Until the beginning of the 20th century, humanity was practically helpless in the face of contagious diseases. Kitazato Shibasaburō paved the way for the treatment of many diseases with the discovery of the tetanus or plague bacteria.
Successful culture of tetanus bacteria and discovery of its antitoxin
The world of Japanese medicine was for many centuries under Chinese influence. If we leave aside the so-called “Dutch studies” (rangaku) of the Edo period (1603-1868), which made their way into Japan through a single point (the artificial island of Dejima, in Nagasaki), we can say that Chinese influence lasted until the beginning of the Meiji era (1868-1912 ), when there was a radical turn to the West. Kitazato Shibasaburō (1853-1931) is the first Japanese eminence in this renewed medicine.
Born in the village of Kitazato, located in the former province of Higo (present-day Oguni municipality, Aso district, Kumamoto prefecture), he studied medicine at the Furushiro Medical School, which later became the Faculty of Medicine of the Kumamoto University, and at the Tokyo Medical School, later the University of Tokyo School of Medicine. Although he obtained a position in the Department of Hygiene of the Ministry of the Interior, following the advice of Constant George van Mansvelt (1832-1912), the Dutch military doctor who was his teacher at the Furushiro school, he went to Germany to complete his training, remaining in the country seven years (1885-1892). There, he received the teachings of who at the time was the world’s highest authority on bacteriology: Robert Koch (1843-1910).
It was at the Koch Institute in Berlin where Kitazato, who combined a great innovative spirit with his diligence and perseverance, achieved, in 1889, something considered impossible: isolate the tetanus bacteria and make a pure culture of it, being the first in the world in getting it. A year later, he rounded off his feat with the discovery of the antitoxin for this disease, thus gaining international renown. The discovery opened a new research panorama, in which Kitazato’s creativity was reflected in a new treatment, serotherapy (1890), applicable among other diseases to diphtheria, which he pioneered with Emil Adolf von Behrin (1854- 1917). Serotherapy consists of using a medicinal serum that contains antitoxins, to prevent or to cure certain diseases. For this achievement, Behrin was awarded the first Nobel Prize in Physiology and Medicine. Back then there were no shared prizes yet. If there had been, it is very likely that Kitazato would also have been awarded. In fact, Kitazato was among the nominees in a later edition.
Antibody drugs, created from the immune system
The antitoxins discovered by Kitazato, what we now call antibodies, work by eliminating bacteria and other foreign bodies that enter the body from the outside. In the blood of people infected by bacteria or viruses, proteins called antibodies are formed, and it is these proteins that are responsible for repelling the attack when bacteria or similar viruses try again to invade that same organism. It goes without saying that the creation of drugs that use the immune system that the body is naturally endowed with (the principle of the antigen-antibody reaction) has contributed greatly to the further development of medicine and clinical treatments.
Currently, no effective vaccines or drugs have yet been created in the treatment of this new coronavirus that is convulsing the world. But it is beyond any doubt that, sooner or later, drugs will be developed that use vaccine antigens of weakened or totally deactivated pathogenicity, all of which is based on the idea of antibodies. In other words, also in the competition to develop drugs between medical institutions in the world that are struggling to create the vaccine, we find that it is the idea of the antigen-antibody reaction proposed by Kitazato and his team that serves as the basis.
But it is not only that, the drugs that use the antibodies contained in the blood are being used, in addition to the treatment of tetanus, in the treatment of other serious infections and diseases of difficult cure for which antibiotics are not effective. And again we find here that the theoretical basis for all these applications is provided by serotherapy, created by Kitazato. Together these drugs are called “antibody drugs” and today they already account for more than half of all new drugs being developed in the world.
