In 1936 a half page report appeared in Nature magazine under the title “A syndrome produced by diverse nocuous agents,” which was authored by Hans Selye of McGill University, Montreal, Canada . The essence of this report was that rats exposed to a variety of nocuous or toxic agents (e.g. cold, surgery, forced exercise, adrenaline, atropine, morphine, formaldehyde, etc.) responded to these diverse stimuli with pathophysiological changes that had some common features. The enlargement of the adrenals, the profound shrinkage of the thymus and of lymphoid organs and hemorrhage, especially in the gastrointestinal tract, has been noted as the most characteristic features of the reaction. If the treatment was continued with relatively slight injuries or small drug doses, the animals became resistant and their organs returned to the normal state. With further treatment the animals lost their resistance and succumbed with symptoms similar to those seen initially.
The terms “general alarm reaction” and “general adaptation syndrome” were proposed for the description of these two phases of the response. Subsequently the word “stress” was coined by Selye to denote the stimuli that are capable of eliciting the alarm reaction. These included physical, chemical agents and emotional factors. Selye’s discovery of the stress syndrome was accidental while he attempted to isolate some hormones from the placenta. During this work it was thought for a while that adrenal enlargement and involution of lymphoid organs was specific for the putative hormone, but extensive attempts to purify the substance failed and the activity was always lost in the end.
At some point it occurred to Selye that the reaction could, in fact, represent a non-specific response to noxious agents and, indeed, when he performed the proper experiments, his suspicion turned out to be correct. This is what was reported in the Nature article. In the same year a longer article was published by him in the British Journal of Experimental Pathology , where he demonstrated that the involution of the thymus was, in fact, mediated by the adrenal gland as it was absent in adrenalectomized animals after stress.
This observation led to an extensive study of steroid compounds in rats and also in chicken. He was the first to establish that the bursa of Fabricius is an organ which is extremely sensitive to steroid hormones. . By 1946 he had a considerable amount of experimental data on the general adaptation syndrome which was presented in a review published in the Journal of Clinical Endocrinology  as the first comprehensive outline of the stress concept. In this paper he predicted that diseases may develop as the result of maladaptation to stressful stimuli. A diagram is presented indicating that after stress exposure the initial reaction is shock, which is followed by a countershock phase and later on by the development of resistance. Eventually, resistance may go into exhaustion and death may ensue. Selye points out that resistance may be specific and/or non-specific and both forms follow the same course; however, the latter “cross resistance” would fall much sooner and may even stay below normal during the period of resistance. A summary figure was presented in this article (Fig. 1) which indicates that non-specific damage acts on the hypophysis which leads to an increase of corticotropic hormone production and to a decrease of gonadotropic lactogenic and growth hormones.
Figure 1. The stress reaction. Selye knew a lot about the mechanisms of stress. He appreciated the endocrine, immune and metabolic changes involved. At that time it was not established that the pituitary gland was regulated by the hypothalamus. This was discovered later and then he included this knowledge into his “hypothalamus-hypophysis-adrenal-thymus axis”. Selye’s original figure (J Clin Endocrinol 1946; 6:117) is in solid and dash lines. We brought this figure up to date; which is indicated with dotted lines.
The corticotropic hormone excess causes enlargement of the adrenal cortex with signs of increased corticosteroid hormone production which in turn causes alterations in the carbohydrate and electrolyte metabolism, as well as the atrophy of the thymus and other lymphoid organs. Actually, this is a fairly accurate outline of the acute phase response, as we call it today, with its neuroendocrine, metabolic and immunological alterations .
In 1949 Selye observed that the injection of egg white to rats evoked an inflammatory response which could be inhibited by cortisone or by the administration of purified ACTH. Deoxycorticosterone acetate, a mineralo-corticoid compound, tended to aggravate the reactions . These experiments initiated his interest in inflammation, which became the most lasting topic in his research and led to the proposition later that diseases like rheumatoid arthritis, anaphylaxis, etc. are in fact diseases of adaptation.
