I 1 Medical Journal December 1942

the development of materia medica IN EDINBURGH

Inaugural Address

By J. H. GADDUM Professor of Materia Medica and Pharmacology A great honour was conferred on me when I was in occupy the Chair of Materia Medica and Pharmao?l?gy> has a very distinguished history. I propose to begin my by an giving you account of my predecessors. The first lectures on Materia Mediea in Edinburgh were given bY Dr Charles Alston (1683-1761), the professor of Botany. in "Was, fact, the first professor of Botany to give sys ^ctures in that subject. He was appointed to the chair inen^ 73 at the age of fifty-five, and until he was seventy-seven he gave; w courses ica. of lectures each year on Botany and Materia e Materia Medica was a large subject in those days. u attending Dr Alston's lectures had to learn the proper les characters of about 60 minerals, 85 different roots, 13 ar w?ods, 86 flowers and leaves, 40 fruits, 40 seeds, an 5? g ' resins and balsams, besides the parts of animals sue and worms and vipers and other less attractive su s an might be used as ingredients of medicines Mate" Unlike eco most other branches of knowledge, has smaner ? it has advanced. There is a notebook, bebng.ngonmng to apparency one of Dr Alston's students, in the museum in Materia Medica. -p. T un His lectures were published by his successor, Hope who was o o tany and ^ 725-1786), appointed professor . th Materia Medica in 1761. He was responsible or Manic rom e garden, where he grew his herbs, here a on ^ the Waverley Station now is, to site Vol. XLIX. NO. 12 J. H. Gaddum

Walk, and for arranging the plants on the Linnaean system, which had been too new-fangled for Dr Alston. In 1768 the chair of Materia Medica was separated from that of Botany, and Dr Francis Home (1719-1813) was appointed the first professor of Materia Medica. He was a very interesting and original person. At the age of twenty-three, though he was not yet qualified as a doctor, he went out to Flanders as surgeon to the 6th Inniskilling Dragoons, and he served with them for six years (1742-1748). In the Regimental Orders which he drew up he says : "... The Dragoons . . . shall drink no water without it be first boiled, and a little brandy or gin be mixt with it." Some of this advice was certainly good. On his return to Edinburgh he soon became qualified, and his M.D. thesis was based on his experience of malaria in Flanders. He became a great clinician and president of the Royal College of Physicians, but he was also a chemist. He was awarded ? 100 for showing that it was better to use dilute sulphuric acid than sour milk in bleaching linen. He wrote a book on the Principles of Agriculture, which was a pioneer attempt to introduce chemistry to the assistance of farmers. In this book, which had several editions, and was translated into French and German, he showed for the first time that there is nutrient matter for plants in air. He discovered that measles could be transmitted from one person to another by soaking blood in cotton-wool and 1 it in an placing incision in the arm of the other person. He was first to the show that the sugar in diabetic urine was fermented by yeast. He wrote a famous treatise on medicine in Latin and a book on Materia Medica, which is really only a list of drugs for his students. Dr Francis Home occupied the chair of Materia Medica for and was thirty years, succeeded in 1798 by his son, James Home (1760-1844), who became "the most popular and approved teacher of Materia Medica in these islands." During his time of the number students in the class rose from 50 to 310 although his lectures were given at eight o'clock in the morning. This was a great achievement; in those days the income of the professor depended upon the number of students. He was the only professor of Materia Medica in Edinburgh who has ever left the chair for another appointment. Andrew Duncan (Junior) (1773-1832) was the next professor- As a young man he had travelled very widely in Europe, and had been much impressed by the importance of Medical Juris- 722 Development of Materia Medica in Edinburgh prudence. When he came to Edinburgh he instigated his famous father to recommend the formation of a chair in this subject, which later became Forensic Medicine, and he himsel was appointed the first professor in 1807. In 1821 he applied or t e chair chair of the Practice of Medicine, or alternatively for the of two Materia Medica. His application was supported by fifty testimonials, followed by thirty-three more ten days later. T ese n o came from such distinguished people as the Archduke Jo Austria, Prince Augustus of Schleswig-Holstein Oldenburg , and Prince George of Holstein Oldenburgh, as well as from we es known doctors all over the world, including Stokes and o ?f Dublin, Magendie and Orfila of , Thomas Young o , and others from Germany, Russia, Poland, Denmar , Portugal, Italy and America. James Home was appointe Professor of Medicine, and Andrew Duncan was appointed professor of Materia Medica without opposition. His most important contribution to knowledge was t e preparation of the Edinburgh New Dispensatory. In 1754? Dr was Lewis of London had written a New Dispensatory which a commentary on the London and Edinburgh Pharmacopoeias with a complete transcription of their contents. Many editions of this valuable work were published, and after the death of Dr Lewis it was replaced by the Edinburgh New Dispensatory, and Professor Duncan was responsible for many editions of it between 1803 and 1830. The twelfth edition, published in 1830, has a over 1000 pages. It is complete textbook of all branches ?f Materia Medica, including pharmacy, pharmacognosy and therapeutics. It contains detailed discussions of the important chemical work which was done at that time, when most of the o more important alkaloids were isolated. The preparation this time. He was massive book took up a large proportion of his n?t content to record the results of others, but did c emica t a experiments himself to settle doubtful points. He showe in a co o cinchona contained a substance which was soluble and precipitated by tannin, and he christened this moresu^stance e ai e cinchonine. His work was overshadowed by the later. analyses of Pelletier and Caventou in Paris seventeen years 1 ? The next professor was Sir Robert Christison 0 797 in I ^hen he was appointed, at the age of thirty-five 32> for tenl already been professor of Medical Jurisprudence years, distinctio and he occupied the chair of Materia Medica with great of his honours the next forty-five years. The list occupies 723 J. H. Gaddum

