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IN the first fortnight of the War (1939) fundamental research was initiated in the Oxford Department of Biochemistry by Peters and carried out under his direction by a group of workers as an extra-mural research with the support of and for the Chemical Defence Research Department, Ministry of Supply; the object was to find antidotes for vesicants, both arsenical such as lewisite (CH.Cl: CH.As.Cl2) and also those of the mustard gas type. In this brief review, the main facts are given about the discovery of the antidote to lewisite known as BAL, owing to its medical importance; more detailed papers based upon the original reports are being prepared. An attempt is made to include the more relevant work from elsewhere and also to focus the main stages in this discovery, as this may prove useful in planning future work of this type.

1. 1. The hypothesis that fluoroacetate is a competitive inhibitor for acetate in tissue metabolism (Bartlett and Barron) has been examined and found incapable of explaining some of the enzymatic effects of the poison. 2. 2. Using a homogenate from guinea pig kidney, free from residual oxidizable substrates, and reinforced with Mg++ and adenine nucleotides, it was found that this readily oxidizes fumarate and citrate. In presence of fluoroacetate, citrate accumulates during the oxidation of fumarate, without an accompanying accumulation of acetate. 3. 3. With the same homogenate, fumarate and pyruvate together give 20–50% increased oxygen uptake as compared with fumarate alone, and there is even formation of citrate in absence of poison. Fluoroacetate produces inhibition without accumulation of acetate, but this is less than with fumarate alone. 4. 4. Fluoroacetate has no action upon the pyruvate dehydrogenase component of the brain pyruvate oxidase system. It also has no effect upon the activity of the enzymes aconitase, oxalosuccinate decarboxylase, fumarase and oxaloacetate decarboxylase, as tested by a pigeon liver preparation. 5. 5. The fact that no single enzymatic reaction has been found to be inhibited by fluoroacetate 6. and yet that the reactions of the tricarboxylic cycle are stopped with accumulation of citrate requires a hypothesis in addition to that proposed by Barron and Bartlett. 7. 6. It is suggested that, in the kidney preparation, fluoroacetate is not the inhibitor but that it is transformed into another substance which is inhibitory. 8. 7. The accumulation of citrate can be observed with concentrations of 0.05 mM (15 μg Nafluoroacetate per bottle) which approximates to the amounts causing toxic effects in vivo. 9. 8. It was confirmed that malonate inhibits the enzymatic decarboxylation of oxaloacetate. 10. 9. Some experiments upon kidney brei are described.

Otto Meyerhof was born on 12 April 1884 in Berlin and died in Philadelphia on 6 October 1951 at the age of 67; he was the son of Felix Meyerhof, who was born in 1849 at Hildesheim, and Bettina Meyerhof, nee May, born in 1862 in Hamburg; both his father and grandfather had been in business. An elder sister and two younger brothers died long before him. In 1923 he shared the Nobel prize for Physiology (for 1922) with A. V. Hill. He received an Hon. D.C.L. in 1926 from the University of Edinburgh, was a Foreign Member (1937) of the Royal Society of London, an Hon. Member of the Harvey Society and of Sigma XI. In 1944 he was elected a member of the National Academy of Sciences, U.S.A. Otto Meyerhof went through his school life up to the age of 14 without delay, but there is no record that he was then brilliant. When he was 16 he developed some kidney trouble, which caused a long period of rest in bed. This period of seclusion seems to have been responsible for a great mental and artistic development. Reading constantly he matured perceptibly, and in the autumn of 1900 was sent to Egypt on the doctor’s advice for recuperation.

The object of this communication is to prove finally that the nervous symptoms in vitamin B 1 deficiency and the change in oxidative behaviour of pigeon’s brain tissue are intimately related and are entirely independent of loss of weight, or general inanition. Previous work (Gavrilescu and Peters, 1931) had shown that the brains or tissues of birds after complete cure had a normal oxidative behaviour in glucose-phosphate solutions, at a time when no increase in weight had taken place. This left little escape from the conclusion that the symptoms were not due to the inanition. Nevertheless, the point was felt to be so important that further proof was desirable, with even more rigorous control. An opportunity for this was presented by the recent discovery (Gavrilescu, Meiklejohn, Passmore and Peters, 1932) of the essential importance of lactate rather than glucose, and of the large in vitro effect of vitamin B 1 concentrates. Accordingly, we have followed the oxygen uptakes in lactate solutions of the brains of pigeons which have been cured of opis-thotonus symptoms by dosing with vitamin B 1 concentrates. A marked increase in the oxygen uptake has been found corresponding with the disappearance of the nervous symptoms, and the restoration is accompanied by a decrease in the effect of the concentrates in vitro . Methods .—These have been as previously described, and the figures quoted in the tables are calculated from the oxygen uptakes at 38° C. of 50-100 mg. of the minced brain tissue, suspended in 3⋅0 c. c. lactate-phosphate solution. The vitamin B 1 concentrate had an activity for the bird of approximately 0⋅05 mg., and the same concentrate was used throughout, both to cure and in the bottles in vitro . The vitamin B 1 concentrates have been given both orally and intramuscularly; symptoms usually disappear within 3 hours in the former case, and 1 hour in the latter. No food was given after dosing, and the amounts of water in the case of the lightly cured birds has been limited to 5-15 c. c. The lactate used for these experiments was made as before from zinc lactate and put up in sterile tubes in amount sufficient for each experiment, the tubes being sterilised by heating on three successive days and thereafter kept in cold store.

