The clinical manifestations of dysentery have been described for centuries, and the prototypic bacterial agent, Shigella dysenteriae, was identified 100 years ago. In the English language there has been remarkably little written about Dr. Kiyoshi Shiga, discoverer of the dysentery bacillus. We submit a brief biography of Dr. Shiga and the circumstances leading to his discovery, which proved the bacterial etiology of nonamebic dysentery.
In 1936, as a senior scientist and honored guest at the tercentenary celebration at Harvard University, Dr. Kiyoshi Shiga began his address as follows: “The discovery of the dysentery bacillus stirred my young heart with hopes of eradicating the disease…Many thousands still suffer from this disease every year, and the light of hope that once burned so brightly has faded as a dream of a summer night. This sacred fire must not burn out .”
Today, 100 years after Shiga's landmark discovery, shigellosis kills hundreds of thousands a year, primarily children in developing countries . The disease occurs endemically worldwide, but certain populations such as refugees, institutionalized persons, and military units under field conditions are especially at risk [3–5]. Large-scale epidemics have also occurred . Shigella species commonly exhibit broad antibiotic resistance, and a safe, effective vaccine against Shigella remains elusive [7–10].
Dr. Shiga (figure 1) was an internationally recognized authority in microbiology in the early part of this century, but there is little English-language information on his life. He was born the fifth child of Shin and Chiyo Sato on 5 February 1871 in Sendai, in northern Japan. His early years were difficult and mirrored the turbulent times as Japan entered the Industrial Age. From 1600 until the mid-19th century Japan was an isolated, agricultural nation under feudal rule. Western nations, motivated by aggressive military and economic policies, forced Japan to open its ports when Matthew Perry sailed American warships into Tokyo harbor in 1853. The Mejii Restoration (1868–1877), initiated by former feudal lords, created radical changes in the social and political structure of Japan.
Shiga's father, a successful administrator of the samurai class under the old regime, lost his position during the Restoration, an event that forced economic hardship on his family. Young Kiyoshi was raised in his maternal family and later adopted his mother's maiden name, Shiga, as his surname. In 1886 his family moved to Tokyo, where Shiga attended high school and studied mathematics and German, among other subjects. He entered the Tokyo Imperial University School of Medicine in 1892.
During medical school Shiga attended a lecture by Dr. Shibasaburo Kitasato, the most prestigious Japanese scientist of the day and a protégé of Robert Koch. Kitasato had achieved international recognition in 1889 with his successful pure cultivation of Clostridium tetani and his discovery of tetanusantitoxin, with the promise of immunotherapy . In 1894 Kitasato had investigated a bubonic plague epidemic in Hong Kong and reported his findings in the Lancet . Kitasato's confident and charismatic personality impressed young Shiga. After graduation Shiga entered the Institute for Infectious Diseases, established and directed by Kitasato, as a research assistant.
Shiga was initially assigned to the tuberculosis and diphtheria wards, but in late 1897 Kitasato directed his attention to the microbiological investigation of a sekiri (dysentery) outbreak. In the older medical literature, the term dysentery was somewhat vague and had been used to “signify violent diarrheal disturbances of almost any cause” . The meaning of the Japanese word sekiri, derived from Chinese characters that indicate “red diarrhea,” is closer to the contemporary definition, which implies frequent, small bowel movements accompanied by blood and mucus, with tenesmus or pain on defecation .
Lösch had described intestinal amebiasis in 1875, and although European, Japanese, and American researchers had postulated that the cause of nonamebic dysentery was bacterial, no one had demonstrated an etiologic agent . Dysentery epidemics, affecting tens of thousands with high mortality, occurred periodically in Japan during the last decades of the 19th century . Shiga described the fear engendered by these seasonal outbreaks as follows: “It [dysentery] has been regarded as the most dreaded disease of children from its fulminating course and high mortality .” The 1897 sekiri epidemic affected >91,000, with a mortality rate of >20%.
Shiga studied 36 dysentery patients at the Institute for Infectious Diseases. Acutely aware of his mentor's regard for Koch's postulates, Shiga employed simple but exacting methods to identify the organism that had eluded so many previous investigators. He isolated a bacillus from stool that was negative by gram-staining, fermented dextrose, was negative in the indole reaction, and did not form acid from mannitol. Subcultures of the organism caused diarrhea when fed to dogs.
The key to his remarkable discovery, however, was a simple agglutination technique. Shiga demonstrated that the organism repeatedly coalesced when exposed to the serumofconvalescent dysentery patients. He published his findings with a gracious acknowledgment of Dr. Kitasato's guidance .
Shiga continued to characterize the organism, initially termed simply Bacillus dysenterie [15, 17]. In particular, he described the production of toxic factors by the organism. One of these factors, now known as Shiga toxin, was recently reviewed in a historical context . In the years immediately following Shiga's discovery of the dysentery bacillus, similar organisms were described by other investigators. Several revisions in nomenclature followed. The genus was first termed Shigella in the 1930 edition of Bergey's Manual of Determinative Bacteriology .
