YALE JOURNAL OF BIOLOGY AND MEDICINE 75 (2002), pp. 221-231.Copyrght © 2002. All rights reserved.

CLASSICS OF BIOLOGY AND MEDICINE

The Incidence of Alkaptonuria: A Study inChemical Individuality

By Archibald E. Garrod, M.A., M.D. OxonPhysician to the Hospital for Sick Children, Great Ormond Street; Demonstrator ofChemical Pathology at St. Bartholomew's Hospital

All the more recent work on alkap-tonuria has tended to show that the con-stant feature of that condition is the excre-tion of homogentisic acid, to the presenceof which substance the special propertiesof alkapton urine, the darkening with alka-lies and on exposure to air, the power ofstaining fabrics deeply, and that of reduc-ing metallic salts, are alike due. In everycase which has been fully investigatedsince Wolkow and Baumann [1] first iso-lated and described this acid its presencehas been demonstrated and re-examinationof the material from some of the earliercases also has led to its detection. The sec-ond allied alkapton acid, uroleucic, hashitherto only been found in the casesinvestigated by Kirk and in them in asso-ciation with larger amounts of homogen-tisic acid [2]. By the kindness of Dr. R.Kirk I have recently been enabled toexamine fresh specimens of the urines ofhis patients who have now reached man-hood and was able to satisfy myself that atthe present time even they are no longer

excreting uroleucic acid. After as much ofthe homogentisic acid as possible had beenallowed to separate out as the lead salt thesmall residue of alkapton acid was con-verted into the ethyl ester by a methodrecently described by Erich Meyer [3] andthe crystalline product obtained had themelting-point of ethyl homogentisate(1200C). Further observations, and espe-cially those of Mittelbach [4] have alsostrengthened the belief that the homogen-tisic acid excreted is derived from tyrosin,but why alkaptonuric individuals pass thebenzene ring of their tyrosin unbroken andhow and where the peculiar chemicalchange from tyrosin to homogentisic acidis brought about, remain unsolved prob-lems.

There are good reasons for thinkingthat alkaptonunria is not the manifestationof a disease but is rather of the nature of analternative course of metabolism, harmlessand usually congenital and lifelong.Witness is borne to its harmfflessness bythose who have manifested the peculiarity

a Originally published in The Lancet, pp. 1616-1620, 1902.

221

222 Garrod: Alkaptonuria

Table 1. Showing the average excretion of homogentisic acid.

Average excretionof homogentisticacid per 24 hours

Age on ordinary mixed diet Names ofNo. Sex (years) (grams) observers

1 M 2.5 3.2 Erich Meyer2 M 3.5 2.6 A.E. Garrod3 M 8.0 2.7 Ewald Stier4 M 18.0 5.9 P. Stange5 M 44.0 4.6 Mittelbach6 M 45.0 4.7 H. Ogden7 M 60.0 5.3 Hammersten8 F 60.0 3.2 H. Embden9 M 68.0 4.8 Walkow and Baumann

without any apparent detriment to healthfrom infancy on into adult and evenadvanced life, as also by the observationsof Erich Meyer who has shown that in thequantities ordinarily excreted by such per-sons homogentisic acid neither acts as anaromatic poison nor causes acid intoxica-tion, for it is not excreted as an aromaticsulfate as aromatic poisons are, nor is itspresence in the urine attended by anyexcessive output of ammonia. However,regarded as an alternative course of metab-olism the alkaptonuric must be lookedupon as somewhat inferior to the ordinaryplan, in-as-much-as the excretion ofhomogentisic acid in place of the ordinaryend products involves a certain slightwaste of potential energy. In this connex-ion it is also interesting to note that, as faras our knowledge goes, an individual iseither frankly alkaptonuric or conforms tothe normal type, that is to say, excretesseveral grammes of homogentisic acid perdiem or none at all. Its appearance intraces, or in gradually increasing or dimin-ishing quantities, has never yet beenobserved, even in the few recorded tempo-rary or intermittent cases. In cases inwhich estimations have been carried outthe daily output has been found to lie with-in limits which, considering the great

influence of proteid food upon the excre-tion of homogentisic acid and allowing fordifferences of sex and age, may bedescribed as narrow. This is well illustrat-ed by Table 1, in which the cases arearranged in order of age:

