a research program of computational
embryology aimed at a



> 
> 
> theory of development [that] would effectively enable one to compute
> the adult organism from the genetic information in the egg. The
> problem may be approached by viewing the egg as containing a program
> for development. (1975: 14)
> 
> 
> 



Philosopher Alexander Rosenberg (1997) endorses this version of
Wolpert's theory as vindication of strong molecular reductionism
in developmental biology. Manfred Laubichler and Gunter Wagner
(2001), alongside other biological theorists, reject this version of
reductionism (see
 Section 10).
 Jaeger, Irons, and Monk (2008) propose to reverse Wolpert's
conceptual shift with their "relativistic theory of positional
information", adding a role for regulative feedback by
responding cells. Vecchi and Hernandez (2014) criticize
Wolpert's and Rosenberg's reductionist computational
embryology as classically preformationist and note explanatory lacunae
of the idea of a genetic program pre-established in the egg. This
follows Keller (2002), who argues that the twentieth-century consensus
on development is essentially preformationist. This brings us to



> 
> 
> the widespread reductionist and deterministic view of development as
> programmed in genes...with the implicit idea that the final form
> of the organism is "already there" in the instructions
> contained in its genome as early as the egg stage. (Minelli &
> Pradeu 2014b: 4)
> 
> 
> 


## 9. Twentieth-Century Genetics: A New Predeterminism



Early twentieth-century embryology highlighted epigenesis. But a new
twist on preformationism soon arose in the form of genetics. This
pointed to the nuclear chromosomes as loci for the causes of
differentiation. Yet unlike Weismann and Roux, new geneticists did not
see the genetic material as divided up into a mosaic to explain
ensuing cell and tissue differences. Rather, the inherited nuclear
material was the same in every cell, but it acted differently
according to an internal program. This interpretation appealed to some
scientists for metaphysical reasons since it focused on the material
units of heredity and apparently of causation. Epistemologically, it
was more difficult to point to evidence that inherited genes explain
development.



This is not the place for a history of genetics, which has been
offered many times elsewhere. The important point here is that
genetics brought a new form of preformationism. Instead of a
dynamically acting organism taking its cues from the environmental
conditions and from the way that cells interact with each cell
division, the twentieth century brought a dominant and popular view
that has often emphasized genes as programmed to carry the information
of heredity, which was also the information necessary to construct an
individual. Of course, there have been calls for alternatives or
interactionist models where heredity and development, epigenesis and
preformation, work together, but these have often been offered as
alternatives than as central interpretations (see
 Section 10).



In the beginning of the twentieth century, at first Thomas Hunt Morgan
resisted the Mendelian-chromosome theory of inheritance that saw
inherited units of heredity carried on chromosomes as determinants of
developed characters. If all the cells contain the same chromosomes,
then how can their inheritance explain anything, he asked. Instead, he
insisted that "We have two factors determining characters:
heredity and the modification during development" (Morgan 1910a:
477). Morgan wrote to a friend that "my field is experimental
embryology" and not the genetics with which he became associated
(Morgan 1908). Like his Woods Hole colleagues at the Marine Biological
Laboratory, Morgan did not see how inherited chromosomes could explain
development of form from non-form. He had rejected Weismann's
interpretations and continued to reject the idea of inherited
determinants.



Also in 1910, however, he was studying many different kinds of
organisms in pursuit of explanations of heredity as well as
differentiation. A white-eyed male Drosophila fly famously caught his
attention, and led him to the conclusion that some inherited factors
must, indeed, cause expression in the emerging organism (Morgan
1910b). It is not that Morgan changed his mind about how to do
science, but rather that the evidence carried him in new directions
(Maienschein 1991a).



