October 13, 1904] 



NA TURE 



591 



stood than the first. It can be proved experimentally that 

 in the living organism muscular work is accomplished by 

 the transformation of a corresponding amount of chemical 

 energy, however imperfectly we may understand how this 

 transformation can occur at the temperature of the body. 

 ISut as regards the participation of oxygen in the process 

 of restitution, we are obliged to frame for ourselves a hypo- 

 thesis and to clothe it in chemical language, according to 

 which each elementary function is represented by a specific 

 kind of living matter, i.e. by an aggregate of living 

 tnolecules each of which is endowed in equal degree with 

 the capacity of discharging the function which it represents. 

 The difficulty lies in this, that the physiologist finds himself 

 compelled to use chemical language in a sense which the 

 chemist does not recognise. What we mean thereby is 

 that the hypothetical living molecule consists of a permanent 

 part which is not concerned in the performance of function, 

 and of a collateral part which is used, i.e. disintegrated in 

 every transition of the molecule from the inactive to the 

 active state, to be immediately re-constituted when action 

 ceases. This notion of restitution is the nutshell in which 

 the difliculty lies. All that we know about it is that the 

 access of oxygen is an essential condition for its accomplish- 

 ment — o.\ygen not as an oxidiser, but as a restorer of 

 functional capacity. 



1 now propose to pass from the general to the particular, 

 I.e. to the consideration of the chemical process of life as 

 it presents itself in particular organs, namely, first in 

 muscle and in nerve centre, and secondly in such glands 

 as have up to this time been investigated — two groups of 

 structures representing what Bichat called respectively 

 animal life and organic life. On the general principle that 

 in all our investigations we should proceed from the known 

 to the unknown, muscle must be taken first, for its meta- 

 bolism is more within reach of investigation and is better 

 understood than that of any other organ. 



When oxygen enters the living substance of muscle it is 

 not as an oxidiser, but as a preparer and builder up of 

 material ready for explosion. For the muscle molecule 

 receives two things from the blood, oxygen and oxidisable 

 material, but these two do not combine as a mere result of 

 juxtaposition or of encountering one another. As Ostwald 

 says, " Der freie Sauerstoff ist ein sehr trager Stoff," at the 

 temperature of the body. It cannot be brought into action 

 in the living organism by a stimulus so long as it is in its 

 free state. It must first become what Pfliiger calls " intra- 

 molecular," and thereby change its Triigheit for mobility. 

 The immediate effect of the access of oxygen is that the 

 living substance of which it becomes a part becomes more 

 susceptible to mechanical and electrical disturbance, i.e. 

 more e.xcitable than it was before. It requires, so to speak, 

 to be wound up so as to become capable of discharging its 

 oxidising function when awakened by a stimulus. Dr. 

 Fletcher's experiments, to which I will return later, show 

 that the more perfect this preliminary anabolic process is 

 the more complete will be the catalysis. 



You will, I think, agree with me that in different stages 

 of the metabolic process which is associated with muscular 

 function oxygen acts in different ways, at one time taking 

 part in an integrating process for which we might, perhaps, 

 employ the word oxygenation, at another in a process of 

 oxidation, the molecule in which this occurs retaining its 

 existence notwithstanding the disintegration of its oxidisable 

 part. 



We have now to pass on to the question how oxygen 

 takes part in the functional activity of the central nervous 

 system. The only part of that system which is within 

 reach of experimental investigation is tlie spinal cord. We 

 have to consider in how far the results of investigations in 

 the cord and in muscle agree or differ 



Let me say on the threshold that our knowledge is largely 

 due to work recently done at Jena and Gottingen under the 

 direction of (or in cooperation with) Prof. Verworn. I 

 must first ask your attention to the method. 



-More than thirty years ago Cohnheim taught us the use 

 of a preparation which we used to call " the salt frog." in 

 which the blood was replaced by physiological salt solution. 

