Dr Moss

Melvin L. Moss
New York, N. Y.

Much of the continuing controversy concerning the roles of’genonlu rrrrd IWII,~~O~I~~
(epigenetic)processes in the regulation (causation) of growth is resoi~~etl 11~ (III tr~cd~.ci\ of
the several types of causation. It cm be shown that the combinatiott (!/’ QCVWIU~C trd
epigenetic factors is c1 necessary cuuse of craniofacial growth. A rcGc~~~ of .somc I’PWW
literature serves to clarlfi this conclusion which is of potential cli~~icd me .sirxc
therapeutic intervention is always an epigenetic event.

Key words: Causation, epigenetics, genetics, craniofacial growth

Almost all active clinical and laboratory scientists were taught that the neo-
Darwinian synthesis satisfactorily explains the regulation of both ontogenetic and
phylogenetic processes. This synthesis unifies the data and concepts of Darwinism and
classic Mendelian genetics’s 2 and integrates them with those of vertebrate paleontology. 3
It postulated (a) that small, random, gradually accumulated mutations spontaneously
occurred at specific points in the genome and (b) that the ontogenetic product of the
genome was subjected to the processes of natural selection, assuring selective survival of
better ontogenetic adaptations of the species to new ecologic conditions. Such adaptation
permitted successful reproduction and, consequently, phylogenetic continuity and the
possibility of evolutionary change. Implicit in this synthesis is the concept that at fertiliza-
tion the diploid genome contains all the information necessary to regulate (or “cause”)
individual ontogenesis, requiring only an appropriately permissive and supportive envi-
ronment for full genomic expression to occur. 4-7 The continuing successes of molecular
biology and of “genetic engineering” appear, initially, to support and extend the correct-
ness of the synthesis. Against this background, it is understandable that clinicians and
laymen who supported common observations of familial resemblances indicate that the
genome has the principal, if not the sole, role in regulation of craniofacial size and
shape.H, 9
Recently, the phylogenetic explanation value of the neo-Darwinian synthesis has been
questioned. lo-l4 Concurrently, alternate hypotheses of ontogenetic regulation emerged.
Broadly denominated here as epigenetic, they suggest that the postfertiiization genome
does not contain sufficient information to regulate all subsequent development. l3 It is pos-
tulated that additional necessary epigenetic information is self-generated concomitant with
the attainment of increasing structural and functional complexity. In this view the interac-
tion of both genomic and epigenetic factors is required to regulate (or “cause”) develop-

From the Department of Anatomy, College of Physicians and Surgeons, Columbia University.
This study was aided in part by Grants DE-0514502 and HD 14371-01, National Institutes of Health.

366 OOOZ-9416/81/100366+10$01.00/0 0 1981 The C. V. Mosby Co.

Volume 80
Genetics. epigenetics, and causation 367
Number 4

MATERIAL FORMAL EFFICIENT 1 FINAL

\/ 1 [ (WHY?)

INTRINSIC EXTRINSIC
PRIOR PROXIMATE
NECESSARY NECESSARY

\/
SUFFICIENT

/\
(0,s) -(GENoME) (EPICENETICS)

Fig. 1. A diagrammatic survey of one classification of causation, the first three of which are considered
in this study. Material cause, roughly, is equated with the fact that all biologic organisms are composed
of cells and extracellular substance, while formal cause is represented by the “rules” or “laws” govern-
ing genomic regulation of molecular biologic events and processes. These two types of cause are
denominated as intrinisic, prior, and necessary for ontogenesis to occur. Also necessary are the
extrinsic, proximate events of efficient causation; both together are required for a sufficient cause of
ontogenesis to exist. (See text for details.)