The fertilized egg cell contains a nucleus made up of chromosomes
inherited from both parents. Along these chromosomes are lined up
units of heredity that serve like Weismann's determinants, now
called genes. These genes correlate with some characters in the
resulting organism, and therefore in some sense the resulting form was
predetermined in the egg. Yet it was not already formed. And, indeed,
the mere correlation of genes and characters tells us virtually
nothing about how the differentiation occurs nor about how form
becomes formed (the problem of morphogenesis). Therefore, yes,
genetics brings a sort of new preformation or more accurately
predeterminism. But that in itself brings a description and a
correlation but no explanation. Or so Morgan initially felt, as did
his embryologist colleagues. Advances in genetics soon changed the
theoretical landscape. In 1934, Morgan posited differential gene
activity as the key to understanding organismal development. On his
view, genes are inherited, their activity controlled by cytoplasmic
factors. The latter are originally heterogeneously distributed in the
egg. Differential gene activity so-driven leads in turn to
differential cytoplasmic factor distribution, and the cycle continues,
influenced by signals from a cell's environment (primarily
neighboring cells). Ideas of preformation and epigenesis are combined
in pre-determined genes acting in response to diverse environmental
factors. Burian (2005) argues that the old theoretical opposition was
reinscribed in the disciplinary separation of embryology and genetics,
particularly in the US. In that context, studies of development
emphasizing the nucleus endorsed preformationism, while those focusing
on cytoplasm and cell lineage differentiation tended to epigenesis.
This theoretical rift was healed when research focus shifted from
"cytoplasm vs. nucleus" to mechanisms of gene expression
(Burian 2005). Theoretical concepts grounded in genetics and molecular
biology thereafter increasingly dominated thinking about
development.



By mid-twentieth century, and especially after the discovery of
DNA's structure (which apparently also explained its function),
researchers began to forget or at least ignore questions about
morphogenesis and epigenesis (see, for example, Olby 1974, Judson
1979). Instead they asked how, actually, genes give rise to
differentiated form? Somehow that works, seemed to be the answer.
Genetics predominated over what C.H. Waddington referred to as the
epigenetics of development (Waddington 1942). Of course not everyone
ignored development, but it became a seriously neglected field and
even professional societies and journals that had focused on
"embryology" shifted to "developmental
genetics" (Oppenheimer 1967). When Robert Briggs and Thomas King
cloned frogs in the 1950s and John Gurdon extended the research in the
1960s, it seemed that nuclear transfer could come from only early
stages of development. Furthermore, the resulting clones were like
their donors from whom the nuclei came rather than like the mothers
from whom the eggs came (Briggs & King 1952; Gurdon & Colman
1999; McLaren 2000). Apparently development brings differentiation
that is unidirectional. Preformationist/ predeterminist thinking
prevailed. Epigenetic development and regulatory response to
environmental conditions seemed to have strict limits for those
adopting the mid-twentieth-century predeterminist emphasis.


### 9.1 Waddington's landscape



In this context, Waddington's theoretical approach was
distinctive, aiming to integrate genetics and epigenetic development.
His main device for doing so was "the epigenetic
landscape", first articulated in 1939 and iconically diagrammed
in *The Strategy of the Genes* (1957). Waddington's
landscape model represents developmental potential as



> 
> 
> a more or less flat, or rather undulating surface, which is tilted so
> that points representing later states are lower than those
> representing earlier ones ... Then if something, such as a ball,
> were placed on the surface, it would run down toward some final end
> state at the bottom edge. (1957: 29).
> 
> 
> 



The model visualizes three "essentially formal" properties
of development: unidirectionality in time (via the landscape's
tilt), multiple discrete termini from a single undifferentiated start
(via branching tracks), and robustness of developmental processes (via
steepness of valley walls).



These topographic features reflect generalizations about animal
development, based mainly on experiments on chick and Drosophila. A
rolling ball's path down the incline corresponds to the
development of some cell or tissue from an early undifferentiated
state to a mature differentiated state.



What controls the path taken by a cell or piece of developing
tissue--a pre-determined genetic program or ongoing orchestration
of stimuli? Waddington (1939, 1940, 1957) identified genes as the
determinants of epigenetic landscape topography. This is depicted in a
companion diagram showing the landscape's
"underside" as a network of interacting biochemical
products "which are ultimately controlled by genes" (1957:
36). Waddington first articulated the landscape analogy in 1939, as a
generalization of time- and dose-effect curves representing the role
of genes in producing specific phenotypic effects. The landscape model
results from including interactive effects of the entire genome on a
particular pathway:



> 
> 
> [o]ne might roughly say that all these genes correspond to the
> geological structure which moulds the form of the valley. (1939:
> 182)
> 
> 
> 



Although he featured genetic control, Waddington's designation
of the landscape as "epigenetic" suggests a view of
development allowing more of a role for epigenesis than more
gene-focused contemporaries. Scott Gilbert (1991) argues that the
branching-track lineage structure unifies development and genetics,
visualizing a formal analogy between cellular, genetic, and organismal
development. Fagan (2012, 2013a) extends this argument, focusing on
Waddington's unification of two complementary landscape images:
robust pathways above, and interacting gene products below, with genes
at the bottom, metaphorically "pulling the strings".
Nicoglou and Merlin (2017) and Nicoglou (2018) discuss this unifying,
integrative feature of Waddington's landscape model as one
strand of twentieth-century epigenetics.