two full pages in his biography. He was president of the Royal Society of Edinburgh and twice president of the College of Physicians. He was tall and energetic and could still climb Arthur's Seat from the University in twenty-two minutes when he was fifty. His method of learning to read German was characteristic. He spent an entire day studying a good German grammar. The next day he started to read Schiller's book on the Thirty Years' War with the help of a dictionary. In fourteen he was days able to read ten pages in an hour, and he then started to apply his new acquisition to its object, which was the study of German books on . He wrote a large book on poisons himself and a large book on Materia Medica founded on the Dispensatory of his predecessor, but greatly enriched with new observations, many of them his own. Inspired by the work of Orfila in Paris, he decided, when he was appointed professor of Medical Jurisprudence, to specialise in Toxicology. His usual method of experimentation was to administer a large dose of poison to an animal and to record the symptoms before death and the appearance of the organs after death. His most important early work was a study of the effects of poisoning by oxalic acid, in which he showed that high con- centrations caused corrosion of the stomach and shock, and that lower concentrations were absorbed and caused direct effects on the heart and central nervous system, which were depressed. He showed that it was impossible to detect the poison in the blood. These effects are interpreted nowadays in terms of the precipitation of calcium in the body. By such experiments he did much to revive the subject of Medical Jurisprudence, which was thought by some not to have justified its existence. He acquired a great reputation as a medical witness in the courts of law, where he gave a precise and accurate account of his investi- gations and of the conclusions which could be drawn from them. H is work as professor of Materia Medica was the natural outcome of this toxicological work. He studied the toxic effects of hemlock, and its active principle coniine, and showed that they were due to depression of the central nervous system and that life could be prolonged by artificial respiration. He under- took an investigation of the effects of the ordeal beans from Old Calabar in West Africa, and came to the conclusion that death was due in some cases to depression of the heart, and in others to depression of voluntary muscles. He supplemented these experiments by taking some himself, and might have killed 724 Development of Materia Medica in Edinburgh

