within it the elements which compel it in the course of growth
to develop an organ, for instance a leg, of quite definite size,
sculpture, number of joints, and so on, or whether it only bears the
somewhat vague power of determining that connective tissue or fatty
tissue is to be produced. In the first case it controls the whole
formation of the part, in the second it only fills up gaps or lays
down fat or other substances within itself if these be presented
to it. Between these two extremes of determining power there are
many intermediate stages. Cells which contain the determinants of
blood-vessels, tracheæ, or nerves need not be so definitely determined
that they always give rise to precisely the same blood-vessels, the
same branching of the tracheæ, or the same bifurcation of nerves; they
may probably possess no more than the general tendency to the formation
of such parts, and the special form taken by the nerves, tracheæ, or
blood-vessels may be essentially determined by their environment. Thus
in the morbid tumours of Man, nerves, and especially blood-vessels,
may develop in a quite characteristic manner, which was certainly not
determined in advance, but has been called forth by the stimulus, the
pressure, and other influences of the cellular basis of the tumour.
In short, the cells were only determined to this extent, that they
contained the tendency to give rise to blood-vessels under particular
influences.
It would be a mistake, however, to think of the primary constituents
of all cell-groups as so indefinite. Let us call to mind, for instance,
the venation of the insect wing. It is well known that this is not
only quite different in beetles, bugs, and Diptera from that in the
Hymenoptera, and different again in the butterflies, but that it is
quite characteristic in every individual family of butterflies, and
indeed in every genus. We cannot conceive of the absolute certainty of
development of these very characteristic and constant branchings as
having its roots elsewhere than in the determinants of the germ-plasm,
which, lying within certain series of cells, ultimately cause
particular cell-series of the wing-rudiment to become the wing-veins.
If this were not so, how would it be possible to understand the fact
that every minute deviation in the course of these veins is repeated
in exactly the same way in all the individuals of a genus, while in
all the individuals of an allied genus the venation turns out slightly
different with equal constancy.
But it is quite certain that all determinations are in some degree
susceptible to modifying influences, that they are in very different
degrees capable of variation.
Many deformities of particular parts in Man and the higher animals
may be referred to imperfect or inhibited nutrition of the part
in question during embryonic development; the determinants alone
cannot make the part, they must have a supply of formative material,
and according as this material is afforded more abundantly or more
scantily the part will turn out larger or smaller. In the same way the
pressure conditions of the surrounding parts must in many cases have a
furthering or inhibiting influence, or may even determine the shape.
But it is quite possible, indeed even probable, that other specific
influences are exerted by the cells or cell-aggregates surrounding an
organ which is in process of being formed, just as the stake on which a
twining plant is growing may prompt it to coil. If the stake be absent,
the predetermined twining of the plant cannot attain to more than very
imperfect expression, if indeed it finds any. The spirally coiled
sheath of muscle-cells which occurs so often around blood-vessels
in worms, Echinoderms, and Vertebrates is probably due to similar
processes, that is, on the one hand, to a specific mode of reaction
characteristic of these cells, and predetermined from the germ; on the
other hand, to the external influence of the cell-surroundings without
which the determination of the muscle-cell is not liberated, that is,
is not excited to activity.
[Illustration: FIG. 93. The development of a limb in the pupa of a Fly
(_Sarcophaga carnaria_). _A_, apex of the limb from a pupa four days
old; the jointing is hinted at; _hy_, hypodermis; _ps_, pupal sheath;
_ph_, phagocytes; _tr_, tracheal branch. _B_, the same on the fifth
day; the lumen of the limb is quite filled with phagocytes (_ph_); the
last tarsal joint (_t_^5) is beginning to show a bifid apex. _C_, the
same on the seventh day; the claws (_Kr_) and the adhesive lobes (_hl_)
are formed.]
But even if every determinant requires a stimulus to liberate it,
whether this stimulus consists in currents of particular nutritive
fluids, in contact with other cells, or, conversely, on the removal
of some pressure previously exerted on the cell by its surroundings,
the material cause of a structure is to be sought for not in these
conditions of its appearance, but in the primary constituents which
have been handed on to the relevant cell or cell-group from the germ,
in other words, through its determinants. How, for instance, could
the blunt rounded knob of the rough and clumsily jointed sac of cells
which represents the insect's leg at the beginning of the pupal period
(Fig. 93, _A_) be incited to thicken, to constrict at the root (_B_),
and to form a joint-surface, to broaden out at the end, and produce
two sharply cut points (_C_), which become incurved and form claws
(_kr_), while beneath these a broad flat lobe (_hl_) grows forward, and
with its regularly disposed cells gradually forms the characteristic
adhesive organ of the fly--how could all this happen if there were not
contained within these cells special formative forces which determine
them not only in their form and the rest of their constitution, but
above all in their power of multiplication? No special external
stimulus affects the still unfinished knob of the fly's leg unless it
be the removal of pressure; but this operates regularly, and cannot
be the cause of the growth, at definite places, of claws and adhesive
lobes with all their characteristically placed hairs.