Waddington's own later theorizing took a mathematical turn,
interpreting the notion of a field in terms of spatial relations and
using Rene Thom's topology to theorize
developmental pathways as an epigenetic system (1968). This work
emphasized the concept of "chreod", a trajectory (directed
path) of normal development within multidimensional space, with axes
for time, three spatial dimensions, and concentrations of chemicals.
Although not fruitful in biology at the time, Waddington's
mathematical approach anticipated twenty-first-century alternatives to
the idea of genetic control (see
 Section 10).
 In that context, the landscape model has experienced a renaissance.
The underside image is replaced by complex gene regulatory networks,
topside surfaces explicated in terms of systems biology and/or stem
cell concepts (Fagan 2012, 2013a). Fusco and colleagues (2014) discuss
recent theoretical proposals (e.g., Wang, Wang, & Huang 2010) to
"rehabilitate" Waddington's landscape as a dynamical
systems model, which require significant changes from the original.
They conclude that landscape models (updated or not) are good for
visualizing cell differentiation but not other important developmental
processes--and so not well-suited for a comprehensive theory of
development. As a metaphorical aid to understanding, however,
Waddington's landscape remains influential. Jan Baedke (2013)
examines its broader impact across the life sciences, extending beyond
organismal development to developmental psychology and cultural
anthropology.


### 9.2 The genetic program



In his influential book *What is Life* (1944)? Erwin
Schrodinger speculated that development is controlled by "a
code-script structure" localized to chromosomes,
information-patterns



> 
> 
> instrumental in bringing about the development they
> foreshadow...architect's plan and builder's craft all
> in one. (1944: 18-19)
> 
> 
> 



Twentieth-century triumphs in genetics bolstered this idea. The main
challenge for such theories is how invariant genes, the same in every
cell of an organism, can control the process of diversification of
those cells, their temporally-orchestrated movements and organization
into tissues, bodily structures, and complex organs. Frank Lillie
(1927) put the point starkly (discussed in Burian 2005):



> 
> 
> The essential problem of development is precisely that differentiation
> in relation to space and time within the life-history of the
> individual which genetics appears implicitly to ignore... Those
> who desire to make genetics the basis of physiology of development
> will have to explain how an unchanging complex can direct the course
> of an ordered developmental stream. (1927: 365-367)
> 
> 
> 



Responses to what Burian has labelled "Lillie's
paradox" hinge on differences in gene expression among cells and
tissues. Chromosomal DNA is a linear template for an mRNA transcript,
which is in turn a template for a sequence of amino acids making up a
protein. Cell phenotype depends on which genes are transcribed and
then translated. But DNA does not express itself. The challenge then
is to account for gene expression in a way that preserves genetic
control of development. The concept of a "genetic program for
development" responds to this challenge.



The idea was forcefully articulated by Francois Jacob and
Jacques Monod:



> 
> 
> During embryonic development, the instructions contained in the
> chromosomes of the egg are gradually translated and executed...
> The whole plan of growth, the whole series of operations to be carried
> out, the order and the site of syntheses and their coordination are
> all written down in the nucleic-acid message. (Jacob 1970 [1973:
> 313])
> 
> 
> 



Jacob and Monod's view was grounded on their pioneering work on
bacterial gene expression (1961a, 1961b). Their key result, the operon
model, explains how gene expression in *E. coli* bacteria is
regulated by environmental signals. Briefly, the model represents
interactions among various components: protein-encoding DNA sequences,
regulatory DNA sequences, the "operator region" of DNA
located near the start of protein-encoding genes, repressor protein,
and small molecules (e.g., allolactose). If a repressor binds the
operator region, this blocks protein synthesis at nearby coding
sequences. Small molecules like allolactose bind the repressor,
inhibiting its inhibition, so the protein-encoding genes associated
with the "de-repressed" operator are expressed. Those
genes encode enzymes involved in metabolizing the small molecules,
neatly closing the regulatory loop. Jacob and Monod singled out DNA as
the controlling molecule of this regulatory system. Furthermore, as
Michael Morange (2000) discusses, they extrapolated the *E.
coli* operon model to gene regulation in general, positing that
all organismal development is controlled by a small set of regulatory
genes.