himself but for the timely use of an emetic. This poison has had a peculiar fascination for workers in Edinburgh, where all the important facts about it have been discovered. an of In his seventy-eighth year he undertook investigation the effects of cocaine on fatigue. In these experiments he repeatedly walked 15 miles at 4 miles an hour, and twice climbed " 2900 feet on Ben Voirlich. He concluded that : The chewing of cuca removes extreme fatigue, and prevents it. Hunger and thirst are suspended ; but eventually appetite and digestion are unaffected. ... I do not yet know its effect on mental fatigue purely. As to the several functions, it reduces the effect of severe protracted exercise in accelerating the pulse. It does not diminish perspiration, so far as I can judge. It probably lessens the hourly secretion of urine solids." These examples of Sir Robert Christison's work must suffice to give an idea of his methods. He was also very active in other fields than Materia Medica, and particularly in chemistry. He did much to improve methods for detecting poisons in the body after death. He was a leading authority on pharmacy and chairman of the committee of the General Medical Council which prepared the first edition of the British Pharmacopoeia (1864). Besides all these things he was greatly loved and greatly respected by the whole , and became the acknowledged ? head of the medical profession in . The next professor was Sir Thomas Fraser (1841-1920), who Was elected in 1877 at the age of thirty-six, and occupied the chair for forty-one years. His formal application as a candidate for the chair is a very impressive document. His testimonials give no evidence of acquaintance with royalty like those of ' Andrew Duncan, but he was supported by a very large number ?f physiologists and pharmacologists whose names are remembered all over the world to-day, including Sharpey, Burdon Sanderson, Ringer, Lauder Brunton, Gamgee, Paul Bert, Vulpian, Liebreich, Boehm, Buchheim, Nothnagel, Carl Ludwig and Schmiedeberg. Eraser had worked as Sir Robert Christison's assistant at a time ) when the atmosphere in Edinburgh must have been particularly his fame inspiring, and the greater part of the work on which was rests was done in these early years. His greatness widely the first recognised ; Liebreich, who had himself introduced in hypnotic, chloral, and was professor of Materia Medica Berlin, of modern Said that Fraser's influence on the development Pharmacology was to be reckoned as epoch-making. B2 vol. xlix. no. 12 725 3 J. H. Gaddum

His graduation thesis (1863) was devoted to the actions of the Calabar bean, which had been studied by Sir Robert Christison eight years before. Fraser analysed the actions on the different parts of the body in detail. He showed that extracts caused constriction of the pupil when applied to the surface of the eye, and this observation aroused great interest and led to the introduction of this drug in medicine. He also studied its effects on the central nervous system, and showed that it also had peripheral effects on the heart, the glands, the voluntary muscles and the intestine, and reached conclusions which are still thought true to-day. He purified the poisonous alkaloid from Calabar bean and called it eserine after the native name of the plant, but he was anticipated in the publication of this result by Jobst and Hesse, who called the alkaloid after the Latin name of the plant. Posterity would have given Fraser much more credit for his work on the pharmacology of this poison if he had used the alkaloid instead of extracts for his experiments. Harnack and Witkowski, who did use the alkaloid in 1876, are quoted more frequently to-day. He published a detailed analysis of the antagonism between Calabar bean and atropine by injecting them both in rabbits at different time intervals, and expressed his results in most interesting diagrams in three dimensions expressing the con- centrations of the two drugs and the time intervals. He thus showed that atropine only acted as an antidote over a limited range of doses since it only counteracted some of the actions of the bean. In some respects the effects of the two drugs were additive. This was a paper of fundamental interest, but it was before its time. It was a contribution to a branch of pharmacology whose existence was scarcely known until Professor A. J. Clark wrote a book about it sixty years later. His most important work was an investigation with Crum Brown, the professor of Chemistry, of the relation between chemical structure and pharmacological action. They showed that when various alkaloids, including strychnine, brucine, the- baine, codeine, morphine and atropine, were converted into quaternary bases, by the introduction of a methyl group attached to nitrogen, they acquired an action like that of curare, paralysing the transmission of impulses from motor nerves to voluntary muscles. This change was sometimes, though not always, accompanied by a loss of the typical pharmacological actions of the alkaloid itself. This paper was the forerunner of the 726 Development of Materia Medica in Edinburgh

