STRESS AND DISEASE: THE CONTRIBUTIONS OF HANS SELYE TO:
NEUROIMMUNE BIOLOGY
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Dr Hans Selye.jpeg
Dr. Hans Selye
 
A PERSONAL REMINISCENCE by:
Dr. Istvan Berczi
Department of Immunology, Faculty of Medicine
Bannatyne Campus, 
The University of Manitoba
471 Apotex Center
750 McDermot Ave
Winnipeg, Manitoba
R3E 0W3, Canada
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When the news came from Montreal in the summer of 1967 that I had been accepted by  Dr. Selye to work in his Institute, I was madly in love with a girl who later became my wife.  So I told her about the legendary Dr. Selye and outlined carefully that my highest desire was to work with him.  After having listened carefully to the story, she asked me what is going to happen to our marriage plans now?  "Well," I said, "would you like to get married before I go, or after I come back?"  The answer was, without much hesitation, that we should get married before, so we did on September 3, 1967, and off I went a few weeks later to Montreal.  The prospect was that we would spend an entire year, the duration of my planned stay in Montreal, separated as the common practice of the Hungarian authorities at the time was not to allow spouses or family members to follow individuals on study trips or other kinds of missions to the West.

     My journey to Montreal by plane impressed me very much in that I flew across the ocean and set foot on another continent on the same day.  I remembered my teenage readings about all the troubles, disease and death that Columbus and other sailors went through during the same trip.  At the airport in Montreal one of my fellow countrymen, Dr. Pal Vegh, was waiting for me and escorted me to my room nearby the University which was rented by the Institute so that I would have a place to come to.  The next morning after receiving directions from my French Canadian landlady, whose English was much better than mine, I set out to find the University on foot, and did so without much trouble.  There it was, majestically standing on the top of a hill, like a cathedral of knowledge and science.  As I learned later, not very far from the University there was indeed, on the hill a Roman Catholic cathedral as well.

University of Monteal.jpg
University of Montreal

     Although I had learned a lot about Dr. Selye and his Institute from my colleague and good friend, Dr. Lorand Bertok, who was the first to go from Hungary, being there in person was not short of surprises.  On the main corridor there were dozens of pictures of scientists, most of which I had only heard about by name, but had no idea what they looked like.  My greatest surprise was that there was even a portrait of Kossa, who was a professor of my alma mater, and I knew that he pioneered histochemistry by the development of a staining method for the deposition of calcium in animal tissues, but I had never seen his portrait before.  At the main entrance, near the elevator, there was the inscription:

     "Neither the prestige of your subject, and the power of your instruments, nor the extent of your learnedness and the precision of your planning, can substitute for the originality of your approach and the keeness of your observation."

     I had never thought about these problems consciously before, but during my stay in the Institute, the message became engraved in my mind through numerous discussions about great discoveries, the history and psychology of science and of personal characteristics of scientists.  In the corridor there was also a world map marked with little flags of all the countries from which students or visiting scientists came to the Institute.  At my arrival there were students/scientists from Russia (even though this was at the height of the cold war after the Cuban crisis), from Korea, Japan, Egypt, Turkey, Italy, Germany, Czechoslovakia, Poland, Argentina, and of course, Canada.  I couldn't help noticing that whenever Dr. Selye met someone in the corridor, frequently he spoke to him/her in his/her native language as he was fluent in Hungarian, German, English, French, and Italian and knew a fair bit of Spanish, Czech, Russian, and several other languages.
     Soon after my arrival, Dr. Selye saw me in his office as he always found the time to greet in a very personal manner newly arrived students/scientists and visitors this way.  After telling him about my trip we settled my project, which was to do experiments on calcifilaxis.  Then he pointed to a bouquet of snow lillies (adelweiss) tied with a red, white and green ribbon, which was framed and hung on the wall, and said: "You see, this symbolizes my heritage and native land, which is Austria/Hungary.  My father was Hungarian and a surgeon in the army and my mother was Austrian.  So, by ancestry, I am neither Hungarian nor Austrian; I am Austro-Hungarian."  I often wondered, why he called my attention to these things right at the beginning.  Perhaps it was because I heard from a number of my colleagues while still at home that he was Hungarian, but then later on I also came across people who were convinced that he was Austrian or German.  In any case, later on I was fortunate and privileged to have numerous private conversations with him through which I have learned a great deal about his personal views, character and attitude towards life in general.  The other thing he pointed out to me in his office was a picture of desperate people that was hanging above the door of his office, and said, "You see, this is stress."   I was given an office in the Institute shared by Dr. Arpad Somogyi down the corridor and began the work.  First I had to learn about the phenomenon of calcifilaxis quickly, which was by reading and by attending the daily rounds with Dr. Selye, when we examined the experimental animals collectively and each investigator had to present his/her animals, especially if symptoms of interest and/or importance were noticeable.  The round finished in the autopsy room where Dr. Selye, with our participation, would look at every experimental animal that was terminated on that day.  Again, the investigator had to call attention to pathological changes of possible importance.