Jacob and Monod's subsequent work emphasized molecular genetic
reductionism and the idea of a genetic program for development. For
example, Jacob began *The Logic of Life* (1970 [1973]) with
reflections on "The Programme":



> 
> 
> ... the structure of macromolecules is determined down to the
> last detail by sequences of four chemical radicals contained in the
> genetic heritage. What are transmitted from generation to generation
> are the "instructions" specifying the molecular
> structures: the architectural plans of the future organism. They are
> also the means of executing those plans and of coordinating the
> activities of the system. In the chromosomes received from its
> parents, each egg therefore contains its entire future: the stages of
> its development, the shape and the properties of the living being
> which will emerge. The organism thus becomes the realization of a
> programme prescribed by its heredity. (1970 [1973: 1-2])
> 
> 
> 



However, extrapolation from bacterial gene regulation to development
in multicellular organisms proved unfounded. Limitations of the operon
model soon became evident. In eukaryotic, multicellular organisms,
gene expression is far more complex. Fifty years of molecular biology
have revealed a menagerie of mechanisms implicated in the complex
cellular machinery of gene expression (see the entry on
 molecular biology).
 And this is not to mention interactions among cells and tissues,
about which classic molecular biology was silent. Brian Goodwin, a
student of Waddington's, charted an alternative theoretical path
that skirted these limitations. In the 1960s, he developed equations
to model genetic oscillation, building on Jacob and Monod's
operon model (Goodwin 1965). But his subsequent theorizing about
development emphasized self-organization due to chemical gradients and
mechanical strain in cytoplasm, presaging dynamic and physical
theories that gained prominence around the turn of the millennium
(Goodwin & Trainor 1985, see
 Section 10.2
 and the entry on
 systems and synthetic biology).



The next experimental milestone for theories of genetic control of
development was Christiane Nusslein-Volhard and
collaborators' painstaking characterization of mechanisms of
body patterning and polarity in Drosophila (e.g., Driever &
Nusslein-Volhard 1988). They distinguished three regions along
the early embryo's anteroposterior body axis (anterior,
posterior, and terminal), the basic patterns and structures of which
are controlled by distinct sets of maternal genes. A few such genes
have long-range "organizing" effects. Notably, Driever and
Nusslein-Volhard (1988) showed that bicoid protein acts as a
morphogen, controlling formation of a fly's anterior (including
head and thorax) in accordance with its concentration gradient.
Significantly, their experimental manipulations were DNA sequence
mutations (known to effect anterior body plan development or bicoid
copy number). The experiments thereby charted a causal pathway from
DNA to mRNA to protein to cell differentiation to morphogenesis. This
demonstration of changes in body-plan correlated with maternal genetic
mutations was powerful vindication of the idea that genes control
development. Moreover, central concepts of the organicist alternative
(gradients and positional information) were brought under the rubric
of that theory. Nusslein-Volhard's gene-based approach
remains influential in developmental biology (see the entry on
 developmental biology).


### 9.3 The regulatory genome



The above and other experimental successes underpin Eric
Davidson's theory of "the regulatory genome" (2006),
which combines new experimental data (mainly from *Drosophila*
and sea urchin) with systems and network concepts--in effect,
updating Jacob and Monod's notion of the genetic program. On
this view, development is controlled by a DNA-encoded program made up
of short sequences that specifically bind transcription factor
proteins and thereby make a difference to gene expression. The first
step of gene expression in higher organisms is typically the binding
of one or more protein factors to a regulatory region of DNA located
near the sequence to be transcribed ("read" into mRNA and
thence to protein). Davidson terms these DNA sequences
"cis-regulatory modules". Each module's effect is
represented as a conditional rule of the form: "If protein
*X* is present, then gene Y is expressed at level Z".
Each gene has a set of such modules associated with it, which
collectively specify its expression pattern under various conditions.
That expression pattern, in turn, determines a cell's phenotype
and developmental fate. Control of development is therefore attributed
entirely to the DNA components of molecular complexes that make a
difference to gene expression. Transcription factor proteins and other
components are conceived as "inputs" to the
information-processing modules, and effects on gene expression as
"outputs".