collaboration between organic chemists and pharmacologists all over the world, which has done so much to transform the whole face of therapeutics. There have been few such generalisations as that which Crum Brown and Fraser made, but the cumulative effect of their example has been immense. When Fraser lectured before the Royal College of Physicians in Edinburgh on this to subject in 1872, he was at pains to prove that it was possible modify the effects produced by drugs by altering their chemical constitution. This conclusion seems obvious enough to-day, largely because of the immense mass of work which has been founded upon it. All the investigations which I have described so far were carried out in Edinburgh before their author was thirty-three. for Mid- He then spent three years as medical officer of health Cheshire. After his appointment to the chair in Edinburgh, he followed up some earlier work which he had done on the action of strophanthus, a plant first brought to his notice in connection "with its use in Africa as an arrow poison. In this earlier work he had confirmed, by means of experiments on animals, the view that strophanthus acted like digitalis. When he became professor ?f Materia Medica, with charge of beds in the Infirmary, he showed that strophanthus could be used clinically in the same way as digitalis, and that it was less liable to cause cumulative effects. He also isolated the active principle, strophanthin, and showed that it was a glycoside, and that it could be used by Ejection. In later years he extended his investigations to other arrow poisons, and also to snake poisons and their neutralisation by serum, but his time was much occupied with activities outside the was a laboratory. He was a brilliant diagnostician ; he medical successful and inspiring teacher ; he was dean of the school and president of the College of Physicians of Edinburgh, and he served on the General Medical Council and on Government in Commissions on plague and scurvy. He was knighted 1902. chair A. R. Cushny (1866-1926), who succeeded Fraser in the ?f " established Materia Medica at the age of fifty-two, had already Britain. He himself as the leading authority on his subject in so that was a son of the manse and had graduated in Aberdeen, he not in was the first occupant of the chair who had graduated to Edinburgh. He had worked as a young man (twenty-four twenty-seven) under Schmiedeberg of Strassburg, who was then the and he had outstanding figure of pharmacology in Europe, in Ann then succeeded J. J. Abel as professor of Pharmacology 727 J. H. Gaddum

Arbor, Michigan (1893). He had worked there for twelve years,, and had then been appointed to the new chair at University College, London (1905-1918). Meanwhile the science of Materia Medica had developed. We have seen that it started as a branch of botany, at a time when all the more important medicines were made from plants and the doctor was himself responsible for making sure that the right plants were used. The importance of this part of medical training has steadily diminished. Chemistry, on the other hand, has always played an important part in the work of the department, and the professors have not only collaborated closely with professional chemists, but have many of them made chemical discoveries themselves. Some of the examples already discussed of the work of Sir Thomas Fraser illustrate the fruits of a new alliance, between materia medica and physiology, which gave birth to the science of pharmacology. Professor Cushny had played an important part in this development. It is impossible to discuss all the many things which he did. His main interests centred round three fields of work : digitalis, the secretion of urine, and the pharmacological effects of optical isomers. On each of these he wrote a masterly monograph. In collaboration with Edmunds in America, he had shown that the clinical condition which had been known to the learned as pulsus irregularis perpetuus was identical with a condition which could be produced in animals by electrical stimulation of the auricles, and for which Cushny proposed the name of auricular fibrillation. He had analysed the action of digitalis on the hearts of animals in great detail, and was able to explain its therapeutic action in auricular fibrillation. His work on the secretion of the urine was directed to the elucidation of its physiology as well as to the action of drugs upon it. His work on optical isomers brought the first clear proof that one optical isomer may be much more potent than the other optical isomer of the same drug. He was always an enthusiastic preacher of the value of the application of physiological methods to the problems of thera- peutics, and in 1899 he brought out the first edition of his great " textbook which was the first severely critical, rigorously scientific and hence really authoritative general textbook to be written in English by an experimental pharmacologist." In this book and 728 Development of Materia Medica in Edinburgh