Stress.jpg
Stress

     After finishing with the autopsy, plans for new experiments were presented by the various investigators to Dr. Selye for his approval.  Each experiment had to be justified on theoretical grounds and this frequently led to vivid discussions of scientific problems, theories and views.  Each autopsy session also had a slide puzzle which was placed under the microscope and was to be viewed by everybody and diagnosed by a secret vote as to what it was.  To my surprise, I noticed that some of the slides were coded in Hungarian which gave the correct answer.  Apparently this strategy worked very well until some of us who understood the code arrived.  One day a chicken experiment was evaluated and Dr. Selye remarked while looking at the carcasses that the lymph nodes along the neck were normal.  Well, I had to tell him with all due respect that those nodules, though looking exactly like lymph nodes, were really the thymus, and that the chicken did not have any real lymph nodes.  This came so quickly in compliance with my character that I hadn't even considered the possible consequences of contradicting this world famous great scientist in public, or even worse, in front of his students and collaborators.  Intuitively, I felt that he would appreciate the information, which came from my training in comparative anatomy, and would not be insulted or take this as a criticism.  This is exactly what happened.  During a similar session weeks later he remarked that we all profit from these discussions and that he learned from me the other day that the chicken has no lymph nodes.

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Discussion in the Autopsy Room

     Being newly wed and separated and determined to be faithful I went to the Institute also on weekends.  I had a lot to learn about my project so that I could propose decent plans for experiments and interpret the results, write up the papers, all of which was required if I was to last for some time in the Institute.  To my surprise and great satisfaction, the Institute had a fantastic library and collection of reprints and I could hardly ask anything from the librarian, Mr. Krzyzanowsky, which was not on my desk by the end of the day.  This was in sharp contrast with the situation in Budapest, where I had to travel frequently to the Central Medical Library, and sometimes wait in line for a particular book or journal for hours, or occasionally I had to return on another day in order to see the article I wanted.  Once I got to see the article I was not allowed to take it out of the building, but had to sit down and very quickly take notes of the salient findings and conclusions.  All these problems were solved by the quick availability of the material and by the use of the Xerox machine which was a wonder for me in the western world.  Among the other wonders, I was most fascinated by the efficiency of the telephone which allowed one to phone instantly all over the world.  The 15 months I spent in the Institute, not only was one of the most memorable periods of my life, but it was also very productive.

     It didn't take long for Dr. Selye to find out that I was there every day as he also was there every day.  For his weekdays he worked 12 hours a day (from 6:00 in the morning until 6:00 in the evening), and during the weekend he took it easy and stayed from 6:00 in the morning until only 4:00 in the evening or sometimes even until 2:00 in the afternoon.  Soon he became a constant visitor to my office during the weekend for personal chats which was most exciting and memorable and I felt very honoured and privileged by this relationship.  We discussed everything from politics to religion, history, personal life, even telling jokes.  He called my attention to the fact that contrary to the prevailing opinion in Hungary, Ferenc Deak, who was responsible for entering into confederation with Austria, was not a traitor, but in fact, a very wise politician.  He said that all I had to do was look around in Budapest and determine when the House of the Opera and a whole list of other beautiful public buildings were erected.  "You will find," he said, "that much was built around the turn of the century between 1867 and 1914."  I was astonished by this logical argument and asked myself, why I didn't think of this before?  He also told me how angry he was about the two world wars, both of which he lived through; the terrible suffering and damage to Europe and, indeed, to mankind, these wars inflicted, and that one of the reasons why he escaped to North America was that science and creativity were virtually paralyzed in pre-Second World War Europe.  "The only aristocracy I respect," he said, "is the aristocracy of intellect.  Politicians," he pointed out, "are trying to guide their countries into the future while thinking in terms of the past, which is based on nationalism."

     During our discussions he never missed the opportunity to point out that science is international and that the only thing which should count is the importance of the contribution.  He had the greatest admiration for Claude Bernard, who was the first to recognize that the internal environment, which he called "millieu interieur", is under sophisticated physiological regulation.[1]  Walter Cannon was the other scientist whom he regarded as his immediate predecessor in terms of thinking.[2]  He also had high esteem for Pasteur and Koch and for many of his contemporaries that were invited to the Institute as "Claude Bernard Professors."

     The visit of the Claude Bernard Professors to the Institute was usually for two days to deliver one or two lectures, participate in rounds, and to withstand the "roasting party" from members of the Institute, which was a very exciting event.  The party was held at Dr. Selye's house in the evening to which, in keeping with good Hungarian customs, all the staff and students were invited.  After having something to eat and one or two drinks to raise our spirits, we sat down around our guest and asked questions which one would not ask under any other circumstances.  Almost anything was allowed, but the topic usually circled around the human factors that drive scientists, about the philosophy and psychology of science, the question of originality, discoveries, and so on.  I met Dr. Aurelia Jancso this way and learned about the discovery of neurogenic inflammation, listened to George Palade, who later on received the Nobel Prize for his work, and got a chance to have some very interesting conversations with Dr. Elwin Kabat, who, as I realized later, was one of the founders of modern immunology.  I can only appreciate now the caliber of Claude Bernard Professors that visited the Institute over the years and the diversity of topics discussed.  These included Sir Macfarlane Burnett, Baruj Benacerraf, and Pierre Grabar, just to name a few.

