Chapter XV: Epilogue: 351 (9)

The result of these observations was to direct the attention of physiologists to the Thyroid gland. It was soon found that the symptoms of Thyroid deprivation could be experimentally produced in animals. Moreover, it was shown by Moritz Schiff of Berne (1823-1890), in 1884, that the results of the removal of the Thyroid might be avoided if the animal were fed regularly on an extract of the glands. The results were soon applied to man and have led to one of the greatest of medical triumphs. By its means sufferers from myxoedema and cretinism can be either cured or improved. A drivelling and idiotic cretinous child, adequately treated with Thyroid, enters on a normal process of development. The improvement is almost incredible, and the child rapidly passes into a healthy and happy state, so that it is literally true to say that his own parents would not recognize him (Fig. 130). Further, the gland may be given in excessive doses, and a condition produced that closely resembles a well-known pathological condition known as ‘Exophthalmic Goitre’, which is similarly susceptible of experimental investigation.

The facts here enumerated justify the deduction that the Thyroid gland secretes something which is essential to normal well-being. The organ has no duct, and the secretion is, therefore, never normally thrown out of the body. The Thyroid is, in fact, an organ of what is called ‘internal secretion’. Investigations on this secretion led to the isolation of the active principle as a pure compound known as _Thyroxin_ in 1916. The story of the Thyroid has recently (1926) been rounded off by the preparation of Thyroxin synthetically. The synthetic product has been given with effect in cases of Myxoedema.

The observations made on the Thyroid directed further attention to other ductless organs of which a number have been shown to have their own ‘internal secretions’. Furthermore, it has been demonstrated that, among organs which throw out their products through a duct, there are those which also send an internal secretion into the blood-stream. Among these are the essential organs of sex, the testicle and ovary. The effect of castration on the general physique is well known. It may be compared with the effect of ‘spaying’ or the removal of the ovary. This operation leads to an assumption by the female, in more or less modified degree, of the secondary sexual characters of the male.

Peculiarly interesting for their practical results have been certain investigations made of late years upon the organ known as the ‘Pancreas’. The Pancreas has a duct which opens into the Intestine just below the Stomach. It has long been known that the secretion of the Pancreas is related to the amount and fate of sugar in the blood. The association of disease of the Pancreas with the symptom known as ‘Diabetes’, in which sugar appears in the urine, was also familiar. Later it became apparent that it was not the Pancreas as a whole that was related to the process but only certain isolated and peculiarly formed nests of cells. It is now possible to administer extracts of these cell-nests with very favorable results on the course of certain types of Diabetes. The extract is now in wide use under the name of _Insulin_.

Among the ductless glands that have been best investigated are the so-called ‘suprarenal bodies’, which lie above the kidneys. As with the thyroid gland, the attention of physiologists was directed to these bodies as a result of clinical observations. These observations date back to the middle of the nineteenth century. In the last years of that century it was observed that an extract of the suprarenal bodies, injected into the circulation, caused a rise in blood-pressure, an effect opposite to that following the extirpation of the glands. The administration of extract from suprarenal bodies has found wide clinical application. Unlike the extract of thyroid, the effect of this extract is very temporary. It is easily oxidized and rapidly disappears from the blood. It belongs to the group of substances which are known as _hormones_. The active element in a suprarenal extract, the ‘suprarenal hormone’, has been recently prepared by a synthetic process.

The nature of hormones has only come clearly into view of late years. The word ‘hormone’ is formed from a Greek word meaning ‘to excite’. The internal secretions have, in general, functions of considerable physiological complexity, and act, for the most part, slowly and continuously. The hormones are, however, exceptions to this rule. They act rapidly and in an excitatory manner. These substances appear to be of relatively simple chemical structure. They are easily oxidizable, so that they rapidly disappear from the body. They act, in fact, as ‘chemical messengers’, producing a state of ‘chemical correlation’ of the different parts of the body which is comparable to the better-known and more widely recognized ‘nervous correlation’.

The hormones represent a very ancient and primitive physiological mechanism. In organisms consisting of but one cell, in which there are very few differentiated organs, the messages from one part of the body to another are necessarily of a chemical or hormonic character. In higher multi-cellular animals the intercommunication between different parts of the body is maintained, for the most part, by a specially developed nervous system. Certain necessary messages are, however, still conveyed by chemical messengers. The development of the conception of hormones has been especially the work of the London physiologist E. H. Starling (1866-1927).

Internal secretions and especially hormones form part of the increasingly complex picture of the working of the animal body. They are not only of great physiological value, but have also entered the department of practical therapeutics. They are, moreover, of philosophical importance, since they yield us a conception of the body in which every part is dependent on every other part, and the whole is subject to a process of ‘integration’ or linkage into a unitary system. We have glanced at the mechanism of chemical integration. We have now to turn to the mechanism of nervous integration.

(b) _Nervous Integration._

If the simple reactions of animal bodies are tested, it will be found that they clearly serve certain ends. Lightly touch the foot of a sleeping child and it will withdraw it. Tickle the ear of a cat and it will shake it. Exhibit savory food to a hungry man and at once his digestive process will get to work--his mouth will ‘water’. These instances might be multiplied a hundredfold. Such reflexes are admirably adapted to their ends. Many of them will continue in an animal in which the spinal cord is severed from the brain. Nevertheless, in the higher animals, and especially in man, they are controllable to a greater or less extent by the will. But to leave the question at that would give a false idea of the extremely complex integrative functions performed by the nervous system. Thus, the spinal cord, which, to the naked eye, is a longitudinal and little differentiated nervous mass, is, in fact, a collection of nerve-centers which have historically, both in the individual and in the race, been formed by the union of a series of separate segments. Each one of these segments is dependent on the action of the next segment in a fashion somewhat similar to that in which the actions of the cord itself are dependent on the brain. Each of the sections governs certain functions or movements of the body. There is thus a very complex process of integration which runs right through the nervous system.

