The Doctrine of Specific Etiology by Rene Dubos

Extracted from Mirage of Health (1959)

Until late in the nineteenth century disease had been regarded as resulting from a lack of harmony between the sick person and his environment; as an upset of the proper balance between the yin and the yang, according to the Chinese, or among the four humors, according to Hippocrates. Louis Pasteur, Robert Koch, and their followers took a far simpler and more direct view of the problem. They showed by laboratory experiments that disease could be prouced at will by the mere artifice of introducing a single specific factor—a virulent microorganism—into a healthy animal.

From the field of infection the doctrine of specific etiology spread rapidly to other areas of medicine; a large variety of well-defined disease states could be produced experimentally by creating in the body specific biochemical or physiological lesions. Microbial agents, disturbances in essential metabolic processes, deficiencies in growth factors or in hormones, and physiological stresses are now regarded as specific causes of disease. The ancient concept of disharmony between the sick person and his environment seems very primitive and obscure indeed when compared with the precise terminology and explanations of modern medical science.

Unquestionably the doctrine of specific etiology has been the most constructive force in medical research for almost a century and the theoretical and practical achievements to which it has led constitute the bulk of modern medicine. Yet few are the cases in which it has provided a complete account of the causation of disease. Despite frantic efforts, the causes of cancer, of arteriosclerosis, of mental disorders, and of the other great medical problems of our times remain undiscovered. It is generally assumed that these failures are due to technical difficulties and that the cause of all diseases can and will be found in due time by bringing the big guns of science to bear on the problems. In reality, however, search for the cause may be a hopeless pursuit because most disease states are the indirect outcome of a constellation of circumstances rather than the direct result of single determinant factors.

It is true that in a few cases—far less common than usually believed—the search for the cause has led to effective measures of control. But it does not follow that these measures provide information as to the nature of the trouble that they correct. While drenching with water may help in putting out al blaze, few are the cases in which fire has its origin in a lack of water. The story of insulin and diabetes well illustrates that the discovery of a therapeutic agent does not necessarily solve the problem of disease causation.

Diabetes was first produced in experimental animals by interfering with pancreatic secretion, and this discovery led to the preparation from pancreas of a substance, insulin, which plays an important role in the metabolism of sugar. Insulin was then shown to be highly effective in the treatment of diabetes in man. This therapeutic triumph is probably the most elegant and spectacular achievement of medical science, but its bearing on the etiology of diabetes is far from clear. While diabetes can be produced in experimental animals by injuring the pancreas and thus interfering with the production of insulin, the disease as it occurs in man is a general metabolic dysfunction affecting the metabolism of protein, fat, and mineral, as well as of sugar. The primary disturbance may be in some part of the body quite remote from the pancreas and the deficiency of insulin may be secondary to it. Treatment with insulin corrects the manifestations of diabetes but it has no effect on the primary lesion of the disease, which remains unknown in many cases. Likewise, cortisone is highly effective against many inflammatory states which do not originate from a lack of this hormone in the patient, just as aspirin, which is a synthetic drug foreign to the body, can alleviate pains and headaches.

Thus, effective therapies do not constitute evidence for the doctrine of specific etiology, and there are many cases in which a given disease can be controlled by several unrelated procedures. The incidence of malaria in a community can be reduced by drugs that attack the parasite, by procedures that prevent mosquitoes from biting man, by insecticides that poison the mosquitoes, or by agricultural practices that interfere with their breeding. The difficulties inherent in the concept of causation of disease are now apparent even with regard to tuberculosis, long thought to have provided the most spectacular demonstration of the doctrine of specific etiology. All textbooks dealing with infectious diseases consider the discovery of the tubercle bacillus as the highest peak of the science of medical micro  biology. The circumstances were indeed dramatic. At that time tuberculosis was by far the most important disease in the Western world. The tubercle bacillus was difficult to visualize by microscopic techniques, and even more difficult to cultivate in vitro. Yet Robert Koch succeeded in demonstrating its presence in all tuberculous tissue that he studied and in producing at will experimental tuberculosis by injecting small amounts of cultures of the bacillus into guinea pigs, rabbits, and mice. flow could one doubt, after these spectacular achievements, that the bacillus isolated by Koch was the cause of tuberculosis? There was, however, another aspect of the problem that had remained hidden from Koch. It can be stated with great assurance that most of the persons present in the very room where he read his epoch-making paper in 1882 had been at some time infected with tubercle bacilli and probably still carried virulent infection in their bodies. At that time, in Europe, practically all city dwellers were infected, even   though only a relatively small percentage of them developed tuberculosis or suffered in any way from their infection. Koch himself was infected. When he injected tuberculin into his own arm in 1890 he suffered one of the most violent allergic reactions on record, evidence of the fact that the tubercle bacillus had at some earlier time multiplied in his body. But Koch did not have clinical tuberculosis, and he remained a vigorous man until he died of cerebral hemorrhage.

Many other well-documented examples could be quoted to demonstrate that multiplication of a virulent microorganism in the body rarely expresses itself in the manifestations of disease. Around 1900 Pettenkoffer in Germany and Metchnikoff in France, with several of their associates, drank tumblerfuls of cultures isolated from fatal cases of cholera. Enormous numbers of cholera vibrios could be recovered from their stools; some of the self-infected experimenters developed mild diarrhea, but the infection did not result in true cholera. More recently human volunteers were made to ingest billions of dysentery bacilli under conditions assumed to be optimal for the establishment of infection. Enteric capsules full of feces obtained directly from acute cases of bacillary dysentery in man were used as additional experimental refinements to increase the chances of establishing the disease. Yet only a few of the volunteers developed symptoms referable to dysentery and most of them remained unaffected by the experimental infection.