     These invitations did not only reflect Selye's ability of judging scientific accomplishment, but also testified to the flexibility of his mind. Lecturers were invited, not only from the well established disciplines in medicine, but also from the area of psychology, as he was always very conscious about looking at the whole organism in its entire complexity.  I will never forget his reaction to the publication by Christian Barnard of the first heart transplantation in man. [3]  He said that transplantation is not the solution to the problem, but rather, prevention of the disease is the right approach.  He also remarked that transplantation will never be suitable for the routine treatment of people with heart disease.  It will be a treatment only for the rich, he said, even if all the technical problems are solved, and stated that this approach may even generate criminal activity.  Over the years I have remembered this many times, admiring how well he saw the problem and how right he was.

     No matter what the subject was, he always challenged your imagination and intellect, therefore touching your emotions.  I don't remember meeting anybody who was neutral towards him.  Some admired him constantly, others were in violent opposition with almost everything he stood for, and there were a fair number of people who had a love/hate relationship with him.  I have to confess that I have had my differences and difficulties, and I didn't always agree with his opinion.  As I said already, I was working on calcifilaxis, and made a lot of effort to catch up with the literature and to produce meaningful results.  But the news of the first heart transplantation in man shifted his interest back to his old favourite subject which was experimental cardiopathies.  Before long, within a few weeks, the most important problem became cardiopathies in the Institute and not calcifilaxis and related phenomena.  Somehow he managed to quickly convince most everybody to switch to this problem, except me.  I felt that I should stick to my original problem as I only had a year to stay, and I planned to do my doctoral work there.  My doctoral thesis would have  to be on a coherent subject and not calcifilaxis and cardiopathy.  In the end he understood my reasons and agreed that I continue with my project for a few more months, and even asked me to co-author a review article [4] with him on the subject which was a great honour.

     As I became more and more familiar with Selye's research interests and achievements, it became clear to me that his conviction was, in fact, that neuroendocrine factors play major roles in most, if not all, diseases.  I learned from him, and also from his popular books, [5-9] that the discovery of the stress syndrome was accidental during his attempts to isolate some hormones from the placenta.  For a while it was thought that the adrenal enlargement and involution of lymphoid organs was specific for a particular hormone, but attempts to purify it always failed as the activity was lost.  At some point it occurred to Selye that this, in fact, could be a nonspecific response to nocuous agents, and, indeed, when he performed the control experiments, that was the case.  He published a short note about his findings in Nature in 1936.[10]  During the same year a longer article was published by him in The British Journal of Experimental Pathology,[11] where he demonstrated that the involution of the thymus was in fact mediated by the adrenal gland as it was absent in adrenalectomized animals if stressed.  His experiments in chickens revealed that the Bursa of Fabricius is also extremely sensitive to steroid hormones.[12]

HPA axis.jpg
Hypothalamus-Hypophysis- Adrenal-Thymus Axis

     A review was published by Selye in 1946,[13] where he already gives a comprehensive theory of the general adaptation syndrome which is supported by experimental facts.  He also talks about the possibility that diseases of adaptation do exist.  He states that, after exposure to stress, initially there is shock, which is followed by a counter shock phase, and this gradually goes into a stage of resistance.  If, however, the stressor persists, resistance may go into exhaustion and death may ensue.  He points out that specific and nonspecific resistance follow the same course but this latter "cross resistance" will fall much sooner and stays below normal during the period of resistance.  He also presents data of blood sugar and chlorine changes and points out that white blood cell counts rise invariably during stress, regardless of the stressor used.  The changes in the adrenal cortex and of thymus involution are also illustrated histologically.  The adrenal cortex becomes wider with loss of lipid granules and the border between the zona fasciculata and reticularis is no longer distinct.  The thymus shows a depletion of cortical thymocytes.  Nuclear debris is evident and pyknotic thymocyte nuclei are abundant.  He notes that this "accidental involution" becomes most pronounced during the countershock phase when the adrenal cortex reaches its maximum development.  Large macrophages engulf the dead thymus cells and carry them away through the lymphatics.  At the same time he noted that thymic reticulum reverts to its origianl epithelial type and the cells become roundish or polygonal and rich in cytoplasm.  When involution is most acute the entire organ is distended with jelly-like edema.  He points out that lymph nodes, the spleen and other lymphatic organs are almost as markedly affected as the thymus, although they do not involute quite as rapidly and their involution cannot be completely prevented by adrenalectomy.  His summary figure is a fairly accurate outline of the acute phase response, as we recognize it today [14].
(Fig 1)
 