In his second major review entitled “Stress and disease,” published in 1955,  a diagram is shown delineating the relationship between stress and inflammation (Fig. 2).
Figure 2. Hormonal regulation of inflammation. This figure is actually valid today. Growth hormone and prolactin do indeed promote the inflammatory response, whereas glucocorticoids inhibit it and the adrenal androgen, dehydroepiandrosterone, promotes the immune and inflammatory reactions. The pituitary gland stimulates inflammation directly by somatotropic (growth) hormone (STH). The adrenocorticotropic hormone (ACTH)-adrenal axis produces pro-inflammatory (P-flogistic) and anti-inflammatory (A-anti flogistic) corticosteroid hormones.
It is suggested that growth hormone (STH) and mineralocorticoids are proinflammatory (or flogistic corticoids: P-C), whereas glucocorticoids are antiflogistic (A-C), thus suggesting a mechanism for the regulation of inflammation by the pituitary gland which is currently the subject of renewed interest. In this review Selye proposes that (i) diseases may be caused by an absolute excess or deficiency of adoptive hormones, such as ACTH, corticoids, growth hormone, which are involved in the stress response. (ii) He suggests that the deficiency may be present in the target organs, tissues, in the form of hypo- or hyperreactivity to these hormones. (iii) A disproportion in the relative secretion of adoptive hormones is also possible during stress and this disturbed balance may lead to disease. (iv) Metabolic derangements caused by stress may alter the target organs” response to adaptive hormones which may lead to abnormal function of the nervous system, liver, kidney, etc., and become the cause of disease during adaptation to stress.
Selye points out that there is an increased corticoid requirement during stress, both in experimental animals and in man. He cites evidence that the antiinflammatory corticoids (cortisone and cortisol) that were shown to inhibit various types of experimental inflammation in laboratory animals, exert similar effects in man with inflammatory disease such as rheumatoid arthritis, rheumatic fever and allergic inflammation. As a matter of fact, Selye”s seminal work on the antiinflammatory action of glucocorticoids preceded the studies of Hench and co-workers who were awarded the Nobel Prize for the application of glucocorticoids in rheumatoid arthritis. Selye also pointed out that antiinflammatory corticoids cause an increased sensitivity to infection. Finally, he called attention to the possible psychiatric effects of steroid hormones.
The study of inflammation has been the interest of Nicholas Jancso and his co-workers at the Medical School, University of Szeged, Hungary. Jancso”s group identified the mast cell as the initiator of the inflammatory response and the work culminated in the discovery of neurogenic inflammation . It turned out that the inflammation induced accidentally by Selye in rats by the injection of egg whites was, in fact, due to the discharge of mast cells. Selye became very interested in the possible relationship between stress, mast cells, inflammation and a variety of other pathological changes in which mast cells and/or inflammation may play a role. In addition to the extensive experimental work performed in relation to mast cells, [9,10] he published a book on mast cells which stands the test of time even to date and is considered one of the most significant works on the subject .
This was the time of my arrival to Dr. Selye”s laboratory (1967). By that time Professor Jancso had passed away so his wife and long time collaborator, Dr. Aranka Jancso-Gabor was invited by Selye to his Institute as a “Claude Bernard Professor.” It was most exciting to hear the story of neurogenic inflammation from someone who participated in its discovery. Selye held Claude Bernard and Walter Cannon in high esteem, and considered them to be his scientific predecessors. To be invited to his institute to deliver a “Claude Bernard” lecture gave an indication of his high regard for the scientific achievement of the lecturer. I also had the pleasure to listen to George Palade, who later on got the Nobel Prize for his work, and to Elwin Kabat, one of the founders of modern Immunology, as Claude Bernard Professors.
