Hans Selye

The syndrome of just being sick

János Hugo Bruno Selye, always Hans, was born in Vienna on 26 January 1907 into a family that had produced four generations of doctors. His father, Hugo Selye, was a Hungarian surgeon who had served as a surgeon colonel in the Austro-Hungarian army and then opened his own surgical clinic, which Selye’s Austrian mother administered. The boy grew up in Komárom, a Hungarian town that the 1920 Treaty of Trianon handed to Czechoslovakia, was taught by Benedictine monks and private tutors, and seemed destined to inherit the clinic.

He chose the laboratory instead. At seventeen he entered medical school in Prague, at the German University, qualified in medicine in 1929 and added a doctorate in organic chemistry in 1931. In his own later telling, the idea that ran through his whole career began there, in his second year, watching a professor diagnose five patients with five different diseases. What struck the student was what the professor ignored: every one of them looked tired, had lost appetite and weight and would rather lie down than stand. Selye called it ‘the syndrome of just being sick’. By his account, his teachers and classmates laughed at it.

A Rockefeller Foundation fellowship took him to Johns Hopkins in Baltimore in 1931. He found it unbearable and was homesick, and he was heading back to Prague when Canadian students persuaded him to try McGill instead. In Montreal he finished the fellowship in the biochemistry department of James Bertram Collip, the discoverer of parathyroid hormone, and by twenty-seven he was an assistant professor of biochemistry. He became a Canadian citizen in 1939.

Cow ovaries, a cold roof and a letter to Nature

Collip’s laboratory was hunting for new sex hormones, and Selye’s job was to find one. As he later told it, he collected cow ovaries, made crude extracts and injected them into female rats. At autopsy the rats showed three things he had not expected: swollen adrenal glands, a shrunken thymus and lymph nodes, and bleeding ulcers in the stomach and duodenum. For a while he thought he had found a new hormone. Then placental extracts and extracts of other cow organs did the same, and it became clear that whatever caused the triad was not a hormone hidden in an ovary. Collip, in the story as McGill tells it, tried to steer his protégé away from ‘the meaningless side effects of disease’ and called the work ‘the pharmacology of dirt’.

Selye turned the failure into the experiment. If damage itself produced the triad, damage of any kind should do it, so he tested damage of many kinds: rats left on the cold roof of the medical building, rats kept running on a revolving treadmill, rats given surgical wounds or a severed spinal cord, rats dosed with sublethal amounts of adrenaline, atropine, morphine or formaldehyde. The changes came back each time. The cruelty was the method: the point was to find what every kind of harm had in common.

The result went to Nature as a 74-line letter, dated 18 May and published on 4 July 1936 as ‘A Syndrome produced by Diverse Nocuous Agents’. It describes a sequence, not a snapshot. In the first 6–48 hours the thymus, spleen, lymph glands and liver shrink, fat disappears, tissues fill with fluid, body temperature and muscle tone fall, erosions open in the stomach and intestine, and the adrenals lose their stored lipid. From 48 hours the adrenals are greatly enlarged and refill, while growth stops, the gonads atrophy and nursing females stop making milk; Selye guessed that the pituitary was switching from growth and sex hormones to the thyroid- and adrenal-stimulating ones ‘more urgently needed in such emergencies’. If the injury continued at a modest level the rats adapted until their organs looked almost normal. Then, after one to three months, they lost that resistance and died with the signs of the first stage.

He called the first stage the ‘general alarm reaction’ and the whole sequence, which seemed ‘a generalised effort of the organism to adapt itself to new conditions’, the ‘general adaptation syndrome’: alarm, resistance, exhaustion. Three things about the letter are worth noticing. It never uses the word ‘stress’. It says nothing about ovary extracts; the hormone-hunting origin story comes from Selye’s later books and memoirs, the kind of self-composed narrative the historian Mark Jackson warns readers to test. And it guessed the wrong trigger, proposing a flood of histamine ‘or some similar substance’ from damaged tissue. By 1950 his explanation had moved to the pituitary and the adrenal cortex.

Adaptation can cause disease

In 1945 Selye left McGill for the Université de Montréal, where he founded the Institut de médecine et de chirurgie expérimentales and directed it until he retired in 1977. It ran at industrial scale; at one point, Siang Yong Tan and A. Yip report, he directed some forty laboratory assistants and worked with 15,000 animals. He wrote at the same pace, eventually more than 1,600 papers and around forty books, and he trained researchers who went further than he did. Roger Guillemin, who won a Nobel Prize in 1977, dedicated his 1952 Montreal thesis ‘to Professor Hans Selye, to whom I owe my training in experimental medicine’.