Jn many other ways he played a great part in spreading the new knowledge of the action of drugs based on exact physiological experiments. He set new standards of evidence and purged Materia medica of a large part of the residues inherited from the Middle Ages. While he held the chair there was great competition among young men from all over the world for the privilege of Working in his department. The successful use of the technique of modern physiology depends upon specialised training and specialised equipment, and it was no longer possible for anyone to work at it with optimal efficiency if he was also responsible for the care of the sick. Fraser's work on pharmacology had undoubtedly suffered r?m the fact that much of his time as professor was devoted to Work in the wards. When Cushny was appointed professor of Materia Medica the work was therefore divided, and the Christison chair of Therapeutics was founded so as to maintain the liaison etween the laboratory work on pharmacology and the practical evelopment of therapeutics. The chair of Chemistry in relation to Medicine was founded at the same time. It was as if a Physician and a chemist had married into the family of Materia edica and had set up separate establishments next door. The success of this method of teaching is attested by the success of the textbook by Professor Clark called Applied tarmacology. The success of this method of research is attested by the spectacular progress of therapeutics in recent Years. In earlier times this progress depended upon crude Undirected trial and error, and since the number of possible treatments is legion, there was a very large amount of trial and a \ery large amount of error. Convincing proof of the value of a new therapeutic agent involves much labour, and it is therefore Particularly important that experiments in therapeutics should not be directed along unprofitable lines. Pharmacology cannot Predict the results of experiments in therapeutics with certainty, ut and it can put new weapons in the hands of the therapeutist, c^n about tell him a great deal about their potential uses and heir potential dangers. The supply of these new weapons is at of Present good and the therapeutists are kept busy. Methods There treating bacterial infections are arousing much interest. ls allied doubtless much more to be discovered about substances *? with similar sulphanilamide, and other groups of substances actions are likely to be available before long. There are many new vitamins and hormones and other drugs of various types. 729 J. H. Gaddum

Some of these will be of value and some will not. It takes many years to work out all the ways of using a new therapeutic tool, and when these ways are found, they are often quite different from what most people expect. It was not immediately obvious, for example, when cestrogens became available, that they could be used for treating vaginal infections in young children. The use of quinidine in auricular fibrillation was only discovered by the accident that some one had both malaria and auricular fibrillation and was unexpectedly cured of both diseases by the drug that was only meant to cure malaria. These examples illustrate the fact that the effects of the stimulus to progress in therapeutics which comes from the possession of new tools are not confined to the applications which are immediately obvious, but may reach very far. The laboratories have been a very fertile source of new tools, and this brings me back to the progress of fundamental research in materia medica. Professor A. J. Clark (1885-1941), who succeeded Cushny in 1926, was an Englishman and a graduate of Cambridge. He had been Cushny's pupil and successor at University College, London, with an interval which had been filled by service in France in the first World War and a short period as professor of Pharmacology in Cape Town. There is no need for me to tell you, who knew him better than that was a I, he great man and a very lovable man. He became the leading pharmacologist in these islands, and his greatest work was done after he came to Edinburgh. He had always been interested in collecting and systematising all the evidence that was " accumulating on the mode of action of drugs on cells," and he published the results of these labours in a book with that title in 1933, and in another book called General Pharmacology, which appeared in 1937- This was something which none of his predecessors in Edinburgh could have done. It was an advance when Christison studied the mode of action of drugs on animals, and another advance when Fraser studied their mode of action on organs ; the study of the action on cells is at once more difficult and more likely to lead to big discoveries. It only became possible because of the developments which were taking place in other sciences. We have seen how materia medica has formed alliances from time to time with botany, with chemistry, and with physiology. In Professor Clark's day materia medica was flirting with nearly all the sciences at once and with other branches of knowledge, such as mathematics, as well. 73? Development of Materia Medica in Edinburgh

