Chapter XIII: Epilogue: 351 (7)

Pasteur had thus before him the task of proving a universal negative--a task impossible in Formal Logic. But Science is not Formal Logic. In the end he clinched the matter by an exquisitely simple experiment which must, at once, carry conviction. A flask with a long S-shaped neck is filled with a putrescible fluid. It is heated to boiling, to kill all organisms, and then left in the still air of a room. Air can enter, but any floating germs that enter naturally fall on the floor of the S-shaped neck of the flask. Months may go by without any change in the liquid, but once the neck is severed, so that organisms can enter freely from the air, fermentation sets in within a few hours, and organisms can be detected in the liquid. Only living organisms from the air can have caused the change.

FIG. 107. PASTEUR’S CRUCIAL EXPERIMENT to prove that fermentation or putrefaction is the result of the action of air-borne organisms. The S-shaped flask contains a putrescible fluid such as meat broth. The flask containing the broth is subjected to prolonged heating to destroy all organisms. It is then left in position with the mouth open. Days, weeks, months, even years, may pass without sign of putrefaction. No organisms reach the broth, since any that enter the open mouth fall on the floor of the neck and remain there. Sever the neck of the flask so that organisms can fall from the air directly on to the surface of the fluid and these multiply. In a few hours putrefaction sets in. This is shown by the formation of a film or scum on the surface just below the severed neck. Microscopically the broth is seen to be teeming with organisms.

]

The first disease which Pasteur was able to demonstrate as causatively related to a living organism was a condition that was devastating the silk-worm industry of France. In 1866 he proved the contagiousness of the disease, showed that it was due to a living organism, and followed the organism through the life-history of moth, egg, worm, and chrysalis.

In 1870 the Franco-Prussian war broke out. Pasteur now decided to make investigations into the diseases of beer, his object being to improve the French brews and to carry the war into the enemy’s camp by making them equal to the German! He succeeded in isolating special organisms, mostly yeasts, which produced defects in beer (Fig. 106). This work naturally led to an enlargement of his views on the nature and action of micro-organisms.

About this time Pasteur was elected a member of the French Academy of Medicine, a very unusual honor for one not a medical man. Lister had already begun his teaching, based partly on the work of Pasteur, and indeed his first important paper on antiseptic surgery had been published in the very year of the Franco-Prussian war. On entering the Academy Pasteur found himself faced by all kinds of ancient prejudices and misconceptions in connection with his new doctrine, and especially with his denial of spontaneous generation. Among his supporters was the physiologist, Claude Bernard (p. 213). His work proceeded to more and more triumphant issues.

The first disease that affects man on which Pasteur was able to throw light was Anthrax, in relation to which his work interdigitates with that of Robert Koch and some other observers. Anthrax is a deadly and highly contagious condition which commonly affects cattle, but sometimes spreads to man. As early as 1855, a German observer had noted microscopic rod-like objects in the blood of beasts dead of the disease. In 1868 an older French contemporary of Pasteur had shown that a bacillus is not simply the inseparable companion of the disease, but also is its cause and its only constantly acting cause. At this time the losses of cattle from Anthrax in France were enormous. The character of the outbreaks had been studied and seemed wholly unexplained by what was known of the bacillus. Farmers found that they lost cattle in fields from which infected animals had been excluded for months or even years. How was it to be explained?

The explanation was, in fact, advanced in 1876 by the German observer, Robert Koch of Berlin (1843-1910), whose work was now beginning. He showed that the anthrax bacilli under certain conditions formed ‘spores’, that is to say small encysted bodies, exceedingly resistant to heat and to other changes of external conditions (Fig. 108). This discovery opened up a new field which was cultivated by Koch and Pasteur and their followers.

The rod-like organisms are growing typically in chains. Some of
the rods have white clear spots in them. These are the highly
resistant ‘spores’.
]

While making his studies on ferments in 1863, Pasteur had witnessed the formation of spores in the organisms of butyric fermentation, but had failed to grasp their significance. In 1869 he had again found spores forming in the organisms of silk-worm disease, and had shown that they resisted prolonged drying. On the basis of their resistance he had explained the persistence and latency of the silk-worm disease. Other observers had had similar experiences. The investigations of none of them, however, approached in brilliance and completeness those of Koch.

Koch found that spores always form in the blood and tissues of animals dead of Anthrax, provided that

(1) the temperature is suitable, and (2) there is sufficient oxygen. These two conditions, temperature and oxygen, were found to be necessary. Below 18° Centigrade spores are not formed; at 30° Centigrade they occur at the end of thirty hours; at 35° Centigrade in twenty hours. The rapidity with which spores are formed is, therefore, proportional to the amount of heat. Oxygen was also found to be indispensable. Anthrax blood, if deprived of oxygen, ceases to be virulent in twenty-four hours without putrefaction. When the blood is allowed to putrefy the virulence also disappears if putrefaction exhausts the oxygen quickly enough to prevent the spores having time to form. If the spores have already formed, putrefaction does not kill them, nor does it prevent them from developing later if circumstances become favorable. The persistence of the disease and its return in an infected country was thus explained. It was the spore which was the agent of preservation, which persisted where the conditions of temperature and of aeration had permitted it to form, and which always held itself in readiness to make new victims.

The matter was carried further by Pasteur in 1877. At that time he did not know of all the work of Koch. He succeeded in obtaining pure cultures of Anthrax. The question was then still being debated in France as to whether Anthrax was caused by a ‘virus’, that is to say a non-living poison, or by a microbe. Pasteur had long been a believer in the microbic theory, and it seemed to him probable that the blood of an animal infected with Anthrax, if sown in a suitable medium, would stock it solely with anthrax bacilli which he could then keep pure for an indefinite time in successive cultures, as he had done with yeast and other ferments.