The information available as to theincidence of alkaptonunria is of greatinterest in connexion with the above viewof its nature. That the peculiarity is in thegreat majority of instances congenital can-not be doubted. The staining property ofthe urine allows of its being readily tracedback to early infancy. This has beenrepeatedly done and in one ofmy cases [5]the staining of the napkins was conspicu-ous 57 hours after the birth of the child.The abnormality is apt to make its appear-ance in two or more brothers and sisterswhose parents are normal and amongwhose forefathers there is no record of itshaving occurred, a peculiar mode of inci-dence which is well known in connexionwith some other conditions. Thus of 32known examples, which were presumablycongenital, no less than 19 have occurredin seven families. One family contained.four alkaptonurics, three others containedthree, and the remaining three two each.The proportion of alkaptonurics to normalmembers is of some interest and Table 2

Garrod: Alkaptonuria 223

Table 2. Showing the proportions of alkaptonuric members to normal members innine families.

Total numberof family Number of Number of(brothers alkaptonuric of normal

No. and sisters) members members Observers

1 14 4 10 Pavy2 4 3 1 Kirk3 7 3 4 Winternitz4 2 1 1 Ewald Stier5 2 2 0 Baumann Embden6 1 1 0 Erich Meyer7 10 1 9 Noccioli and Domenici8 5 2 3 A.E. Garrod9 3 2 1 W. Smith Garrod

Totals 48 19 29

embodies such definite knowledge uponthis point as is at present available regard-ing congenital cases.

The preponderance of males is veryconspicuous. Thus, of the 40 subjectswhose cases have hitherto been recorded29 have been males and only 11 females.

In a paper read before the RoyalMedical and Chirurgical Society in 1901the present writer pointed out that of fourBritish families in which were 11 congen-itally alkaptonuric members no less thanthree were the offspring of marriages offirst cousins who did not themselvesexhibit this anomaly. This fact has suchinteresting bearing upon the etiology ofalkaptonuria that it seemed desirable toobtain further information about as manyas of the other recorded cases and espe-cially of those which were presumablycongenital. My inquiries of a number ofinvestigators who have recorded suchcases met with a most kindly response,and although the number of examplesabout which information could still beobtained proved to be very limited, somevaluable facts previously unknown havebeen brought to light and indications areafforded of points which may be inquiredinto with advantage regarding cases which

may come under observation in the future.In a number of instances the patients havebeen lost sight of, or for various reasonsinformation can no longer be obtainedconcerning them. To those who have triedto help me with regard to such cases, andhave in some instances been at great trou-ble in vain, my hearty thanks are no lessdue than to those who have been able tofurnish fresh information [6].

The following is a brief summary ofthe fresh information collected. Dr. ErichMeyer [7], who mentioned in his paperthat the parents of his patient were related,informs me that as a matter of fact they arefirst cousins. Dr. H. Ogden [8] states hispatient is the seventh of a family of eightmembers and that his parents were firstcousins. The three eldest children died ininfancy; the fifth, a female, has three chil-dren, but neither is she nor are they alkap-tonuric. There is no record of any otherexamples in the family. The patient, whosewife is not a blood relation has three chil-dren none of whom are alkaptonuric.Professor Hammarsten [9] states that theparents of an alkaptonuric man, whosecase he recently described, were firstcousins. The patient, aged 61 years, hasthree brothers and the only brother whose

224 Garrod: Alkaptonuria

Table 3. Showing the large proportion of alkaptonurics who are offspring of mar-riages of first cousins.