The investigation of the bodily functions of a chemical and physical nature reveals that these activities are far more largely under nervous control and discipline than was at one time conceived to be possible. Thus, the main factor in the activity of any part is its blood-supply, but the blood-supply is largely determined by the state of contraction of the vessels of supply, which are in their turn under nervous control. So it is with the state of nutrition of the muscles, with the action of the sweat glands of the skin, with the mechanism of childbirth, and with a thousand bodily states with which both physician and biologist are concerned.

The investigation of nervous integration is especially associated with the name of Sir Charles Sherrington of Oxford. As the outcome of his work the picture formed of the nervous apparatus is that of a machine in which some parts work spontaneously, automatically, and with complete uniformity; others, though mainly automatic, are susceptible of various degrees of alteration and adjustment; others need intermittent or constant attention, and demand for their functioning fresh supplies of energy at longer or shorter intervals; while, finally, others have hardly yet taken a fixed form and are improvised as occasion demands. Thus the nervous system is a system of systems of every degree of independence.

These systems, each with a certain individuality of its own, date from every stage of Evolution, the more ancient being, as a rule, the more automatic and the less dependent on other systems. The most ancient, the chemical messenger or ‘hormonic’ system (pp. 306-8), we share with the lowest living things which consist of only one cell. Very recent are the factors in the nervous system that are specially developed in man as contrasted with the higher apes. Such are those associated with the delicate co-ordination of sensory impressions and motor impulses involved in such acts as speaking, reading, writing and the like. Each of these systems, high or low, ancient or recent, has its own place in the body. For many the exact position of the controlling center is demonstrable and some of the lower systems can function without the aid of any other systems save those which control their nutrition.

Among these nervous relations there is one which calls for special mention on account of its great clinical importance. The state of ‘shock’, the general nature of which is vaguely understood by everybody, has been given a more exact physiological meaning of late years, especially by the American surgeon G. W. Crile (1864-). It has been found possible to localize ‘shock’ experimentally. If a section of the spinal cord of an animal be cooled to a point just above freezing, the part of the body below the cooled level passes into a state of ‘shock’, that is to say, its reflexes no longer respond to irritation in the normal fashion. This shock effect is due to the removal of some influence exercised by the higher parts of the nervous system. In the experiment the shock effect is induced by an external agent, but there is an internal mechanism within the nervous system itself, which can cause it under appropriate conditions.

(c) _Vitamins._

There are no current medical problems that are more discussed than those of nutrition. It has long been recognized that articles of diet may be classified according to their constitution into ‘proteins’, ‘carbohydrates’, and ‘fats’. If an animal is fed on a diet containing these in correct proportion, but in a perfectly pure state, it will become ill and ultimately die. The onset of illness and death will be the more rapid if it be a young animal. This fact, observed as long ago as 1880, was reinvestigated by F. Gowland Hopkins of Cambridge in 1906, from whence dates our real knowledge of a very important subject. He found that, in the case of rats, the addition of a very small quantity of milk to this chemically pure diet would induce normal growth. The milk must therefore contain some growth-promoting substance or substances other than protein, fat, or carbohydrate. The result of many similar experiments by a large number of observers has shown that almost all fresh food contains such growth-promoting substances. They have been named ‘vitamins’.

Several of these vitamins have been distinguished. None, however, has been isolated, and we depend for our knowledge of them on our investigation of their mode of action. One, known as _Vitamin A_, is produced in the growing green parts of plants, and is especially necessary for the promotion of growth. Vitamin A is abundant in cod-liver oil. It has been shown that the necessity for Vitamin A can to some extent be evaded if the animal is exposed to sunlight or ultra-violet rays. Moreover, it has been shown that the absence of Vitamin A or of some allied substance is associated with the disease of the bones known as ‘Rickets’ or ‘Rachitis’. The history of this disease (p. 181) is made intelligible by our knowledge of these facts. Rickets can be shown to be most prevalent under precisely those social conditions in which articles of diet containing Vitamin A are scarce and the amount of sunlight is inadequate.

Our knowledge of this topic is in the process of active extension. The question of the actual influence of sunlight and of the rays of various wave-length which go to make it up is still too uncertain for discussion here. There is a special aspect of this topic, however, to which we may refer. It has been demonstrated that stable-fed cows, fed not on fresh food but on oil-cake, yield milk of little antirachitic power. It has, however, been shown that this milk becomes antirachitic after exposure to ultra-violet light. Therefore, some antirachitic substance is produced in the milk, as in the body, by the action of ultra-violet light. Now recent research has shown that the antirachitic elements are associated with a chemical substance known as _Cholestrol_ which is of the nature of a complex alcohol. Nevertheless chemically pure Cholestrol has no antirachitic power, though it, too, acquires it by exposure to ultra-violet light. By chemical means 99·9 per cent. of rayed and antirachitic Cholestrol has been recovered as pure Cholestrol without antirachitic power. Therefore the antirachitic power, that is the vitamin factor, resides in the remaining one-tenth per cent. of rayed Cholestrol. The further investigation of this fraction may be expected to yield results of great importance both theoretically and practically.