Experiment proved this to be the case, and showed that the anthrax organism multiplied abundantly in urine made neutral or slightly alkaline. From that time the problem was solved. Take a series of cultures of the organism, transferring each time one drop from the preceding culture into 50 c.c. of fresh urine. The first dilution is 1/1000, the second one in a million, the third one in a thousand million. After ten cultures it falls to such a figure that the original drop of blood has been drowned in an ocean. Everything that it carried with it, to which we might attribute the production of Anthrax--red corpuscles, white corpuscles, granules of all sorts--is either destroyed by the change of medium or is widely disseminated in this ocean and is lost. Only the organism can escape the dilution. Why? Because it has multiplied in each of the cultures. A drop from the last culture killed a rabbit or guinea-pig as surely as a drop of anthrax blood. It was, therefore, to the organism that the virulence belonged. A conclusion of the first rank was firmly established.

With a ‘pure culture’ of Anthrax in his possession Pasteur was able to experiment in a way which none had previously attempted. The most interesting stage of his work was now entered upon. He perceived that there are some species of animals which are refractory to Anthrax. Such are the birds. Nevertheless, the blood of a bird, when drawn from the animal, is an excellent culture medium for the bacterium. Why does it resist infection in the animal? Pasteur showed that the anthrax organism will not live in the bird because the living-blood in full circulation is filled with an infinite number of corpuscles which, in order to live and perform their physiological function, need free oxygen. When, therefore, the anthrax organism enters normal blood of living birds, it meets competitors ready to seize the oxygen for their own use. But the blood of other animals besides birds contains corpuscles eager for oxygen. Why can anthrax grow in them and not in birds? This question Pasteur answered by a convincing series of experiments (1878). The normal temperature of birds is higher than that of mammals and is, moreover, higher than that at which the growth of the anthrax organism is most vigorous. Thus the blood corpuscles of the bird have the anthrax bacteria at a disadvantage. But if, by a cold bath, the temperature of a bird be lowered to that of a mammal, and if anthrax organisms be injected into the blood-stream, they will grow and flourish at the expense of the bird.

The experiments with Anthrax on fowls led to experiments on the same creatures with another disease, the virulence of which was known to vary, Chicken Cholera. Thus arose naturally Pasteur’s ideas and observations in the department of Immunity (p. 261).

If Pasteur can be said to have laid the foundations of the knowledge of the nature of infection, it is to Koch that we owe the main basis of the technique by which diseases are now studied. He it was who elevated Bacteriology into the position of a separate science. Soon after his work on Anthrax he published a remarkable research which placed our knowledge of wound infection on a firm footing. He is thus among those who helped to create modern surgical technique. Many other communications came from him. None was of more far-reaching importance than his demonstration of the organism of Tuberculosis in 1882. All subsequent work in connection with Consumption and allied conditions has been rendered possible only by this discovery of Koch. Other investigations associated with his name are on Cholera and on Sleeping Sickness. Koch was unquestionably the greatest bacteriologist that the world has seen. His genius was limited as compared to that of Pasteur, but his exquisite technical skill and acumen have never been excelled.

Since the time of Pasteur and Koch, the study of infectious disease has developed along various special lines. The work of these two men, however, has determined the direction of those lines, and they themselves are the most typical, as well as the greatest, representatives of the most important of all movements in modern Medicine.

§ 7. _Anaesthesia._

The aspect of surgical practice was dramatically changed during the course of the nineteenth century by two discoveries, that of Anaesthesia and that of the Antiseptic method. It will be convenient to consider Anaesthesia first.

There were from the earliest times many devices for producing more or less complete unconsciousness during surgical operations. An idea of the extremes to which surgeons at the beginning of the nineteenth century were put in this matter can be gathered from a glance at some of their devices (Fig. 108a).

The new era began in 1846 when the dentist, William Thomas Green Morton (1819-68), demonstrated at the Massachusetts General Hospital the simplicity and safety of Ether anaesthesia. The idea immediately caught on. Before the year was out Ether was being used for surgical purposes in England. In January, 1847, Sir James Young Simpson (1811-70) was using it in Edinburgh for obstetric purposes. A few months later he adopted Chloroform, which had been prepared by Liebig in 1832.

The use of the drugs spread very rapidly and almost as rapidly changed the character of surgical technique. Until the adoption of anaesthesia, speed was of primary importance in surgical procedure. Excessive speed now became a matter of less importance, and operative neatness and completeness took its place as the chief quality of good surgery. Moreover, operations of a more drastic character could be undertaken since the shock to the patient was minimized. Women in labor were found to bear Chloroform peculiarly well and safely, and its use in midwifery steadily spread despite some foolish and fanatical opposition.

Soon after the introduction of anaesthetics efforts were made by various methods to secure a painless state of a part without involving unconsciousness. The first successes were obtained in 1884 at Vienna with applications of solutions of the alkaloid (p. 325) Cocaine, first to the eye, then to the nose and other parts. Cocaine, or some derivative of it, has ever since been much used in Medicine. It was soon being given by injection under the skin for small superficial operations. Next, good results from injecting solutions of it into the nerves were obtained by several American surgeons, earliest of whom was W. S. Halsted (1852-). His work of 1885 was extended in 1898 by Harvey Cushing (1869-). Yet another American surgeon, J. L. Corning (1855-), introduced the method of so-called ‘spinal anaesthesia’. This is secured by injecting a solution of Cocaine or one of its derivatives into the spinal canal and thereby inducing insensibility to pain (‘analgesia’) below the site of injection. In 1908 the American G. W. Crile (1864-) introduced a valuable method of combining local and general anaesthesia, whereby he minimized the effects of ‘shock’ (pp. 310-11) during the progress of the operation.