ment. The genome is not viewed as containing some pre-existent blueprint that merely
requires an appropriate environment within which it can become phenotypically expressed.
As unconformable as the epigenetic hypothesis may seem to commonly accepted
clinical views, I suggest that many of the difficulties are diminished after analysis of the
term causation and after a review of some pertinent data and concepts.
Causation. A classic categorization of causation, oversimplified, is useful (Fig. 1).
The four primary causal types answer corresponding questions: (1) What is acted upon?
(material); (2) by what set of rules? (formal); (3) what was the immediately preceding
event? (efficient); and (4) for what purpose? (final). Biologically, the answers could be (1)
a set of cells and extracellular substance (material); (2) a program encoded in the genome
(formal); (3) an immediately antecedent, epigenetic event (efficient); (4) some consequent
use (final, and a topic not considered further here).
Correctly, the former pair is intrinsic, while efficient cause is extrinsic; the former pair
is prior and the third is proximate. An analogy may clarify this categorization. An
extrinsic finger pushes a button (efficient), immediately causing a bell to ring (the event
observed). Prior to the act of pushing, the building and streets must be intrinsically wired
and a generator must be constructed and connected (formal). Further, electrical blueprints
and the “laws” of electricity (for example, Ohm’s law) must exist (formal). Clearly while
both extrinsic and intrinsic causes are necessary, neither alone is sufficient; only their
combination can cause a bell to ring.
Clinical expression of the genomic hypothesis. Clinical interest in craniofacial growth
regulation is ontogenetic. Familial studies consider neither the phylogenetically significant
Fig. 2. This equation expresses the interaction between formal, material, and efficient causes noted in
Fig. 1 to be necessary and sufficient for the regulation of growth and development. Any function (F)
(formal cause) of the material cause (C,S), (that is, any genomically related event) causes a mor-
phogenetic state(M) to be created in the presence of a certain epigenetic state or condition(E). It is this
epigenetic (efficient cause), interaction and regulation with the formal material causes, that causes the
M to be created. As any M state is created, it, in turn, immediately alters the epigenetic condition or
environment through which the next function of the material cause must pass. This equation also
indicates that an epigenetic condition is, under appropriate circumstances, capable of direct regulation
of the genone itself. (See text for references to such processes.) Clinical interest in this equation is
warranted since all therapy is a direct “epigenetic” experiment; that is, all therapy is efficient causation.

topics of speciation (micro) or supraspecific (macro-) evolution. While few clinicians

might agree that “the morphology of all of the bones of the craniofacial complex is under
the rather rigid control of hereditary forces,“‘” most believe that the genome is primarily
causative of some significant portion of craniofacial form.‘7m1” This position is well
expressed in a paraphrase of Krogman 2othat, in craniofacial genetics, we deal with growth
changes that are the result of the interplay of genes plus the environment, an interplay
termed multijiictorial inheritance that is a polygenic predisposition interacting with the
(supportive and permissive) environment to give a quasicontinuous distribution of certain
metrically expressed parameters. Interestingly, when faced with the frequent clinical
observation of skeletal form alteration following functional changes, some claim that “the
response of bone to functional demands may itself be under genetic control. “‘I a concep-
tual regression that must end at the newly fertilized diploid genome.
Parenthetically, the genomic hypothesis is extended in others to “sociobiology” and
to the development of language and other mental abilities. 22--24Critiques of these, to me
unwarranted, hypotheses are available. ~3 26
Data unconformable with the genomicx hypothesis. Despite the simplicity and inclu-
siveness of the genomic hypothesis, certain data sets do not easily conform to it. Consider
the relationship between genotype and phenotype of man and the great apes. In terms of
chromosomes (not genes), man and the great apes show close karyotypic relationshipszi
“ . . . Therefore the differences observed at the chromosomal level between man and
chimpanzee appear to be of no consequence to their phenotype.” “Such a remarkable
degree of (karyotypic) similarity makes difficult a precise explanation of the large bio-
logical differences observed between these two species, “”
Some argue that it is the genie and not the chromosomal structure that is significant.
In the overwhelming number of skeletal “genetic diseases, ” the chromosomes are nor-
mal, and it is urged that the defect lies in the genes. 2g In reply, it is evident that the
genome may be described as consisting of DNA in a semantically significant sequence
whose procedural meaning is a series of commands. They specify that this protein should
be assembled, in this order, using these out of twenty amino acids, stopping at this point.
Accepting this, note that the polypeptides (a product of genomic activity) of man and
chimpanzee are 99 percent identical, while the two species display great anatomic and
physiologic differences, lo an example of great observable phenotypic difference and little
Volume 80
Genetics, epigenetics, and causation 369
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PHYLOGENY

Fig. 3. This figure shows schematically that any discussion of epigenetic regulation (causation) of
individual ontogenesis is totally independent of consideration of phylogenetic mechanisms. Since on-
togeny is initiated at fertilization and phylogeny (in sexually dimorphic forms) requires both gonadal
maturation and a generationally specific addition of a haploid genome, any discussion of epigenetic
regulations of growth and development cannot be equated, in any sense, with a neo-Lamarckian
hypothesis. The possible role of epigenetic factors in regulation of phylogenetic processes is not con-
sidered in this arlicle.‘“, I1