 He discovered that notwithstanding the defect of haemo- 

 globin, and consequently of oxygen, the chief functions of life 

 could be carried on. With much more perfect methods 

 Wrwnrn has followed Cohnheim. The improvement consists 



NO. 1824, VOL. 70] 



in this, that the circulation is maintained liv mechanical 

 means, so that by varying the rate of flow and the percentage 

 of oxygen in the liquid the supply of o.xygen to the cord can 

 be increased or diminished at will. The effect produced is 

 judged by the mechanical responses to reflex excitation, 

 the indications given by which are rendered more delicate 

 by the previous administration of a trace of strvchnine. 

 The first step in the experiment is to establish a norrnal state 

 of thmgs by the circulation of salt solution which has been 

 freely exposed to air or o.xygen. Under these conditions the 

 response to stimulation of the surface consists of a succession 

 of brief tetani, each lasting two or three hundredths of a 

 second. The next step is to substitute salt solution which 

 has been deprived of oxygen, and to observe that the reflex 

 centre is gradually paralysed, as indicated by the fact that 

 single tetani have taken the place of the serial responses, 

 that on renewing the supply of oxygen the former state 

 of things is restored, and, finally, that these changes may 

 be repeated over and over again with the same result. 



AH these facts come under the general statement that 

 while o.xygen has no power of acting as a stimulus it in- 

 creases the e.xcitability of the centre, enabling it when 

 excited to discharge itself so completely that after the dis- 

 charge it is wholly incapable of responding. It further 

 shows that o.xygen shortens the time required for restitution 

 to the normal — reintegration following disintegration — 

 anabolism following katabolism so immediately that they 

 may almost be considered as simultaneous. 



If we compare the behaviour of o.xygen in the centre with 

 its behaviour in the muscle, we shall find that they differ 

 chiefly in one particular, namely, in their time-relations. 

 In both cases oxygen acts as a predisposing, not as an 

 exciting cause of functional activity. In both cases a 

 tertium quid is wanted — a liberating or letting off 

 mechanism ; but in the muscle the functional cycle is accom- 

 plished in scarcely more than i/ioo sec, whereas in the 

 centre the effect occupies a few hundredths of a second, and 

 the preparation for it a much longer period. There is 

 therefore no difficulty in understanding why the so-called . 

 refractory period can be so easily observed and measured 

 in the centre (while in the muscle its presence can only be 

 inferred), a circumstance which is helpful as affording an 

 additional evidence of the anabolic action of oxygen ; for 

 it is easy to show that the period in question is shortened 

 by supply of oxygen, protracted by its absence. 



We now come to the last point which I am anxious to 

 submit to you — that of the relation of oxygen to the function 

 of glands. I must begin by saying that it is in this part 

 of our subject that the crux lies, for the investigation of the 

 intimate metabolism of glands is beset with difficulties even 

 greater than those of muscle and spinal cord. 



Mr. Barcroft, to whose admirable researches we shall 

 have occasion to refer repeatedly to-day, found as the result 

 of his estimate of the o.xygen and carbonic acid yielded by 

 the blood circulating through the submaxillary gland under 

 different conditions that this gland takes from the blood 

 much more o.xygen when excited by the chorda tympani 

 than when at rest, no such effect occurring when the excita- 

 tion had been rendered ineffectual by the previous adminis- 

 tration of atropine. These observations gave good reason 

 for believing that oxygen promotes the action of the cells, 

 but afforded no evidence that this action is attended by a 

 corresponding discharge of carbon dioxide. Similarly Prof. 

 Starling, whose experiments were made with Mr. Barcroft's 

 cooperation, found that when the pancreas is made to act 

 by the injection of secretin a similar want of relation pre- 

 sented itself between the quantity of oxygen taken in and 

 of carbon dioxide discharged. Finally, the comparison 

 which has been recently made by Dr. Brodie (who will, I 

 hope, explain to us his very admirable method) of the state 

 of activity of the kidneys with the state of rest, points to 

 the same conclusion as regards that organ. When diuresis 

 was produced by the injection of urea, the clearest evidence 

 was given of the increased demand for o.xygen, the intake 

 of which was very largely increased, but there was no in- 

 dication that the ultimate products of oxidation found their 

 way into the blood in quantities proportionate to the oxygen 

 supplied. 



Taking these data as our point of departure, what can 

 we infer from them as regards the resemblances and differ- 

 ences between the two processes we have been considering. 



