La risorsa globale per le prove scientifiche sulla sperimentazione animale

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The work and responsibilities of the pathologist

Delivered 19th June 1928
by Sir Bernard Spilsbury
 
The pathologist is a specialist in the study of the scientific aspects of disease, considering them from the point of view of the essential causes of disease, of the changes, visible and microscopical, which they produce in the body, and of the .reactions which they provoke in the  patient. Employing laboratory methods, and with the aid of instruments of precision such as the microscope, the pathologist applies his skill and knowledge to the diagnosis and the treatment of disease. The growth of scientific knowledge during the last 50 years, and the elaboration of laboratory methods of investigation, have greatly increased the labours of the pathologist, and they are bringing about a division of the work between the pathologist, using the term in the narrower sense, the bacteriologist, and the chemist. In this address Iemploy the term "pathologist" to include these three groups of workers.

It would be impossible in the time at our disposal to attempt any comprehensive account of the work of the pathologist, as it would be necessary to deal in detail with the technical aspects of the subject. I therefore propose to give a few illustrations of the achievements of pathology in the study of the causes and processes of disease, and to indicate some of the applications of this knowledge to the diagnosis and treatment of the sick person. I will take first what I like to call the romance of anthrax. Anthrax is a very fatal disease, to which sheep, cattle, and horses are specially susceptible, men being infected directly from these animals or from their hides and wool; in this country where the disease is a rare one, it is from imported hides and wool that the disease arises in almost all cases.

The disease has been recognised from very early times; the murrain of cattle recorded in Exodus is supposed to have been anthrax. In the Middle Ages wide-spread epidemics were recorded in Europe and Asia, in which cattle and sheep were decimated, and it has been one of the factors in the production of famines. About the year 1850, tiny bodies were observed under the microscope in the blood of animals suffering from the disease, and it was claimed that blood containing these bodies produced the disease when it was introduced into a healthy animal. The matter was still under dispute when, in 1870, Koch, at that time a country practitioner in Germany, devised methods of growing the organism outside the body in tubes of culture media; he showed that these cultures had distinctive characters, and he reproduced the disease in healthy animals by injections of the cultures, obtaining the same organisms again from the experimental animals when they succumbed to the infection. Koch afterwards discovered the organisms of tuberculosis and of cholera, and the application of his methods by other workers has resulted in very notable discoveries of the causative agents in disease.

Koch’s proof of the cause of anthrax was utilised by Pasteur—who had already begun his investigations on infectious diseases—to develop a method of protecting animals against disease. Starting from the known fact that an animal which had recovered from an attack of anthrax was protected against the disease, he experimented with cultures of the anthrax bacillus until he succeeded in so reducing the virulence or potentiality to reproduce the disease, that on injection of the attenuated cultures into healthy animals they developed protective powers which enabled them to resist the subsequent injection of virulent cultures of the organism. The method of protective inoculation has been widely employed in countries where the disease is prevalent, with the result that the mortality in cattle and sheep has been greatly reduced. In France, for example, where millions of inoculations are made in the course of the year, the death rate in animals has been reduced to about one-twentieth of what it was before inoculation methods were employed.

The success of this method led Pasteur to attack the dread disease hydrophobia, of which the mortality in dog and man was very high. He did a very considerable amount of experimental work on animals, and he showed that rabbits could be infected from rabid dogs and from patients who had died from the disease. He found that the virus or active principle of the disease was always present in the spinal cord of the rabbits used in the experiments, and that healthy dogs could readily be infected by injections made from this material. On keeping the spinal cords of the rabbits under carefully controlled conditions he found that the virus rapidly lost its strength, until at length it failed to reproduce the disease in dogs. Taking advantage of the fact that persons bitten by rabid dogs did not develop the disease usually for some weeks, he injected into patients preparations from the spinal cord of the experimental rabbits, using first a very attenuated virus, and repeating the injections with virus of increasing virulence. By that means he succeeded in protecting the patient before the natural disease had time to develop. The result of this treatment, carried out in the Pasteur institutes in different parts of the world, has been to reduce the fatalities to less than one per cent, of those treated.

I have described the investigation of anthrax and hydrophobia, because they are pioneer examples of the pathological methods used in the discovery of the cause and the treatment of infectious disease. In some infections the protective powers conferred upon the patient or the animal are present in the blood, and advantage is taken of this fact to treat patients who are suffering from one of them by injections of the blood fluid, or serum, of an animal which has been protected or immunised against that particular infection. The animal used for this purpose receives a number of injections, containing the organism or its specific poison, in carefully graduated doses. The animal after each injection develops in its body and blood substances which counteract the effects of the poison which has been injected; after a number of injections, the protection conferred upon the animal is a very high one. A part of its blood is then withdrawn from the animal, and from it is separated the serum which is used for injection into the patient, where it acts as an immediate antidote to the poison produced by the disease. One of the most frequent applications of serum treatment is in diphtheria, and it has been clearly proved that the mortality from the disease is greatly reduced by the injection of the specific scrum; the beneficial effects are very striking when the patient is treated at an early stage of the illness, but is less effective with every day's delay in the use of the serum.