A. Families the offspring of marriages of first cousins

Totalof known

Total number alkaptonurcNo. of family members Observers

1 14 4 Pavy2 4 3 R. Kirk3 5 2 A.E. Garrod4 1 1 Erich Meyer5 8 1 H. Ogden6 4 1 Hammersden

Total 36 12

B. Families whose parents were not related and not alkaptonuric.

Totalof known

Total number alkaptonuricNo. of family members Observers

1 3 2 Armstrong, Walter Smith,& Garrod

2 2 1 Ewald Stier3 10 1 Noccioli & Domenici4* ? 2 Marshall & Futcher

Total 6

C. Family in which alkaptonuria was directly inherited from a parent.

Totalof known

Total number alkaptonuricNo. of family members Observers

1* ? 1 Osler & Futcher

Total 1

*B4 and Cl refer to two generations of one family. No information is forthcoming as to theabsence of alkaptonura in previous generations. Ebstein and Mullers case, which is notincluded in the table for reasons given above, would raise the number of families in list B to

urine has been seen is not alkaptonuric. Ihave learned from Professor Noccioli [10]that the parents of the woman whose casehe investigated with Dr. Domenici werenot blood relations. The patient, a twin,who is one of two survivors of a family of

ten states that none of her relations haveexhibited the condition. Dr. Ewald Stier[11] informs me that the parents of hispatient were not related and it is men-tioned in his paper that they were not alka-ptonuric. Professor Ebstein [12] states that

Garrod: Alkaptonuria 225

the parents of the child with "pyrocatech-inuria" whose case was investigated byhim in conjunction with Dr. Muller in1875 were not related, but I gather that hewould not regard this as an ordinary caseof alkaptonuria, the abnormal substance inthe urine having been identified as pyro-catechin. Lastly Professor Osler suppliesthe very interesting information that oftwo sons of the alkaptonuric man previ-ously described by Dr. Futcher [13] one isalkaptonuric. This is the first knowninstance of direct transmission of the pecu-liarity. The parents of the father, who hasan alkaptonuric brother whose case wasrecorded by Marshall, [14] were not bloodrelations. The above particulars areembodied with those of the congenitalBritish cases previously recorded in thefollowing tabular epitome (Table 3).

It will be seen that the results of fur-ther inquiries on the continent of Europeand in America confirm the impressionderived from the British cases that of alka-ptonuric individuals a very large propor-tion are children of first cousins. Theabove table includes 19 cases in all out ofa total of 40 recorded examples of the con-dition, and there is little chance of obtain-ing any further information on the pointuntil fresh cases shall come under obser-vation. It will be noticed that among thefamilies of parents who do not themselvesexhibit the anomaly a proportion corre-sponding to 60 percent are the offspring ofmarriages of first cousins. In order toappreciate how high this proportion is it isnecessary to form some idea of the totalproportion of the children of such unionsto the community at large. Professor G.Darwin, [15] as the outcome of an elabo-rate statistical investigation, arrived at theconclusion that in England some four per-cent of all marriages among the aristocra-cy and gentry are between first cousins;that in the country and smaller towns theproportion is between 2 and 3 percent,whereas in London it is perhaps as low as

1.5 percent. He suggests three percent as aprobable superior limit for the whole pop-ulation. Assuming, although this is, per-haps, not the case, that the same propor-tion of these as of all marriages are fruit-ful, similar percentages will hold good forfamilies, and assuming further that theaverage number of children results fromsuch marriages they will hold good forindividuals also. A very limited number ofobservations which I have made amonghospital patients in London gave resultswhich are quite compatible with the abovefigures. Thus, among 50 patients simulta-neously inmates of St. Bartholomew'sHospital there was one whose parentswere first cousins. On another occasionone such was found among 100 patients,and there was one child of first cousinsamong 100 children admitted to my wardat the Hospital for Sick Children. It is evi-dent on the one hand, that the proportionof alkaptonuric families and individualswho are the offspring of first cousins isremarkably high, and, on the other hand itis equally clear that only a minute propor-tion of the children of such unions arealkaptonuric. Even if such persons areonly 3 percent of the community theirnumbers in London should exceed 50,000,and of this multitude only a few are knownto be alkaptonuric. Doubtless there areothers, but that this peculiarity is extreme-ly rare is hardly open to question. A care-ful look-out maintained for several yearsat two large hospitals has convinced me ofthis, and although the subject has recentlyattracted much more attention than for-merly the roll of recorded examplesincreases but slowly.