genetic difference. Further, sibling species of Drosophila, and of certain mammals, show
genetic differences an order of magnitude greater, an example of little observable phe-
notypic difference and great genomic difference. lo In addition, it has been noted that many
groups of closely related species which do not differ much in form, behavior, and even
general genetic constitution do display outstanding differences in the number and form of
chromosomes. In horses the number of chromosomes ranges between 32 and 62,30 for
example, such data warrant the conclusion that genomic differences, per se, seem “quite
unrelated to phylogenetic differences. “8
The epigenetic hypothesis. The deep lack of correspondence between the genomic
hypothesis and much experimental and observational data led to the development of the
epigenetic hypothesis. 11, 31-34 Epigenetics involves the production of new information
during development as structure and function became increasingly complex. Both struc-
ture and function evolve alterations in the biomechanical, biophysical, biochemical, and
bioelectric parameters of the developing organism, both intra- and intercellularly.35, 36
These alterations of state (that is, new information) act significantly to regulate subsequent
developmental stages, as well as to regulate genomic reaction to these altered environmen-
tal states (Fig. 2). In this hypothesis, “environment” is not just permissive and supportive
but also regulative. Clearly, epigenetics is not a revival of a metaphysical vitalism; nor is
it a neo-Lamarckianism; in any case, that would be a phylogenetic consideration, and we
deal presently only with ontogenesis (Fig. 3).
 !
370 #Mo.s.\

3
/
2

I A/si?h
Fig. 4. Ontogeny is depicted by as a hierarchically arrayed series of stages in which, as development
progresses, formerly relatively independent processes (level 7) are “combined,” as it were, into a new,
“higher” level of activity (level 2) a combinatory process that is continued through levels 3 and 4 in this
schematic figure. It is stressed here that as each new and higher developmental level is reached, new
properties emerge that were unpredii from an examination of properties of the “lower” properties
encompassed by the new, higher state (See literature15s 54-56for details.)

Epigenetic events and processes

1. The functional matrix hypothesis has demonstrated repeatedly that the presence,
and growth changes in size, shape, and location, of all craniofacial skeletal attributes are
epigenetically regulated. The phenotypic expression of the mandibular coronoid process is
not regulated by genomic information residual in the sclerocytes of that process but does
reflect responses to the functional parameters of the temporalis muscle.37, 3x In summary
form, the functional matrix hypothesis explicitly claims that the origin, growth, and
maintenance of all skeletal tissue and organs are always secondary, compensatory, and
obligatory responses to temporally and operationally prior events or processes that occur
in specifically related nonskeletal tissues, organs, or functioning spaces (functional ma-
trices). This statement is a modern restatement of the central position of Wilhelm His,3g
who enunciated the doctrine of the “physiology of the plastic,” indicating that the
biologic structure was alterable and could be intentionally changed. This concept was
extended by Wilhelm Roux (and by Hans Driesch) at the turn of the century, by the term
Entwicklungsmechunik (developmental mechanics) whose principal theme indicated that
both normal and abnormal development was capable of experimental study, subsequent
analysis, and description as a series of temporally and operationally sequential events.
Each event or process could be shown to be productive of, or to be followed by, specific
morphologic and functional results. In this view, development could be described as a
hierarchical series of proximate, efficient extrinsic, and necessary causes. The entire field
of modern experimental embryology that is still extremely active was derived from this
concept. Data supporting epigenetic regulation of the skeleton are abundant.40-47
2. Hierarchical arrays is a phenomenologic description of the way increasing struc-
tural complexity arises in a developing organisn (Fig. 4). Any arbitrary developmental
state (or stage) of an organism may be described by certain attributes. The next higher,
more complex state not only incorporates all of the attributes of the several lower states
Volume 80
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Genetics, epigenetics, and causation 371

Fig. 5. This figure shows how boundaries might be analogously demonstrated to operate in the
epigenetic regulation. If the ball at the top of the figure is taken to represent a cell, or a tissue, capable of
rolling down the convoluted surface shown, then the developmental pathway will be regulated by the
convex ridges of that inclined surface. These epigenetic boundaries will effectively prevent the ball from
passing into adjacent grooves, and thus determine the developmental pathway. (Adapted from Wad-
dington: New Patterns in Genetics and Development, New York, 1962, Columbia University Press.)