We require to assume that each of the cells composing the primary
rudiment of the limb possessed a determining power which made it grow
and multiply under the given conditions of nutrition and pressure in a
prescribed manner and at a prescribed rate; and we must make the same
assumption in regard to all the daughter and grand-daughter-cells,
and so on. The strictest regulation of the power of multiplication of
each of the implicated cells is a necessary condition of the constant
production of the same two claws and adhesive lobes, the same form of
tarsal joint, the same regular covering of hair, and so on. This exact
determination of the cells can only take place through material vital
particles, and it is these which I call determinants.
I have already said so much about the assumed 'determinants' of the
germ-plasm that it might perhaps be supposed that we have now exhausted
the topic; but the assumption of such 'primary constituents' is so
fundamental, not only for my own germ-plasm theory of to-day and
to-morrow, but also--unless I am much mistaken--for all future theories
of development and inheritance. In point of fact, the conception of
determinants has as yet penetrated so little into the consciousness of
biologists, that I cannot remain content with what I have already said,
but must endeavour to test and to corroborate my thesis by additional
illustrations.
As far as I am aware, only a few zoologists have expressly and
unconditionally agreed with the assumption of determinants; on the
other hand, several biologists have rejected it as fanciful and
untenable, while others have set it aside as a useless playing with
ideas. The last, I am inclined to believe, have not taken the trouble
to think out what the idea is. It has even been objected that there
can be no determinants because we can see nothing of them, and that
they must therefore be pure figments of the imagination, invented to
explain facts which could be explained much more easily and simply in
some other way. From the very first I have stated emphatically that
they have not been, and never will be seen, because they lie far below
the limit of visibility, and thus can at best only become visible
when they are collected in large aggregates like chromatin granules.
Nor have I any objections to make if any one chooses to describe all
the details of their activity as mere hypotheses, such, for instance,
as their distribution during development, their 'maturation,' their
migration from the nucleus, and the manner in which they control the
cell. All this is really an imaginative picture which may be correct
to a certain degree, but may also be erroneous; no formal proof of it
can be obtained at present; and I am content if it be simply admitted
to be possible. On the other hand, the existence of determinants seems
to me to be, in the sense indicated, indubitable and demonstrable.
Let us return for a moment to the claws and adhesive lobes which
are developed on the foot of the fly. It may perhaps be thought
that it is possible to do without the assumption of determinants
for these parts, by assuming that although 'external' influences in
the ordinary sense could not possibly have determined that certain
cells of the apex of the leg should form claws and others adhesive
lobes, the result might be due to the differences of intercellular
pressure within the apical knob; these may have been stronger in one
direction, weaker in another, thus prompting the cells to grow here
into claws and there into adhesive lobes. If we had merely to explain
from the constitution of the germ-plasm the ontogeny or development
of these parts in an individual fly there might perhaps be no radical
objection to this view, though it would hardly be possible to explain
the assumed differences in pressure otherwise than as due to a
different intensity of growth in the cells in the various regions of
the limb-apex, which again would have to be referred to differences in
the germ-plasm. But when we reflect that these parts vary hereditarily
and independently of other parts, and owe their present form to their
power of doing so, and that they are differently formed in every
genus and species, we see at once that they must be represented in
the germ-plasm by particular vital particles, which are the roots of
their transmissible variability, that is, which must have previously
undergone a corresponding variation if the relevant parts themselves
are to vary. Without previous variation of the determinants of the germ
no transmissible independent deviation on the part of the claws or
adhesive lobes of the animal is conceivable.
All the opponents of my theory have overlooked this fact; both Oscar
Hertwig and Kassowitz have forgotten that a theory of development
is not a theory of heredity; they only aim at the former, and
they therefore dispute the logical necessity for an assumption of
determinants.
But as this is the very foundation of the theory, let me further submit
the following considerations in its favour.
