THE SUPPRESSION OF GROWTH AND THE CAPACITY

TO GROW.’

By THOMAS B. OSBORNE AND LAFAYETTE B. MENDEL,

WITH THECO~PERATIONOFEDNA L. FERRYANDALFRED J. WAKEMAN.

(From the Laboratory of the Connecticut Agricultural Experiment Station

and the Shefield Laboratory of Physiological Chemistry in Yale
Univers?.ty, New Haven, Connecticut.)

(Received for publication, April 21, 1914.)

Although the capacity to grow has been the subject of consider-

able speculation, comparatively little experimental study has been
devoted to it. Many of the current statements are scarcely more
than dogmatic assumptions based upon hypothesis rather than
controlled evidence. In general the dominant impression seems
to be that the capacity to grow belongs essentially to the earlier
periods of the life cycle; or at any rate it is believed to be more
characteristic of that time. Accordingly it would appear that this
unique property of living substance is sooner or later lost-at least
in so far as it pertains to the higher animal forms.
Quite aside from any consideration of the ultimate cause of
growth, the capacity to grow is currently further associated with
a youthful character of the cells involved. Age is thereby made a
factor of importance in the possibility of growth. An embryonic
condition of the cells appears, from this viewpoint, to be most
favorable to true growth. In dealing with this function Minot
has emphasized his conception of the influence of age by the
statement that “the rate of growth depends on the degree of
senescence. ))2
1 The expenses of this investigation were shared by the Connecticut
Agricultural Experiment Station and the Carnegie Inst>itution of Washing-
ton, D. C.
2 Minot: The Four Laws of Age, Popular Science Monthly, lxxi, p. 523,
1907.
95

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96 Suppression of Growth

From a purely theoretical standpoint it by no means follows

that the familiar cessation of growth is due solely to a loss of a
capacity to grow incidental to age. It is quite conceivable that
natural inhibitory factors develop in the course of time. How
firmly the idea that the growth-power inevitably declines and is
lost with age has become rooted in physiological literature is read-
ily disclosed by a few quotations from well known writers.
Development and the changes involved in growing old are, however, by
no means synonymous, so that although in those animals with a fixed size
there are always to be found undeveloped cells, yet it is not a correct infer-
ence that these cells are also young in the sense that they might still com-
plete their development. It appears, rather, that the capacity for under-
going expansive change is transient, and that those cells which fail to react
during the proper growing period of an animal have lost their opportunity
forevei-.3

W’ir wissen eigentlich gar nicht, ob die Natur ein absolut gleichmassiges
tagliches Wachstum verlangt, oder ob Remissionen zulassig oder gar zweck-
massigsind. Nur das steht sicher, dass die Behinderung desWachstumstrieb-
es, wie dies wirklich vorkommt, nicht wahrend der ganzen Wachstumsper-
iode andauern darf, da sonst allerdings die Griisse des Individuums dauernd
Schaden leidet. Verlorene Kiirpergriisse in der Jugendzeit kann naeh
Vollendung der Wachstumsperiode nimmermehr abgeglichen werden4

Again we read:
Das schliessliche Versagen des Wachstums hiingt au& natiirlich nicht
mit einer ungeniigenden Ausbildung der Resorption der Nahrung zusammen;
ein eben ausgewachsenes Individuum kann das Mehrfache an Nahrung
resorbieren von dem, was an Unterhalt notig ist, den Wachstumstrieb wird
man nimmer ‘wecken. . . . . Das Tier hart bei geringer Ernahrung
auf, iiberhaupt au wachsen? vollzieht aber seine sonstige biologische
Entwicklungsperiode. Obschon also das Wachstum kiinstlich gehemmt
werden kann und somit latent bleibt, verliert sich trotzdemder Wachstums-
trieb. Die Wachstumsfahigkeit kann in ihrer Begrenzung nicht von einer
nur im Wachstum selbst entstehenden Schadigung oder einem mit der
Zellmasse und Zellbildung unmittelbar zusammenhangenden Vorgang
gebunden sein, weil sie such da schliesslich schwindct, wo sie iiberhaupt
nicht in Anspruch genommen worden ist.5
3 Donaldson, H. H. : The Growth of the Brain, New Pork, 1903, p. 37.
4 Rubner, M.: Das Problem der Lebensdauer und seine Beziehungen zu
Wachstum und Ern(ihrung, Miinchen und Berlin, 1908, p. 82; also Emlrhungs-
vorglinge beim Wachstum des Kindes, Arch. f. Hygiene, lxvi, p. 82, 1908.
5 Rubner, M. : Kraft und Sto$ im Hnushnlte der Natur, Leipzig, 1909, pp.
116-17.
 T. B. Osborne and L. B. Mendel 97