Figure 1. Functional interrelations during general adaptation syndrome.Schematized drawing indicating that non-specific damage causes clinical shock, loss of body weight and nitrogen, gastro-intestinal ulcers, temporary rise in plasma potassium with fall in plasma Cl, through unknown pathways (nervous stimulus?, deficiency?, toxic metabolites?) but manifestly not through the stimulation of the hypophyseoadrenal mechanism. This is proven by the fact that the above manifestations are not prevented either by hypophysectomy or by adrenalectomy; they even tend to be more severe in the absence of either or both of these glands. 
                    Non-specific damage, again through unknown pathways, also acts upon the hypophysis and causes it to increase corticotropic hormone production at the expense of a decreased gonadotropic, lactogenic and growth hormones. The resulting corticotropic hormone excess causes enlargement of the adrenal cortex with signs of increased corticoid hormone production. These corticoids in turn cause changes in the carbohydrate (sugar active corticoids) and electrolyte metabolism (salt-active corticoids) as well as atrophy of the thymus and the other lymphatic organs. It is probable that the cardiovascular, renal, blood pressure and arthritic changes are secondary to the disturbances in electrolyte metabolism since their production and prevention are largely dependent upon the salt intake. The changes in g -globulin, on the other hand, appear to be secondary to the effect of corticoids upon the thymicrolymphatic apparatus. 
                   We do not know as yet, whether the hypertension is secondary to the nephrosclerosis or whether it is a direct result of the disturbance in electrolyte metabolism caused by the corticoids. Similarly, it is not quite clear, as yet, whether corticoids destroy the circulating lymphocytes directly, or whether they influence the lymphocyte count merely by diminishing lymphocyte formation in the lymphatic organs. Probably both these mechanisms are operative. (Taken from Ref.13.)

     Today we know that a variety of insults, including trauma and infection stimulate the release of chemotactic-, proinflammatory cytokines, and a whole host of other mediators from a variety of cells in the damaged area that include mast cells, endothelial cells, platelets.  The released mediators attract blood borne leucocytes, such as neutrophilic granulocytes, monocytes/macrophages, lymphocytes, eosinophils and basophils that release additional mediators, and thus contribute to the inflammatory response.  In some cases certain cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-a (TNF-alpha) and interleukin-6 (IL-6), become detectable in the blood and function as acute phase hormones.  They act on the brain causing fever and other functional modifications (IL-1, TNFalpha), release certain pituitary hormones and inhibit others (much of which is indicated in the graph reproduced from his article), promote general catabolism, (mediated primarily by TNF-alpha, also known as cachectin), stimulate the production of new serum proteins known as acute phase reactants in the liver (the joint action of IL-6, glucocorticoids and catecholamines), and also elevate the production of leucoytes in the bone marrow, the mechanism of which is not fully elucidated.[14,19]  (For further reference, please see also the papers by Asa and Kovacs, Besedovsky and del Rey, Gaillard, and Nagy and Berczi in this volume.)  Thus, with the recent discovery of cytokines and our increasing recognition of their functions, we have begun to fill in the gaps in Dr. Selye's adaptation syndrome outlined nearly half a century ago.

     In 1949 Selye discovered that an inflammatory reaction, which can be induced in the rat by the parenteral administration of egg white, is inhibited by cortisone or by purified ACTH.  On the other hand, desoxycorticosterone acetate, a mineralcorticoid compound, tends to aggravate the reaction.[15]  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 as stated in numerous publications.  In his review article in Science,[16] entitled "Stress and disease", he shows a diagram of the stress response with inflammation clearly in mind.(Fig. 2).
 
 

figure 2.png

Figure 2. Diagram illustrating the principal pathways of the stress response. A-C: glucocorticoids, also known as antiphlogistic corticoids; ACTH: adrenocorticotrop hormones; P-C: the mineralocorticoids, also known as prophlogistic corticoids; STH: somatotropic (growth) hormone. (Taken from Ref.16).

    The paragraphs in this article that contain important conclusions and theoretical considerations are as follows:

    "Certain recent experiments suggest that, depending on the conditions, ACTH may cause a predominant secretion of one or the other type of corticoid.  However, be this as it may, the `growth hormone,' or somatotrophic hormone (STH), of the pituitary increases the inflammatory potential of connective tissue very much as the prophlogistic corticoids do; hence, it can sensitize the target area to the actions of the prophlogistic corticoids. . .

    "Among the derailments of the general adaptation syndrome that may cause disease, the following are particularly important:

     (i) an absolute excess or deficiency in the amount of adaptive hormones (for example, corticoids, ACTH, and STH) produced during stress; (ii) an absolute excess or deficiency in the amount of adaptive hormones retained (or `fixed') by their peripheral target organs during stress; (iii) a disproportion in the relative secretion (or fixation) during stress of various antagonistic adaptive hormones (for example, ACTH and antiphlogistic corticoids, on the one hand, and STH and prophlogistic corticoids, on the other hand); (iv) the production by stress of metabolic derangements, which abnormally alter the target organ's response to adaptive hormones (through the phenomenon of `conditioning'); and (v) finally, we must not forget that, although the hypophysis-adrenal mechanism plays a prominent role in the general-adaptation syndrome, other organs that participate in the latter (for example: nervous system, liver, and kidney) may also respond abnormally and become the cause of disease during adaptation to stress. . .

