Archibald E. Garrod

THE INCIDENCE OF ALKAPTONURIA : A STUDY IN CHEMICAL INDIVIDUALITY.

All the more recent work on alkaptonuria has tended to show that the constant feature of that condition is the excretion of homogentisic acid, to the presence of which substance the special properties of alkapton urine, the darkening with alkalies and on exposure to air, the power of staining fabrics deeply, and that of reducing metallic salts, are alike due. In every case which has been fully investigated since Wolkow and Baumann [1] first isolated and described this acid its presence has been demonstrated and re-examination of the material from some of the earlier cases also has led to its detection. The second allied alkapton acid, uroleucic, has hitherto only been found in the cases investigated by Kirk and in them in association with larger amounts of homogentisic acid [2]. By the kindness of Dr. R. Kirk I have recently been enabled to examine fresh specimens of the urines of his patients who have now reached manhood and was able to satisfy myself that at the present time even they are no longer excreting uroleucic acid. After as much of the homogentisic acid as possible had been allowed to separate out as the lead salt the small residue of alkapton acid was converted into the ethyl ester by a method recently described by Erich Meyer [3] and the crystalline product obtained had the melting-point of ethyl homogentisate (1200C). Further observations, and especially those of Mittelbach [4] have also strengthened the belief that the homogentisic acid excreted is derived from tyrosin, but why alkaptonuric individuals pass the benzene ring of their tyrosin unbroken and how and where the peculiar chemical change from tyrosin to homogentisic acid is brought about, remain unsolved problems. There are good reasons for thinking that alkaptonunria is not the manifestation of a disease but is rather of the nature of an alternative course of metabolism, harmless and usually congenital and lifelong. Witness is borne to its harmfflessness by those who have manifested the peculiarity

Concerning Pads upon the Finger Joints and their Clinical Relationships

On 4nother occasion a patient was seen with a small elastic swelling near the head of the right epididymis. It felt like one of the cysts which are so commonly met with in that situation, but it was not translucent. A small trochar and cannula were used to empty the supposititious cyst, butonlya little blood ran out, and the lumen of the trochar was partially blocked with a scrap of soft tissue. This was pronounced by the pathologist to be sarcomatous. The testicle was removed and a small sarcomatous tumour found in the body of the testis close to the head of the epididymis. In conclusion, you will remember when confronted with a young and ambiguous tumour to assume ain attitude of intellectual humility, and carefully eschew diagnostic omniscience and infallibility.

WHERE CHEMISTRY AND MEDICINE MEET

THBRE was a time, not so very long ago, when this country could challenge comparison with any other as regards the number of able and zealous woJkers who weie engaged in the study of the chemical aspects of disease. Those were the days of Prout, of Alexander Marcet, and of Bence Jones, and others whose names occupy distinguished places in the roll of honour of British medicine, and who, following in their footsteps, carried on and extended their work. Of these, the veteran Dr. Pavy is still among us, and hands Qn the tradition to younger generations. Yet it must be admitted, with regret, that of recent years we have tended to fall behind, and to leave to investigators in other lands in which the organization of research has been more developed than with us, the task of unravelling many of the problems which await solution. Our workers in this field are not less zealous than their predecessors, but their numbers are fewer in proportion, and the develop. ment of fresh fields of pathological study has opened out many attractive lines of investigation in other directions. Although the profession at large, in this country, gives an angrudging recognition to the importance of chemical pathology, it prefers for the most part to admire at a distance, and to a medical audience a dis. .course on this subject is not always acceptable. This is in part the fault of the labourers in the field, who have somewhat neglected the task of exposition. It the workers are few, textbooks are still fewer, and the results obtained are seldom discussed in our medical societies. Yet in these days of press activity the omiseion to add largely to the bulk of the writings with which the busy medical man is expected to cope will be regarded leniently as a vice which makes a near approach to virtue. May the scantiness of such writings in our own language serve as an excuse for my incursions into the chemical field, in response to the invitation to address you with which I have been honoured. In few branches of scientific investigation have greater advances been made of recent years than in that which deals with the chemistry of living things, but it is no easy task which he enters upon who sets himself to investigate the metabolic processes at work in the animal organism, and the derangements which these processes undergo in disease. It may be compared with that which confronts a man who wishes to study the manifold activities of great chemical factory which he is forbidden to enter. We is able to examine the raw materials which are brought to the factory, the finished products which emerge from it, and the waste substances which are washed away in the drains, escape from the chimneys, or are thrown upon the dust heap. Upon such examinations, slupplemented by an occasional peep through the windows, he must rely for his information ai to what goes on within. Nevertheless, with no better means at their disposal, chemical physiologists and pathologists have found out much about the chemistry of the human body, and are year by year making fresh incursions into the vast territory of the unknown. All such knowledge is of importanee to us as practical medical men. It enables us to gain clearer ideas of many problems which confront usi, it arms us with new weapons for our fight with disease, and corrects many misconceptions which have been handed down for generations, and which tend to warp our practice. It is of the general beariDgs of this increased knowledge upon our science and art that I propose to speak this afternoon, and I hope to te able to show that no special chem.ical training beyond that which forms an essential part of medical education is necessary for the appreciation of its import, whatever may be the case as regards the more technical details. briefly to the immense advances made in the study of that great group of complex compounds in which all albuminous substances are included. The proteins are the essential constituents of living organisms, and it is upon tbeir properties that the very possibility of life depends. Tbanks to the labours of a body of indefatigable workers, among whom the great German chemist Emil Fisoher stands preeminent, our knowledge of proteins is no longer limited to