A branch of science comes of age when it becomes quantitative, and Clark was particularly interested in the light thrown by- quantitative measurements on the fundamental problems of pharmacology. He collected numberless examples of measure- ments of the relation between the dose of a drug and the time it required to act, on the relation between dose and effect, on individual variation in the response to drugs, on the rates of absorption, excretion and destruction of drugs and other such quantities. He showed that much of the discussion of such data was valueless, and proposed general methods of dealing with data of the various types. Fundamental thinking of this kind is only likely to bear fruits after many years, and although the importance of this work is generally recognised and although Jt has already influenced pharmacological thought in many Ways, its full practical results cannot yet be foreseen. Professor Clark also did great service to the community by his campaign against secret remedies, which has already had Practical results in the form of new legislation. The progress of modern pharmacology can conveniently be illustrated by continuing the story of the Calabar bean. The Work of Fraser was followed by work all over the world confirming his results, filling in details and adding new facts. Eserine was found to increase the excitability of cholinergic nerve endings, which are so called because they act by liberating acetylcholine. It was shown that, in the presence of eserine, these nerves appeared to liberate more acetylcholine than in its absence, and that this was because the acetylcholine was normally destroyed by an enzyme, and that this enzyme was inhibited by eserine. The enzyme was also shown to destroy other choline esters besides acetylcholine, and is known as cholinesterase. Meanwhile the department of Medical Chemistry in Edinburgh had been carrying out a comprehensive investigation of the chemistry of eserine. Dr Stedman, working at first with Professor larger and later with Mrs Stedman and others, discovered the chemical constitution of eserine, found that its activity depended on the fact that it was a methylcarbamic ester, and synthesised a large number of other such esters, which were f?und to have pharmacological actions similar to those of eserine. Stedman drew attention to the significance of the fact that the niethylcarbamic esters were inhibiting an enzyme that destroyed was to the fact that choline esters, and suggested that this due as the they combined with the enzyme in the same way choline 7 3i J. H. Gaddum esters and so occupied the places in the enzyme which would otherwise have been actively destroying acetylcholine. The action of eserine was, in fact, due to what is known as substrate competition. This theory was confirmed by careful quantitative studies of the interaction of the enzyme, the inhibitors and the substrate in vitro. Meanwhile the analysis of the pharmacological actions of eserine or physostigmine had been proceeding along other lines. It was shown that the twitching of voluntary muscle which eserine causes could be abolished by curare, and it was shown that, when a muscle had been paralysed with curare, it could be revived with eserine (1900). This led Dr Mary Walker, thirty-four years later, to try the effect of eserine in the treatment of myasthenia gravis, which is a disease in which the patient behaves as if he has been poisoned by curare. It produced a dramatic, though temporary, abatement of the symptoms. This observation was immediately confirmed and accepted ; it accorded well with the results of fundamental researches which had then just showed that acetylcholine was liberated at the nerve endings of motor nerves in voluntary muscle. It was obvious that the action of physostigmine was due to the preservation of this acetylcholine from the enzyme cholinesterase, though it is still undecided whether the fundamental fault in myasthenia gravis is a small production of acetylcholine, a local excess of enzyme, or a poison acting like curare. It was soon shown that prostigmine acted better than physostigmine. This advance was a result of the work of the department of Medical Chemistry on the structure of physostigmine and its analogues. This work by Dr Stedman on eserine was the first important " " application of the concept of substrate competition or " " competitive inhibition in pharmacology ; there is evidence that this theory is likely to be a very fruitful one. It is probable that, just as the action of eserine is due to the preservation of acetylcholine, so the action of ephedrine is due to the preservation of adrenaline in the tissues. The action of sulphanilamide is also probably due to the same mechanism. This drug appears to inhibit the growth of bacteria by combining with an enzyme which plays an essential part in the utilisation of para-aminobenzoic acid by the bacteria. This substance appears to be an essential metabolite for them, and they cannot use it when the enzyme is saturated with sulphanilamide. This discovery is likely to lead to the introduction of new drugs, since there are many 7 32 Development of Materia Medica in Edinburgh substances, besides para-aminobenzoic acid, which are essential for these bacterial growth ; and substances which resemble other essential metabolites in their chemical structure in such a way that they combine with the appropriate enzymes, have been found to inhibit growth in the same way as sulphanilamide. This Work by D. D. Woods, H. Mcllwain and others working under Dr P. Fildes is an excellent example of how academic research in a are to fundamental problem may lead to results that likely be of great practical importance. The study of the mode of action of drugs on cells, and on the enzymes which they contain, thus shows promise of bearing fruit on a commercial scale, but the commercial exploitation of pharmacology has not awaited this development. Great advances have been made by procuring the synthesis of hundreds of new substances, chosen more or less at random and by testing them all on animals. There has thus been ample confirmation of Crum Brown's and Fraser's conclusion that by altering chemical structure it is possible to alter the pharmacological effect. This type of Work is expensive and can only be undertaken where large resources are available. Hitherto it has been mostly done by large commercial undertakings in Germany. University laboratories are not generally successful in this field except when they act in close collaboration with manufacturing chemists. The progress ?f science in the discovery of fundamental mechanisms encourages the hope that academic laboratories will contribute more to Practical therapeutics in the future than they have in the past. The an study of the actions of drugs on enzymes will play important Part in pharmacology and in medicine. I must refer briefly to the branch of Pharmacology which deals with Biological Assays. In this work pharmacological methods are used to detect and measure substances, such as vitamins, hormones and bacteriological and immunological Products, which cannot, in the first instance, be detected or either o measured in any other way, since chemical methods n?t exist or are much less sensitive than the pharmacologica the c emica methods. Such assays have been used to control Work which has led to the isolation and synthesis of so many vitamins and hormones for which therapeutic uses are gra ua y being found. When the active substance has been isolated and sometimes When its chemical structure has been established, it is meth(xi Possible to replace the biological assay by a chemical has occurred wit which is simpler and more accurate. This 733 J. H. Gaddum vitamin C, which was identified as ascorbic acid and is now estimated colorimetrically, but it is unlikely that this will be possible in every case. The methods of biological assay used in connection with the isolation of active substances are generally crude, but more accurate and specific methods have been devised for special purposes. There is no immediate prospect of a chemical test for insulin, and the successful use of this hormone depends entirely on biological assays. A great deal of complicated work has been done to make these assays accurate. The same is true of many other hormones and bacteriological products. Another branch of work in which biological assays are used, and in which accurate and specific methods are particularly important, though far from universal, is devoted to substances like histamine and acetylcholine whose chemical structures are known, but which are commonly present in concentrations too low for chemical methods. Our knowledge of the physiology of acetylcholine, which has thrown so much light on the mechanism of nerve endings, is all based on biological assays, since the quantities of acetylcholine liberated are so small that their presence cannot be demonstrated in any other way. The application of these methods to the study of disease may well lead to interesting results, though the work has not gone far yet. It has been shown, for example, that histamine is normally present in human blood and biological methods of estimating the blood histamine have been developed. A certain amount of information is available regarding the changes in blood-histamine in various pathological states, but our information is still too scanty for the painting of a coherent picture. Some recent work under Professor Jimenez Diaz in Madrid, which was published at the end of last year, is an interesting example of the possibilities of this type of work. These Spanish workers collected urine from patients suffering from migraine, and found in it a substance with the pharmacological properties of acetylcholine. This substance was present in samples collected during an attack, but not before or after the attack. They suggest that the cause of the symptoms and signs of migraine is an over- production of acetylcholine. There was also evidence that another active substance, which has not been identified, is excreted in the late stages of an attack. It is to be hoped that this work will soon be confirmed and extended ; that is one way in which I believe that pharmacology will develop. 734 Development of Materia Medica in Edinburgh

