PRESIDENTIAL ADDRESS. 659 
several possible lines along which a given physiological substance 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 rejected as not physiological. 
In a second method dependent upon this eclecticism of the body, substances are 
administered which so far differ from the normal that, instead of suffering a 
complete breakdown, 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 intermediate products accumu- 
late; or again when, as may happen, the successive changes wrought upon a 
substance 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. Extra- 
ordinarily profitable have been the observations made upon individuals suffering 
from those errors of metabolism which Dr. Garrod calls ‘metabolic sports, the 
chemical 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 experimental. 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 successful 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 till 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 intermediate 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 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 substance accumulates is by itself no 
measure of ifs 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 inter- 
mediate 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 of any one intermediate product must be equal to the rate at 
which it changes into the next, and so throughout the series. Else individual 
intermediate products would accumulate or disappear, and the equilibrium be 
upset. Now 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 proportional to 
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