Another substance of the same order exists in the husks of rice. If animals such as fowls be fed on a diet of rice deprived of its husks, they develop a nervous affection. Now a somewhat similar nervous affection known as ‘Beri-beri’ is known in the East among natives who live on milled rice. The disease, whether in human beings or chickens, may be cured or avoided by giving the husks of the rice separately. The substance thus conveyed has been named _Vitamin B_. There is yet another disease, Scurvy (p. 170), which occurs in those who have been deprived of fresh food. _Vitamin C_, which cures this, is specially found in the juices of oranges and lemons. Our knowledge of ‘deficiency diseases’, of which Scurvy is one, is only just beginning. It may well be that they are of wider occurrence than has been supposed, and vitamins may be important curative and preventive agents.

§ 19. _Knowledge of the Eye and its Disorders._

From an early date the treatment of ailments of the eye has stood somewhat apart from the rest of medical practice. Moreover, the knowledge of the structure and functions of the parts of the eye has not kept closely parallel with that of other departments of anatomy and physiology.

The eye is a roughly spherical organ, enclosed in a tough capsule, the _Sclerotic coat_ (Fig. 131). The transparent front of this capsule, the _Cornea_, is the curved window through which we look upon our world. There is a watery space, the _Anterior Chamber_, behind the Cornea, at the back of which is situated the _Lens_, a horny transparent structure. In front of the Lens is a ring-shaped pigmented muscle which shuts out light from the Lens, except at the center, and gives the characteristic color to the eye. This circular colored muscle is the _Iris_, and the hole in its center is the _Pupil_. The pupil becomes smaller or larger with contraction or expansion of the Iris. This change is a reflex and unconscious act, depending on the amount of light and also on the degree to which the eye is adjusted to examine near objects.

The edge of the Lens of the eye is attached by the circular _Suspensory Ligament_ to the circular _Ciliary Muscle_. The Ciliary Muscle, by contracting or relaxing, alters the form of the Lens (Fig. 132). This change in form of the Lens is part of the process of adjustment to near or distant vision. Behind the Lens is the large _Posterior Chamber_, containing a transparent gelatinous substance. At the back of the posterior chamber is the sensitive area or _Retina_, which is the essential organ of vision, and is backed by a pigmented coat, the _Choroid_. The Retina is continuous with the _Optic Nerve_, along which an artery enters the globe of the eye. At the point where this artery pierces the Retina there is the so-called _Blind Spot_.

A ray of light penetrating the eye from the center of the Cornea through the center of the Lens falls on or near a specially sensitive area, the _Yellow Spot_, and images formed there are more distinctly perceived than those formed elsewhere. When an object is examined closely, the observer makes the attempt to bring the image of it on to his Yellow Spot. Any injury to the Yellow Spot causes a great diminution in clearness of vision. Man and his allies, the zoological group known as the ‘Primates’, are the only mammals, except the cat tribe, that possess a Yellow Spot. There can be little doubt that the possession of this Yellow Spot has done much to raise the importance of vision among the senses in the Primates. It has thus been a very potent factor in the evolution and elevation of Man himself.

The eye is an optical instrument which, like other instruments, performs its functions with something less than perfection. Most purely optical errors of the eye can be remedied by spectacles. These aids to vision are of very great importance, since, by the time middle life is reached, few are fortunate enough to read in comfort without them. The introduction of spectacles, therefore, enormously extended the active intellectual life. Their social effects are incalculable.

The commoner optical errors may be classified under four heads.

First and commonest there is ‘old sight’. When a healthy eye adjusts to near vision, the Ciliary Muscle contracts towards its attachment at the junction of Conjunctiva and Sclerotic. This draws forward and relaxes the Suspensory Ligament. The elasticity of the Lens, no longer constrained by the Ligament, causes it to assume a more convex form. This more convex form is appropriate to the correct focussing of a near object on the Retina. At or about the age of forty-five the Lens usually begins to lose its elastic power, and thus has difficulty in adapting to near vision. The trouble is remedied by the use of convex glasses for reading or other near work.

A second common error is the so-called ‘far sight’. In this form--save in extreme cases--the eye is competent for distant objects, but those that are near are not clearly seen. The incapacity for near vision is due to a deformity--usually innate--of the eye. The eye is too short along the axis _xy_ (Fig. 131). The resulting optical error can be remedied by the use of convex spectacle lenses.

FIG. 132. DIAGRAM TO SHOW THE NATURE OF ACCOMMODATION OF THE EYE TO NEAR VISION. The Ciliary muscle, by contracting, pulls forward the lateral attachment of the Suspensory Ligament to the Sclerotic. Thus the ligament is relaxed and in turn relaxes its pull on the Lens. The Lens thereon becomes more convex. As age advances the Lens loses this power and so the sight fails for near vision.

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Thirdly, there is the so-called ‘near sight’. In this state near objects can be clearly seen, but vision fails with those that are more distant. Near sight is usually an acquired condition. The eye is too long along the axis _xy_ (Fig 131). The resulting optical error can be remedied by the use of concave spectacle lenses.

Fourthly, there is ‘irregular sight,’ known as ‘astigmatism’. In extreme cases of this condition no perfectly clear image can be formed of any object, whatever its distance. It is in some measure both congenital and acquired, and is due to an irregular deformation of the optical apparatus of the eye. The remedy for astigmatism is a compensatory deformation of the spectacle lens, which may need, in other respects, to accord to the convex or concave form, according as the deformation of the eye is of the far-sighted or near-sighted type.