If I have spoken too much about pharmacological research, is not because I do not realise the supreme importance of good pharmacological teaching. I hope that there will be no break the fine teaching tradition of the department, but that it will develop as the science itself is developing. Therapeutics is passing from the empirical stage when it was only necessary to learn what drugs were the traditional remedies for each disease and how to recognise and use these drugs, to the more logical stage when drugs are given scientifically to produce definite effects of various kinds. In the past students had to learn masses ?f dull illogical facts. Now they must try to apply the scientific outlook and the scientific knowledge, acquired in their first two Years as medical students, to the practical problems of thera- peutics. This is a difficult thing to do, and it may sometimes seem as if the work that is done in laboratories has no relation to the actual cure of disease. Pharmacology, with the other sciences taught in the third year, should help to bridge the gap which is too apt to appear between the laboratory and the wards. To do this it must teach not only the results of pharmacological research, ut also the methods by which new discoveries are actually made, harmacological teaching has tended to overemphasise results compared with methods, so that the medical profession has failed to appreciate fully that pharmacology is an experimental science which has produced great changes in the practice' of medicine. reater emphasis on methods would give a truer picture of the state of pharmacology to-day, and would perhaps make it easier students to remember the nature of scientific evidence at a time when they are making their first contacts with patients. tudents are apt to think that they have done with science when they start clinical work. In later life they receive advertisements Presenting scientific, and pseudo-scientific, evidence in favour of new remedies, and they have to decide for themselves which drugs are worth trying and which are not. Their decision largely in depends on what they can remember of their training not to aboratories. For this reason, amongst others, it is enough earn rules of thumb for the cure of disease. The successful the doctor must think for himself, and must understand language of the laboratories well enough to get full benefit without r?tti the discoveries that are coming from them, all the lasting his time, and losing his patients, by following without real fads which are so apt to sweep over medicine any Justification. 735 J. H. Gaddum

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