After a survey of Dr. Selye’s principal areas of research during his entire scientific career, which spanned half a century, one may observe that the topics seem very different. However, there is a common thread which reflects his profound interest in the neuroendocrine mechanisms that are relevant to the pathogenesis of diseases. Once he decided to work on an area, he made a thorough survey of the relevant literature which was usually published as a book. In his books the relation of neuroendocrine mechanisms to the subject was never neglected even in the event of not much information being available [12,13].
Although he made seminal contributions to many areas of biology and medicine, I feel most competent to comment on his discoveries in relation to the field of immunology, which are major indeed. He discovered that steroid hormones regulate the size of lymphoid organs such as the thymus, lymph nodes and bursa of Fabricius. He showed that thymic atrophy is mediated by the ACTH-adrenal axis during stress with glucocorticoids being the final effector molecules (Fig. 3).
Figure 3. The hypothalamus-hypophysis-adrenal-thymus axis. Although Selye made many contributions to biology and medicine, he considered the discovery of this axis the most significant.
He was the first to describe the antiinflammatory action of steroid hormones. He and his co-workers made significant contributions to our understanding of the role of mast cells in various pathological phenomena. These contributions were made without knowing the function of the thymus, lymph nodes or of the bursa of Fabricius. The function of these organs was understood only a few years prior to my arrival in Montreal. I followed these developments closely because my major interest has always been immunology, and the profound influence of stress and of the ACTH-adrenal axis on lymphoid organs was fascinating to experience in his laboratory. Why should the immune system be affected, regardless of the insult/stimulus used? What does the immune system have to do with non-specific injury? If glucocorticoids suppress the immune system, what other hormones would act to antagonize this effect? I discussed these questions with Dr. Selye on several occasions and we agreed that there was no satisfactory answer to them at the time. It is only now that we are beginning to realize that the immune system does not only provide specific defence against pathogenic microorganisms and other foreign agents that may harm the host, but also the immune system is activated during injury, which is essential for the elimination of damaged cells and tissues and also for regeneration .
One of Selye’s major dilemmas was that he was never able to give a precise definition of stress. In his first comprehensive review  he talks about the alarm reaction which consists of shock and countershock phases, the recovery phase which leads to resistance and eventually if stress lasts, breakdown. However, 20 years later when I got into his laboratory he recognized already that not only damaging, unpleasant or even dangerous events, agents, but also pleasurable experiences, evoke a similar, if not identical, neuroendocrine response. As a matter of fact, I think he realized that the stress response is barely distinguishable, if at all, from an exaggerated physiological response to exaggerated stimulation. For this reason, he began to talk about the stress of life and divided stress into two subgroups, eustress and distress, the former referring to pleasurable and the latter to unpleasant or dangerous impulses. Another difficulty was the realization that there is a great variance in individual susceptibility towards stress and that the same stimulus which could be pleasant to one individual may be very stressful to another. I remember when he gave the example of the frustrated businessman who experienced severe stress because he was forced to take a holiday by his family while he had so much to do.
Figure 4. In the autopsy room. Every working day Selye and his research colleagues and students looked at all the experiments in progress and then gathered in the autopsy room for looking at all the experimental animals that were terminated on that day. He looked personally at each animal, no matter who did the experiment. During this time there were vivid discussions which dealt mostly with the scientific problems we were investigating but could be anything else what came up. There was every day also a microscopic slide quiz. We all had to look at the slide and say what we think it was. From left to right: Beatrix Tuchweber, Hans Selye, Istvan Berczi, Pavel Rohan, Arpad Somogyi.
Selye’s thinking was not appreciated by his contemporaries in a scientific atmosphere where strict definitions, isolation and characterization of molecules and in general, preoccupation with details, was considered to be scientific. The lack of knowledge and primitive methodology prevented the validation of the stress concept in his lifetime. It is only now that his concepts and predictions can be subjected to the test of scientific analysis with powerful modern tools that make experiments commonplace which were inconceivable to achieve only a few years ago. As we progress in our understanding of neuroimmune biology, Selye’s originality, wisdom and foresight is gradually understood and greatly appreciated. An example of this is the concept of pluricausal diseases in which he implies that there are a number of diseases which cannot be attributed to a single cause, but rather the coincidence of several causes is required . The relationship between MHC antigens and autoimmune disease can be quoted as a perfect example in support of this hypothesis where a given MHC type may be involved but is not sufficient for the development of a particular disease .