Further:
Alle Mittel, alle Versuche unsere alternden Zellen mit verjiingender Kraft
zu versehen, sind eitel; nichts kann den Verfall hemmen. Nur die Befrucht-
ung vermochte neues Leben zu schaffen. Diese Hilfe ist uns aber versagt,
sie gilt nur den Fortpfianzungszellen, der neuen Generation, der Zukunft.’
In der Regel ist, bei den verschiedenen Tieren verschieden stark, der
Wachstumstrieb in der Jugend am stlrksten, nimmt allmahlich sb und
verliert sich im Alter. Die Natur des Wachstumstriebes ist dunkel. Sie
ist eine Funktion der Zellen, im besonderen der jugendlichen Zellen. \Velche
Faktoren diesen Zelltrieb regulieren, wissen wir nicht, vor allem nicht,
warum er allmahlich aufhiirt. Ob hier die Zeitdauer seiner Wirksamkeit,
ob die erreichte Griisse des Individuums den Ausschlag fur das Abklingen
des Wachstumstriebes gibt, ist bis jetzt nicht entschieden.’

d somewhat different view is expressed by Friedenthal :

Inwieweit eine Zelle wachstumsfahig ist, hangt. in hohem Masse von der
Zahl der bereits abgelaufenen Zellteilungen ab, welche zur Bildung dieser
Zelle von der befruchteten Eizelle her ftihrte. Wir durfen jeder befruchteten
Eizelle die Mdglichkeit der Erzeugung einer artmassig verschiedenen Zahl
von Zellteilungen zuschreiben, nach deren Ablauf die Regenerationskraft
des Organismus erschopft ist, so dass der Tod als notwendige Folge der nun
irreparabel gewordenen Schadigungen der Arbeitsmaschine des Lebewesens
anzusehen ist. Je mehr wir imstande sein werden, den Rhythmus der
Zellteilungen beim Menschen zu verlangsamen, urn so heher we&n wir
die Lebensdauer und die Gesamtleistung des Menschen zu steigern vermbgen.

The facts gleaned from the study of the regeneration of parts,

as it is exemplified in the lower forms of animals, suggest a further
alternative. It may be that the capacity to grow is limited by the
exercise of this capacity rather than by age, as such. The problem
cannot be solved by a priori considerations. It is amenable to
experiment.
Before presenting our own experience in this field we must point
out a distinction between growth, as we understand it, and the
related process of repair or regeneration of depleted parts and
6 Rubner, M.: ibid., p. 180.
r Aron, H. : Wachstum und Ernbhrung, Biochem. Zeitschr., XXX, p. 207,
1910.
8 Friedenthal, H. : Das Wachstum des Korpergewichts des Menschen
und anderer Saugetiere in verschiedenen Lebensaltern, Zeitschr. f. all-
gemeine Physiol., ix, p. 487, 1909; also Arbeiten au.s dem Cebict der exp. Phys-
iol., ii, p. 51, 1911.
98 Suppression of Growth

organs. There are indications already available that the chemical

or metabolic processes of repair are by no means identical with
growth. They may not involve the destruction and resynthesis
of an entire protein molecule or of the entire protoplasmic cell
structure. Furthermore it is a matter of common experience
that repair or recuperation can take place at all ages and even
after the completion of normal growth; though it may be deair-
able to consider the ability to recuperate with reference to age.
There is a common belief that children recover weight more
promptly than adults. We have repeatedly observed that animals
which have declined markedly in body weight regain the weight
normal for their age when returned to a proper diet and health
conditions, at a rate far surpassing that observed in the original
growth of individuals through the same range of body weight. The
process of restoration is accomplished with wonderful rapidity.g
A striking illustrative instance of this is depicted in the Appendix
(Chart I). Nevertheless it must be admitted as possible, though
scarcely probable, that restored individuals may not be in all
respects normal. Qualitative changes not appreciated by the cur-
sory examination may have become permanently engrafted.‘O
That growth can be retarded or even suppressed for brief periods
at an early age without loss of the capacity to complete it is known.
Hatai, for example, has found that “so far as the weight of the
body and central nervous system are concerned, the effect of a
twenty-one day period of partial starvation on albino rats thirty
days old is eventually completely compensated.“l’
To Hans Aron we owe elaborate experiments on the influence of
the suppression of growth during the early period of life upon the
capacity of animals to complete their normal development. He
accomplished this retardation by underfeeding. The earlier experi-