Evidence has been produced by several workers tending to support the view that vitamin B 1 possesses an ultra-violet absorption band with a maximum at about 260 mμ. Bowden and snow (1932) stated that the preparation studied by them possessed such a band, which disappeared simultaneously with the vitamin activity on irradiation with monochromatic light of wave-length 25 mμ. The absorption curve published by Windaus et al . (1931) for their preparations also showed a maximum near 260 mμ. Heyroth and Loufbarrow (1932) have studied a large number of preparations of varying vitamin activity, and have shown that much of their ultra-violet absorption can be attributed to inactive purine and pyrimidine derivatives. Nevertheless, they conclude that there is a significant correlation between absorption at 260 mμ and biological activity (see also Ohdake, 1932). It is therefore somewhat surprising that the preparations recently made at Oxford (Kinnersley, O'Brien and Peters (1932-1933), which can claim to be the most potent yet produced, have their maximum absorption at a definitely different wave-length, namely 245-9 muμ, while at 260 mμ their absorption curves only show a barely perceptible hump, protruding from the steeply descending portion of the main band. An attempt to connect this discrepancy with a possible effect of hydrion concentration on the wave-length of the maximum led to the discovery of a curious phenomenon.

THE problem of the specificity of the pyruvate oxidation system in pigeon's brain tissue has been studied more fully by us, not only in the hope that it would throw fresh light upon the path of complete oxidation of pyruvic acid, but also in the belief that knowledge of the behaviour of other simple oc-ketoacids would contribute further to the elucidation of the metabolism of some of the oxidation products of the ac-amino-acids. In particular it was hoped that some definite indication would be obtained as to whether the three reactions found to account quantitatively for the aerobic oxidation of pyruvic acid [Long, 1938] were entirely separate or were interrelated. This objective, we think, has been realized. We have now obtained evidence that the rate of oxidation (p mol./hr.) is the same for pyruvic acid and ac-ketobutyric acid; but whereas the latter gives as end-product C02 and presumably the next lower fatty acid, a change requiring 1°O per mol., part of the pyruvic acid disappearing is much more fully oxidized. This suggests that there is a common path for the initial stage in the oxidation, intermediate compounds of similar type being formed from pyruvic and oc-ketobutyric acids, the sole difference being that in the case of pyruvic acid a further system intervenes capable of oxidizing this unstable intermediate to C02 and water. The intermediate formed from oc-ketobutyric acid can only break down without 0° uptake to C02 and, by analogy, propionic acid. Hence the scheme for pyruvic acid oxidation suggested by Long [1938]

Recent work has defined a lowered power of oxygen uptake in certain parts of the pigeon’s brain in glucose-phosphate Ringer (Gavrilescu and Peters, 1931). The partial restoration of oxygen uptake which takes place upon addition of small amounts of vitamin B 1 concentrates, excluded lowered substrates alone as the cause of the effect. This could have been excluded upon other grounds, as several observers (Loebel, 1925; Meyerhof and Lohmann, 1926) have shown that lactate will prolong the oxygen uptake of brain tissue, and it is known that the avitaminous brain has more lactate than the normal. Since therefore the abnormality is concerned with the enzyme systems, it remains to be shown whether the effect is general, as would be expected from much of the previous literature upon the subject (see references in previous papers), or whether it is confined to an enzyme system for special substrates. In the latter case the vitamin would be concerned with one substrate and hence one phase of metabolism; in the former it would perhaps form part of the respiratory enzyme system (Warburg, 1928; Keilin, 1929). Holmes (1930) and Krebs (1931) have given reasons for the belief that glucose oxidation in brain proceeds via lactic acid, as the metabolism is disconnected between glucose-lactate stages in presence of fluoride or iodoacetic acid. A lesion affecting the intermediary metabolism is disconnected between the glucose-lactate stages in presence of fluoride or iodoacetic acid. A lesion affecting the intermediary metabolism of carbohydrate might be confined to glucose and lactate and not found with succinate (Quastel and Wheatley, 1931). Since the matter seemed crucial, we have compared the oxygen uptakes of normal and avitaminous brains in the presence of these three substrates, succinate being regarded as typical of another system. Since cyanide inhibits the uptake of oxygen for all three substrates, any difference in their behaviour in avitaminosis indicates that the vitamin acts specifically and not upon the indophenol oxidase. Our results show that a tissue may behave normally to succinate and yet abnormally to lactate, and are therefore consistent with the view that vitamin B 1 deficiency is connected essentially with the intermediary metabolism of carbohydrate.