From first to last almost all the pioneer work upon anaesthetics and analgesics has been of American origin. Even the word _anaesthesia_ is an American invention. It was introduced or at least familiarized by Oliver Wendell Holmes (1809-94), the distinguished and brilliant author of the ‘Breakfast Table’ series. Laughing Gas was first applied to dental purposes a short time before Ether was given its surgical application, and its introduction for this purpose was the work of the American dentist Horace Wells (1815-45), of Hartford, Connecticut.

FIG. 108a. SCREW adapted to the lower limb, as used by surgeons in the eighteenth century and the early nineteenth century, to compress the nerves in order to secure analgesia during amputation. Its application, however, was extremely painful in itself and injurious to the part operated on.

]

§ 8. _The Revolution in Surgery._

This history of antiseptic surgery is inseparably linked with the name of Lord Lister (1827-1912), whose work naturally dovetails into that of Pasteur. Lister’s attention was first called to the work of Pasteur in 1865. But Pasteur’s views on the life of micro-organisms came to a mind that had been prepared for them. Lister had had, moreover, a long and varied surgical experience and had been present at the first operation performed in England under Ether anaesthesia in 1846.

At that time and for long after, Surgery was cursed by the constant fear of sepsis. A vast amount of death and suffering was due to this cause, and surgeons were reluctant to perform many operations that we should now regard as trivial. Lister’s first attempt to make any scientific analysis of the septic state is to be found in a paper by him on _The Early Stages of Inflammation_ (1853). He showed that the effects of irritation on the tissues are twofold. Firstly, there is a dilatation of the arteries which is developed through the nervous system. Secondly, there is an alteration in the tissues on which the irritant acts directly. This alteration imparted, as Lister thought, an adhesiveness to both the red and the white corpuscles, making them prone to stick to one another and to the walls of the vessels, and so giving rise to stagnation of blood and ultimately to obstruction.

Some years before (1847) A. V. Waller (1816-1870), a pupil of Magendie, had shown that during the process of inflammation there is an active migration of white blood corpuscles through the walls of the capillary blood-vessels. Waller’s observations attracted but little attention at the time. They were, however, amply confirmed in 1878 and the following years by the German pathologist Julius Cohnheim (1839-84), a pupil of Virchow. Cohnheim showed that this process of migration of white blood corpuscles is the essence of inflammation and that when inflammation goes on to suppuration the pus that is formed consists largely of white blood corpuscles in a dead and disintegrating state.

Irritation, and the reaction of the body against it, ‘inflammation’, are encountered in all injuries in which the healing is not direct and healthy. It was those cases of injury in which the healing was indirect and unhealthy which then formed the surgeon’s chief problem. Of these there are a variety, now rare, then very common and fatal, as Blood-Poisoning, Erysipelas, Pyaemia, Septicaemia, Hospital Gangrene, and that form, then so common as to be almost normal, simple suppuration of a wound.

About 1861 Lister began to teach publicly that the occurrence of suppuration in a wound is determined ‘simply by the influence of decomposition’. The nature of decomposition was revealed to him by the writings of Pasteur. From him he learned that putrefaction was, in fact, a fermentation, and that it was caused by the growth of minute microscopic organisms borne by the air. It was generally supposed that air was the cause of sepsis, and precautions were taken to exclude it from wounds. But Lister now saw that not air but that which it carried was the mischief-maker.

The general course of action was now clear to him. As a laboratory proposition the destruction of the organisms of the air was simple. The problem was to exclude them from wounds during and after operation. The solution of that problem developed as ‘Antiseptic Surgery’, which later became ‘Aseptic Surgery’. At first he paid most attention to air, as the source of infection. He recognized, however, that he must also deal with the germs present in the wound and on his hands. Of the methods available for ridding the air of its germs, viz. heat, filtration, and chemical action, he chose the last.

At that time carbolic acid was in use as a means of treating sewage. At first, therefore, Lister tried lint soaked in crude carbolic. This he found liable to cause superficial sloughing and death of the tissues. He next obtained a purer acid, using a solution in oil. A putty formed of common whitening and a solution of carbolic acid in linseed oil was used as a dressing. He adopted later a system of spraying the part during operation (Fig. 109).

FIG. 109. THE ‘DONKEY ENGINE’, an apparatus designed and used by Lord Lister to maintain a carbolic spray over a part during operation. The engine is worked by the up and down movement of the handle to the right and the spray is delivered through the tube to the left.

]

When Lister began his work, amputation of a limb was a very fatal operation. Yet it had to be performed in most cases of severe fracture in which the bone was exposed because, without it, death from sepsis was almost certain. The improvement in Lister’s own records of amputation, incident upon his adoption of the antiseptic method, is well brought out by his own figures:

_Years._ _Cases._ _Recovered._ _Died._ _Mortality._
1864-66 35 19 16 43% without antiseptics
1867-70 40 34 6 15% with antiseptics

These results were considered extraordinarily good in their day. It is an index of the further advance since Lister’s first attempts that results ten times as good would now be regarded as unsatisfactory. Moreover not only has the further development of Lister’s method rendered amputation safer, but also it has enabled the surgeon to treat many cases without amputation, when before he would have been compelled to resort to that measure.