9 Cf. Morgulis, S. : Studies of Inanition in its Bearing upon the Problem

of Growth, Arch. f. Entwicklungsmechanik der Organismen, xxxii, p. 169,
1911.
lo Cf. Donaldson, H. H.: President’s Address before the Philadelphia
Neurological Society, Journ. of Nervous and Mental Disease, xxxviii, p.
257, 1911.
11 Hatai, S. : Effect of Partial Starvation Followed by a Return to Normal
Diet, on the Growth of the Body and Central Nervous System of Albino
Rats, Amer. Journ. of Physiol., xviii, p. 309,1907.
 T. B. Osborne and L. B. Mendel 99

ments,lz carried out on dogs, demonstrated that despite the con-

siderable inhibition of growth which was not, however, extended
throughout the entire period of adolescence, the animals still
retained a capacity to grow vigorously. This is in contrast to the
added observation that if the restriction in the diet and the in-
hibition of growth has been extended throughout the ent.ire custo-
mary period of growth, the capacity to grow is apparently lost.
For example, of two dogs approximately three months in age, one
was nourished normally and the other kept at approximately
constant weight of about 2400 grams over a period of 310 days.
At the end of this period the normal animal had reached a weight
of 6800 grams. The stunted individual was now fed abundantly,
whereupon it added considerable fat to its body. Nevertheless
at the end of 500 days it had showed little increase in body length
despite the increment of body weight, and it remained consider-
ably behind its normal companion in size. More recent experi-
ments by Aron13 on rats along the same lines have shown that at
an early age the growth of these animals may be retarded by under-
feeding for considerable periods of time and yet a capacity for
subsequent vigorous growth be retained. This investigator
remarks, however : “Allerdings scheinen die Tiere weder in Ge-
wicht noch in G&se ihre normalen Rrudertiere viillig zu erreichen
und das Versaumte nicht ganz nachholen zu konnen.” Taken in
their entirety, therefore, these experiments still leave the question
as to the relation of age to the capacity to resume growth unsettled.
Although Rubnerr* has only lately maintained that the capacity
t.o grow finally disappears even when it is not called into use,
ArorP has pointed out in a more recent review of the subject of
growth that the experimental evidence is contrary to this assump-
I2 Aron, H.: Wachstum und Erniihrung, Biochem. Zeitschr., xxx, p. 207,
1910; Nutrition and Growth, I, Philippine Journal oj Science, vi, SW. B,
p. 1, 1911.
Ia Aron, H. : Weitere Untersuchungen iiber die Beeinflussung des Wachs-
tums durch die Erlihrung, Verhandlung der 29 Versammlung der Gesell-
sch. f. Kindcrhilk. in der Ahteilung f. Kinderheilk. der 84 Versamml. d.
Gesellsch. deutsch. Naturjorsch. u. Aerzte in Mtinster, 1912, 103.
I4 Rubner, M.: Krajt und Stoff im Haushalte der Natur. Leipzig, 1909,
pp. 116-117.
I6 Aron, H. : Biochemie des Wachstums des Menschen und der htiheren
Tiere, Handbuch der Riochernie, ErgBnzungsband, Jena, 1913, p. 70.
100 Suppression of Growth