These basic "cis-regulatory" units are organized into
systems of interacting modules. Because transcription factor proteins
are products of gene expression, the regulatory modules that control
their expression are sites of "primary core control" for
development. These core control modules form an interconnected
network, reflecting the influences of transcription factor proteins on
one another's expression. All organisms have a genetic
regulatory network composed of DNA sequences distributed throughout
its genome, which constitutes a stable underlying program for
development. Collectively, DNA modules act as "a vast,
delocalized computational device" that processes regulatory
states of a cell (Davidson 2006: 185). Furthermore, regulatory DNA
sequences are (for the most part) invariant across cells of an
organism, and organisms of a species, with a relatively small set of
"hub" transcription factors conserved throughout much of
the animal kingdom. The regulatory genome therefore offers a unified
explanation of animal evolution and development. However, there are
good reasons to think the role of DNA sequences in gene expression is
not distinctive, causally or informationally (see the entries on
 gene, 
 genetics, and
 reductionism in biology). 
 Other recent theoretical approaches tend toward more
inclusive, less gene-centric explanations of development.


## 10. Twenty-First-Century Alternatives: A New Epigenesis?



The end of the twentieth century brought discoveries that challenged
prevailing genetic determinism, and also began to replace the extreme
forms of either preformationism or epigenesis with the sorts of
interactionist models that were only offered as outlying alternatives
in earlier decades. A modified form of epigenesis, in which the
organism is seen as beginning from an inherited egg and sperm that do
include genes, seems to be on the rise again. Research on cell
development, stem cells, and tissue engineering shows that the
identity of any particular cell is not predetermined, but also depends
on interactions with its neighbors and context. Ian Wilmut's
team's success in cloning Dolly, reported in 1997, and John
Gearhart and James Thomson's successes with developing human
stem cell lines, both reported in 1998, challenged prevailing
assumptions (Wilmut et al 1997, Wilmut, Campbell, & Tudge 2000;
Thomson et al. 1998; Shamblott et al. 1998; Gearhart 1998). Both
suggested that development is a good deal more flexible, plastic, and
interactive than preformationist interpretations allow. These
experimental results, alongside conceptual issues, spur alternative
theories of development. Gilbert (2004) notes increased emphasis on
interaction, change, emergence, and reciprocal
"determination" relations between whole and component
parts. His own work emphasizes the need for multiple perspectives in
understanding development; notably diversification in the location of
causal control beyond genes alone (see the entry on
 evolution and development).
 This section focuses on philosophical efforts along these lines.


### 10.1 Developmental systems and cycles



Susan Oyama's monograph *The Ontogeny of Information*
(1985 [2000a]) critiques gene-based theories of development. She
argues that genetic information for development is causally
derivative, existing as such only in the context of an ongoing
developmental process. That process, in all its contingency and
historical specificity, is causally primary. Neither DNA nor
environmental factors are causes of development outside the
interactive context that makes features of the physical world an
organism's environment and induces patterns of gene activation
within cells. Genetic information emerges from the interactions of
heterogeneous, dispersed, developmental resources. Central to
Oyama's view is the



> 
> 
> conception of a developmental system, not as the reading off of a
> preexisting code, but as a complex of interacting influences, some
> inside the organism's skin, some external to it, and including
> its ecological niche in all its spatial and temporal aspects. (1985
> [2000a: 39])
> 
> 
> 



As in earlier organicism, patterns and form emerge from ongoing
interaction, within and among multiple levels of organization, on
multiple time-scales. But unlike the organicists, Oyama has an
established theoretical alternative to contend with. Much of her
argument is negative, rejecting the gene/environment dichotomy,
primacy of genes as causes, and lingering preformationism of the idea
of a genetic program for development. Her theoretical perspective aims
to overcome entrenched (and often unrecognized) dichotomies in
biological thought. Although criticized for their complexity, apparent
incompatibility with scientific generalization, and lack of connection
to experimental practices, Oyama's ideas about developmental
systems have been influential in twenty-first-century philosophy of
biology.