Corticoid requirements during stress:During stress, the corticoid requirements of all mammals are far above normal.  After destruction of the adrenals by disease (as after their surgical removal), the daily dose of corticoids, necessary for the maintenance of well-being at rest, is comparatively small, but it rises sharply during stress (for example: cold, intercurrent infections, and hemorrhage), both in experimental animals and in man. . .

Anti-inflammatory effects of corticoids:  The same antiphlogistic corticoids (cortisone and cortisol) that were shown to inhibit various types of experimental inflammations in laboratory animals exert similar effects in a human being afflicted by inflammatory diseaes (for example, rheumatoid arthritis, rheumatic fever, and allergic inflammations). . .
"Sensitivity to infection after treatment with antiphlogistic corticoids.  In experimental animals, the suppression of inflammation by antiphlogistic hormones is frequently accompanied by an increased sensitivity to infection, presumably because the encapsulation of microbial foci is less effective and perhaps partly also because serologic defense is diminished. . .

Psychological and psychiatric effects of corticoid overdosage:  It has long been noted that various steroids - including desoxycorticosterone, cortisone, progesterone, and many others - can produce in a variety of animal species (even in primates such as the rhesus monkey) a state of great excitation followed by deep anesthesia.  It has more recently been shown that such steroid anesthesia can also be produced in man, and, of course, the marked emotional changes (sometimes bordering on psychosis) that may occur in predisposed individuals during treatment with ACTH, cortisone, and cortisol are well known.  Several laboratories reported furthermore that the electroshock threshold of experimentl animals and their sensitivity to anesthetics can be affected by corticoids."

      He concludes as follows:

     "If I may venture a prediction, I would like to reiterate my opinion that research on stress will be most fruitful if it is guided by the principle that we must learn to imitate - and if necessary to correct and complement - the body's own autopharmacologic efforts to combat the stress factor in disease."

     The prediction by Selye that the pituitary gland has the capacity to both stimulate and inhibit inflammatory reactions is the subject of recent investigations and is proven correct.[17,18]  The notion of prophlogistic steroids has not been studied to a great extent to date, but the antiinflammatory effect of glucocorticoids is firmly established and it is clear today that the adrenal gland plays an important physiological role in the regulation of immune and inflammatory responses.[19]  The disproportion of hormones and other mediators, altered responsiveness in tissues and the significance of metabolic derangements during acute phase reactions related to sepsis, severe trauma and shock are the subject of current investigations and deemed to be highly relevant to prognosis.  The involvement of the central nervous system, the liver and of other organs, such as the kidney, is also substantiated.[14] That "conditioning" may also play a role in host defence is also gaining ground.[20]  Some hard evidence is forthcoming regarding the corticoid requirements during infection and other forms of stress.[14]  The antiinflammatory effect of cortisone and cortisol are well recognized and are widely applied in medicine today.  That corticosteroids increase the sensitivity to infection is of common knowledge.  The phenomenon of stress related anesthesia is well recognized, but opioid peptides rather than steroid hormones are considered to be the mediators.

     My colleague, Dr. Lorand Bertok, upon his return to Budapest from Selye's Institute, brought the news that the study of mast cells was in the focus of interest and he also brought a copy of the book written by Dr. Selye:  The mast cells.[21]  As it turned out, the inflammation Dr. Selye induced years earlier in rats by the injection of egg white was due to the discharge of mast cells.  Because of my intentions to go to Dr. Selye's laboratory, I studied this book and was struck by the importance of mast cells in various pathological phenomena.  At that time the role of mast cells in immune mechanisms had not been firmly established.  However, a related cell type, the basophilic leucocyte's role in immune mechanisms was known already.  Selye was interested in mast cells mainly because they play a major role in inflammation and he was puzzled by the powerful effects of mediators released by mast cells which could play a role in various pathological processes, such as inflammation, necrosis, calcification or thrombohemorrhagic phenomena.[4,21-24]  After my arrival in Montreal, the name of Professor Jancso and coworkers came up frequently during discussions because of their discovery that the stimulation of sensory nerves induces inflammation.[25] By 1967 Professor Jancso had passed away so his wife and long time collaborator, Dr. Aurelia Jancso, was invited to the Institute as a Claude Bernard Professor.  It was most exciting to hear the story of neurogenic inflammation from someone who participated in its discovery.

     Looking at Dr. Selye's principal areas of research during his scientific career, which spanned half a century, one may observe that even if they seem to be very different, all of them were inspired by the profound conviction of Dr. Selye that neuroendocrine mechanisms play a role in what he called "diseases of adaptation."  Once he decided to work on an area, he thoroughly surveyed the literature which was usually published then in the form of a book.  In these books [21,26-34] a possible role of neuroendocrine mechanisms in relation to the subject was never neglected, even in the event of not much information being available.  Then he presented related findings from his own laboratory, which also appeared in numerous publications (his lifetime output was 1,325 papers).  His contributions to modern immunology are major indeed.  He discovered that steroid hormones regulate lymphoid organs such as the thymus, spleen, lymph nodes and Bursa of Fabricius.  He demonstrated that thymic atrophy is mediated by the ACTH-adrenal axis during stress with glucocorticoids being the final effector molecules.  He also described the antiinflammatory action of adrenal steroid hormones.  He and his coworkers made significant contributions to our understanding of the role of mast cells in various pathological phenomena.  Selye made all these contributions without knowing the function of the thymus, lymph nodes or 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.

