Tohru Ishigami was born in 1857, in the midst of a tempestuous period in Japanese history. The American fleet led by commodore Perry had arrived in Yokohama in 1853, and Japan slowly began to veer away from its isolationist policies, opening up to a flood of Western influence in various arenas. Importantly, transfer of power from Shogun to Emperor occurred at this time (the Meiji Restoration) and brought with it drastic changes in socioeconomic aspects. The field of medicine was no exception. Chinese herbal medicine had heretofore been the mainstream of medicine, but after the Meiji Restoration, Western medicine prevailed in both clinical and research aspects. Ishigami began his medical studies under a master of oriental medicine in Kumamoto, where he was born, but by 1876 had oriented himself toward Western medicine. Eager to absorb as much knowledge as possible by going abroad, Ishigami entered the Japanese Navy as a medical officer.
At 31, he went to Adelaide, Australia and visited a leper colony. He was so intrigued by the patients and their underlying faith in God that he soon converted to Christianity [1, 2]. Four years later, in 1891, he had a chance to visit Europe, where he marveled at the facilities of public health and the progress in the study of infectious diseases. There he met a Japanese bacteriologist, Shibasaburo Kitasato, at the Robert Koch Institute in Berlin, who later co-discovered the infectious agent of bubonic plague, almost simultaneously with Alexandre Yersin. Back in Asia, Kitasato founded the Institute for Study of Infectious Disease in 1892 and hired Ishigami as a member of a Hong Kong research team studying bubonic plague epidemics.
Soon after, Ishigami founded his own research institute in Osaka in 1897 and later opened a tuberculosis sanatorium in 1902. Inspired by the works of Walter Cannon regarding adrenal secretion and physical excitation, Ishigami conducted both clinical and animal studies exploring the relationship between various mental states and tuberculosis progression and prognosis, the effect of mental state on glucose and adrenaline levels, and the effect of glucose and adrenaline on the opsonic index, i.e. the efficiency of phagocytosis.
Beginning in 1906, he conducted a series of clinical studies in a large number of tuberculosis patients . In these studies he confirmed previous observations that the opsonic index of patients with advanced tuberculosis was lower than in the less advanced cases, and that proper treatment brought an increase of the index. In untreated case, this index was generally higher in those with a more favorable prognosis. When the index fluctuated constantly, with occasional high index but kept usually low, the prognosis was invariably unfavorable.
Interestingly, he found that a high febrile condition of patients along with decreased opsonic index could sometimes be related to a psychological precipitant, such as receiving a piece of bad news or worrying. The depressed opsonic index lasted only a few days as usual, but if mental stress were prolonged, the return to the normal opsonic index would also be delayed. In this kind of ‘cumulative negative phase’, the course of the disease was gradually worse, with appetite loss, insomnia and persistent high fever. Nervous individuals with a history of major life stressors were especially prone to attacks of this type, and the prognosis was generally bad. On the other hand, patients who were judged optimistic and unfazed by negative events had a comparatively high opsonic index and a disease that followed a favorable course.
Furthermore, in the clinical studies, he observed that a substantial number of tuberculosis patients had glycosuria or transient glycosuria. Ishigami reported that ‘they were all nervous individuals, being easily excited by trivial things, and the opsonic index was low in each case’.
Since he was familiar with Walter B. Cannon’s findings that adrenaline secretion and blood sugar increased in association with psychic excitation, he sought to investigate the influence of adrenaline and glucose on the opsonin reaction in in vivo and in vitro experiments. Using guinea pigs, rabbits and rats, he examined phagocytosis after intraperitoneal (i.p.) injection of a mixture of adrenaline or glucose and emulsion of tubercle bacilli, and i.p. injection of the emulsion into animals which were pretreated subcutaneously with adrenaline and glucose. In both cases, phagocytotic indices more or less decreased with administration of adrenaline and glucose. The inhibitory action of adrenaline and glucose on phagocytosis was further confirmed by tube experiments, in which the opsonic index was investigated in a mixture of normal or patients’ serum, guinea big leucocytes, and tubercle bacilli emulsion. He found that phagocytosis was decreased at the time when glycosuria was present due to emotional excitement, and that an addition of adrenaline or glucose to the test-tube mixture further decreased the reaction. Phagocytic activity was much higher in the less severe cases than in the more advanced ones.
With these studies, Ishigami demonstrated that psychic acts influenced the course of pulmonary tuberculosis unfavorably because they were associated with a rise in glucose and adrenaline and thus accompanied by a lowering of the opsonic index. He pointed out, as supporting evidence, the subnormal resistance of diabetic patients to infections such as tuberculosis and furunculosis which according to his theories would involve a high glucose level inhibiting phagocytic activity.
Ishigami used the results of his research projects to explain epidemiological trends such as the finding that greatest percentage of mortality from tuberculosis in Japan was among primary school teachers.(actually, the relative number of young individuals suffering from tuberculosis happened to be greatest at that time in Japan). He concluded that unsatisfactory educational system (e.g., extremely severe entrance examinations) caused overtaxation of the mind of youths, resulting in the high mortality of young consumptives. Therefore, he suggested that an improvement in the educational system and in the treatment of teachers was necessary in combating tuberculosis.
These last results and recommendations were published posthumously in 1919. In this early scientific paper Ishigami was probably the first to address the relationships between mental state, immunological changes and ability to fight infection. Moreover, he was probably the first to link clinical observations to experimental work in this field. Today, we know that the immunological response to tuberculosis is much more complex, involving other hormones, neuro- and immune-mediators. Nevertheless, this paper by Ishigami represents a shift in thinking, and an introduction to the interplay between the brain and the immune system that laid some of the foundation for the field of psychoneuroimmunology and neuroendocrine-immunology.
A Hashiramoto – Division of Rheumatology, Graduate School of Medicine, Kobe University
T Katafuchi – Department of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Taguchi F. 2003. Tohru Ishigami (1). Japan Medical Journal. 4118:41-43.
Taguchi F. 2003. Tohru Ishigami (2). Japan Medical Journal. 4119:43-46.
Ishigami T. 1919. The influence of psychic acts on the progress of pulmonary tuberculosis. Am. Rev. Tuberc. 2: 470-484.