218 
and under stress of circumstances, new chemical 
accomplishments, is in general able to deal only with 
what is customary to it. This circumstance has 
yielded two methods of determining the nature of 
intermediate products in metabolism. Considerations of 
molecular structure will, for instance, suggest several 
possible lines along which a given physiological sub- 
stance may be expected to undergo change. We may test 
these possibilities by administering various derivatives 
of the substance in question. Only those which prove 
on- experiment to be fully metabolised, or to yield 
derivatives in the body identical with those yielded by 
the parent substance, can be the normal intermediate 
products of its metabolism. All others may be re- 
jected as not physiological. In a second method 
dependent upon this eclecticism of the body, sub- 
stances are administered which so far differ from the 
normal that, instead of suffering a complete break- 
down, they yield some residual derivative which can 
be identified in the excreta, and the nature of which 
will throw light upon the chemical mechanism which 
has produced it. For instance, a substance with a 
resistant (because abnormal) ring structure, but 
possessing a normal side chain, may be used to 
demonstrate how the side chain breaks down. Again, 
we may sometimes obtain useful information by 
administering a normal substance in excessive 
amounts, when certain intermediate products may 
appear in the excreta. Another most profitable method 
of experiment is that in which the substance to be 
studied is submitted to the influence of isolated organs 
instead of to that of the whole animal. Under these 
conditions, a series of normal reactions may go on, 
but with altered relative velocities, so that inter- 
mediate products accumulate; or again when, as may 
happen, the successive changes wrought upon a sub- 
stance by metabolism occur in different organs of the 
body, this use of isolated organs enables us to dissect, 
as it were, the chain of events. Extraordinarily profit- 
able have been the observations made upon indi- 
viduals suffering from those errors of metabolism 
which Dr. Garrod calls ‘‘metabolic sports, the chem- 
ical analogues of structural malformations.” In these 
individuals, nature has taken the first essential step 
in an experiment by omitting from their chemical 
structure a special catalyst which at one point in the 
procession of metabolic chemical events is essential 
to its continuance. At this point there is arrest, and 
intermediate products come to light. 
As you know, most ingenious use of this ready- 
made experimental material has added greatly to our 
knowledge of intermediate metabolism. | Admirable 
use, too, has been made of the somewhat similar 
conditions presented by diabetes, clinical and experi- 
mental. Every day our knowledge of the dynamics 
of the body grows upon these lines. 
I know that the history of all these efforts is 
familiar to you, but I am concerned to advertise the 
fact that our problems call for ingenuity of a special 
sort, and to point out that an equipment in chemical 
technique alone would not have sufficed for the suc- 
cessful attack which has been made upon them. But 
I am even more concerned to point out that the direct 
method of attack has been too much neglected, or has 
been in the hands of too few; I mean the endeavour 
to separate from the tissues further examples of the 
simpler products of metabolic change, no matter how 
small the amount in which they may be present; an 
endeavour which ought not to stop at the separation 
and identification of such substances, but to continue 
until it has related each one of them to the dynamic 
series of reactions in which each one is surely playing 
a part. The earliest attempts at tracing the inter- 
mediate processes of metabolism looked for informa- 
tion to the products which accumulate in the tissues, 
but it seemed to be always tacitly assumed that only 
NO. 2294, VOL. a2h 
NATURE 
[OcToBER 16, 1913 
those few which are quantitatively prominent could 
be of importance to the main issues of metabolism. 
It is obvious, however, upon consideration, that the 
degree to which a substances accumulates is by itself 
no measure of its metabolic importance; no proof as 
to whether it is on some main line of change, or a 
stage in a quantitatively unimportant chemical by-— 
path. For, if one substance be changing into another 
through a series of intermediate products, then, as 
soon as dynamical equilibrium has been established 
in the series, and to such equilibrium tissue processes 
always tend, the rate of production ot any one inter- 
mediate product must be equal to the rate at which 
it changes into the next, and so throughout the series. 
Else individual intermediate products would accumu- 
late or disappear, and the equilibrium be upset. 
the rate of chemical change in a substance is the 
product of its efficient concentration and the velocity 
constant of the particular reaction it is undergoing. 
Thus the relative concentration of each intermediate 
substance sharing in the dynamic equilibrium, or, in 
other words, the amount in which we shall find it at 
any moment in the tissue, will be inversely propor- 
tional to the velocity of the reaction which alters it. 
But the successive velocity constants in a series of — 
reactions may vary greatly, and the relative accumu- 
lation of the different intermediate products must vary 
in the same degree. It is certain that in the tissues 
very few of such products accumulate in any save 
very small amount, but the amount of a product 
found is only really of significance if we are concerned 
with any function’ which it may possibly possess. 
It is of no significance as a measure of the quantita- 
tive importance of the dynamical events which give 
rise to it. 
To take an instance. 
always asserted itself in our conceptions concerning 
nitrogenous metabolism because of the large amount 
in which it is found in the muscle. It may be of 
importance per se, and abnormalities in its fate are 
certainly important as an indication of abnormalities 
in metabolism, but we must remember that the work 
of Gulewitsch, Krimberg, Kutscher, and others has 
shown us that a great number of nitrogenous basic 
bodies exist in muscle in minute amounts. Maybe 
we shall need to know about each of these all that we 
now know, or are laboriously trying to know, about 
creatin, before the dynamics of basic nitrogen in 
muscle become clear. Fortunately for the experi- 
menter, most of the raw materials required for tissue 
analysis are easily obtainable; there is no reason save 
that of the labour involved why we should not work 
upon a ton of muscle or a ton of gland tissue. 
I am certain that the search for tissue products of 
simple constitution has important rewards awaiting 
it in the future, so long as physiologists are alive to 
the dynamical significance of all of them. Such work 
is laborious and calls for special instincts in the 
choice of analytical method, but, as I mentioned in 
an earlier part of this address, 1 am sure that high 
qualifications as an analyst should be part of the equip- 
ment of a biological chemist. Ee: 
I should like now to say a few words concerning 
the actual results of this modern work upon inter- 
mediate metabolism, and will return to the amino- 
acids. It is clear that what I can say must be very 
brief. 
We know that the first change suffered by an 
a-amino-acid when it enters the metabolic laboratories 
is the loss of its amino group, and, thanks to the 
labours of Knoop, Neubauer, Embden, Dakin, and 
others, we have substantial information concerning 
the mechanism of this change. The process involved 
1 A product of metabolism can only be said to havea “ function’ in a 
cell or in the body when, being the end-product of one reaction, it initiates 
or modifies reactions in another milieu. 
Now 
The substance creatin has — 