Historically optical errors of the eye were relieved by spectacles before the nature of the defects was understood. The first suggestion of the use of convex lenses as an aid to old sight was made by Roger Bacon (1214-94) in the thirteenth century. Spectacles with convex lenses for old or for far sight first came into use about 1300. By the fifteenth century they were widely known. It may well be that their adoption, by prolonging reading life, had an important effect upon that process of extension of knowledge that we dub the ‘Revival of Learning’. Concave lenses for the relief of near sight came in towards the end of the fifteenth century, but were not widely used till the eighteenth century. Astigmatic lenses were not contrived till well into the nineteenth century.

In 1874 S. Weir Mitchell (1830-1914), a very able American physician, showed that the eye strain resulting from astigmatism was associated with many nervous conditions. Weir Mitchell’s name is familiarly associated with a line of treatment of these conditions. Since his discovery it has been the practice to examine for optical error all sufferers with headache and other neurotic symptoms.

For long there was no means of estimating the degree of error, whether of old sight, far sight, or near sight, save by trial on the part of the patient himself. Spectacles were a common object of the hawker’s trays, and from them the sufferer selected the specimen that suited him best. The first essential improvement in this state of affairs was an elucidation of the mode of action of lenses. The paths of light rays in their passage through a lens were first correctly determined at the beginning of the seventeenth century by the astronomer Johannes Kepler (1571-1630). Knowledge of optics advanced during the seventeenth and eighteenth centuries, but the optical errors of the living eye were not accurately estimated until the time of the great Dutch ophthalmologist Frans Cornelis Donders (1818-89). The system of prescribing and fitting spectacles that is now in vogue dates from the publication of his work, _The Anomalies of Refraction and Accommodation_, in 1864. Hardly less important was the invention of the ophthalmoscope by Hermann von Helmholtz (p. 213). Very important also was the introduction of ‘test types’ for examining errors of vision by the Dutch ophthalmologist Hermann Snellen (1834-1904).

One of the most remarkable minds that has ever applied itself to medical problems was that of the Quaker physician Thomas Young (1773-1829). He was a man of immense learning, and is remembered for having been the first to decipher Egyptian hieroglyphics. Young explained the power of the eye to ‘accommodate’ for near vision. This faculty of ‘accommodation’ was, he showed, due to changes in the curvature of the crystalline lens (Fig. 132). In his memoir _On the Mechanism of the Eye_ (1801), Young gave the first scientific account of Astigmatism. His theory of color vision and his doctrine that light is due to waves in the ether are still important. His ‘wave theory’ of light completely replaced the old view, the so-called ‘emission theory,’ that light is due to something material which goes forth from the luminous object. While we are referring to Young we may remind the reader that his work on ‘Energy’ lies at the back of all modern Physics, in the history of which he takes an extremely important place.

The operative treatment of the eye is of great antiquity. The most important operative procedure is that for ‘cataract,’ a condition caused by an opacity of the lens. ‘Couching’ for cataract, that is depressing the opaque lens, was practised by Alexandrian surgeons in the third century B.C. It is described by Celsus (p. 43) in the first and mentioned by Galen (p. 50) in the second Christian century. Contemporary with these authors are descriptions of the actual extraction of the lens affected with cataract.

In Imperial Roman times there were surgeons who devoted themselves exclusively to cataract operations. These were practised during the Middle Ages by the Arabs and to a less extent by the Westerns. For the most part the operations were performed by wandering quacks, who were, however, often very skilful. In the sixteenth century operations on the eye began to pass into the hands of recognized medical practitioners. The advances in the knowledge of the anatomy and physiology of the eye in the eighteenth century enabled the French surgeon Jacques Daviel (1696-1762) to explain the real nature of cataract, which is usually nothing but a senile change in the lens of the eye. His knowledge made it possible for him greatly to improve the operation for extraction, so that, over a large range of cases, he had only 11 per cent. of failures.

The modern era of ophthalmic surgery was ushered in by Donders (p. 319), von Helmholtz (pp. 213 and 319), and Albrecht von Graefe (1828-70). The last was a professor at Berlin who greatly improved the operation for cataract and introduced or improved many other important operations on the eye. He was one of the first to make important clinical observations with the ophthalmoscope, and he showed how the instrument may be made to yield information not only of the condition of the eye itself, but also of the brain and of its membranes, an application which has become of the greatest value in later medical developments. Though he died before the most important work of Pasteur and Lister had become generally accepted, von Graefe was yet practising a system of surgery which was not far from aseptic.

As with most departments of Medicine, so also with Ophthalmology, the most significant advances during the last generation have been in the direction of prevention rather than cure. Prominent among these measures are, firstly, school inspection with the consequent early detection and isolation of infectious cases of conjunctivitis; secondly, maternity welfare accompanied by prompt notification and treatment of the very dangerous and sight-destroying ‘Ophthalmia of the New-born’; thirdly, improved light regulation in factories and schools; and, fourthly, adequate provision of spectacles for school children with errors of vision.

The recognition of the infectious character of the very chronic and sight-destroying disease known as _Trachoma_, or ‘Granular Conjunctivitis,’ has been of great importance for the Public Health. The disease is common in the near East and in Eastern Europe and by no means rare in slum quarters in the West. A rigid system of inspection of immigrants, together with quarantine combined with treatment, has done much to diminish its ravages in the United States.