Lister first recorded his observations on the antiseptic system of surgery in 1867. Apart from the technical advances that he then set forth, he recorded also many new pathological facts that have since proved of great practical importance. Thus he showed that an uninfected clot, if undisturbed, can become organized into a living tissue, and that a piece of dead bone may be absorbed in an aseptic wound. These are now matters of common knowledge, but then they were instrumental in introducing a radically new outlook.

Lister gradually perfected his technique, chiefly in the direction of using milder antiseptics and adopting heat for the sterilization of instruments and dressings. The antiseptic system was given its military application in France during the war of 1870. It was soon taken up also by German surgeons. The history of surgery since Lister’s day has been very often told. An important element in it is the gradual supersession of ‘antiseptic’ by ‘aseptic’ methods (p. 248).

The Listerian system, in rendering surgery safer, had also the effect of opening up many fields of operation that had previously been regarded as impracticable. Especially is this the case with abdominal surgery, which effectively dates from the introduction of the antiseptic system. Lister was often misunderstood and some of his contemporaries, and some even of those who opposed him, were really practising his system without knowing it.

Among the most important reactions of antiseptic surgery was that upon the conduct of labor. Here Lister had a predecessor, as he gladly and generously acknowledged. This was the unfortunate and almost insane Viennese genius, Ignaz Semmelweis (1818-65). At the great lying-in hospital at Vienna in which he was an assistant the death-rate at one time rose to thirty per cent., the so-called ‘puerperal fever’ being the active cause. The women were attended by students or physicians who were visiting the post-mortem room. Semmelweis showed that the infective material that conveyed the fever was brought by the hands of the operator from the dead bodies and he showed that puerperal fever was caused by decomposed animal matter. By insisting on the hands of the operators being sterilized, Semmelweis succeeded in 1846 in enormously reducing the mortality. After the acceptance of Lister’s antiseptic system the methods of Semmelweis were universally introduced into the practice of Midwifery. Another predecessor of Lister was Oliver Wendell Holmes. As early as 1843 he pointed out that the mysterious ‘puerperal fever’ was contagious, and carried by the hands of the operator. He suggested precautions not dissimilar to those of Semmelweis.

§ 9. _Some Modern Surgical Advances._

Among the most capable surgeons of Lister’s own day was Thomas Spencer Wells (1818-97) of London. This great operator had been opening the abdomen successfully for certain conditions since 1858. By 1867 his methods were approaching the Listerian. Under Lister’s inspiration he further improved his technique and did more than any other man to raise the possibilities of abdominal surgery. Spencer Wells stands out for the extreme simplicity, directness, and effectiveness of his methods (Fig. 111), and for his exceptionally conscientious care as an operator. His name is commonly attached to an instrument of his invention of catching the bleeding ends of cut blood-vessels. The familiar ‘Spencer Wells forceps’ is at this day probably more frequently used than any other surgical instrument (Fig. 110).

FIG. 111. SPENCER WELLS performing an abdominal operation about 1870. The picture illustrates the extreme simplicity of the methods of this great surgeon. It also shows a method of administering chloroform. Air is pumped through a bottle into a mask held at a variable distance from the face of the patient.

]

Since the time of Lister many branches of Science have contributed to the development of surgical technique. No addition to the surgical armory has, however, been more important than that made by the physicist Wilhelm Conrad Röntgen (1845-1923). In 1895 he found that when an electric discharge passes through a high vacuum rays are emitted that are far more penetrating than ordinary light. These rays have since then been placed in series with light rays, ultra-violet rays and infra-red rays, and it has been shown that they differ from these only in their wave-length. The surgical application of the Röntgen or X-rays was at once made to the examination of bone. Since then the more accurate knowledge of the properties of these rays has made them of value in exploring almost every organ of the body. Radiography is now constantly applied in the diagnosis of medical and surgical conditions of the organs of the chest and abdomen.

The more dramatic achievements of modern surgery, the drastic operations that surgeons are now able to perform on the great cavities of the body--head, chest, and abdomen--have attracted much public attention. Nevertheless few surgical advances have relieved so much suffering and disability as the unsensational development in the treatment of fractures.

After the advent of Listerian methods the technique of the treatment of compound fractures was gradually perfected. Simple fractures--which are far commoner--continued, however, to be treated with splints in the traditional fashion. Plaster of Paris bandages, which came into wide use in the ’seventies, were some improvement; but prolonged immobilization of a limb, in either splints or plaster bandages, always involves much subsequent pain and stiffness, lasting, at best, for months. To obviate this, Massage--a practice of immemorial antiquity in Folk Medicine--had been introduced into Surgery in the sixteenth century by Ambroise Paré (pp. 92-94). The subject was little heard of till the last thirty years of the nineteenth century. The pioneer was the Dutch surgeon Johann Mezger (1839-1900), through whom some scientific advance was made.

The semi-conscious patient lies face downward on an elaborately carved bed. The bearded surgeon, dressed in his ordinary clothes, is trephining his skull and is rotating the trephine between his hands. Against the side of the bed lounges a gallant to whom a servant brings refreshment. In the background are two women assistants. A male assistant is spreading a plaster and another warming a towel over a brazier. Note that all present, surgeon, nurses, assistants, &c., wear their ordinary dress. No arrangements are made for washing. In the foreground is a cat playing with a mouse. ]

The introduction of X-rays into Surgery made for very accurate diagnosis of the state of fractures. It has thus gradually become possible to treat a large proportion of these injuries without immobilization either by splints or plaster. In many cases the injured limb is merely held in correct position between sandbags and massage used from the first. Much stiffness and disability is thereby avoided and the length of the period of treatment greatly shortened. The rise of a class of scientifically trained Masseurs has made possible a wider application of this valuable curative procedure.