One impact is further articulation of developmental systems theory
(DST; see the entries on 
 inheritance systems
and
 replication and reproduction). 
 In the introduction to
their 2001 edited volume, *Cycles of Contingency*, Oyama, Paul
Griffiths, and Russell Gray set out DST's major themes and
commitments: joint determination by multiple causes (causal parity),
context sensitivity and contingency, extended inheritance, development
as construction, distributed control, and evolution as construction.
Another core tenet is rejection of opposed dualities such as
nature/nurture, gene/environment, and biology/culture--not
arguing that an adequate theory of development must include both sides
of opposition, but that the oppositions themselves have no place in an
adequate theory of development. Relatedly, genes are not privileged
causes of development (Griffiths & Knight 1998). This
"parity thesis" is sometimes misunderstood as a
theoretical claim that all causes of development are equally
important. But it is better understood as a constraint on theories of
development (and evolution): to not presuppose any fundamental
distinction between genes and all other causes (Oyama et al. 2001: 3).
DST's other themes are similarly arrayed against
twentieth-century predeterminism. In this way, DST entails a
conceptual reorientation in thinking about inheritance, development,
and evolution, and a point of departure for philosophical exploration
of alternatives to gene-centrism and entrenched dichotomies. Much of
this research focuses on integrating development and
evolution--i.e., evo-devo theories (see the entry on
 evolution and development).
 DST-affiliated projects that focus on organismal development are
discussed here.



A developmental system is



> 
> 
> a heterogeneous and causally complex mix of interacting entities and
> influences that produces the life cycle of an organism. (Oyama 2000b:
> 1)
> 
> 
> 



James Griesemer (2000a, 2000b, 2014a, 2014b) further articulates this
idea by conceptualizing development as part of a more general theory
of reproduction (see the entry on
 replication and reproduction).
 In this theory,



> 
> 
> development is the acquisition of the capacity to reproduce, where
> reproduction involves material propagation of developmental capacities
> from parents to offspring. (2014b: 199)
> 
> 
> 



If development is so conceived,



> 
> 
> ...then it turns out all traditional life cycles are
> complex...[i.e.] there is typically at least one substantial
> change of developmental context or niche, with multiple generations of
> progenerants, before a life cycle is completed. (2014b:
> 191-192)
> 
> 
> 



Complex life cycles of parasites and viruses, then, are not
idiosyncratic but rather exemplars of complex, context-dependent
developmental processes. Griesemer's theoretical reorientation
departs from the traditional idea of development as proceeding
linearly from egg to embryo to adult. Instead, developmental
capacities are properties of life cycles involving multiple organismal
forms. This motivates a new theoretical concept: scaffolding
interactions that bring a developing entity and aspects of the
environment into such close association as to qualify as a new
"hybrid" entity with new developmental potentialities
(Griesemer 2014a). The original entity and environment are as
"parents" to the new "hybrid" developmental
system (e.g., HIV integrated into host genome vs. free virus and
uninfected human cell/genome). Genes are demoted to "a special
kind of evolved class of scaffolding developmental mechanisms"
(2014b: 198).



Biologist Alessandro Minelli (2009, 2014) endorses a similar view of
development, arguing that the first step toward a satisfactory theory
is characterizing the full range of developmental processes, beyond
the traditional "adultocentric perspective" tracing the
formation of a mature organism from an egg cell. Although Minelli does
not theorize development in terms of reproducers, he does
conceptualize the process in terms of life cycles (see also Bonner
1974). Life cycles can be multigenerational, multigenomic,
unicellular--and so developmental processes include these too,
implicating haploid stages in sexually-reproducing organisms,
alternation of generations, mixed sexual/asexual reproduction as in
colonial tunicates and plants, etc. Minelli proposes to use this
expanded view of "developmental disparity", encompassing
the full range of diversity of life cycles of living things, alongside
"traditional, or naive, concepts of development" to
arrive at a satisfactory general framework (2014: 228).