His large claim of these years was that adaptation itself could make people ill. The 1950 treatise The Physiology and Pathology of Exposure to Stress, published in Montreal by Acta, sums up the argument in three steps: any systemic stress ‘elicits an essentially similar syndrome’; ‘This syndrome helps adaptation’; and ‘Adaptation can cause disease.’ The pituitary and adrenal cortex pour out hormones that raise resistance to infection, poison, cold or nervous strain, but the resulting ‘endogenous hormone-overdosage’ may cause cardiovascular, kidney and joint disease. Many of the commonest human maladies, he concluded, were ‘Diseases of Adaptation’, ‘the by-products of abnormal adaptive reactions to stress’. The evidence came from rats again: cold or protein poisoning could produce hypertension, malignant kidney damage and inflamed arteries, and so could pituitary preparations or the synthetic corticoid desoxycorticosterone.

The timing looked perfect. As he finished the treatise, Philip Hench’s group at the Mayo Clinic had just shown rheumatoid arthritis improving dramatically on cortisone, and Selye folded the result straight in: in animal experiments one class of adrenal hormones, the ‘mineralo-corticoids’ such as desoxycorticosterone, aggravated rheumatic and allergic lesions and another, the ‘gluco-corticoids’ such as cortisone, calmed them. The adrenal cortex looked like the switchboard between adaptation and disease. Hench’s cortisone work won a Nobel Prize in 1950; Selye, nominated repeatedly from 1949, never won. In June 1950 he gave the Heberden Oration, printed in the British Medical Journal as ‘Stress and the General Adaptation Syndrome’.

He saw the obvious objection himself. ‘Perhaps the strongest argument against our type of reasoning,’ the treatise concedes, ‘is the fact that the same degree of damage or stress does not necessarily always elicit the same response.’ His answer was conditioning: diet, salt and other factors could sensitise the body to one outcome or protect it from another. The answer kept the theory intact, and it also made it hard to refute.

Smoking as a diversion

The least flattering part of the record is in the tobacco industry’s own files, released through litigation and now searchable in UCSF’s Truth Tobacco Industry Documents. Mark Petticrew and Kelley Lee reconstructed it in the American Journal of Public Health in 2011. On their reading, Selye approached the American Tobacco Company for money in 1958 and was turned down. On 14 September 1959 Edwin Jacob of the law firm Davis Polk & Wardwell, preparing to defend cigarette makers against lung-cancer suits, wrote offering him a $1,000 honorarium for a memorandum on three theses, the first being that ‘the establishment of a statistical association between cigarette smoking and cancer does not establish a cause and effect relationship’. Petticrew and Lee report that he wrote two memos but would not testify.

The relationship resumed in 1966–67 with lawyers working for Philip Morris, Lorillard and other companies. An outline the attorney William Shinn sent to Philip Morris counsel Alexander Holtzman on 19 May 1967 sets out the plan in plain words. Selye’s theory held that destructive stress could be avoided ‘by deviation – a diversion of energy’; smoking could be one such diversion; the theory ‘should be promulgated through articles, books, TV appearances’; and the goal was the ‘creation of image of smoking as “right” for many people’. The same outline records, as Shinn understood it, Selye’s private opinion that smoking ‘does cause some cancers to develop, may cause heart disease in some people and does cause bronchitis’, and that he would give no opinion on smoking as a cause of disease because he did not consider himself qualified.

In March 1969 the industry’s Council for Tobacco Research gave him a three-year special-project grant of $50,000 a year, matched by the Canadian manufacturers, for a programme called ‘Stress and Relief from Stress’ that began that April; it was renewed in 1972. On 12 June 1969 he appeared before the Canadian House of Commons health committee, which was considering restrictions on cigarettes. He began by saying he had no special competence on the dangers of tobacco and that ‘only recently’ had he been able to ‘convince the Tobacco Industry to provide funds’ for stress research. Then he made the case in his own idiom: the soldier smoking before battle, the expectant father filling the ashtrays, the policeman offering his captive a cigarette; the question was ‘not “to smoke or not to smoke”, but to smoke or drink, eat, drive a car’; ‘crusades of enlightenment’ were creating hypochondriacs, and children scared off cigarettes might take ‘to marijuana or even LSD’ instead. He disclosed the grant. The text of the testimony kept in the industry’s files says nothing of his advice to its lawyers since 1959.

The meetings continued. After a visit in July 1969, Philip Morris’s Helmut Wakeham noted that Selye thought an education programme on stress ‘much more important, from the point of view of the tobacco industry’, than further experiments on whether cigarettes caused disease, and that it ‘should point out that there are benefits to smoking’. Petticrew and Lee follow him to a 1972 Philip Morris conference on smoking motives in the French Antilles, whose proceedings CTR subsidised, and into a 1976 Tobacco Institute film, The Answers We Seek. In June 1977 an R. J. Reynolds memo recorded that Selye, now running a stress institute and seeking support, ‘considers that for some people, smoking is a judicious way of combatting stress’. Petticrew and Lee conclude that his undeclared consultancy concealed a lack of independence and lent scientific credibility to the industry’s fight against tobacco control; companies were still using the stress argument in the 1990s.