but, importantly, now creates newer attributes that come into being concomitantly with
creation of this newer complexity. 48-51Importantly, despite an apparently continuous and
uninterpreted developmental process, deeper consideration reveals marked discontinuities
between hierarchical levels; biologic systems are shown to be open, nonlinear, ther-
modynamic systems existing far from equilibrium. These same systems catastrophically
jump from a lower-order structure to a higher one during development.52-55 At a given
stage of development the “structure” of the organism finds itself in a certain “environ-
ment. ” The organism receives input that it actively assimilates and accommodates in
terms of its structure and regulation of the genome at that time. There is an attenpt to reach
a type of dynamic equilibrium. Some inputs overcome this attempt at equilibration and a
“jump” occurs, involving the active construction of novel structures and equally novel
regulation of the genome. Thus, the phenotype is not (as the neo-Darwinians see it)
merely a surface manifestation of the genotype which later suffices to regulate develop-
ment. Rather, the phenotype is the result of a hierarchy of self-regulatory processes that
integrate epigenetic genomic factors into an orderly sequence of increasingly structured
ontogenetic changes whose description of Piaget’s structuralism is paraphrased above. 56,57
3. Position or location of a cell within a developing organism is a significant source of
epigenetic information.58-60 Here instructive interactions between cells, and the length of
time a cell or cell mass occupies a specific location, are among the factors held capable of
locully providing epigenetic information capable of regulating genomic expression of cells
in the immediate neighborhood. For example, in a developing limb, the sequential devel-
opment of the typical pentadactyl appendage is not a phenotypic expression of genomic
information totally encoded in the fertilized ovum. In a very real sense, it is self-generated
by the developing organism itself. In this limb model, the activation of a given mesen-
chymal cell mass to chondrogenesis, at fhis specific site, for rllar period of time, and to
produce that amount of cartilage in that direction, is viewed as epigenetically regulated by
positional information, among other things. Further, the derepression of the mesenchymal
cell genome to permit phenotypic differentiation into a chondroblast is itself an expression
of epigenetic regulation and not of the activity of some intrinsic genomic “clock. “(il (;Ii
4. Neurotrophic regulation of the muscle cell genome is another type of epigenetic
information.6” Recently, in studies of skeletal muscle fiber following motor denervation,
marked changes in many of the RNA sequences present in the muscle cells were noted.
These data give strong support to the hypothesis that the motoneurons are able to control
gene expression of muscle fibers. This most probably indicates that the normal adult stable
epigenotype of muscle fibers is maintained by interactions such as those that occur be-
tween the muscle and spinal motoneurons.“”
Epigenetic mechanisms. The brief, selected review of some epigenetic phenomena
above is made more useful by consideration of some possible epigenetic mechanisms.
1. Nonnuclear cytoplasmic inheritance must be mentioned here, if only to indicate
why some examples of “inheritance” are clearly non-Mendelian in nature. “. 66-6’ Other
reports of non-Mendelian inheritance, such as those of cleft lip and palate in man,“”
probably reflect epigenetic factors rather than cytoplasmic inheritance, but a rigid adher-
ence to the genomic hypothesis may inhibit consideration of epigenesis as efficient and
necessary causal factors.
2. The genome is not correctly conceived of as a series of fixed, finite beads on a
string. Rather, it is hypothesized that a set of pseudogenes exists, consisting of two or
three copies of partially altered genes. “It is as if these are genes coming and going in
various states achieving functional integrity. “‘O This is descriptive of a genomic state,
potentially more susceptible to epigenetic regulation than the older static model could
accommodate theoretically. While most of the data and concepts of molecular biology are
based upon studies of Escherichia coli, it is quite reasonable to suggest that prokaryote
and eukaryote genomic processes may not be similar.”
3. Genomic regulation by extracellular epigenetic factors seemingly involves control
of the production of specific m RNA’s. 65,67Intracellular, cytoplasmic factors are shown to
be equally capable of nuclear genomic regulation. 72The possible role of retroviruses in
alteration of the nuclear genome is of interest but is not considered further here.
4. A graphic model of epigenetic regulation is provided by the depiction of an
“epigenetic landscape”~57~is (Fig. 5). The ball may be considered, for example, as a
simple, totipotential cell with its complete, genomically encoded information regulatory
of the full range of species-specific polypeptide synthesis. The subsequent history of this
cell and its descendants is a function of which developmental pathway (or “Chreod”) it
moves along. Some initial epigenetic factor or process determines the initial path selected,
at which time portions of the genome become, respectively, repressed and derepressed, so
that initial cytodifferentiation occurs. This new state, or epigenetic environment, keeps
the vital material moving along this particular pathway until another bifurcation point
occurs (Fig. 5). Once again, the instantaneous epigenetic state regulates this decision, and
a “catastrophic ’ ’ event occurs; that is, a new structually higher-order state or path is
evolved. These pathways become “deeper” (have higher “walls”) as they progressively
become hierarchically more complex. This represents, in such a model, the fact that there
is an increasing ability to withstand lateral, homeostatic perturbations during “move-
Vohne 80 Genetics, epigenetics, and causation 373
Number 4

ment” along the landscape. This movement is termed homeorrhesis. In this model, the
selection of pathways is not genomically but epigenetically regulated. Yet the genomic
information must be present to permit synthetic activity by the cell and is one type of
intrinsic, necessary information needed for ontogenesis to occur. The constantly added
epigenetic information is the other type of necessary causation required. There is no
reason for conflict between the genomic and epigenetic hypotheses of ontogenetic regula-
tion when it is perceived that they are interdependent, yet different, categories of neces-
sary causes and that only their unity provides the sufficient condition for growth and
development to occur. 74

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