Improvements in methods of operation have been very numerous during the last generation. Many can be appreciated only by those with technical knowledge. In 1886 Ernst von Bergmann of Berlin (1836-1907) introduced steam sterilization of dressings and thus moved toward the replacement of antiseptic by aseptic methods. W. S. Halsted, then of New York, had been working to the same end. In 1890, finding it impossible to sterilize the hands completely, he introduced the rubber gloves now universally employed by surgeons during operations. Much important work in experimental surgery has been done by Alexis Carrel of New York (1873-) and some of his laboratory methods have become available in surgical practice. The technique of abdominal surgery has been greatly advanced by many workers, important among whom are J. B. Murphy (1857-1916) of Chicago and the brothers Charles and William Mayo (1865 and 1861) of Rochester, Minnesota. The surgery of the brain was prosecuted in England by Rickman Godlee (1849-1925), the nephew and biographer of Lister, by Victor Horsley (1857-1916), and above all by William Macewen (1848-1926), a successor to Lister’s chair at Glasgow and one of the finest exponents of Listerian methods. The surgery of the nervous system in general, and that of the brain in particular, has been carried to extraordinary refinements in America by Harvey Cushing. There can be no doubt that during the twentieth century advances in Surgery have been more important and more numerous in the United States than in any other country.

Only those directly concerned with the operation are present in the room. All wear aseptic clothes and aseptic rubber gloves. Every source of infection is guarded against and all breathe through masks. The patient is covered by aseptic cloths and only the part operated on is exposed.

]

§ 10. _Bacteriology becomes a special Science._

We have seen the microbic view of the origin of disease demonstrated as a reality by Pasteur (pp. 224-35) and extended to special disease conditions by him and by Koch (pp. 229-32). While the French observer stood above all men for the clearness and steadiness of his vision and for his persistence and resource in following what he had seen from afar, his German colleague had a genius for visualizing particulars and for adapting mechanical devices and scientific discoveries to particular ends. Koch thus vastly improved and elaborated the methods for detecting and examining minute organisms. The significance of his results was at once recognized, but the complexity of the technique involved and the time and training necessary demanded the elevation of the subject into the position of a special science.

Though but fifty years old, the science of Bacteriology has itself undergone repeated subdivision. Noteworthy though the results of this process of constant subdivision have proved, it must be emphasized that the state of scientific subdivision cannot be final, and is indeed without meaning unless it lead to a subsequent synthesis--an event which we still await. It is the general Laws reached by these special sciences that are philosophically important, and the specialist himself is often ill-placed and ill-equipped for the estimation of the true significance of such Laws. The philosophic thinker who deals with generalities and centuries must often be content to pass the details in silence. Nor is this true only of the professed philosopher. It applies no less to the philosophical physician. It is his task to try to see life steadily and see it whole. He must think both in terms of the individual life and of the community life, and for him the results of the bacteriologist, the physiologist, and of all their colleagues are as means to an end. It is from this standpoint that we should seek to visualize the fruits that bacteriological science in this last age has laid at the feet of humanity.

With Koch’s work on Anthrax in 1876, on the bacteria that commonly infect wounds in 1878, and with his great discovery of the bacillus of Tuberculosis in 1882, the study of the infective diseases entered on a new stage. The enemy had been seen and was now known for what he was. The bacteriologist had succeeded in making prisoners. These had been isolated and made to live in test-tubes. Moreover, the organisms had been compelled to dwell alone without mixing with other species. They had been obtained, as bacteriologists say, in ‘pure cultures’, and delicate methods of detecting and differentiating them had been developed. With a pure culture in his hands, the bacteriologist can determine the influences favorable or unfavorable to the growth of the disease organism, and he can investigate conditions that can exalt, destroy, or modify its activity (p. 233).

An important series of criteria established by Koch have remained the tests by which the disease-bearing character of these organisms can be established. To prove that an organism is the inseparable cause of any disease we need to demonstrate:

1. The constant presence of the organism in every case of the disease.

2. The preparation of a pure culture, which must be maintained for repeated generations.

3. The reproduction of the disease in animals by means of a pure culture removed by several generations from the organisms first obtained.

These conditions have been fulfilled for many diseases. Evidently the third test can be applied only in conditions to which animals other than man are susceptible. Now in this matter the organisms that produce disease vary greatly. Some, for instance those of Anthrax, are easily conveyed to a variety of species of animals; others, for instance those of Syphilis, are with difficulty conveyed to very few species of animal; yet others, for instance human Malaria, cannot be conveyed to any animal save man.

Some light is thrown on the life-history of the second and third classes by recent discoveries. The science of Comparative Pathology, that is the knowledge of the relations of the diseases of different species of animals, is of very recent growth. It has already demonstrated, however, the existence of organisms bearing some resemblance, for instance, to those of human Syphilis and human Malaria as the cause of disease in animals. By studying the life-history of these organisms in animals and by studying their effect on animals, valuable side-lights have often been thrown on the allied diseases in man. Moreover, in exceptional cases and in some special diseases, it has been possible to convey a disease experimentally to man.