The question of the ability of childrenof consanguineous marriages to exhibitcertain abnormalities or to develop certaindiseases has been much discussed, but sel-dom in a strictly scientific spirit. Thosewho have written on the subject have toooften aimed at demonstrating the deleteri-ous results of such unions on the one hand

226 Garrod: Alkaptonuria

or their harmlessness on the other, ques-tions which do not here concern us at all.There is no reason to suppose that mereconsanguinity of parent can originate sucha condition as alkaptonuria in their off-spring, and we must rather seek an expla-nation in some peculiarity of the parents,which may remain latent for generations,but which has the best chance of assertingitself in the offspring of the union of twomembers of a family in which it is trans-mitted. This applies equally to other exam-ples of that peculiar form of hereditywhich has long been a puzzle to investiga-tors of such subjects, which results in theappearance in several collateral membersof a family of a peculiarity which has notbeen manifested at least in recent preced-ing generations.

It has recently been pointed out byBateson [16] that the law of heredity dis-covered by Mendel offers a reasonableaccount of such phenomena. It asserts thatas regards two mutually exclusive charac-ters, one of which tends to be dominantand the other recessive, cross-bred organ-isms will produce germinal cells (gametes)each of which, as regards the characters inquestion, conforms to one or other of thepure ancestral types and is therefore inca-pable of transmitting the opposite charac-ter. When a recessive gamete meets one ofthe dominant type the resulting organism(the zygote) will usually exhibit the domi-nant character, whereas when two reces-sive gametes meet the recessive characterwill necessarily be manifested in thezygote. In the case of a rare recessive char-acteristic we may easily imagine thatmany generations may pass before theunion of two recessive gametes takesplace. The application of this to the case inquestion is further pointed out by Bateson,who, commenting upon the above obser-vations on the incidence of alkaptonuria,writes as follows [17]: "Now there may beother accounts possible, but we note thatthe mating of first cousins gives exactly

the conditions most likely to enable rare,and usually recessive, character to showitself. If the bearer of such gamete matewith individuals not bearing it the charac-ter will hardly ever be seen; but firstcousins will frequently be the bearers ofsimilar gametes, which may in suchunions meet each other and thus lead to themanifestation of the peculiar recessivecharacters in the zygote." Such an expla-nation removes the question altogether outof the range of prejudice, for if it be thetrue account of the matter it is not the mat-ing of first cousins in general but of thosewho came of particular stocks that tends toinduce the development of alkaptonuria inthe offspring. For example, if a man inher-it the tendency on his father's side hisunion with one of his maternal firstcousins will be no more liable to result inalkaptonuric offspring than his marriagewith one who is in no way related to himby blood. On the other hand, if membersof two families who both inherit the strainshould intermarry the liability to alkap-tonuria in the offspring will be as great asfrom the union of two members of eitherfamily, and it is only to be expected thatthe peculiarity will also manifest itself inthe children of parents who are not related.Whether the Mendelian explanation be thetrue one or no there seems to be little roomfor doubt that the peculiarities of the inci-dence of alkaptonuria and of conditionswhich appear in a similar way are bestexplained by supposing that, leaving asideexceptional cases in which the character,usually recessive, assumes dominance, apeculiarity of the gametes of both parentsis necessary for its production.