     One of Selye's major dilemmnas was that he was never able to define stress.  In his comprehensive review published in 1946 [13] he talks about the alarm reaction that is comprised of shock and counter shock, the recovery phase which leads to resistance and eventually, if the stress lasts, to breakdown.  However, 20 years later when I got to his laboratory he recognized already that not only damaging, unpleasant or even dangerous events/agents, but also pleasurable experiences evoke a neuroendocrine response that involves the ACTH-adrenal axis.  As a matter of fact, I think he realized that the pituitary gland constantly reacts to our internal and external environment, which enables us to function normally.  Therefore, 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 referring to unpleasant or dangerous impulses.[35,36]  Another difficulty was the realization that there is great variance in individual reactivity towards stressors and that the same stimulus which could be pleasurable to one individual may be very stressful to another.  I remember him talking about the frustrated businessman who was forced to take a holiday by his family while he had so much to do.  Perhaps this is why he showed me the picture of desperate people above the door in his office because that was the best definition he could provide.  Looking at a picture we all formulate an idea of what it could mean though we are not absolutely certain, and it is likely that each person who looks at it will have somewhat different impressions.

     The prediction by Dr. Selye of the pluricausal nature of most diseases is really the recognition that living organisms have evolved multiple mechanisms to defend themselves against harmful agents.  For this reason, in most cases, it is necessary to interfere with these defense mechanisms at more than one point to cause disease.  The redundancy of immune effector mechanisms [14,37] or the recent recognition that it is necessary to deregulate more than one gene to cause cancer, [38] certainly supports this view.  In his last years he turned his attention to the protective power of certain hormones against various toxins and other noxious stimuli and created the term "catatoxic steroids" [29,35] for those hormones that have protective effect.  A book of two volumes entitled "Hormones and Resistance" [27] has also been published by him on the same topic.  That hormones are important in immunological and other forms of resistance is the subject of current scientific inquiry.[14,17,18]

     Selye faced many criticisms and by the time I came to his laboratory he had been highly regarded only by psychologists, whereas most scientists in other disciplines had ignored his ideas.  It was widely held that his experiments were highly artificial and hence not relevant to pathophysiological processes that occur in real life.  It was also a problem that stress was not and could not be defined.  In most disciplines scientists were busy working to discover and characterize basic interactions like the interaction of antigen presenting cells, T cells and B lymphocytes within the immune system, and were not concerned about stress.  Another difficulty was that neither the basic knowledge nor the tools necessary to study and understand further the stress problem were available.  Clearly, one could not possibly study the effect of interleukin-1 and of other cytokines on the release of pituitary hormones before these mediators were discovered.

     He knew about this criticism already in 1955 and refers to it in his article in Science [16] as follows:

     "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.'"

     Only a scientist with very strong convictions of being right would maintain his position in the face of such mounting criticisms and he did so.  Moreover, he dedicated his entire scientific career to furnishing more and more proof for the importance of neuroendocrine mechanisms in the development of disease.  After his forced retirement at the age of 70 he organized the International Institute of Stress and remained active in promoting his cause.

     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. [5-9]  These books have been translated into many languages.  Of his popular books I was most impressed by the one having the title: "In vivo." [5]  This is a collection of lectures dealing with his philosophy of the scientific process, with the human factors involved, and giving advice to scientists with regards to what is important and what is not so important.  On the first page there is a quotation from Albert Szent-Gyorgyi:

     "In studying life, you keep diving from higher levels to lower ones until somewhere along the way life fades out, leaving you empty handed.  Molecules and electrons have no life."

     The main message of the book is that one always should try to view the entire organism in its complexity and not to get lost with tiny little details without even considering how it relates to the whole organism.  He considers that although intellect is important in science, instinct is indispensable as well.  He classifies scientists into problem finders and problem solvers as follows:

     "In problem finding, the principal requirement is inspiration, perhaps with a certain amount of opportunism, a tendency to follow the line of least resistance rather than the steadfast pursuit of what we set out to find.  On the other hand, problem solving is based on careful planning and persistence on a steady course until the aim is reached.  It requires patience and the courage to resist all temptations to start on something new in the hope of quick returns.  Here perspiration is often more effective than inspiration.  Yet, even in problem solving, it is rarely possible to be guided merely by the laws of logic."

     The roles of logic, intellect and of hypotheses in science are summarized by him as cited below:

     "No matter how distasteful this may be to many scientists, we must accept the fact that intellect is not always the safest approach to exploration and the acquisition of knowledge.  The homing pigeon's `knowledge' of geography, the bat's understanding' of radar are very effective though not intellectual; it is not through the logical rules of grammar that a child learns his native tongue. . .  .