§ 20. _Investigation of the Nature and Action of Drugs._

(a) _Entry of Vegetable Drugs into the Pharmacopoeia._

An examination of the list of drugs that are in use at the present day--apart from those which have been introduced by the scientific movement of the last generation--yields some surprising results. Some thirty per cent. of the crude vegetable drugs in the modern official Pharmacopoeia were known in remote antiquity. The Egyptian medical papyri mention, among others, Aloes, Caraway, Castor Oil, Coriander, Dill, Fennel, Juniper, Mint, Myrrh, and Turpentine. Among Egyptian mineral remedies still in use are salts of copper and of lead. Assyrian medical tablets refer to most of the Egyptian drugs as well as to a number of others, among which are Almond Oil, Aniseed, Galbanum, and Liquorice. Among Assyrian mineral remedies that are used by us to this day are Alum and Bitumen. Early Indian medicine had a very copious pharmacopoeia. _Cannabis indica_, known as ‘Hashish’ or ‘Indian hemp’, Cardamoms, _Cassia fistula_, _Datura stramonium_, and _Nux vomica_ are among the valuable Indian herbs now in use in scientific medicine, while Mercury preparations were perhaps ultimately of Indian origin.

The medical herb lore of the Greeks comes to us chiefly from Dioscorides (p. 43), who mentions about five hundred plants. A large number of these are still in our own Pharmacopoeia. Among these, besides those of Egyptian, Assyrian, and Indian origin, are Ammoniacum, Belladonna, Camomile, Catechu, Cinnamon, Colchicum, Colocynth, Crocus, Galls, Gentian, Ginger, Hyoscyamus, Lavender, Linseed, Male Fern, Mallow, Marjoram, Mustard, Poppy, Rhubarb, Sesame, Stavesacre, Storax, Terebinth, Tragacanth, and Wormwood. About thirty-seven per cent. of our Pharmacopoeia was known to the later Greeks. From them the Arabs derived, adding, however, enormously to their drug-lists, so that we may say that about fifty per cent. of our drugs were in use by the Arabic-speaking physicians of the Middle Ages. With the discovery of America further important additions were made. Of these we have already discussed the introduction of Cinchona, Ipecacuanha, and Tobacco (p. 95). Few important additions were made in the eighteenth century, though among them was Digitalis (p. 328).

(b) _Active Principles._

One of the things that separate the practice of Medicine of our time from that of previous ages is our power to give drugs in ‘pure’ form. This means not only that we can secure drugs without adulteration, but also that the active substances in drugs can be chemically isolated and given without admixture. Most drugs used in Medicine are, in fact, of vegetable origin. The possibility of giving them in chemically pure form depends upon the discovery, early in the nineteenth century, that plants owe their poisonous and remedial properties to small quantities of _Active Principles_, which are susceptible of chemical extraction and isolation. Thus the science that deals with the action and nature of drugs, _Pharmacology_, really took its rise about a hundred years ago, though many had experimented with drugs at an earlier date.

Further progress in the same direction has been made by the so-called ‘synthetic’ preparation of drugs. Certain substances of vegetable origin do not readily yield their active principles and to extract them very complex chemical processes may be involved. There are special obstacles to the complete purification of other drugs, even when they have been obtained in a relatively pure state. These difficulties can sometimes be surmounted by the preparation of the drug from inorganic materials. This synthetic process of preparation is now possible for many substances that are of medical application. Furthermore, when a drug can be thus synthetically prepared, it is often possible to try chemical variants upon it, and thus to obtain a more effective preparation.

In former times a vast number of drugs were habitually employed by physicians, and they were often given in very complicated prescriptions. ‘Polypharmacy’, the giving of many drugs, is a vice from which Medicine has now in large part freed itself. The number of drugs given by scientific physicians is far fewer that it was. For this there are several reasons. Firstly, many drugs were found useless for the purpose for which they were administered, and were at times even dangerous. Secondly, since attention has been drawn to the active principles of drugs rather than to the crude natural drugs, it has been seen that, in fact, many of the drugs that were being given were merely duplicates one of another, and that often the administration of the active principle itself was more effective and more reliable than that of the source from which it was obtained.

What then is the nature of the drugs now being administered by scientific physicians? They fall into a number of classes. The nature and action of some of these is so simple that no prolonged discussion of them is necessary. There are, for instance, the inorganic acids and alkalis, the primary action of which, when taken internally, can be determined by a series of experiments on gastric juice in a test-tube kept at body temperature. Again, there are soluble inorganic salts, which are absorbed unchanged from the alimentary canal. These have the effect of increasing secretions. Their purgative effect is well known, though the physiological details of their action are not yet clear. There are yet other substances, such as metallic Mercury in ‘grey powder’ or Bismuth, which act mechanically, even when administered internally. Over and above these simpler substances, and in addition to the traditional vegetable substances which have been in use as medicines for centuries, there are others which have only been accessible during the last few generations. We have already discussed under separate headings the derivatives from animal glands, such as of the Thyroid (p. 305), of the Adrenals (p. 307), or of the Pancreas (p. 306), as well as the bacterial Vaccines (p. 261) and Antitoxins (p. 267). We now turn to pure chemical substances of vegetable origin. Of these mention may be made especially of the groups known as the _Alkaloids_ and the _Glucosides_.

(c) _The Alkaloids._

By ‘Alkaloid’ is understood a nitrogenous substance, usually of vegetable origin, which forms salts with acids. The alkaloids are mainly obtained from the dicotyledonous plants. Generally they occur in nature in combination with plant acids such as citric or tartaric acid. The alkaloid group contains some of the most important drugs that we possess. Among them are Morphine, Strychnine, Cocaine, Atropine, and Quinine.