The pathologist, as part of his routine work, is asked to diagnose infectious disease by the discovery of the organism. In many cases this is accomplished by microscopical examination, aided by the examination of cultures made from the patient. In some cases these methods fail, and recourse may be had to animal experiments to enable the diagnosis of the disease to be obtained. A disease in which this method of investigation is often required is tuberculosis, for in some obscure and early cases, the search for the organism by microscopical methods is very like seeking for a needle in a haystack. In such a case an injection of the suspected material is made into a guinea-pig, and after allowing sufficient time for the disease to develop, the animal is killed. The changes produced by the tubercle bacillus are characteristic  and the presence of these changes in the dead body of the animal enable a diagnosis to be made in many cases where other methods have failed. Another difficulty with which the pathologist has to contend is that some of the bacteria which produce specific diseases have their doubles, i.e., organisms which are exactly like them in appearance, and it may be also in the growth of cultures made from them, but which are themselves harmless, and recourse may have to be made to an animal experiment to distinguish the two organisms. I recall in that connection the case of a schoolboy who developed diphtheria, and from whom I obtained the organism of the disease. The boy made a good recovery, and as a precaution he was examined again to be certain that no diphtheria organisms were still present in his throat so as to render him a danger to others. I found the organism in small numbers, and the treatment was continued and the boy kept in isolation. Repeated bacteriological examination, extending over more than two months, always showed the presence of a few organisms. At last it was decided to inject the organisms into a guinea-pig; this was done, and the animal suffered no ill effects, as it would have, if the organism had been an active diphtheria bacillus; it was proved in this way that the boy had got rid of the diphtheritic infection, and was harbouring its harmless double.

There is much misunderstanding of the nature and effects of inoculation experiments upon animals. In the vast majority of cases the animal suffers no worse effect, at the time of introduction of the material, than the prick of a hypodermic needle. In some cases the development of the disease quickly ends in death; in others, as for example tuberculosis, the animal presently shows signs of the disease sufficient to indicate that it should be destroyed and its dead body examined. Such an animal suffers far less than the patient in whom the disease terminated fatally. It is only in a very small proportion of cases that serious suffering, in the sense of pain, attends inoculation experiments, and in these cases it is usually shortlived owing to the rapid progress of the disease.

I will now deal with the chemical problems which are presented to the pathologist. Shortly after the outbreak of war I was asked by a London coroner to make a post-mortem examination of a man who had died from jaundice. The man had been working at one of the newly established aeroplane works at Hendon, in a building in which the wings of the aeroplane were constructed and varnished, and he was exposed to the heavy fumes of the varnish or "dope" given off from the wings after the varnish had been employed. Other workers in the building had suffered, but less severely, and it was suspected by the workers that the fumes of the dope were responsible for their ill-health. My examination of this man showed that his death was due to severe disease of the liver, similar in some respects to a rare form of severe jaundice, but differing in certain particulars; the presence of this disease, and the fact that other workers were suffering in a similar manner, strengthened the suspicion  that some form of poison was responsible for the illness. My colleague, Sir William Willcox, who had examined the man during his illness, was called in, and was furnished with samples of the dope and of its separate ingredients, which included a number of volatile substances, namely methylated spirit, acetone, benzine, and a substance called tetra-chlorethane.These substances were all present in the vapour given off by the varnish as it dried, and it was a matter of considerable importance to determine which, if any, of these substances acted as a poison. This could only be done by experiments on animals, and a number of rats were exposed to the action of the fumes for some hours daily for about a week. One rat was subjected to the vapour given off by the varnish itself, and others to that of the four volatile ingredients separately. It was proved during the experiments that the animals exposed to the varnish and to tetra-chlor-ethane suffered in health, being drowsy, taking less food, and not increasing in weight like the other animals. At the end of a week the animals were killed, and their organs were examined microscopically, and it was found that the effect of tetra-chlor-ethane had been to produce severe damage to the liver, dope itself producing less severe effects, whilst the other three ingredients of the dope produced no ill effects. By this means information was obtained as to the cause of the illness, which could not have been gained in any other way. The result of the investigations was that improved ventilation systems suitable to this form of vapour were introduced into the factories, since the work was urgent and could not be stopped; the workers were subjected to regular medical inspection; later it was found possible to substitute a non-poisonous medium for the poisonous tetra-chlor-ethane. In all some 70 persons suffered severely, and 12 died, most of the illnesses having been contracted before the cause had been ascertained; by this means poisoning by tetra-chlor-ethane eventually ceased, no case occurring during the later years of the war.

Another poison on which investigation was required during the war was tri-nitro-toluene, more familiarly known as T.N.T. Here the problem was a different one, because the substance is a pure chemical and is a solid and not a vapour, and the question in cases of poisoning was as to the portal by which the poison entered the system. Here again experimental work served a very useful purpose in indicating the measures to be employed to reduce the risk of handling the substance. Another chemical poison is carbon monoxide, the poisonous constituent of coal-gas and a product of incomplete combustion. In this case the experiments on mice carried out by Professor J. S. Haldane, established the mechanism by which the poisonous action was produced, and demonstrated the proper method of treating those who were suffering from its effects.

You will have noted that in the inadequate survey of the work of the pathologist I have continually directed your attention to the use of experiments upon animals, both in the study of the origins of disease, and as an aid in diagnosis and treatment. A large part of our knowledge of bacteriology is based upon experimental work; this is inevitable in the present state of our knowledge, for an important means of testing suspected organisms is by the reproduction of the disease in living animals. It is also required for the diagnosis of infectious disease in the patient, and pathologists are finding themselves compelled to have a Home Office licence for vivisection in order to perform the necessary tests on living animals. For this reason, in recent years, the number of licences granted to pathologists all over the country has greatly increased. With regard to the responsibilities of the pathologist, he is a medical practitioner, who, like his clinical colleague, has to apply his skill and knowledge to the best advantage for his patients. He must avoid error as far as possible, employing exact methods, which must include, at present, animal experiments. The scientific advances of the last 50 years in relation to medicine, have been largely based on experimental work, and have gone far to revolutionise the treatment of some diseases ; as a result there are infections, which at one time were widespread, with which the modern practitioner is scarcely acquainted. If our forebears of a century ago could see the work which has been done in modern science and medicine, they would exclaim, " Had we but had your knowledge what an enormous amount of suffering would have been prevented."


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