Hitherto nothing has been recordedabout the children of alkaptonuric parents,and the information supplied by ProfessorOsler and Dr. Ogden on this point hastherefore a very special interest. WhereasProfessor Osler's case shows that the con-dition may be directly inherited from aparent Dr. Ogden's case demonstrates that

Garrod: Alkaptonuria 227

none of the children of such a parent needshare this peculiarity. As the matter nowstands, of five children of two alkap-tonuric fathers whose condition is knownonly one is himself alkaptonuric. It will beinteresting to learn whether this low pro-portion is maintained when larger numbersof cases shall be available. That it will beso is rendered highly probable by theundoubted fact that a very small propor-tion of alkaptonurics are the offspring ofparents either of whom exhibits the anom-aly. It would also be extremely interestingto have further examples of second mar-riages of the parents of alkaptonurics. Inthe case of the family observed by Dr. Kirkthe only child of the second marriage ofthe father, not consanguineous, is a girlwho does not exhibit the abnormality. Theonly other available example is recordedby Embden. The two alkaptonurics studiedby Professor Baumann and himself were abrother and sister born out of wedlock, andas far as could be ascertained the conditionwas not present in the children of the sub-sequent marriages which both parents con-tracted. The patient of Noccioli andDomenici was a twin, and I gather fromProfessor Noccioli's kind letter that theother twin was also a female, did not sur-vive, and was not alkaptonuric. Furtherparticulars are wanting, and the informa-tion was derived from the patient herself,who is described as a woman of limitedintelligence but who was aware that in herown case the condition had existed frominfancy. It is difficult to imagine that oftwins developed from a single ovum oneshould be alkaptonuric and the other nor-mal, but this does not necessarily apply totwins developed from separate ova.

It may be objected to the view thatalkaptonuria in merely an alternative modeof metabolism and not a morbid condition,that in a few instances, not included in theabove tables, it appears not to have beencongenital and continuous but temporaryor intermittent. In some of the cases

referred to the evidence available is notaltogether conclusive and it is obvious thatfor the proof of a point of so much impor-tance to the theory of alkaptonuria nothingcan regarded as wholly satisfactory whichfalls short of a complete demonstration ofthe presence of homogentisic acid in theurine at one time and its absence at anoth-er. The degree and rate of darkening of theurine vary at different periods apart fromany conspicuous fluctuations in the quan-tity of homogentisic acid which it con-tains. The staining of linen in infancy is amuch more reliable indication, especiallyif the mother of the child has had previousexperience of alkaptonuric staining. InGeyger's case [18] of a diabetic man theintermittent appearance in the urine of anacid which he identified with the glyco-suric acid of Marshall was establishedbeyond all doubt, and the melting-pointand proportion of lead in the lead salt ren-der it almost certain that he was dealingwith homogentisic acid. In Carl Hirsch'scase [19] a girl, aged 17 years, with febrilegastro-intestinal catarrh, passed dark urinewhich gave the indican reaction for threedays. Professor Siegfried extracted byshaking with ether an acid which gave thereactions of homogentisic acid and formeda sparingly soluble lead salt. Neither themelting-point of the acid nor any analyti-cal figures are given. After three days theurine resumed its natural colour and reac-tions.

Von Moraczewski [20] also records acase of a woman, aged 43 years, who short-ly before her death passed increasinglydark urine, rich in indican, from which heextracted an acid which had the melting-point and reactions of homogentisic acid.Such increasing darkening of the urine aswas here observed not infrequently occurswith urines rich in indoxyl-sulphate, asBaumann and Brieger first pointed out, andthis was probably a contributory factor inthe production of the colour which firstcalled attention to the condition. Stange