The investigation of the alkaloids began with the nineteenth century. Morphine was isolated from Opium by the Parisian apothecary Charles Derosne (1780-1846) in 1803. He failed, however, to recognize its chemical affinities, which were first grasped by the German apothecary Adolf Sertürner (1783-1841). Their work, however, attracted but little notice until attention was drawn to it by the great French chemist Joseph Gay-Lussac (1778-1850), in 1817. The result was the concentration of much scientific ability on the alkaloids. Prominent among the early investigators were the French pharmacologists Pierre Joseph Pelletier (1788-1842) and Joseph Caventou (1795-1878). Between 1818 and 1820 they isolated from Cinchona (p. 95) certain alkaloids allied to Quinine, from Nux vomica the alkaloid Strychnine and certain of its allies, and from Coffee the alkaloid Caffeine. Pelletier in conjunction with the distinguished chemist Jean-Baptiste Dumas (1800-84) followed this by a quantitative examination of a number of alkaloids in 1823. The first alkaloid to be used as such in medicine was Strychnine. It was introduced in 1821 by the French physiologist François Magendie (1783-1855), the teacher of Claude Bernard.

In the thirties and forties of the nineteenth century Liebig, who had developed his doctrine of radicles (p. 206), attempted to determine the formula of alkaloids. He was followed by Wöhler (p. 206). Since then an immense amount of work has been done in investigating the chemical nature and physiological action of alkaloids. The general result has been to reveal the fact that each alkaloid-yielding plant contains not one but a number of alkaloids. Those from the same plant often have similar but not identical action upon the animal body. The differences in physiological action of allied alkaloids have occupied much of the attention of pharmacologists. The accurate knowledge of these differences has made possible a far greater finesse in the administration of alkaloid drugs than was previously possible. Some alkaloids can be prepared synthetically, but the process is mostly of theoretical rather than practical importance.

(d) _The Glucosides._

The Glucosides are an ill-defined group which have in common the property of yielding a sugar-like substance--usually glucose itself--as a result of certain chemical processes. They are mostly of vegetable origin and the history of their investigation has been parallel with that of the alkaloids. The first glucoside to be isolated was Salicin, which was obtained from willows in 1819. It is the active principle of the very ancient remedy for rheumatism, ‘Oil of Wintergreen’. Salicylic acid was introduced into Internal Medicine in 1873 and its derivative, Aspirin, in 1899. Both drugs are of great importance, and many other derivatives of Salicin are in use. Salicin and its derivatives can be prepared synthetically, and the synthetic products are in use in Medicine.

Of all the glucoside-yielding plants, perhaps medically the most important is the Foxglove, _Digitalis purpurea_. The use of the plant was known to some of the medieval herbalists, and is, moreover, recommended in the German and English printed herbals of the sixteenth and seventeenth centuries. Foxglove is mentioned as a folk remedy in George Eliot’s _Silas Marner_, the story of which refers to a period round about 1750 before the Industrial Revolution, ‘when the spinning-wheels still hummed busily in the farm-houses’ (Fig. 89). It was introduced into scientific Medicine in 1785 by William Withering (1741-99) of Birmingham in his _Account of the Foxglove_, which gives details of numerous cases treated with it.

Digitalis long resisted the attempts to extract an active principle, but since the seventies it has yielded to investigators a whole series of glucosides. Digitalis and its derivatives have become of much importance, especially in the treatment of cardiac conditions. Despite the success in obtaining glucosides from the Foxglove, the extract of the plant itself continues in wide use.

(e) _The Study of Pharmacology._

Since the middle of the nineteenth century the investigation of the physiological action of drugs has been mainly in German hands. The most prominent exponents of the method have been Karl Binz (1832-1912) and Oswald Schmiedeberg (1834-1921), both professors at Dorpat, where there has been a pharmacological laboratory since 1849. The first pharmacological laboratory in America, that at Ann Arbor established in 1893, and the first in England, that at University College, London, established in 1905, were successively occupied by A. R. Cushny (1866-1926). The work of these and of other pharmacologists has not tended to increase but to reduce the number of drugs. Nevertheless, some new drugs of great importance have been introduced by them. Of these, among the more valuable is Amyl nitrite, the inhalation of which was first recommended by T. Lauder Brunton (1844-1916) as early as 1867 as a remedy in certain cases of sudden heart seizure.

Improvements have been made not only in the drugs themselves but also in modes of administration. The ancient methods of inunction and inhalation, as well as other older methods, have been greatly elaborated in modern times, and are now of wider application than they were. No advance of this order compares in importance with the introduction of the Hypodermic Syringe by the ingenious French surgeon Charles Gabriel Pravaz (1791-1853). By means of this instrument various drugs can be injected directly into the subcutaneous tissues or into the veins. This mode of administration is more accurate and under better control than any other, and the action of the drug so injected is swifter and more sure.

(f) _Chemotherapy._

During the twentieth century the outlook on drug treatment has been modified by the success obtained in the _specific_ treatment of certain diseases, that is to say, treatment by remedies which strike at a particular disease and no other. Until quite recently scientific Medicine recognized very few specific remedies. It had been ascertained that Cinchona owes its value in Malaria to the alkaloid Quinine (p. 326), which acts as a specific exterminator of the malaria parasites, and not simply as a remedy for fever in general. It had also been ascertained that Ipecacuanha owes its value in tropical Dysentery to the alkaloid Emetine, which acts similarly as a specific exterminator of the protozoal organisms which are the infective agents. Quinine and its allied alkaloids and Emetine and its allied alkaloids were practically the only specifics the value of which had been scientifically proved, except Mercury for Syphilis.