tion.‘” IIe refers in particular to our published observations17

in which the capacity to grow was shown to be maintained at the
age of 314 days after an inhibition of 276 days. Data are quoted
to support the belief that the final adult size of the body may be
markedly affected by very prolonged undernutrition during the
period of adolescence. In discussing the growth of children
Boa9 has noted that although retardation of early growth is made
up by abnormally rapid development at a later period, an unduly
prolonged retardation cannot be entirely compensated for; accord-
ingly excessive early inhibition of growth may be detrimental to
the individual. Although the growth of the body in recuperation
is very rapid in children whose development has been temporarily
disturbed by disease or other unfavorable conditions, what will
happen to them in the latter portions of the span of life has yet
to be determined in order to answer the question whether the
partial starvation in early life has any influence either on longev-
ity or on the onset of old age.lY Aron points out that most of the
scanty experimental evidence heretofore collected on this topic
pertains to subjects which have been stunted in their growth by
underfeeding; and he raises the question as to whether the con-
clusions drawn from such a mode of inhibition apply equally well
to other conditions of retarded growth.
Die Rachstumsf%higkeit, und die Intensitiit dcs Wachstumstriehes kann
nach den Erfahrungen der beschriebenen Versuche nicht mehr vornehmlich
als eine Funktion des Alters, d. h. der nach dem Befruchtungsvorgang
verstrichenen Zeitspanne oder der im Korper abgelaufenen Zahl der Zell-
teilungen betrachtet werden, such nicht von der umgesetzten Kalorienzahl
abhgngig sein. Massgebender als das Alter scheint die endgiiltige G&se
des Individuums zu sein, wie die folgende Beobachtung dartun sol1 : Weib-
lithe Ratten erreichen ausgewachsen nur ein erheblich geringeres Gewicht
als mgnnliche Geschwistertiere; ihre Wachstumskurve verflacht sich friiher

I6 Schulz, P. : Wachstum und osmotischen Druck bei jungen $Iunden,

Zeitschr. f. Kinderheilk., iii, p. 251L56, 1911.
I7 Osborne and Mendel: Beobachtungen tiber Wachstum bei Ftitterungs-
versuchen, Zeitschr. f. ph,ysioZ. Chem., lxxx, pp. 307-70, 1912; The R.81e of
Gliadin in Nutrition, this Journal, xii, pp. 473-510, 1912.
I* Boas, F.: The Growth of Children, Science, Dec. 13, 1912, p. 815.
I@ Cf. Hatai, S.: Effect of Partial Starvation followed by a Return to
Normal Diet, on the Growth of the Body and Central Nervous System of
Albino Rats, Amer. Journ. of Physiol., xviii, p. 315, 1907.
 T. B. Osborne and L. B. Mendel IO1

und ihr Wachstum stockt vor dem der Brudertiere glinzlich. Hemmt man
nun eine junge mgnnliche Ratte im Wachstum so lange bis tin Schwestertier
ausgewachsen ist und das gehemmte Brudertier erheblich an Gewicht
iibertrifft, und fiittert jetzt erst das gehemmte Brudertier auf, so erreicht
endgtiltig doch das mSinnliche Tier trotz der Wachstumshemmung noch
ein betriichtlich hKheres Gewicht als das Schwestertier, ein Ausdruck
der iiberragenden Wirkung der kongenitalen Anlage (dcs Wachstumstriebcs)
auf den Ablauf der Wachstumsvorg%nge gegeniiber sekundgren Momenten.

EXPERIMENTAL PART.

In testing the capacity of albino rats to continue their growth

after more or less prolonged inhibition of this function, as mani-
fested by an approximately stationary body weight, we have
attempted the suppression of growth by a variety of procedures.21
Instead of the method of underfeeding with rations of suitable
qualitative make-up we have induced effective stunting by a variety
of other ways such as: the use of diets containing an adequate
protein, but with the inorganic salts supplied in the form of a
mixture of pure chemicals, as used by Riihmann, together with
sucrose and starch as the carbohydrate component (Chart IV) ;
by restriiting the protein content of the dietary below the mini-
mum required for growth; by furnishing, as the exclusive source
of nitrogenous intake, proteins which lack some amino-acid group
indispensable for growth (Charts III and IV).22 In all of these
experiments care has been exercised to prevent any prolonged
decline of body weight on the dietary r6gimes employed. Since
some of them are unsuited even for brief maintenance alone, it
has become necessary to resuscitate the rats at int,ervals, by
administration of some perfect nutrient like our milk-food mixtures.
As soon as the animals were brought back in this way to their
previous maximal weight, or even somewhat above it, the inhibi-
tory diet was renewed (see Charts IV and V).