A second important factor has gradually come into prominence with the extension of bacteriological knowledge. It is evident that not all men are subject to all human diseases. Even in the most destructive epidemic there are some that escape. These lucky ones may be naturally ‘immune’. Many diseases, such as Measles, seldom recur in individuals who have been infected, so our lucky ones may thus have an ‘Acquired Immunity’.

The general nature of Immunity we shall presently discuss (p. 259), but we note here that Immunity may be relative or absolute, and may, moreover, vary according to the circumstances of the individual. Thus, for instance, a well-fed, well-housed person of temperate habits, living an open-air life, is unlikely to develop consumption. Restrict his diet, confine him in an office, deteriorate his mode of life, and he may well fall a victim to it. The investigation of facts such as these on a large scale has demonstrated that the _soil_ in which disease grows is of no less import than the _seed_ from which it grows. The problem of disease causation is thus immensely complex. We are only just beginning to draw up general laws on the subject, and in approaching it we are beyond the frontiers of our positive knowledge. Turned back from this difficult borderland, we must content ourselves with surveying a part of the better-known territory and considering a few specific bacteriological achievements. These we may now consider under the headings of the diseases associated with them.

§ 11. _Some Important Bacteriological Results._

_Diphtheria_ is a disease for which physicians now habitually demand a bacteriological diagnosis. Bretonneau of Tours (p. 185), working on clinical and post-mortem material, and without the use of a microscope, was able to distinguish Diphtheria as a specific disease (1826). Half a century later (1883) Edwin Klebs (1834-1913) of Zürich, a pupil of Virchow, described the specific organism of the disease. In the following year Friedrich Loeffler (1852-1915), a Prussian and an assistant of Koch, succeeded in cultivating it. The organism has since been known as the ‘Klebs-Loeffler Bacillus’. Its study has thrown much light on the nature of bacterial action in general and has, moreover, led to important therapeutic developments (p. 263).

Of all diseases destructive of human life, none is so dramatic as _Plague_, the scourge of mankind throughout history. The bacillus of Plague was discovered independently by the Japanese Shibasaburo Kitasato (_c._ 1860-), a pupil of Koch, and by the Frenchman Alexandre Yersin (1863-), a pupil of Pasteur, during an epidemic at Hong Kong in 1894. These two observers cultivated the organism and reproduced the disease by inoculation of pure cultures in animals. It had long been observed that outbreaks of a deadly disease of rats and mice were liable to precede Human Plague. These ‘epizootics’ which precede ‘epidemics’ are now known to be due to the bacillus of Plague. A mass of evidence has been collected to show that the normal carrier of the Plague infection is the rat flea. This knowledge has led to the formulation of effective measures for the control of Plague. These measures are based on the wholesale extermination of the rat population which harbors the infective fleas. The study of the Natural History of the Plague Bacillus has also led to prophylactic measures for the safety of individuals.

FIG. 114. BACILLI OF DIPHTHERIA FROM A CULTURE. Highly magnified. In cultures these bacilli are liable to degenerate into thick club-shaped forms several of which are here seen.

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_Malta Fever_ is a disease of much wider distribution than its name implies. Not only is it found throughout the Mediterranean area, but it is also encountered in China, South Africa, and parts of both North and South America. It is a long, tedious and wearing disease, and though the mortality from it is low, yet it was at one time one of the main causes of disability in the British army at Malta. In 1887 an English military surgeon, David Bruce (1855-), succeeded in cultivating a characteristic bacillus from the spleen of a patient dead of the disease, and he established its causal relation to Malta Fever. In 1904 its mode of propagation was studied by a British Government Commission. The goat was shown to be the normal host of the bacillus, and in Malta 50 per cent. of these animals were found to be infected. The disease, it was discovered, is usually transmitted by goat’s milk. The knowledge has led to the application of very effective precautions (Fig. 116).

FIG. 116. DIAGRAM SHOWING THE INCIDENCE OF MALTA FEVER in the British garrison at Malta immediately before and immediately after the institution of the preventive measure of cutting off the supply of unboiled goats’ milk. The figures of 1905--before the new regulation came into force--are represented in black. The figures in the margin refer to the number of cases per ten thousand of strength. The figures for 1907 are represented in white on the same scale. There is a drop in the maximum monthly incidence from 94 to 2. The size of the garrison itself remained almost constant throughout the period. ]

Among the most anciently described diseases is the condition known as _Tetanus_ or ‘Lockjaw’. There are unmistakable references to it in the _Hippocratic Collection_ and notably in the _Aphorisms_. Two of these

references we have already quoted (p. 23). A general association of Tetanus with wounds has long been recognized. In the eighties the disease was shown to be transmissible from animal to animal. It was, moreover, experimentally produced in animals by the inoculation into them of garden mold. In 1889 Koch’s pupil, Kitasato, obtained the Bacillus of Tetanus in pure culture and conveyed the disease to animals. He found the organism would grow only in the absence of Oxygen. It is, in fact, a type of a large and now well-known group, the ‘anaerobic’ bacteria. The natural habitat of the Tetanus Bacillus has been proved to be soil, and especially richly manured soil. The knowledge of the bacillus, of its habitat, and of its mode of growth has led to the development of a valuable protective process.