About the beginning of the twentieth century arose the new ‘Chemotherapeutic’ movement as it came to be called. This movement was initiated by the studies of natural Antibodies (p. 262) by Paul Ehrlich of Frankfurt (1854-1915). Antibodies are strongly antagonistic to the parasitic organism the toxin of which has elicited them, but, on the other hand, they are quite harmless to the animal body in which they reside. Here are ideal remedies provided by Nature herself. Ehrlich compared them to magic bullets, constrained by a charm to fly straight at their objective and to injure no other. No such perfect artificial drugs have yet been produced. The problem of Chemotherapy is rather how to poison the parasite as much as possible while poisoning the host as little as possible.

When Ehrlich began the study of Chemotherapy observers had long known that certain aniline dyes have a special affinity for certain cells or organisms. Indeed the affinity of certain of the dyes for certain bacteria had made possible the work of Koch on Tuberculosis and on other diseases. As far back as the seventies and eighties much work had been done on the subject, and the action of these dyes had interested a large variety of investigators. Ehrlich’s first results were on a protozoal parasite, which infests dogs. By injecting small doses of a certain aniline dye into the veins of the infected animal it was found possible to destroy the parasites while doing very little injury to the dog.

FIG. 133. THE ORGANISMS OF SYPHILIS IN A SMEAR FROM THE LOCAL INFECTION. Highly magnified. They are best seen by means of a special optical arrangement in which the outlines of the objects appear glistening white and the background black. The round objects are pus corpuscles, the two spiral objects the organisms of syphilis. ]

At this point Ehrlich turned aside from the aniline dyes to study the effects of much more toxic substances. He selected the compounds of arsenic for the purpose. After prolonged research, he obtained an arsenical derivative which proved very toxic to parasitic protozoa and little toxic to their animal hosts. When a vast number of experiments had been made, this substance was tried in 1910 in cases of human Syphilis. This disease had been shown by Fritz Schaudinn (1871-1906) in 1905 to be due to a protozoal parasite, the _Spirochaeta pallida_ (Fig. 133). The results obtained by the new remedy were very satisfactory and a valuable specific was thus added to the medical armory. The drug became widely known as 606, since this is its number in the series of the arsenic derivatives with which Ehrlich had experimented. In the meantime others had been at work along lines suggested by the aniline experiments. Their investigations led in 1920 to the discovery of a specific against the deadly _Sleeping Sickness_ or _Negro Lethargy_. This drug is known as _Bayer 205_ from the firm that prepared it and the number in the series of substances that were tested.

Since the first preparation of 606 and 205 some interesting facts have emerged concerning their action as well as the action of Quinine, Emetine, and other specific remedies. It has been found that the toxicity of these substances to the parasites against which they are aimed is much greater when the parasites are within the body than when the drugs are applied to the organisms outside the body. In other words, the drugs do something to the body, or the body does something to the drugs, that is inimical to the parasite. The nature of that something is still under discussion. In the case of Quinine it seems that the Quinine so affects the red blood corpuscles that the malarial parasites cannot enter them and so cannot go through their sexual cycle (Fig. 123). Thus the Quinine does not act as a direct poison but attacks the parasite in a much more subtle manner. In the case of other parasites the action of the specifics is more difficult to understand. It should be pointed out, however, that the chief victories of Chemotherapy have been in dealing with the protozoal rather than the bacterial diseases. A main task of future Medicine will be the discovery of means of eliciting antibodies against the various bacterial infections. For this there is more immediate hope from the use of remedies of vital origin than from those synthetically produced.

§ 21. _Interpretation of Collective Medical Data._

The drawing of a deduction of scientific value from experience is by no means a simple process. In many sciences the investigator has the power to control experience; in other words he can _experiment_. But even the interpretation of experiment needs special precautions. The physical experimenter must, for instance, make sure that he has but one ‘variable’. Thus, if examining the effects of pressure on a gas, he must see that in raising or lowering pressure he is not altering temperature, or if recording the effects of temperature he must satisfy himself that he is eliminating those of pressure. In experiments upon living things the limitation of the field of action to one simple factor is often--perhaps always--impossible. The biological investigator is therefore accustomed to accompany his experiment with ‘controls.’ Thus, if he wishes to ascertain the effect on the growth of animals of feeding with milk that has been boiled, he must feed one series of animals on unboiled milk while he is experimenting with a series fed with the boiled milk. He must take steps to ensure that the two series are similar as regards age, strength, size, &c., and that the conditions under which they live are identical, except as regards the one factor the results of which he seeks to ascertain.

When the observer is dealing with human material, it is very seldom that he can either restrict the number of variables to one or secure an adequate series of controls. Physicians are habitually in a position in which action of some kind is demanded. They cannot await the conclusion of laboratory researches, which may extend over years, for the patient must be relieved at once or die. Being often unable to use those most reliable instruments of science, experiment or observation under control conditions, physicians have come to rely on what is called ‘a general experience of disease’.