Jason Scott Robert (2004) extends Oyama's critique of the
prevailing view that



> 
> 
> development is now standardly construed as the epigenesis of something
> preformed in the DNA. (2004: 35)
> 
> 
> 



This combination of old theoretical opposites, he argues, is
unbalanced in favor of preformationism. Robert proposes instead
"creative development":



> 
> 
> the organism's semi-autonomous self-constitution from a range of
> ontogenetic raw materials,
> 
> 
> 



co-constructed with its environment (2004: 87). Burian (2005)
similarly challenges the adequacy of genetic determinism for
understanding development, arguing that experimental results better
support multilevel causation. Although grounded in experimental
practices and associated concepts rather than abstract theory,
Burian's arguments motivate search for new theories to account
for robustness of developmental processes and outcomes.


### 10.2 Physical and dynamic systems



Another strand of theorizing development draws on physics of
materials. Stuart Newman (2003) argues that physical factors played a
major role in the early evolutionary history of multicellular
organisms. Living tissues undergoing development have properties of
liquid-like "soft matter", such as viscous flow,
elasticity, surface tension. They are also
"excitable",



> 
> 
> simultaneously hav[ing] chemical, mechanical, and electrical
> properties, they behave in a multiscale fashion, continuously and
> simultaneously changing their composition and organizational
> properties on several temporal and spatial scales. (2003: 96)
> 
> 
> 



These material properties allow living tissues to be analyzed in terms
of physical theories and constraints. Although developmental processes
in organisms today appear to follow pre-determined genetic programs,
physical forces and constraints are at the origin of developmental
systems and still play a vital role within them.



Newman's theoretical approach "link[s] the modern physics
of materials with contemporary knowledge of genetic
determinants" (2014: 107; see also Newman 2003; Forgacs &
Newman 2005). A core thesis of this theoretical approach is that
excitable soft matter can exhibit self-organization in the absence of
any pre-existing program; e.g., synchronized oscillations, local
diffusion gradients, compartment-formation via cell adhesion. (This
theoretical approach is anticipated in the work of Brian Goodwin, see
 Section 9.2.)
 Newman posits that the earliest multicellular organisms underwent
development spurred by these physical processes, together yielding a
basic body plan. Over long evolutionary timescales, gene regulatory
networks are overlaid upon physics-driven self-organizing processes.
The result is a highly-conserved set of dynamical patterning modules
(DPMs) that make basic shapes in a developing embryo: layers, lumens,
folds, tubes, segments, etc. Importantly, DPMs are not predetermined
genetic programs, but more inclusive systems capable of
self-organization. Newman and colleagues use computer simulation to
study the possible patterns generated by dynamical gene network models
representing DPMs (Salazar-Ciudad, Newman, & Sole 2001).
This method brings in dynamical systems theory, which has recently
become central to systems biology (see the entry on
 systems and synthetic biology).



Dynamical systems approaches to development, being committed to holism
and temporal unfolding, echo classic epigenesis and early
twentieth-century organicism. These earlier ideas are brought to bear
on new high-throughput quantitative datasets using simulation
technology--updating and revitalizing the earlier systems
theoretic approaches of D'Arcy Thompson and von Bertalanffy.
Although most work in systems biology focuses on single-cell organisms
and intracellular networks, some researchers look to dynamical systems
theory to construct a general theory of development. Following
Goodwin's theories, Johannes Jaeger and colleagues seek to
identify a finite core set of basic developmental processes
implemented by genetic-epigenetic-cellular regulatory systems (e.g.,
Jaeger & Sharpe 2014). They use computer simulation of regulatory
network models to identify classes of geometrically similar networks
that perform specific functions (such as producing stripe patterns).
The goal is a rational classification scheme for
functionally-characterized developmental mechanisms, which can in turn
serve as groundwork for a general theory of development. It remains
unclear, however, if biological functions in development can be
characterized in a context-independent (modular) way, allowing for a
tractable theory. Relatedly, Jonathan Bard (2011, 2013) posits a
relatively small set of developmental networks driving
"patterning, signaling, proliferation, differentiation, and
morphogenesis", "themes used over and over again" in
networks of signaling pathways. Bard's graphical network
approach is distinctive in cutting across spatial scales and levels of
hierarchical organization. Core processes (as networks) are
distributed across levels; there is no preferred level of
developmental activity, but all involved simultaneously. The resulting
network structures are quite complex.