Looking backward from the standpoint of present-day knowledge we can trace _Typhoid Fever_ far back in history. Nevertheless, it was not till 1837 that the distinction between the two distinct conditions known now as ‘Typhoid’ and ‘Typhus’ was first clearly made. This was the work of an American physician, William Gerhard (1809-72), of Philadelphia. The English were backward in adopting the distinction. The organic cause of Typhoid Fever was first seen in 1880 by Karl Joseph Eberth (1835-1927), a pupil of Virchow, and after him it is known as ‘Eberth’s Bacillus’. It was not isolated, however, until some years later. It is an inhabitant of the intestine, and its natural history was obscured by confusion with certain other and very similar organisms, which also dwell in the intestine. These have now been fairly differentiated from each other, and in the course of this process the ‘flora’, both normal and pathological, of the intestinal canal has become well known. Moreover, it has been shown that typhoid organisms are not always of the same species, but that several closely allied forms produce several closely allied diseases. Lastly, certain of the effects wrought by the typhoid group of organisms on the body, which is their host, have been exactly investigated. These investigations have led to improved methods of recognition of the disease, that is to say, _diagnosis_, and also of prevention of its incidence, that is to say, _prophylaxis_. To these methods of diagnosis and of prophylaxis we now turn.

FIG. 117. BACILLI OF TETANUS FROM A CULTURE. Highly magnified. The drum-stick forms are very typical.

]

FIG. 118. BACILLI OF TYPHOID FEVER FROM A CULTURE. Highly magnified. The long flagellae, which are constantly in motion and are very characteristic of these organisms, are well seen. ]

§ 12. _The Study of Immunity._

In the production of disease by living organisms two main factors are involved. There is, firstly, the multiplication of the organisms themselves, and there is, secondly, the production by the organisms of poisonous substances or _toxins_. The former phenomena are spoken of as _infection_, the results of the latter come under the title of _intoxication_ or _toxic_ effects. The first toxins to be investigated were those isolated from putrefying substance and named _ptomaines_ (1876, by false formation from Greek _ptoma_ ‘a corpse’). These are, in fact, definite chemical substances of the group known to chemists as ‘alkaloids’ (p. 325). Later, toxins were prepared from actual disease organisms such as those of Typhoid and Tetanus (1888). The method was introduced of filtering the bacteria away from their fluid cultures and thus obtaining a bacterium-free liquid containing the poisonous bacterial products. This was the starting point of the scientific study of toxins. These, it soon became clear, were either substances which were normally sent out by the bacteria, _exotoxins_, or they were normally retained within the bacteria and could only be obtained in solution by breaking up the bodies of the bacteria, _endotoxins_. The use of these toxins has been essential for the scientific study of Immunity.

The word _Immunity_ is derived from a Latin word which means ‘exemption from military service’. In Medicine it indicates an exemption, relative or absolute, from the incidence of a disease. Immunity in the medical sense is of various kinds. There is ‘species immunity’, some species not being liable to diseases to which others fall victims. There is relative and there is absolute immunity. There is innate and acquired immunity. Of acquired immunity there is a natural immunity resulting from the ordinary contraction of a disease, and there is an ‘artificial immunity’. It is only artificial immunity that is in the hands of the physician.

Artificial immunity itself is of two kinds, and both kinds are of use and of importance in Medicine. There is an _Active Immunity_, which is produced directly by injection of disease organisms or their products. It is found, however, that if a high degree of active immunity be attained the blood serum of the immunized animal, when injected into a second animal, may itself produce a state of immunity. The state thus indirectly produced is described as _Passive Immunity_.

The early observers found that when organisms are cultivated outside the body they lose their virulence to a greater or less degree. Pasteur found this for Chicken Cholera (p. 234). He found, moreover, that such ‘attenuated cultures’, when inoculated, protect against the disease. By the use of attenuated cultures he succeeded in establishing a state of ‘Active Immunity’ against Chicken Cholera. But there are many other ways of attenuating the virulence of an organism. Thus, in 1882, Pasteur showed that to grow Anthrax bacilli at a high temperature would reduce their virulence. These bacilli of reduced virulence could be injected into a sheep. They would give the animal the disease in a mild form and protect it against further attacks of the disease. They acted, in fact, in the same way as did the old ‘Inoculation’ of Small-Pox (p. 183).

It has been found, however, that the same kind of immunity which is produced by administering attenuated cultures is sometimes given even by dead cultures. Nearly all active immunization is therefore done by inoculating such killed cultures. These are usually called ‘Vaccines’ from the analogy which they bear to vaccination. The most familiar and effective ‘vaccine’ is that against Typhoid. Moreover, it has been found that in certain cases the principle of the induction of Active Immunity may be applied directly in the treatment of disease. The conditions that respond best to this line of treatment are those which present some localized infection, such as a boil or carbuncle. In such cases we must suppose that, while the local capacity for resistance is lowered, yet reserves of resistance in other parts of the body can be brought into play. These reserves are called up by the signal that reaches them by the reaction of the body against the Vaccine.

It has been shown that, for the production of Active Immunity, the actual bodies of the disease organisms are not always necessary. In some cases, toxins obtained from these disease organisms are themselves sufficient to induce Active Immunity. The matter may become of great medical importance in the future and is already applied for Diphtheria (p. 265).

We turn to ‘Passive Immunity’. The fact that Immunity can be transferred from one animal to another via the serum proves that the immunizing serum contains substances antagonistic to the bacterium or toxin against which immunity is conveyed. These antagonistic substances are spoken of as _Antibodies_. A series of very important observations on Antibodies has been made, and may in time profoundly modify not only our views of Disease but also our whole conception of the workings of the living body. We find that it is not only toxins that stimulate the formation of antibodies. Antibodies can be elicited also by the introduction into the tissues of the living body of red blood corpuscles, of embryonic tissue, and of various soluble tissue-constituents of animal or vegetable origin. We are still only on the threshold of the investigation of this subject, which may be as important philosophically as it is therapeutically.