In insects which undergo metamorphosis, not only the external but the
internal parts of the caterpillar or larva go through a more or less
complete transformation. In the flies (Muscidæ), for instance, the
whole intestinal tract of the larva is reconstructed in the pupa; in
fact it breaks up into a loose, flocculent, dead, but still coherent
mass of tissue. Within this there arises a new intestine, as I have
shown in an early work (1864); and Kowalewsky and Van Rees have since
made us aware of the interesting details of this reconstruction,
showing that the new intestine arises from definite cells of the
old one, which are present in the larval gut at certain fairly wide
distances, and which do not share in the general destruction, but
remain alive, grow, and multiply, and form islands of cells in the dead
mass. These living islands, continually extending, ultimately come
into contact and again form a closed intestinal canal which differs
entirely from that of the larva in its form, in its various areas,
and in its differentiation. In this case those formative cells of the
imago-intestine must have contained the elements which determined
their descendants in number, power of multiplication, arrangement,
and histological differentiation. In other words, each of these
cells must contain the determinants of a particular limited section
of the intestine of the imago. The other cells of the intestinal
epithelium could not do this, even though they were under exactly the
same conditions, were included in the same intimate cell-aggregate,
and had the same nutritional opportunities. They break up when the
formative cells begin to be active, for till then the latter had
remained inactive, and had not multiplied, although they lay regularly
distributed among the other cells. Whence, then, could the entire
difference in the behaviour of these two sets of cells arise, if it
does not depend on the _nature of the cells themselves_, and how could
this difference of nature have developed during the racial history of
insect-metamorphosis if determinants did not reach the cell from the
germ-plasm--determinants which conditioned that some cells should be
hereditarily modified into the cells of the imago-intestine and others
into the larval intestine? Quite similar processes have been recently
demonstrated in regard to the reconstruction of the larval intestine
in other insect-groups. Deegener has done this, for instance, for the
water-beetle (_Hydrophilus piceus_); and it is certain that all these
reconstructions start from particular cells, which lie indifferently
between the active cells during the larval period, and contain the
primary constituents for the formation of a section of the intestine,
but which only become active when their hitherto living neighbours die
and break up.
The whole of the reconstruction of the external form of the fly takes
place in a similar manner. Not only the limb, the head, the stigmata,
but the skin itself is formed anew from imaginal disks. In each of
the abdominal segments three pairs of little cell-islands are formed
during larval life, and these only enter on the stage of formative
activity after pupation, when they multiply rapidly and grow together
to form a segment, whose size, form, and external nature is determined
by them. But it is well known that the abdominal segments of the fly
differ from those of the larva very markedly and in every respect,
so that each cell-island must contain determinants which are quite
different from those in the skin-cells of the corresponding larval
segments. These last break up at the beginning of pupahood, while the
former begin to grow vigorously, and to spread themselves out. The most
remarkable fact about the whole business, and it seems to me also the
most instructive, is that these imaginal disks frequently appear for
the first time during larval life, as I found in the case of a midge,
_Coretha plumicornis_, in regard to the disks of the thorax, and as
Bruno Wahl[23] has recently demonstrated in the case of the abdominal
cell-islands. Since in the young larva the position of the subsequent
imaginal disks is occupied by cells which apparently in no way differ
from the rest of the skin-cells, and are also exposed to precisely the
same external and internal influences, the origination of the imaginal
cells from these can only depend on differential cell-division; the
primordial cell of each imaginal disk must have separated at the
beginning of disk-formation into a larval and an imaginal skin-cell.
[23] Bruno Wahl, _Ueber die Entwickelung der hypodermalen
Imaginalscheiben im Thorax und Abdomen der Larve von 'Eristalis' L.,
Zeitschr. f. wiss. Zool._, Bd. lxx. 1901.
In insects in which the larva and the imago differ widely, the perfect
insect, as regards all its principal parts, is already represented
in the larva, namely, in particular cells which lie among those of
the corresponding larval parts, and do not visibly differ from these,
although they are equipped with quite different determinants, and
consequently enter on their formative activity much later, and give
rise to quite different structures. As the determinants of the whole
animal with all its parts are contained in the ovum, so those of
the parts of its imaginal phase are contained in these cells of the
imaginal disks.
In addition to all this, we have incontrovertible evidence in favour
of the theory of determinants in the independent phyletic variations
of the individual stages of development, on which depends the whole
phenomenon of 'metamorphosis' which we have just been considering. How
could the larval stage have become so different from the imago-stage,
if the one were not alterable by variation arising in the germ
without the other being affected? If this absolute independence of
the transmissible variability of the individual stages were not an
indispensable assumption in the explanation of metamorphosis and other
phenomena of development, I should regard an attempt at a theory of
development without determinants as justifiable. But I am forced to
see in this fact alone an invalidation of all epigenetic theories of
development, that is, of all theories which assume a germ-substance
without primary constituents, which can produce the complicated
body solely by varying step by step under the influence of external
influences, both extra- and intra-somatic. It is possible to conceive
of an ovum in which the living substance is of such a kind that it
must vary in a definite manner under the influence of warmth, air,
pressure, and so on, that it must divide into similar, and subsequently
also into dissimilar parts, which then interact upon each other in
diverse ways and give rise to further variations, which in their turn
result in differentiations and variations, till ultimately we have the
whole complicated organic machine complete and 'finished' in every
detail. Certainly no mortal could make any pronouncement as to the
constitution of such a substance, but even if we assume it, for the
nonce, as possible, how can we account for the transmissible variation
of the individual parts and developmental stages, on which the whole
phylogenetic evolution depends?