### 10.3 Stem cells and lineages



Results of stem cell experiments prompt re-examination of now-standard
assumptions about the nature of development. At early stages of
mammalian development when embryonic stem cells are most plentiful, in
the blastocyst stage just before implantation, stem cells can be
harvested and cultured to become a large number of different kinds of
cells (Thomson et al. 1998). In theory, they have the capacity to
become any kind of differentiated cell, but it is impossible to prove
that conclusively (Fagan 2013b). Position in the organism and with
respect to other cells seems to be decisive in directing
differentiation. Although genetics provides information about the
range of possibilities, regulation of gene expression involves diverse
factors--and stem cells' plasticity and context-dependence
fits a more epigenetic view. Cell reprogramming, for example, is a
method of producing stem cells (induced pluripotent stem cells) from
more differentiated cells, effectively reversing normal development
(Takahashi & Yamanaka 2006). This contradicts any strict principle
of development as irreversible and internally-directed, undermining
the notion of a fixed program for development (Brandt 2010). Melinda
Cooper (2003) examines how central concepts of stem cell research
(potency, differentiation, form, and regeneration) fit within the long
tradition of theorizing about epigenesis and self-organization, dating
from seventeenth-century revivals of Aristotelian embryology.



Ariane Droscher (2014) traces the history of conceptual change
concerning stem cells via lineage tree diagrams, a form of visual
representation common to studies of development and of evolution.
Lineage diagrams track relations between generations of reproducing
entities. From Haeckel's speculative image of the Tree of Life
and Weismann's introduction of "cytogenetic tree
diagrams", Droscher examines this cell-centric way of
understanding development from the mid-nineteenth century onward.
Scott Gilbert (1991) shows that branching tracks have been used to
represent cell development since the late nineteenth century, most
prominently in cell lineage diagrams that track cell pedigrees and
division events. In these models, branch-points represent cell
division events and branching tracks represent genealogical relations
among cells. Other cell characteristics are also represented, such as
position within the developing embryo, morphology, and developmental
fate. Waddington's landscape is a model of this type (see
 Section 8.1).
 Fagan (2013a) uses this modeling approach to characterize cell
development in general. Any process of cell development produces a
cell lineage tree with a specific topology, representing developmental
and reproductive relations between cells. Different stem cell concepts
correspond to models that differentially constrain the space of
possible topologies for cell lineage trees. This framework provides a
systematic representation of the many different varieties of stem
cell.



Fagan (2013a, 2017) extends this cell lineage framework to
cell-molecular and cell-organism relations, yielding a cell-centric
multi-level model of development. Her view of the cell-molecular
relation is that of systems biology: a cell state is a pattern of gene
expression and molecular interactions that determines a cell's
structural and functional characteristics. The cell-organism relation
is "enkaptic"--that is, cells reproduce and
differentiate (the two defining stem cell abilities) and are collected
or encapsulated into a higher-level system: gastrula, tissue, organ,
or an experimentally-produced organoid or embryo-like structure. The
higher-level system emerges via formation of a boundary separating it
from its environment. So different levels or scales of a developmental
process are related by "boundary-formation". On this view,
development is a process comprised of multi-layered interactive
networks, arranged in strata (layers) related by an encapsulating
boundary. Each network is related to the one below by
boundary-formation, conceived as emerging out of (and imposing
constraints on) smaller-scale interactions such that an encapsulating
system is distinguished from its environment.



Jane Maienschien and Kate MacCord offer a suggestive look at
regeneration as a response of complex systems to injury through
repair. (Maienschein and MacCord, 2022) The repair draws on inherited
and in some ways predelineated organization, as well as on responses
to changing environments. Both Fagan's stem cell-based
alternatives to predetermined development and Maienschein and
MacCord's suggestions about regeneration across all scales of
life hark back to Morgan's suggestion that



> 
> 
> a process of pure epigenetic development, as generally understood
> nowadays, may also be predetermined in the egg. (Morgan 1901: 968)
> 
> 
> 



The nowadays of the twenty-first century may take us back to some of
the understanding and insights of the early twentieth, a time when a
balance of epigenesis and preformation seemed likely.