Another example may be the process of oncogenesis in that the deregulation of a single gene is insufficient to cause cancer, but rather a whole series of oncogenes and tumor suppressor genes need to be deregulated to develop a malignant disease . Clearly, Selye had predicted the fail safe and redundant nature of biological regulatory and defence mechanisms in higher animals long before compelling evidence had been produced for it. In his last years he turned his attention to the protective power of certain steroid hormones against toxins and other noxious agents and created the term “catatoxic steroids” for those hormones that have protective effect . A book of two volumes entitled “Hormones and Resistance” has also been published by him on the same topic. Again, the role of hormones in host defence to injury and infection is becoming fully appreciated only now, as attested by this online reference.
As already alluded to, Selye faced many criticisms from his contemporaries and had been highly regarded only by psychologists throughout his career. This is not accidental, as contrary to the thinking in other scientific disciplines, psychologists were always conscious about examining the relationship between pathological processes and the neuroendocrine system. Selye was keenly aware of these criticisms and already in 1955, in his article in Science  he remarks:
“Pasteur, Koch, and their contemporaries introduced the concept of specificity into medicine, a concept that has proved to be of the greatest heuristic value up to the present time. Each individual, well-defined disease, they held, has its own specific cause. It has been claimed by many that Pasteur failed to recognize the importance of the ”terrain,” because he was too preoccupied with the pathogen (microorganism) itself. His work on induced immunity shows that this is incorrect. Indeed, at the end of his life he allegedly said, ”Le microbe n”est rien, le terrain est tout.””
A scientist who maintains his position in the face of such mounting criticisms must feel very strongly about being right, and he did so. He dedicated his entire scientific career to furnish more and more proof for the importance of neuroendocrine mechanisms in the development of disease. Even after his forced retirement at the age of 70, he organized the International Institute of Stress and remained active in promoting this cause until his death.
Selye did not only present his findings in scientific journals, but also wrote popular books about the process of scientific research, about stress and related subjects [18-22]. These books have been translated into many languages. Indeed, he was the grand ambassador of science to the public. In his popular book entitled, “In vivo,”  he writes:
“You can never learn what a mouse is like by carefully examining each of its cells separately under the electron microscope any more than you could appreciate the beauty of a cathedral through the chemical analysis of each stone that went into its construction.”
This metaphor gives a powerful emphasis to the significance of his multi-disciplinary scientific approach. Indeed, he was not only much ahead of his time in science, but also with his views on politics and society. His efforts to popularize science and to teach important general principles to his young colleagues was just as important as his scientific activity. Undoubtedly, the time is coming when he will be properly remembered and generally appreciated by the scientific community.
I am much obliged to Madame Louise Dreve Selye and to Dr. Beatrice Tukweber-Farbstein, President of the Hans Selye Foundation, for providing material and valuable information for this manuscript.
I Berczi – Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB Canada R3E 0T5
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Jancso N, Jancso-Gabor A, Szolcsanyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Br J Pharmacol 1967; 31: 138-51.
Selye H, Gabbiain G, Tuchweber B. The role of mastocytes in the regional fixation of blood bone particles. Br J Exp Path 1963; 44: 38-46.
Selye H. Mast cells and necrosis. Science 1966; 152: 1371-2.
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Selye H. The Story of the Adaptation Syndrome. Montreal: Acta Inc. Med. Pub., 1952.
Selye H. The Stress of Life. New York: McGraw Hill, 1956.
Selye H. From Dream to Discovery. New York: McGraw Hill, 1964.
Selye H. The Stress of My Life: A Scientist”s Memory. New York: Van Nostrand Reinhold, 1979.