228 Garrod: Alkaptonuria

[21 ] has described a case in which the pres-ence of homogentisic acid was very fullyestablished, but he clearly does not regardthe mother's evidence as to the intermittentcharacter of the condition as conclusive.Zimnicki's case [22] of intermittent excre-tion of homogentisic acid by a man withhypertrophic biliary cirrhosis is publishedin a Russian journal which is inaccessibleto me, and having only seen abstracts of hispaper I am unacquainted with the details.Of hearsay evidence the most convincingis afforded in Winternitz's cases. [23] Themother of seven children, three of whomare alkaptonuric, was convinced thatwhereas two of her children had been alka-ptonuric from the earliest days of life thishad not been so with the youngest child inwhom she had only noticed the peculiarityfrom the age of five years. This is special-ly interesting as supplying a link betweenthe temporary and congenital cases. In asomewhat similar case described byMaguire [24] the evidence of a late onset isnot so conclusive. Slosse's case [25] inwhich, as in von Moraczewski's, the con-dition apparently developed in the laststages of a fatal illness, completes the listof those falling into the temporary class.Evidently we have still much to learn abouttemporary or intermittent alkaptonuria, butit appears reasonable to suppose that thosewho exhibit the phenomenon are in a stateof unstable equilibrium in this respect, andthat they excrete homogentisic acid underthe influence of causes which do not bringabout this result in normal individuals.There is reason to believe that a similarinstability plays a not unimportant part indetermining the incidence of certain formsof disease in which derangements ofmetabolism are the most conspicuous fea-tures. Thus von Noorden, [26] after men-tioning that diabetes occasionally developsat an early age in brothers and sisters andcomparatively seldom occurs in the chil-dren of diabetic parents, adds that in threeinstances he has met with this disease in

the offspring of marriages of first cousins.In one such family two out of six children,in another two out of three, and in the thirdthe only two children became diabetic atages between one and four years.

The view that alkaptonuria is a"'sport" or an alternative mode of metabo-lism will obviously gain considerably inweight if it can be shown that it is not anisolated example of a chemical abnormal-ity, but that there are other conditionswhich may reasonably be placed in thesame category. In the phenomenon ofalbinism we have an abnormality whichmay be looked upon as chemical in itsbasis, being due rather to a failure to pro-duce the pigments of the melanin groupwhich play so conspicuous a part in animalcolouration than to any defect of develop-ment of the parts in which in normal indi-viduals such pigments are laid down.When we study the incidence of albinismin man we find that it shows a strikingresemblance to that of alkaptonuria. It,too, is commoner in males than in females,and tends to occur in brothers and sistersof families in which it has not previouslyappeared, at least in recent generations.Moreover, there is reason to believe thatan undue proportion of albinos are the off-spring of marriages of first cousins.Albinism is mentioned by most authorswho have discussed the effects of such andArcoleo [27], who gives some statistics ofalbinism in Sicily, states that of 24 fami-lies in which there were 62 albino mem-bers five were the offspring of parentsrelated to each other in the second canoni-cal degree. On the other hand, Bemiss [28]found that of 101 children of 34 marriagesof first or second cousins five were albi-nos. In a remarkable instance recorded byDevay [29] two brothers married two sis-ters, their first cousins. There were noknown instances of albinism in their fami-lies, but the two children of the one mar-riage and the five children of the otherwere all albinos. After the death of his wife

Garrod: Alkaptonuria 229

the father of the second family marriedagain and none of the four children of hissecond marriage were albinos. Again,albinism is occasionally directly inheritedfrom a parent, as in one instance quoted byArcoleo, but this appears to be an excep-tional occurrence. The resemblancebetween the modes of incidence of the twoconditions is so striking that it is hardlypossible to doubt that whatever laws con-trol the incidence of the one control that ofthe other also.