z0 Aron, H. : Biochemie des Wachstums des Menschen und der hiiheren

Tiere, Handbuch der Biochemie, Erggnzungsband, Jena, 1913, p. 71.
21 Cf. Osborne and Mendel: Beobachtungen iiber Wachstums bei Fiitter-
ungsversuchen mit isolierten Nahrungssubstanzen, Zeitschr. f. physiol.
Chem., lxxx, pp. 307.-70, 1912.
** Cf. Osborne and Mendrl: Amino-acids in Nutrition and Growt.h, this
Journal, xvii, p. 325, 1914.
102 Suppression of Growth

The results of some of these trials are presented graphically in

appended charts. In interpreting them it is necessary to bear in
mind the usual duration of the normal period of growth. This is
extremely variable; but it rarely exceeds 335 days. Rigid limits
in respect to duration of growth and the maximum size attained
cannot be given. The males invariably grow to a larger size t)han
the females. Only four out of 110 rats, all females, increased in
weight after one year of age; out of 38males only four increased in
weight after 300 days. Beyond the age noted above, increase in
body weight is extremely slow, if it occurs at all; and probably it
represents depositions of reserve materials, like fat, &her than
growth in the sense of developmental changes.
In some of the stunted animals the momentary body weight on
the day in which an effective diet for growth was resumed is below
that which they had reached at some previous date. An incre-
ment in weight up to the figure for the previous maximum cannot
in fairness be considered as new growth, inasmuch as it may rep-
resent something merely analogous to repair. Therefore we have
indicated by a “basal line” in some of the curves the point at which
the weight began to increase above the previous maximum, and
considered this as the beginning of new growth.
In Rat 5319, Chart II, the capacity to grow was not lost at, the
age of 532 days, or after more than half the life-span of most of the
rats kept under our conditions of housing and caging.2” This
animal, it must be noted, was already well grown to a size of 170
grams before the stunting period on corn gluten food24 checked
further increase in weight. Rat 5699, Chart III, similarly stunt,ed,
at 160 grams of body weight, showed a vigorous growth response
at the age of 480 days. Chart IV exhibits the resumption of
growth at 418 days of age after a period of very prolonged sup-
pression of growth by the method of alternate feeding of imper-
fect and perfect nutrient mixtures (indicated by the straight and
interrupted lines respectively)‘. A similar experience is indicated
by Chart V in which the inhibition of growth and nutritive

2a Slonaker (down. of ~4nimalBehneior, ii, p. 20-42,1912) has kept, albino

rats alive for more than one t,housand days in the laboratory.
E4 Cf. Osborne and Mendel: Nutritive Properties of Prot,eins of thcs
Maize Kernel, t,his Journal, xviii, p. 1, 1914.
 T. B. Osborne and L. B. Mendel 103

decline was due to the interrupted use of gelatin as the exclusive

source of nitrogen in the dietary.
The illustrative experimental results here reviewed give no
support to the widespread view that the capacity to grow-
Wachstumstrieb, Wachstumsfahigkeit, or growth impulse, as it
has been variously termed-is lost with age, independently of
whether it has or has not functioned during the period usually
associated with increase in size. The difficulties of continuing the
trials of the sort here exemplified over periods of years, rather
than months, are great; so that we are not in a position to say that
the growth impulse will never become exhausted in ungrown ani-
mals in the course of time. Rut it appears as if the capacity to
grow is only lost by the exercise of this fundamental property of
animal organisms.
These conclusions have not been attained by a single procedure;
for our animals were prevented from growing by a variety of
methods. Whether the span of life can be prolonged by delaying
the completion of growth has not yet been ascertained under
conditions that preclude disease or other anomalies of nutrition.
Like the questions relating to possible changes in morphological
or chemical make-up of the tissues incident to suppression of
growth, this one is open to experimental study.
 104 Suppression of Growth

APPENDIX.

CHART I, showing curves of repair after a considerable fall in body

weight due to feeding with a defective diet. Note that lost weight is
regained far more rapidly than during normal growth at the same size.
CHART II, showing capacity to grow at 532 days of age and 170 grams of body weight; and 344 days and 137 grams respectively.
240

I
/
220
/

II II IIIIIII Ill Ill L-k---I II

CHART 111, showing capacity to grow at 480 days of age and 167 grams of body weight.

CHART IV. showing capacity to grow at 417 days of age and 104 grams of body weight.
 CHART V, showing capacity to grow at 370 days
JOURNAL OF BIOLOGICAL CHEMISTRY, xviii, No.1. C
 / I
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of age and 127 grams of body weight.

kborne and Mendel: Suppression of Growth.