    "Even the construction of hypotheses is much less dependent upon logical reasoning than most people think.  No hypothesis can be arrived at by logical reasoning alone since it must be based on insufficient evidence, or else it is not a hypothesis at all but a factual conclusion.  Indeed, the more a lack of facts forces a hypothesis to depend upon imagination, the more ingenious it is."

     The importance of originality is illustrated through the example of Mendel who had no laboratory and, as a matter of fact, was not even a scientist, yet he discovered the basic laws of genetics.  Then he describes the discovery of penicillin, which is attributed to Fleming.  He points out that the phenomenon described by him had, in fact, been described repeatedly before, namely that bacterial colonies will not grow around colonies of mold on solid agar containing medium.  He speculates that there could have been a lot more people who saw the phenomenon but did not publish it as it indicates sloppiness in work.  Normally, he remarks, mold is not supposed to grow in bacterial cultures.  The importance of Fleming's discovery was fully realized after Florey and Chain demonstrated its practical value.  Indeed, he says, it may be asked whether even Fleming himself fully appreciated all the potentialities of what he had found since he abandoned this field for many years in favour of less important investigations.

     Discovery, he states, is the realization that something new exists.  This necessarily means that the finding is of something unpredictable, but discovery does not necessarily imply importance.  To be important the discovery must not only be unexpected, but also generalizable, i.e. applicable to many situations.  Only this gives it real scope.  In contrast, development is the further exploration of an already discovered fact.  Because discoveries cannot be planned, intuition and "peripheral vision" play the most important role in this process.

     In defence of in vivo research he remarks:

    "It would hardly have been possible to discover anaphylaxis, yellow fever, and the phenomenon of homograft rejection by the use of electron microscope or of cell chemistry.

    "You could 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."

     While he acknowledges that specialization is unavoidable in research, he emphasizes a need for "general practitioners" of science:

    "Nowadays, you rarely meet a mature scientist who has retained at least the recent medical graduate's general knowledge of, say histology, physiology, biochemistry, pharmacology, clinical medicine and surgery.  Most of them try to specialize and become experts in one field.  This is undoubtedly the sound attitude for the vast majority whose primary interest is the solution of well-defined problems.  But we shall always need at least a few general practitioners of medical research, men whose minds are open to the many things that come their way.  We shall depend upon them in research just as we shall always require general practitioners of clinical medicine who can look at the patient as a whole and at least determine to which kind of specialist he ought to be sent."

     While I was at the Institute of Experimental Medicine and Surgery, one of my colleagues, Dr. Cirpilli, who came from Turkey, remarked that Dr. Selye could have become equally as well a writer, a linguist, a philosopher, or a politician.  Indeed, he was not only much ahead of his time in science, but also with regards to his views on politics and society.  His efforts to popularize science and teach important general principles to his young colleagues was just as important as his scientific activity.

     If you ask me what did I learn from him, the answer is very simple:  a lot.  I became convinced by his work that the immune system is under neuroendocrine regulation and never gave up my intentions to do research in this field, despite the funding difficulties, which sometimes seemed insurmountable.  I never forgot Selye's teaching about originality and that one must keep an open mind and adjust the theories to the facts found and not the other way around.  Ever since we started to work on the role of the pituitary gland in immune function with my dear colleague, Dr. Eva Nagy, we trusted in vivo research and it was not disturbing for us that for years we were unable to demonstrate a reproducible effect of prolactin or growth hormone on in vitro immune reactions.  We always reasoned that mother nature is more reliable than our primitive in vitro experiments and that if it does not work in the bottle, there must be some important detail that we don't know and this is why we cannot do it.  Erythropoietin and some of the colony stimulating factors that regulate bone marrow function have already been produced by recombinant DNA technology, which could be considered as a triumph of in vitro research. [37]  However, the role of pituitary hormones in hemopoiesis has never been uncovered by these experiments.

     In contrast, one can find good indication for such a role in the old literature [38] and we saw it very clearly in our in vivo experiments. [39]  So again the in vitro experiments, although highly sophisticated and successful, did not give a complete picture and it was necessary to investigate hemopoiesis in vivo in the complexity of the organism in order to uncover further aspects of the regulatory network involved in bone marrow function.

     Through my endeavours I have learnt over the years that there is much truth in the old literature.  Many consider old papers to be useless and irrelevant, yet with proper insight one can gain a lot of information and even confidence from the results of early investigators.  Consequently I cannot help but be fascinated and puzzled by the foresight and wisdom of those scientists who, with primitive methodology and with enormous gaps in knowledge, predicted biological laws which got forgotten only to be rediscovered later again.  Hans Selye was one of these geniuses.  He saw very clearly what his contemporaries were unable to see.  It is only now that we are beginning to understand what he was really talking about.  Indeed, I realized myself that I have evolved over the years to appreciate more and more of what he was saying, which deepened my admiration towards him.  I feel very fortunate and privileged to have been associated with him.


 

ACKNOWLEDGEMENTS

     I am much obliged to the Hans Selye Foundation, to Mme. Louise Drevet Selye and to Dr. Beatriz Tuchweber-Farbstein, President of the Hans Selye Foundation, for providing material and valuable information for this chapter.
This text is reprinted from the book "Advances in Psychoneuroimmunology", Plenum Press, 1994;pp.1-15.

