October 24, 1907] 



NA TURE 



653 



and those who have studied the chemistry of the natural 

 silicates will be aware of the extension which mineralogists 

 have been compelled to give to the conception of iso- 

 morphism. It would therefore be altogether surprising if 

 the crystallised natural proteins should turn out to be 

 single substances. 



Of the numerous attempts to unravel the constitution of 

 the proteins by analytical means, the only method which 

 has given useful results hitherto is that of hydrolysis. 

 Hydrolysis can be effected by acids or by alkalis, and also 

 by digestive enzymes ; the products, it is well known, 

 besides ammonia, are albumoses, peptones, and ultimately 

 amino-acids. The wide range of variation in composition 

 of these amino-acids is shown by examining a list of all 

 the substances hitherto prepared from the proteins. 



The proportions in which the various amino-acids are 

 obtained from the different proteins vary very consider- 

 ably. In some cases they are altogether lacking, as may 

 be proved by application of the definite tests for tyrosine, 

 tryptophane, or glycine ; but it is worthy of note that, 

 as a rule, the amino-acids isolated from the mixtures pro- 

 duced by subjecting albuminous substances to hydrolysis 

 all occur almost without exception, especially is this true 

 of the important proteins which play the chief part in 

 animal or vegetable metabolism, so that the conclusion 

 must be drawn that none of them can be dispensed with 

 in organic life. With the exception of diaminotri- 

 hydroxydodecanoic acid, they have all been so thoroughly 

 investigated that their structure is well established. The 

 majority also have been synthesised, proof of their struc- 

 ture having, in fact, been given in this way. Only 

 oxyproline, histidine, and diaminotrihydroxydodccanoic acid 

 remain still to be synthesised. 



With the exception of glycine, all the amino-acids 

 derived from natural sources are optically active ; but when 

 prepared bv ordinary synthetic methods, as is well known, 

 they are obtained in the first instance in the racemic form. 

 The resolution of the racemoids into their optically active 

 components has been effected quite recently in most cases. 

 Asoaragine, however, which is closely related to aspartic 

 acid, had been resolved into the two active forms bv re- 

 crystallising the inactive synthetic product from water 

 arid separating the two constituents mechanically. More- 

 over, in the case of some other amino-acids, for example, 

 leucine, the antipode of the natural form had been obtained 

 bv partially fermenting the synthetic product with moulds. 

 The complete synthesis of the active amino-acids which 

 are obtained from natural sources was first accomplished 

 by the method I introduced based upon the use of the acyl 

 derivatives. The method has been applied with success to 

 the majority of the synthetic products ; its extension to 

 the remaining cases, proline, lysine, tryptoohane. and. 

 cystine, is not likely to be attended with any difficulties. 



-As the amino-acids are formed from the proteins, not 

 only when these are subjected to the action of hot acids 

 and alkalis, but also at moderate temperatures bv the 

 agency of the digestive enzymes, they are to be regarded 

 as the true foundation stones of protein molecules. 

 Opinions adverse to this hypothesis are only occasionally 

 met with ; they centre round the arbitrary suoposition 

 that complicated atomic re-arrangements may take place 

 during hvdrolysis. 



Were one inclined to regard such objections as of 

 moment, all the experiments on the delerminntion of the 

 constitution of orsranic compounds by degradation methods 

 would be useless ; moreover, the conclusions which have 

 been drawn in other cases from the resuits obtained by 

 the dissection of compounds have been too freciuentlv con- 

 firmed by their synthesis. It is now possible to make this 

 claim on behalf of the proteins, as it has been found to be 

 possible, by a process the reverse of hydrolysis, to associate 

 amino-acids in such a m.anner that substances are produced 

 which, in the case of th'' simpler terms, closely resemble 

 pentones, whilst the more complex resemble proteins, 



I have termed these synthetic products polvhrttlidrs. in 

 view of their relationshin to the neotones and to farilitnte 

 systematic treatment of the group on the lines of the 

 carbohydrates. 