One of the commonest fallacies of such general experience is assignment of causative relationship between two conditions, simply on the ground that they frequently occur in association. Thus it is a fact--and one to which attention has been drawn by medical observers--that rheumatic affections and red-headedness are often found together. But both conditions are common and it has not been satisfactorily demonstrated that the association of the two is any commoner than their frequency in the population at large would render probable. Such general experience is therefore very fallible and is incapable of scientific expression, though it is often very valuable and sometimes indeed entirely indispensable. To give such experience scientific expression, to place it in terms of the ‘primary qualities’ of the founders of modern Science (pp. 106-7), it is necessary to put it into statistical form. Statistical statement thus becomes of the highest importance for medical progress. Medical statistics, when prepared from proper material and drawn up with the requisite skill, are at once the most exact and the most generalized expression of medical experience.

FIG. 134. DIAGRAM ILLUSTRATING THE ALTERATION IN THE PERCENTAGE OF AGE-DISTRIBUTION OF THE POPULATION OF ENGLAND AND WALES FROM 1891 TO 1926. It will be observed that the people of England and Wales have been getting steadily older. ]

Statistical statements, however, vary greatly in their value and ease of interpretation. The simplest statistical statements with which the medical man has to deal are perhaps those which relate to surgical operations. The categories in which the patient may be placed are here limited; he may die, recover, improve, or get worse. If the operation is a quite simple one, and if the surgeon is perfectly honest, and also--which is rarer--quite unbiased, a small body of statistics may carry immediate conviction as to the value of an operation. Thus, Lister’s first results with amputation, as obtained under his antiseptic conditions, at once satisfy the mind, although the conclusions are based on only forty cases (p. 240). No surgeon at once both able and willing to appreciate these results would hesitate to adopt the new method.

The operation of amputation is, however, in a statistical sense, a particularly simple matter. The patient must either undergo the operation or not, and the proportion of cases in which the necessity is doubtful is very small. Further, he either recovers or dies--for the operation could hardly be in itself unsuccessful, nor the surgeon in doubt as to whether the patient had recovered or not. Many operations, however, are not of this order. They may be performed for conditions as to the exact nature of which the surgeon is uncertain, and for symptoms which may be only partially relieved. Thus, the removal of the appendix for Appendicitis may be most urgently necessary for the saving of life in one case and may be a matter of convenience for the relief of more or less indefinite symptoms in another. Further, what one surgeon calls appendicitis another may not. One surgeon may have every appendix that he removes submitted to skilled pathological examination before he accepts the case as one of appendicitis and places it among his statistics. Another may be quite content with naked-eye appearances of the nature of which he alone is witness, judge, and reporter. It is, therefore, clear that any collective statement as to the results of such an operation must be cautiously scrutinized before conclusions of the slightest scientific value can be drawn from them.

FIG. 135. DEATH-RATE FROM CANCER OF THE TONGUE. It will be observed that it is not a common cause of death till about 45 years of age, but that it then increases rapidly to fall again in both sexes in old age. These features are clearly related to various factors in the causation of the condition. One of these is certainly Syphilis, which is most frequently contracted between 20 and 30 and more often by men than women. The so-called ‘tertiary’ effects of this condition, some of which lead to Cancer of the Tongue, do not usually make themselves felt, however, for many years after infection. Contrast Fig. 136 and Fig. 137. ]

There is a common and rather foolish saying that ‘Statistics may be made to prove anything’. This is true, but it is true only in the sense that _evidence_ may be made to prove anything. The matter turns on the questions, firstly whether the evidence is of a good or a bad order, and secondly whether the investigator is in a good or bad position to interpret the evidence. A statistical statement may be well or ill founded and well or ill interpreted, but statistical statement is, in fact, the only scientific method open to us for presenting long series of data. The conclusions to be drawn from those data, though sometimes evident and easily elicited, at other times demand specially skilled and specially trained interpreters. Moreover, to be of value to others, such interpreters must also be skilled in expression, so that the main body of those who have no statistical training may be in a position to understand the essential elements in their conclusions. In no medical department is literary power of greater importance than in that which deals with statistics. Thus has arisen the small but highly important class of medical statisticians. The rise of medical statistics into a vocation places the crown on Medicine _as a science_. It is not given to many medical men to be proficient in this department. But the duty lies on all medical men, and indeed on all citizens, to appreciate the value of this study and to seek to appraise its simpler and more established conclusions.

It is remarkable how frequently a straightforward statistical statement may remove a false impression, even when the impression is based on evidence not of a wholly unscientific character.

FIG. 136. DEATH-RATE FROM CANCER OF THE LIP. It will be observed that this curve resembles in form that of the death-rate from Cerebral Haemorrhage as shown in Fig. 137, but differs from that of the death-rate from Cancer of the Tongue as shown in Fig. 135. The chances of dying from Cancer of the Lip are negligible till middle age is past and then increase progressively throughout life. In the causation of Cancer of the Lip Syphilis is not an important factor. On the other hand the continuous irritation of pipe-smoking, which acts not at one age but throughout life, has to be considered as a causative element. Hence the resemblance to Fig. 137 rather than to Fig. 135. ]

FIG. 137. CHART OF DEATH-RATE FROM CEREBRAL HAEMORRHAGE AND ALLIED STATES. These conditions are extremely rare in the young, but among the commonest causes of death in later life. The liability to them increases progressively to extreme old age. This is explained by the fact that Cerebral Haemorrhage, etc. follows on the rupture of a blood-vessel in the brain and the rupture of the vessel is conditioned by the hardness and brittleness of its coat. The hardness of the arteries increases progressively in later life, whence the saying ‘a man is as old as his arteries’.

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