Some further Observations on Urinary Hæmatoporphyrin

IN a former comimunication1 it was stated that not only is haematoporphyrin present in small quantities in very many specimens of morbid urine. but also that in the urine of healthy individuals minute traces of this pigment can usually be detected by a method which was there described. A number of additional examinations which I have since made have only tended to confirm these statements, and to convince me that the substance which is present in traces in normal urines is identical with that which occurs in larger amounts under matny pathological conditions. I should however mention that I have found that the washing of the phosphate precipitates obtained by the soda method is apt to remove small quantities of the hbwmatoporphyrin which they contain, and that when searching for minute traces it is best to treat the filtered precipitate with acidulated alcohol, without any preliminary washing. In the present paper I propose to discuss a series of observations and experiments undertaken with the object of ascertaining in what form or forms the pigment exists in the urine as it is excreted. Three different lines of enquiry suggested themselves as likely to throw light upon this question, viz.: 1. The direct spectroscopic examination of urines iich in haematoporphyrin, without the addition of any reagent. 2. The study of the results obtained by the addition to normal urine of hwematoporphyrin in neutral form. 3. The examination of concentrated extracts obtained by shaking specimens of urine with solvents of haematoporphyrin which do not mix with water.

Some further observations on the reaction of urochrome with acetaldehyde.

IN a note which appeared in this Journal in 18971 it was pointed out by the present writer that when acetaldehyde is added to an alcoholic solution of urochrome a dark spectroscopic absorption band gradually appears, and that a substance is formed which, in its spectroscopic and other properties, resembles urobilin as closely as do the products formed by the action of reducing agents upon baematin and bilirubin respectivelv. Further stuidy of this reaction has brought to light some fresh points relating to it which will be discussed in the short paper which follows. 1. The reaction is not due to aldehyde itself Further experience showed that the reaction under consideration is not obtained with all specimens of aldehyde, and fresh samples obtained during the winter months were usually found to be quite inert in this respect. However, such inert specimens were found to become active after being kept for some time, and especially after they had been exposed to bright light and summer temperatures. One was therefore led to infer that the reaction with urochrome was not due to the aldehyde as such, but to some product which is formed in it, by polymerisation or otherwise, under the influence of light and warmth. A parallel at once suggests itself to the Adamkiewicz reaction of proteids, which has been shown by Hopkins and Cole2 to be due to glyoxylic acid formed in the acetic acid employed in the test. Further investigation showed that this supposition was undoubtedly correct. A specimen of aldehyde which had become highly active after being kept, but which when originally obtained had failed to yield any reaction with urochrome, was subjected to fractional distillation. The fradtion which distilled over at 30° C. proved to be quite inactive, wbereas the residue was as active as before, and like results were obtained with