Discovery of plague bacteria in Hong Kong
Kitazato’s merits don’t end there. In 1894, when he was in Hong Kong, he discovered the plague-causing bacteria simultaneously with Alexandre Yersin (1863-1943), from the Pasteur Institute (France). Both researchers found it at the same time and in the same laboratory, but independently. This disease, feared as “the black death”, ravaged Europe in the fourteenth century, after which it repeated its lethal attacks until the eighteenth century, causing enormous damage throughout the world. With its enormous power, this acute contagious disease produced dramatic changes in the politics, economy, society and culture of those times. In the second half of the 19th century, the plague spread again, this time in the Manchuria region (north of China) and it was then that the attempts of Kitazato and Yersin to identify the pathogen were crowned with success in Hong Kong. It was a brilliant achievement, the result of the application of bacteriological methods, which already responded to the so-called Four Postulates of Koch. The postulates are: for each disease it must be possible to extract a certain microorganism; This must be able to be isolated and reproduced in pure culture; it must be possible to produce the same disease when inoculated into another organism, and again it must be able to be isolated by extracting it from the lesions produced. Subsequently, there have been many other discoveries in the field of bacteriology. Shiga Kiyoshi (1871-1951) discovered the dysentery bacillus; Fritz Schaudinn (1871-1908) and Erich Hoffmann (1868-1959), the bacteria that cause syphilis. It was the time when bacteriology entered a new phase, that of microbiology, when researchers realized the existence of microorganisms even smaller than bacteria, today called viruses.
Leadership also in the creation of laboratories, medical and pharmaceutical schools
Another of Kitazato’s great achievements is the creation, two years before discovering the plague bacteria, of the first contagious disease research laboratory in Japan (1892), for which he had the help of great personalities, such as the writer and man of culture Fukuzawa Yukichi (1835-1901), the high official of the medical services Nagayo Sensai (1836-1902), or the industrialist Morimura Ichizaemon (1839-1919). The Contagious Diseases Laboratory, dependent on the Japanese Hygiene Association (private), became the National Institute for Contagious Diseases (Ministry of the Interior), which over time would acquire world fame, reaching the same level as the French Pasteur or the American Rockefeller.
However, in 1914, against Kitazato’s wishes, the Institute of Contagious Diseases was transferred to another ministry, that of Education, becoming an organization subordinate to the Imperial University of Tokyo (now the University of Tokyo). The measure aroused the ire of Kitazato, who resigned “in full” with all the personnel and stood up to the Government by creating the Kitasato Institute, which he financed with his own money. From that moment on, both institutions, public and private, have held academic controversies that eventually served to raise the level of medical research in Japan. The antagonism between these two institutions was not in any negative sense for Japan, since the correct exposition of opposite academic positions contributed to raise the level of studies in this field.
In addition to founding his institute, Kitazato displayed great leadership in other initiatives. He created the Japan Medical Association in 1916, in 1920 the Keiō School of Medicine, the first in the country to be formed within a private university, in 1921 the Termo joint-stock company, which manufactured thermometers and other medical instruments, and in 1923 the Society Japonesa de la Tuberculosis, among other entities.
A vaccine developed on a false hypothesis
The antagonism between the Kitasato Institute and the National Institute of Contagious Diseases was exacerbated by the so-called “Spanish flu”, a pandemic that broke out in 1918. The two entities competed to develop a vaccine and effective treatments. However, at that time the existence of viruses was not yet known. Kitazato and Richard Pfeiffer (1858-1945) erroneously assumed that there must be a “flu bacteria” and based on that “discovery” they devised a vaccine. The rival institute, for its part, estimated that it must be a “filtering” pathogen, that is, being smaller than bacteria it circumvented the filters used at the time.
Unfortunately, the world was in the bacteriological phase, prior to that of microbiology. It was regrettable that Kitazato struggled to develop a vaccine on the wrong premise, but it can only be said that it was due to limitations in scientific thinking inherent at the time. The existence of viruses, microorganisms much smaller than bacteria, could only be verified in 1933, when electron microscopes were already available. But Kitazato had died of an illness two years ago. Throughout his life he continued making contributions to the development of bacteriology and it was after his death that virological studies began. Despite this latest episode, the seed spread by Kitazato has borne many great fruits and the current educational institution Instituto Kitasato continues to be the cradle of great doctors and researchers who are leaders in the world.
Timeline of Kitazato’s life
* On a blue background, other milestones in the history of medical research.
Header photo: Photograph by Kitazato Shibasaburō (National Diet Library Digital Collection).