§ 13. _Some Practical Applications of Immunity._

We may now consider a few special applications of our knowledge of the defences against bacterial action.

_Diphtheria_ is a disease in which the characteristic organisms are found only locally, and in artificially produced cases only at the site of inoculation. It therefore seemed probable from the first that the symptoms were due not to the organisms themselves but to poisons that they threw off, that is to their ‘exotoxins’. This was given demonstrational form in 1889 by two pupils of Pasteur, Pierre Roux (1853-) and Alexandre Yersin (1863-), who investigated many of the properties of these toxins. In the following year (1890) Emil von Behring (1854-1917), a Prussian Army Surgeon, and Kitasato showed that it was possible to produce a Passive Immunity against Tetanus by a serum from an infected animal, the immunity being efficient against 300 times the fatal dose of Tetanus. Their paper contains for the first time the word _antitoxic_. Immediately after, von Behring showed that against Diphtheria, too, immunity could be obtained by injecting serum from an animal that had been previously injected with living cultures of the Diphtheria bacillus. This epoch-making discovery of von Behring was soon given a practical application. It was found possible to induce a degree of immunity even after the onset of the disease. The first human case was a child in a clinic at Berlin in 1891. Antidiphtheritic serum was placed on the market in 1892. In a few years’ time its administration had become a routine part of the treatment of the disease. Diphtheria antitoxin is one of the greatest additions to therapeutics. With competent administration the case mortality of Diphtheria is one-half or one-quarter of what it is without the use of Antidiphtheritic serum. (Fig. 119.)

FIG. 119. DEATH-RATE OF CASES OF LARYNGEAL DIPHTHERIA IN PUBLIC HOSPITALS IN LONDON. Antitoxic serum came into use in London in 1895 and into full use in 1896. As its application became more general and as the method of administration improved the death-rate from this very grave condition progressively fell. ]

An important aspect of the reaction of the body to the Diphtheria toxin was revealed by B. Schick of Vienna in 1908. The technique of inducing it was perfected by him in 1913, and the test is known by his name. He showed that susceptibility to the disease could be detected by the behavior of the skin after injection of minute doses into it. It has thus been found that new-born infants are seldom susceptible and that the proportion of susceptibles increases up to two years of age, but that then it diminishes. The actual proportions of susceptibles, as estimated in a large number of cases in New York City in 1919, are as follows:

Of those under 3 months 15% are susceptible
Of those between 3 months and 6 months 30% are susceptible
Of those between 6 months and 1 year 60% are susceptible
Of those between 1 year and 2 years 70% are susceptible
Of those between 2 years and 3 years 60% are susceptible
Of those between 3 years and 5 years 40% are susceptible
Of those between 5 years and 10 years 30% are susceptible
Of those between 10 years and 20 years 20% are susceptible
Of those over 20 years 15% are susceptible

These figures show why Diphtheria is mainly a disease of childhood and is relatively seldom encountered in adults. They also make it evident that steps for protecting individuals against contracting the disease--‘prophylactic measures’ as they are called--need only be taken with a fraction of the population. The useful term _Prophylaxis_ is derived from a Greek word meaning a watchman or guard. It is used to describe preventive measures against disease in general, but is more specially applied to that form of protection which is achieved through the artificial production of Immunity.

Such prophylactic measures are now available against Diphtheria. They differ from those in use against any other disease, since the substance injected is neither the living infective material as in vaccination against Small-pox (p. 184), nor is it a killed culture of the organisms as in immunization against Typhoid (p. 268), nor is it the serum of an immunized animal as in the protective measures against Tetanus (p. 267). The Toxin itself (mixed with an experimentally determined proportion of its antitoxin) is now in wide and effective use as a prophylactic against Diphtheria. The method was proposed by von Behring (cp. p. 264) in 1913. The details, however, have since been worked out in the laboratories of the New York City Department of Public Health and have been mainly the work of W. H. Park (1863-). The susceptibles are first determined by the Schick test and are then immunized against the disease. The immunization reduces the likelihood of contracting the disease to about one quarter.

Plague differs from Diphtheria in that the organisms, instead of being local, pullulate throughout the body of the victim. As in the case of most diseases of this type, the toxins of Plague are chiefly _endotoxins_, unlike those of Diphtheria, which are _exotoxins_ (p. 263). Thus, the filtrate of a culture of Plague Bacilli is but little toxic and confers little or no immunity. Protective vaccines of a killed culture of Plague Bacilli are, however, prepared, and these confer considerable immunity. It is claimed that they reduce the liability to the disease by about three-quarters, and the case mortality by about one-half. Prophylactic inoculation against Plague is associated especially with the name of the Russian investigator Waldemar Haffkine (1860-), a pupil of Pasteur, who was for many years in the service of the British Government in India, the Plague center of the world.

After Diphtheria one of the earliest diseases of which the toxins were investigated was _Tetanus_. Kitasato found in 1891 that the filtrates of pure cultures injected into animals are very toxic. A peculiar feature is the incubation period of some days that occurs between the inoculation and the advent of the symptoms. This fact had been referred to, more than two thousand years earlier, in the _Aphorisms_ of Hippocrates (p. 23). Moreover, it has been found that, soon after inoculation, the Tetanus toxin disappears from the blood-stream. This, it has been shown, is due to its affinity for nervous tissue, with which it rapidly enters into some sort of combination. The fact is of clinical significance and of therapeutic application.