Today Shigella is classified as follows: S. dysenteriae (group A), the original organism described by Shiga; S. flexneri (group B); S. boydii (group C); and S. sonnei (group D). They exist as nonmotile, gram-negative rods that do not ferment lactose (except for group D) and fail to produce H2S in triple-sugar-iron agar. Unlike the other species, S. dysenteriae does not ferment mannitol. The genus is well-characterized antigenically, with multiple serovars within each species except S. sonnei .
In addition to work on the pathogenesis of bacillary dysentery, Shiga focused his efforts on the development of a Shigella vaccine. In his autobiography he describes how he initially prepared a heat-killed whole-cell vaccine and injected himself as the first study subject. The resulting local reaction was severe and required incision and drainage . He then developed a serum-based passive immunization and later an oral vaccine, which was administered to thousands of Japanese citizens. These experiments were conducted before the advent of controlled clinical trials, and his observations were published primarily in German- and Japanese-language journals. Shiga later expressed reservations about the efficacy of vaccines for the control of enteric diseases and emphasized the importance of public health practices .
Shigellosis is the most communicable of the bacterial enteric diseases, and experiments with volunteers have demonstrated that as few as 10–100 organisms can cause symptoms [22, 23]. The low inoculum dose and highly contagious nature of shigellosis present a public health challenge. Recent advances have characterized many of the virulence factors of Shigella species [24–26]. Insight into the pathogenesis of shigellosis has led to novel approaches in vaccine design, and vaccine development efforts continue worldwide [27–33].
In 1900 Shiga married, and he and his wife, Ichiko, had the first of their eight children the next year. He was soon on his way to Germany, where he entered Paul Ehrlich's laboratory as a research assistant at the Institut für Experimental Therapie in Frankfurt. During his time with Ehrlich, Shiga worked on various projects, including early studies of chemotherapy for trypanosomiasis. He returned to Japan to work in Kitasato's laboratory in 1905. By this time Shiga had developed an international reputation, and in 1906 he presented his research on epidemic shigellosis at the first Congress for Asian Tropical Medicine in Manila, the Philippines .
In 1914 the Japanese government undertook an organizational restructuring of the Institute for Infectious Diseases. Kitasato resigned in protest, and Shiga followed him to establish the Kitasato Institute, an institution that continues today. Shiga was named a division director of the Institute.
Shiga was appointed professor in the medical faculty of Keio University in Tokyo in April 1920. Later that same year, at the request of the Japanese government, Shiga left for Korea, a Japanese colony at the time, to serve as the director of the National Hospital of Seoul. He held an additional post in the Seoul Technical College of Medicine. From May to November 1924 he visited medical schools and lectured in Europe and the United States.
In 1926 Keijo University (Seoul University) was founded, and Shiga was named the Dean of the School of Medicine. He became President of the University in 1929 and served until 1931, when he resigned and returned to Japan to pursue his main interest, research, at the Kitasato Institute. His long-time mentor and colleague, Dr. Kitasato, died that same year. Shiga continued active laboratory investigations, with interests ranging from dysentery to tuberculosis, until 1945.
The war years brought personal tragedy to Shiga. His wife died of stomach cancer in 1944. His oldest son, Naoshi, a university professor in Taipei, was killed at sea while returning home to attend his mother's funeral. Another son, Akira, contracted tuberculosis during the fighting in China and died after the war. Shiga's Tokyo house was destroyed during a bombing attack, and he returned to Sendai to live with his son, Makoto. In retirement Shiga received guests, corresponded with friends overseas, and continued to write. He completed his autobiography as well as a Japanese-language biography of his friend and mentor, Paul Ehrlich.
Near the end of his life Dr. Shiga composed the following calligraphy: “Follow the mentor's spirit, not the mentor's footsteps” (figure 2). As the protégé and contemporary of giants in the field of microbiology, Shiga could easily have been obscured by their imposing shadows. However, he earned a place in the milestones of microbiology by his creative thinking and contributions to research in the etiology, pathogenesis, and immunization of enteric diseases.
Dr. Shiga died at the age of 85 years on 25 January 1957. His obituary in the New York Times stated that “he could be considered one of the four or five most eminent men in bacteriology in his most active years” . Perhaps more significant than his scientific achievements, however, was his status as an international ambassador of goodwill during the troubled early years of this century.
Shiga closed his remarks on that summer day at Harvard in 1936 by quoting Louis Pasteur in words that well described his own life, urging his listeners to persevere “until the time comes when you…have contributed in some way to the progress and good of humanity .”
We thank the Shibasaburo Kitasato Memorial Museum at the Kitasato Institute (Tokyo), for permission to use the photograph of Dr. Shiga and his calligraphy (figure 1 and 2). We also thank Ms. Mihoko Okubo of the museum for her assistance. Dr. Trofa thanks T. Larry Hale, Ph.D., for his patient instruction on the pathogenesis of shigellosis during their work together at the Walter Reed Army Institute of Research (Washington, DC).