A third condition which suggestsitself as being probably another chemical"sport" is cystinuria. Our knowledge of itsincidence is far more incomplete and atfirst sight direct inheritance appears toplay here a more prominent part.However, when more information is forth-coming it may turn out that it is controlledby similar laws. In this connexion a mostinteresting family, described by Pfeiffer[30] is very suggestive. Both parents werenormal, but all their four children, twodaughters and two sons, were cystinuric.The elder daughter had two children nei-ther of whom was cystinuric. A number ofother examples of cystinuria in brothersand sisters are recorded, but informationabout the parents is wanting, except in thecases of direct transmission. In some ofthe earlier cases such transmission throughthree generations was thought to be proba-ble, but the presence of cystin in the urineof parent and child has only been actuallydemonstrated in two instances. In Joel's[31] often-quoted case it was only shownthat the mother's urine contained excess ofneutral sulphur. Pfeiffer [32] found cystinin the urine of a father and son and in afamily observed by Cohn [32] the motherand six of her children shared the peculiar-ity. As more than 100 cases are on recordthe proportion of cases of direct inheri-tance has not hitherto been shown to be atall high and Pfeiffer's first case showsthat, as with alkaptonuria, the children of acystinuric parent may escape. A large

majority of the recorded cystinurics havebeen males. There is as yet no evidence ofany influence of consanguinity of parentsand in only two cases about which I haveinformation the parents were not related.Neither has it yet been shown that cystin-uria is a congenital anomaly, although inone case, at any rate, it has been tracedback to the first year of life. Observationsupon children of cystinuric parents fromtheir earliest infancy or upon newly-bornbrothers or sisters of cystinurics would beof great interest and should in time settlethis question. Lastly, it seems certain that,like alkaptonuria this peculiarity of metab-olism is occasionally temporary or inter-mittent. The so frequent association withcystinuria of the excretion of cadaverineand putrescine adds the difficulty of theproblem of its nature and upon it based theinfective theory of its causation. However,it is possible that, as C.E. Simon [34] hassuggested, these amines may themselvesbe products of abnormal metabolism.Unlike alkaptonuria and albinism, cystin-uria is a distinctly harmful condition, butits ill effects are secondary to its deposi-tion in crystalline form and the readinesswith which it forms concretions. Itsappearance in the urine is not associatedwith any primary morbid symptoms. Allthree conditions above referred to areextremely rare and all tend to advertisetheir presence in conspicuous manners. Analbino cannot escape observation; thestaining of clothing and the colour of theurine of alkaptonurics seldom fail toattract attention, and the calculous troublesand the cystitis to which cystinurics are soliable usually bring them under observa-tion sooner or later. May it not well be thatthere are other such chemical abnormali-ties which are attended by no obviouspeculiarities and which could only berevealed by chemical analysis? If suchexist and are equally rare with the abovethey may well have wholly eluded noticeup till now. A deliberate search for such,

230 Garrod: Alkaptonuria

without some guiding indications, appearsas hopeless an undertaking as the prover-bial search for a needle in a haystack.

If it be, indeed, the case that in alkap-tonuria and the other conditions men-tioned we are dealing with individualitiesof metabolism and not with the results ofmorbid processes the thought naturallypresents itself that these are merelyextreme examples of variations of chemi-cal behaviour which are probably every-where present in minor degree, and just asno two individuals of a species areabsolutely identical in bodily structureneither are their chemical processes car-ried out on exactly the same lines. Suchminor chemical differences will obviouslybe far more subtle than those of form, forwhereas the latter are evident to any care-ful observer the former will only berevealed by elaborate chemical methods,including painstaking comparisons of theintake and output of the organism. Thisview that there is no rigid uniformity ofchemical processes in the individual mem-bers of a species, probable as it is a priori,may also be arrived at by a wholly differ-ent line of argument. There can be noquestion that between the families, generaand species both of the animal and vege-table kingdoms, differences exist both ofchemical composition and metabolicprocesses. The evidences for this areadmirably set forth in a most suggestiveaddress delivered by Professor Huppert[35] in 1895. In it he points out that wefind evidence of chemical specificity ofimportant constituents of the body, such asthe haemoglobins of different animals, aswell as in their secretory and excretoryproducts such as the bile acids and thecynuric acid of the urine of dogs. Again, intheir behaviour to different drugs andinfecting organisms the members of thevarious genera and species manifest pecu-liarities which presumably have a chemi-cal basis, as the more recent researches ofEhrlich tend still further to show. To the