No useful puroose will be served bv my giving an 

 account of the synthetical methods on the present occasion, 

 especially as I had the honour, six months ago, of de- 



NO. 1982, VOT,. 76] 



scribing to you the preparation of an octadecapeptide 

 derived from fifteen molecules of glycine and three mole- 

 cules of /-leucine, a substance which in its external proper- 

 ties closely resembles many natural proteins. I may say 

 that more than one hundred of these artificial polypeptides 

 have already been synthesised. 



Many of them, it is true, belong to the lower stages, 

 but all the amino-acids previously mentioned, with the 

 exception of diaminotrihydroxydodecanoic acid, have been 

 made use of in their preparation. The synthesis of the 

 higher terms has been restricted hitherto to the combin- 

 ations of glycine, alanine, and leucine ; there is not a 

 shadow of doubt, however, that all the remaining amino- 

 acids could be associated in complicated systems with the 

 aid of our present methods. The knowledge of the 

 artificial polypeptides thus acquired has opened up new 

 ways of investigating the peptones and albumoses 

 analytically. During more than fifty years, physiological 

 chemists have "endeavoured without much success to isolate 

 homogeneous substances from these ill-defined materials ; 

 all the products described by them, however, bear indubit- 

 able evidence of being mixtures. By making use of new 

 methods based on the study of the polypeptides, it has been 

 possible during the last two years to isolate and detect 

 with certainty quite a number of dipeptides among the 

 decomposition products of the proteins. 



In spite of encouraging successes, I am fully aware of 

 the difficulty of discovering the nature of all the com- 

 ponents of the various peptones and albumoses ; but in 

 preparing the way for the synthesis of the natural proteins 

 this is not even necessary. Probably the work can be 

 restricted to the reconstruction of the original system 

 from the major products of cleavage formed in the process 

 of hydrolytic dissection. I am indeed venturesome enough 

 to cherish the hope that I may be able to solve this 

 problem in the case of silk fibroin, one of the simplest 

 proteins. To deal with the whole of the proteins will 

 be a gigantic task ; so large a number of separate investi- 

 gations will be necessary that nothing less than the life- 

 work of a whole army of inventive and diligent chemists 

 will suffice to complete it. Probably, too, the unpleasant 

 discovery will be made that the natural proteins as we 

 know them to-day are only to be obtained by mixing the 

 homogeneous artificial products. 



I have sketched this prospect merely to indicate the 

 manner in which synthesis must play the leading part in 

 this field of work. The nature of the more complicated 

 carbohydrates, as I have already pointed out, will also 

 have to he determined in the future, I imagine, mainly by 

 the application of synthetic methods. Obviously the con- 

 ditions are very similar in the case of the dextrins and 

 gums to those met with in the case of the proteins, and 

 starch, which has hitherto been regarded as a homogeneous 

 substance, appears also to come into the same category, 

 according to Maquenne's observations. 



Not only do the proteins constitute the major part of 

 living protoplasm, but they appear also to be the material 

 from which the organism prepares its most wonderful 

 agents — the ferments or enzymes. In many of the more 

 thoroughly investigated biological processes their cooper- 

 ation has been demonstrated, and there is good reason to 

 suppose that they take part in all changes occurring 

 within the living cell. So much is certain, the physio- 

 logical chemistry of the future will be largely concerned 

 with the study of fermentative changes ; many indications 

 that this must be the case are to be met with in tracing 

 its latest developments. 



The number of the enzymes has been rncreased to an 

 extraordinarv extent during the last ten years. I may 

 allude to the newly discovered enzymes correlated with 

 the carbohydrates : maltase, lactase, mellibase, trehalase, 

 amygdalase, inulase ; to the various oxidases : laccase, 

 tyrosinase : to the lipases, erepsin, enterokinase, arginase, 

 the sucroclastic and glucosidoclastic enzymes, and finally 

 to the zymase of alcoholic fermentation. Much valuable 

 information has been accumulated as to the manner ir 

 which thev act, as to their formation from zymogens, and 

 as to their assistance by co-ferments and their retard- 

 ation bv chemical agents or by anti-ferments. The specific 

 character of their action, in other words, their dependence 

 on the structure and configuration of the object they 