It is hardly necessary for me to refer to my appreciation of the great honour conferred in asking me to give this lecture. It might be thought that the title is more suited to a detective novel and that it was somewhat frivolous for the occasion! Curiously enough I hope that some of the points with which I shall deal to-day will make the path of would-be poisoners somewhat more thorny; and in a way there has been a little of the detective atmosphere about the research. My main theme is the biochemistry and physiology of the poison fluoroacetic acid; this is, as I think, the first instance of ‘lethal synthesis’ in the sense that fluoroacetic acid becomes lethal only when it has been transformed by the action of the tissue enzymes. It is the biochemistry which makes it lethal, the poison being a biochemical product of the tissue which is poisoned.

John Beresford Leathes who died at Montreux on 14 September 1956, in his 92nd year, was born on 5 November 1864. He was the second son of the Reverend Stanley Leathes, D.D., a Professor of Hebrew at King’s College, London, and Prebendary of St Paul s. His mother was Matilda Butt, who counted among her ancestors a Dr Butt, a physician to Henry VIII. His brother was Sir Stanley Leathes, K.C.B. He married Sonia Marie Natanson in 1896 in London, a Russian by birth, and a fine pianist. They had one daughter Margaret, who married Lionel Penrose, M.D., F.R.S., Professor of Genetics at University College, London. Leathes was educated at Winchester College, being a classical scholar from 1878 to 1883. While there, he had, as Prefect of Hall, to deliver the speech on the occasion of the visit of Mr Gladstone. This was in Latin and Mr Gladstone replied in English. Leathes was also Captain of the Winchester College football fifteen in 1883. His interest in classics was lifelong, and gave him pleasure in his retirement. It is said that on one occasion, he surprised Sheffield University Classical Association with a learned and delightful paper on Greek poetry. At Winchester, it is recorded that there were no science laboratories when he started his education, and evidently he had little teaching in science there.

In his autobiography entitled From Kansas farm boy to scientist , Elmer McCollum gives a vivid description of his early life on a farm near Fort Scott in the State of Kansas. His forebears, of Scottish origin, had emigrated to the United States in 1763 and all had been farmers. His own parents were people of little education, who by dint of hard work and frugal living had become prosperous by local standards and had built a ‘frame house’ in which Elmer was born in 1879, the fourth child and the elder of two sons. Owing to his father’s ill-health, he was put to all types of farm work from an early age. It was a mixed farm with cows, pigs and poultry, as well as crops. By the age of eleven he was experienced in the planting and harrowing of crops as well as in the care of farm animals, which remained an asset in his later life when many of his researches were concerned with their nutrition.

The object of this communication is to extend our knowledge of the relation between the interfacial tension of long chain carbon compounds dissolved in benzene and the hydrogen-ion concentration of the aqueous phase with which they may be placed in contact. To this extent, it forms an extension of earlier work by Hartridge and Peters. The stimulus of the work was in large part the desire to throw light upon the question of ionisable interfaces in the living cell. Historical . It is well known in a general way that the Hydrion concentration (C H ) of the aqueous phase influences the interfacial tension between solutions of a fatty substance dissolved in a lipoid solvent and an aqueous solution, and that the fall in interfacial tension which takes place with increasing alkalinity is produced by the presence of soap. The first experimental indication that there was a direct relation between (C H ) and the interfacial tension (I. T.) of such a system appears to have been given by Reinders. This relation, highly significant so far as biochemical processes are concerned, seems to have attracted little attention. Though it is mentioned by Freundlich, interest has been concerned in the main with emulsification. In 1920-22, Hartridge and Peters found a direct relation between p H and interfacial tension in the system olive oil in benzene-aqueous buffered solution. A fall in I. T. commenced to the alkaline side of p H 4.5, which started rather abruptly and appeared to pursue an almost straight line to p H 9•0, the degree of fall being independent of the buffer used. The drop weight method was used for most of the experiments, but was checked against a ripple method. In accordance with expectation, with a series of pure substances, the only ones showing a change of I. T. were those containing a —COOH group, but a change also appeared with —COOH combined in a triglyceride. The relation was not quite simple, because the strength of the buffer solution influenced the results. Below a certain concentration of phosphate for instance, 0•005 M. in the case of a buffered solution of p H 7.6, no lowering of I. T. took place. In explanation it was suggested that the effects only appeared when sufficient alkali was present to form alkali salts of the fatty acids at the interface.