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Volume Editors: Istvan Berczi and Andor Szentivanyi

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Volume Editors: Rainer Straub and Eugenio Mocchegiani

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REFERENCES


[1] Bernard C., Lecons sur les phenomenes de la vie communs aux animaux et auxvegetaux. Balliere, Paris 1878.
[2] Cannon WB. The emergency function of the adrenal medulla in pain and the major emotions.  Am J Physiol 1914;33:356.
[3] Barnard CN. A human cardiac transplant, an interim report of a successful  operation performed at Groote Schuur Hospital, Cape Town, S  Afr.  Med J 1967; 41:1271.
[4] Selye H, and Berczi I. The present status of calciphylaxis and calcergy. Clin Orthop Related Res. 1970;69:23. 
[5] Selye H. In Vivo: The Case for Supramolecular Biology. New York:Livesight Pub Co, 1967.
[6]  Selye H. The Story of the Adaptation Syndrome. Montreal,Quebec,Canada: Acta Inc. Med. Pub., 1952.
[7] Selye H. The Stress of Life. New York: McGraw Hill, 1956.
[8] Selye H. From Dream to Discovery. New York: McGraw Hill,1964.
[9] Selye H. The Stress of My Life: A Scientist's Memory. New York: Van Nostrand Reinhold, 1979.
[10] Selye H., A syndrome produced by diverse nocuous agents. (Lond) Nature 1936;138:32 .
[11]  Selye H. Thymus and adrenals in the response of the organism to injuries and Intoxication, Brit J Exp Path 1936;17:234.
[12] Selye H. Morphological changes in the fowl following chronic overdosage with various steroids. J Morph 1943; 73:401.
[13] Selye H. The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol 1946;6:117.
[14] Berczi I, Nagy E. Neurohormonal control of cytokines during injury. In:NJ Rothwell and F Berkenbosch, editors. Brain control of Responses to Trauma.  Cambridge University Press 1994. 
[15] Selye H. Effect of ACTH and cortisone upon an anaphylactoid reaction. Can Med Assoc J 1949; 61:553.
[16] Selye H. Stress and disease. Science 1955;122:625 .
[17] Berczi I. Immunoregulation by pituitary hormones. In: Berczi I, editor .Pituitary Function and  Immunity. Boca Raton, FL: CRC Press, 1986.
[18] Berczi I. The role of the growth and lactogenic hormone family in immune function. Neuroimmunomodulation 1994;1:201-216.
[19] Besedovsky HO, Del Rey A. Immune-neuroendocrine circuits: Integrative role of cytokines. Front Neuroendocrinol 1992:13:61.
[20] Ader R, Cohen N. The influence of conditioning on immune responses. In: Ader R, Felten DL, Cohen N, editors. Psychoneuroimmunology II. Academic Press, 1991.
[21] Selye H. The Mast Cells. Washington: Butterworth, 1965.
[22] Selye H, Gabbiani G, Tuchweber B. The role of mastocytes in the regional  fixation of blood borne particles. Brit J Exp Path 1963;44:38.
[23] Selye H. Mast cells and necrosis. Science 1966;152:1371.
[24] Selye H. Thrombohemorrhagic Phenomena. Springfield:CC Thomas, 1966.
[25] Jancso N. Jancso-Gabor A, Szolcsanyi J. Direct evidence for neurogenic inflammation and its prevention by denervation and by pretreatment with capsaicin. Brit J Pharmacol 1967;31:138.
[26] Selye H. Anaphylactoid Edema. Warren H Green, St. Louis,1968.
[27] Selye H. Hormones and Resistance: 2 vols., New York:Springer-Verlag, 1970.
[28] Selye H. The Pluricausal Cardiopathies. Charles C Springfield:Thomas Pub, (1961.
[29] Selye H. Catatoxic steroids. Can Med Assoc J 1969; 01:51.
[30] Selye H. Stress. Montreal, Quebec,Canada: Acta Inc,1950.
[31] Selye H. The Chemicla Prevention of Cardiac Necroses. New York:Ronald Press, 1958.
[32] Selye H. Calciphylaxis. Chicago:Univ. Chicago Press,  1962.
[33] Selye H. Experimental Cardiovascular Disease. New York :Springer-Verlag, 1970.
[34] Selye H. Stress in Health and Disease. Boston: Butterworth, 1976.
[35] Selye H. Hormones and resistance. J Pharm Sci 1971; 60:1. 
[36] Selye H. Forty years of stress research: Principal remaining problems and misconceptions. Can Med Assoc J 1976;115:53.
[37] Clark SC, Kamen K. The human hematopoietic colony-stimulating factors. Science 1987;236:1229.
[38] Berczi I, and Nagy E. Effects of hypophysectomy on immune function. In:Ader R, Felten DL, Cohen N, editors. Psychoneuroimmunology II. , Academic Press 1991.
[39] Nagy E, and Berczi I. Pituitary dependence of bone marrow function. Brit J Haematol 2989;71:457.

 

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