above examples may be added the resultsof F.G. Hopkins's [36] well-knownresearches on the pigments of the pieridaeand the recent observations of theprecipitation of the blood proteids of onekind of animal by the serum of another.From the vegetable kingdom examples ofsuch generic and specific chemical differ-ences might be multiplied to an almostindefinite extent. Nor are instanceswanting of the influence of natural selec-tion upon chemical processes, as forexample, in the production of such protec-tive materials as the sepia of the cuttle-fishand the odorous secretion of the skunk, notto mention the innumerable modificationsof surface pigmentation. If, then, the sev-eral genera and species thus differ in theirchemistry we can hardly imagine thatwithin the species, when once it is estab-lished, a rigid chemical uniformity exists.Such a conception is at variance with allthat is known of the origin of species. Norare direct evidences wanting of such minorchemical diversities as we have supposedto exist within the species. Such slightpeculiarities of metabolism will necessari-ly be hard to trace by methods of directanalysis and will readily be masked by theinfluences of diet and of disease, but theresults of observations on metabolismreveal differences which are apparentlyindependent of such causes, as for exam-ple, in the excretion of uric acid by differ-ent human individuals. The phenomena ofobesity and the various tints of hair, skin,and eyes point in the same direction, and ifwe pass to differences presumably chemi-cal in their basis idiosyncrasies as regardsdrugs and the various degrees of naturalimmunity against infections are only lessmarked in individual human beings and inthe several races of mankind than in dis-tinct genera and species of animals.

If it be a correct inference from theavailable facts that the individuals of aspecies do not conform to an absolutelyrigid standard of metabolism, but differ

Garrod: Alkaptonuria 231

slightly in their chemistry as they do intheir structure, it is no more surprising thatthey should occasionally exhibit conspicu-ous deviations from the specific type ofmetabolism than that we should meet withsuch wide departures from the structuraluniformity of the species as the presenceof supernumerary digits or transposition ofthe viscera.

Chandos-street, W.

NOTES1. Wolkow and Baumann. Zeitschrift furphysiologiche Chemie. Band xv., p.228,1891.

2. Kirk, R. J. Anat. Physiol. 1889, vol xxiii.,p. 69. Huppert: Zeitschrift fur physio-logiche Chemie. Band:412, 1897.

3. Meyer, E. Deutsches Arcive fur KlinischeMedicin, 1891 Band lxx:443.

4. Mittelbach. Ibid., Band lxxi:56.5. Garrod, A.E. The Lancet, Nov 30th 1901.

p. 1484; Transactions of the Royal Medicaland Chirugical Society. Vol. lxxxv:69,1902.

6. To Hofrath Professor Huppert and toProfessor Osler my very special thanks aredue for invaluable aid in collecting infor-mation, and I would also express my mostsincere gratitude to Professor Hammarsten,Geheimrath Professor Ebstein, GeheimrathProfessor Furbringer, GeheimrathProfessor Erb, Professor Noccioli, andProfessor Deniges. Also to Dr. F.W. Pavy,Dr. Kirk, Dr. Maguire, Dr. Futcher, Dr.Erich Meyer, Dr. H. Ogden, Dr. H.Embden, Dr. Mittelbach, Dr. Ewald Steier,Dr. Grassi, Dr. Carl Hirsch, and Dr.Wintemitz, all of whom have been kindenough to help the inquiry in various ways.

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Chemie. Band xx:236, 1895.9. Hammarsten. Upsala Lakareforenings

Forhandlingar Vol. vii:26, 1901.10. Noccioli and Domenici. Gazetta degli

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Sciences Medicales. Bruxelles Tome iv:89,1895.

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35. Hupp. Ueber die Erhaltung derArteigenschafter. Prague, 1896.

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