The ease and predictability with which Pasteur, Koch, and their followers produced disease at will in experimental animals seem miraculous in view of the difficulties that have so often been encountered in subsequent attempts to produce disease in man. Their success seems incompatible with the course of natural events. The fact of the matter is that Pasteur and Koch did not deal with natural events, but with experimental artifacts. The experimenter does not re-produce nature in the laboratory. He could not if he tried, for the experiment imposes limiting conditions on nature; its aims are to force nature to give answers to questions devised by man. Every answer of nature is therefore more or less influenced by the kind of questions asked.

The art of the experimenter is to create models in which he can observe some properties and activities of a factor in which he happens to be interested. Koch and Pasteur wanted to show that microorganisms could cause certain manifestations of disease. Their genius was to devise experimental situations that lent themselves to an unequivocal illustration of their hypothesis—situations in which it was sufficient to bring the host and the parasite together to reproduce the disease. By trial and error, they selected the species of animals, the dose of infectious agent, and the route of inoculation, which permitted the infection to evolve without fail into progressive disease. Guinea pigs always develop tuberculosis if tubercle bacilli are injected into them under the proper conditions; introduction of sufficient rabies virus under the dura of dogs always gives rise to paralytic symptoms. Thus, by the skillful selection of experimental systems, Pasteur, Koch, and their followers succeeded in minimizing in their tests the influence of factors that might have obscured the activity of the infectious agents they wanted to study. This experimental approach has been extremely effective for the discovery of agents of disease and for the study of some of their properties. But it has led by necessity to the neglect, and indeed has often delayed the recognition, of the many other factors that play a part in the causation of disease under conditions prevailing in the natural world—for example, the physiological status of the infected individual and the impact of the environment in which he lives.

Since several distinct determinants usually play a part in the causation of disease processes, it is customary to consider that there are several categories of causes with different levels of importance. Textbooks contrast “initiating,” “exciting,” or “immediate” causes with “contributory” causes, which play their part merely by bringing the patient under the influence of the initiating causal agent. Simpler and more useful, perhaps, is the recognition of predisposing causes, precipitating causes, perpetuating causes. However, the qualificative appended to a cause is to a large extent a reflection of the present state of knowledge and of prevailing interest. While these differentiations are of help in teaching, they often paralyze thought, and they rarely constitute useful guides for action.

Consider, for example, the evolution of the knowledge of cholera during the past hundred years. John Snow achieved fame for recognizing that an outbreak of cholera in London affected only persons using the water supplied by one particular public pump located on Broad Street. He concluded that cholera was water-borne and he controlled the outbreak by the mere artifice of removing the handle from the pump. Bad, impure water was for John Snow the initiating, precipitating cause of cholera. It is now known that those who used the Broad Street pump contracted cholera because the water that they obtained from it contained cholera vibrios. As a result, the vibrio is presently considered the cause of the disease. But this statement is not so meaningful as appears on first sight since, as already mentioned, vibrios can be ingested in enormous numbers and persist in the stools without seriously inconveniencing the infected person.

The most that can be said, therefore, is that, once the vibrios have become established in the intestinal tract, some other factor can convert the infection into disease. There is still mystery concerning the circumstances which transform cholera from the minor nuisance of the bazaar into a raging pestilence or concerning the factors which bring about the spontaneous termination of catastrophic outbreaks. But, while knowledge of the cholera vibrio has not yet proved very helpful in the understanding of epidemics, much progress has been made in the treatment of the cholera patient. Effective therapy has followed recognition of the fact that the most important symptoms of the disease are due to the loss of fluid and electrolytes from the intestinal tract. Cholera can be successfully treated merely by replacing fluid and electrolyte, without any serum or antimicrobial drug to combat the infection. Thus, the mechanisms which increase permeability of the gut might be regarded as the real cause of the disease since they account for its symptomatology and since treatment of the effects usually results in cure.

The complexity of most ecological systems renders it difficult to single out any one particular component of the system as playing a role of unique importance in the causation of disease. Until 1940 all medical textbooks agreed that the green streptococcus was by far the most frequent cause of subacute bacterial endocarditis. And indeed it was shown around 1945 that this otherwise fatal disease could often be arrested with doses of penicillin large enough to inhibit the streptococcus. Unfortunately it was soon recognized that disappearance of the streptococcus was not uncommonly followed by infection of the heart valves with other kinds of bacteria normally present in the intestinal or respiratory tract, which penetrate sporadically into the blood stream and settle wherever conditions are favorable for them. Thus, both the initial organic lesions on the heart valve and the various kinds of bacteria that can proliferate on them in succession can be properly regarded as causes of subacute bacterial endocarditis.

The same difficulty is met in trying to determine the cause of deaths during and after episodes of smog. During the winter of 1952 a few days of smog in London resulted in the death of some 5,000 persons, and likewise recent episodes of smog over the Meuse Valley in France or in Donora, Pennsylvania, greatly increased mortality. In general, the deaths that occur during or immediately after a smog are listed in official records as being due to cardiac accidents and bronchitis. On the other hand, there is no doubt that heart disease is extremely widespread and has many different origins, and that bronchitis is associated with the activity of viruses and bacteria ubiquitous in all human communities. What, then, are the causes of deaths that follow smogs? The vascular lesions which are so common in modem man? The bacteria and viruses which almost everyone carries in his respiratory tract? or the poisonous substances in the air which reach everybody but kill only a few?