As the development of the butterfly exhibits the three main stages of
caterpillar, pupa, and perfect insect, each of which is independently
and hereditarily variable, and therefore implies a something in the
germ, whose variation brings about a change in the one stage only, so
the ontogeny of every higher animal is made up of numerous stages,
which are all capable of independent and transmissible variation. How
else should we human beings, in our embryonic phase, still possess the
gill-arches of our fish-like ancestors, although much modified and
without the gills? Truly, he who would seek to deny that the stages of
individual development are capable of independent and transmissible
variation must know very little about embryology. But if the facts
are as stated, how can they be reconciled with the conception of a
germinal substance developing in epigenetic fashion? Every variation
in this substance would affect not only the whole _succession of
stages, but the whole organism with all its parts_. In this way too,
then, we are driven to the conclusion that there must be something in
the germ whose variation causes variation only in a particular part
of a particular stage. This something we define in our conception of
the 'primary constituents' (_Anlagen_)--the determinants. These are
not to be thought of either as 'miniature models,' or even as the
'seeds' of the parts; they alone cannot produce the part which they
determine, but they effect changes in the cell in which they become
active, causing it to vary in such a manner that the formation of the
relevant part results. While I conceive of development as a continuous
process, I supplement this with the idea that from within, namely, from
the nuclear substance, new, directive, 'determining' influences are
continually being exerted on the developing cells.
I can hardly think of a better proof of the necessity of this
assumption than that furnished by Delage, one of the most acute
biologists of France, who, in his comprehensive book on _Heredity_, has
striven to replace the theory of determinants by something simpler.
Delage rejects all 'primary constituents' (_Anlagen_) in the germ, all
'particules représentatives,' as much too complicated an assumption,
and thinks it possible to work with the conception of a germ-plasm
which is about as simple as the cell-substance of a Rhizopod, that
is to say, a protoplasm of definite chemico-physical constitution
and composition. Leaving out of account the consideration that the
protoplasm of an amœba is scarcely of such extreme simplicity, but is
certainly made up of numerous differentiated and definitely arranged
biophors, how could such an extremely simple ('éminemment simple')
constitution of the ovum as is here assumed give rise to such a
complicated organism, the individual parts of which are capable of
independent and transmissible variation? According to Delage it does so
because the ovum, though not containing 'all the factors requisite for
its ultimate resultant,' does contain 'un certain nombre des facteurs
nécessaires à la détermination de chaque partie et de chaque caractère
de l'organisme futur'! Determinants after all, it may be said, but
that is far from the truth! It is not primary constituents that the
germ contains, according to Delage, it is chemical substances, for
instance muscle substances, probably 'les substances caractéristiques
des principales catégories de cellules, c'est-à-dire, celles qui, dans
ces cellules, sont la condition principale de leur fonctionnement.' All
these must be contained in the ovum. How they are to reach their proper
place in the organism, how the 'characteristic chemical substance' of a
mole is to land just behind the right or left ear of the fully formed
man, is not stated. But apart from this, there is a much deeper error
in this assumption of specific chemical substances in the ovum as an
explanation of the phenomena of local hereditary variation, and I have
already touched upon it: chemical substances are not vital units, which
feed and reproduce, which assimilate and which bear a charm against
the assimilating power of the surrounding protoplasm. They would
necessarily be modified and displaced in the course of ontogeny, and
would therefore--no matter where they had been placed at first--be
incapable of performing all that Delage ascribes to them. Either the
germ contains 'living' primary constituents, or it is, as Delage
maintains, determined chemico-physically; but in the latter case there
is no scope for hereditary local variation. Delage must either renounce
the attempt to explain this, or he must transform his 'substances
chimiques' into real and actually living determinants.
Thus from all sides we are forced to the conclusion that the
germ-substance on the whole owes its marvellous power of development
not only to its chemico-physical constitution, whether that be
eminently simple or marvellously complex, but to the fact that it
consists of many and different kinds of 'primary constituents'
(_Anlagen_), that is, of groups of vital units equipped with the forces
of life, and capable of interposing actively and in a specific manner,
but also capable of remaining latent in a passive state, until they
are affected by a liberating stimulus, and on this account able to
interpose successively in development. The germ-cell cannot be merely
a simple organism, it must be a fabric made up of many different
organisms or units, a microcosm.
Yet another train of thought leads us to the same idea, and this has
its roots in the extraordinary complexity of the machine which we call
the organism.