Abstract
Professor Satoshi Ōmura was awarded the 2015 Nobel Prize in Physiology or Medicine. He is the third to win the award for research on antibiotic, following Fleming’ (UK, 1945, discovery of penicillin) and Waksman (USA, 1952, discovery of streptomycin), and the second person after Waksman to receive the award for research on actinomycetes. By focusing his research on macrolides stemming from leucomycin research rather than β-lactams like penicillin or aminoglycosides like streptomycin, Prof. Ōmura realized many scientific achievements. These efforts finally led to the discovery of avermectin and its semi-synthetic derivative, ivermectin, considered a monumental contribution to the human race. In this manuscript, I will outline the chronicles of the epoch-making antibiotic exploratory researches preceding Prof. Ōmura.
Exploratory research on penicillin-producing fungiCitation1)
Penicillin was originally discovered in 1929 by Fleming and rediscovered in 1940 by Florey. It was effective against Streptococcus pneumoniae and capable of curing patients with pneumonia. Penicillin was highly esteemed as a breakthrough in treating micro-organism-caused infectious diseases that were out of reach of other contemporary medicines. For this, both Fleming and Florey were awarded the Nobel Prize in 1945. News of penicillin (Dr. Kiese’s review) traveled to Japan in the fall of 1943 via German submarine. Upon hearing of the great medicine, the Penicillin Committee was formed in the Army Medical School in the midst of the World War II in February 1944, commencing penicillin research and development. This was the dawning of antibiotic research in Japan (Table ). Summoned by the principal of the Army Medical School, scientists from diverse fields such as fundamental medicine, physics, clinical medicine, chemistry, agricultural chemistry, pharmaceutical science, and plant science formed the committee. Later that year, owing to the tremendous contributions of Major Katsuhiko Inagaki, the organizer of the committee, and Dr. Hamao Umezawa, the research leader, Japanese penicillin emerged.
Table 1. Remarks on discovery and development of penicillin, streptomycin, and kanamycin.
During the first committee meeting (February 1), they engaged in discussion about Kiese’s findings, Dr. Fleming’s papers, and other research. It was decided that fungi from all over Japan would be collected and cultured; Dr. Hamao Umezawa and his colleagues would conduct in vitro studies on the antimicrobial properties of the culture media and animal testing to investigate the efficacy. Major Inagaki collected strains from all over the country, procured and distributed the necessary research materials, contacted each research facility, surveyed the research progress, collected and distributed literature and information, and had a role in committee meetings. Major Inagaki was well aware that only the military was capable of promoting these studies, and he therefore felt that the weight of penicillin research was on his shoulders as an unsung hero and that the Army Medical School should provide full cooperation.
There were twists and turns, but in October, they finally harvested the fruits of their hard work. At the subcommittee meeting held on October 9 at the Kinichiro Sakaguchi Laboratory of Tokyo University, Dr. Umezawa reported that the yellow concentrated liquid obtained from two bacterial strains extracted and enriched from the fermentation filtrate in Teijiro Yabuta’s Laboratory following the method in Dr. Kiese’s review had completely prevented the growth and development of Staphylococcus 1600–3200-fold and displayed a strong protective action against infection by S. pneumoniae in mice. Then, on October 30 at the 6th Committee Meeting, Prof. Sumio Umezawa (Keio University) reported the antibacterial substance from Dr. Hamao Umezawa’s concentrate comprised barium and calcium salts, and those physicochemical properties coincided with the properties of purified penicillin noted in Dr. Kiese’s review.
They missed achieving their intended goal, August, by two months but succeeded. Hiroshi Kanbayashi, the Director of the Medical Bureau, Department of War, expressed his gratitude:
Previously, the research system in our country was in a state of disunion, academia hid away in their own realm and had the bad habit of keeping to themselves. Nevertheless, top-level scientists from various backgrounds—medical, pharmaceutical, agricultural, and scientific—joined forces for research on penicillin, shared knowledge, discussed about new research, mutually helped and encouraged one another, overcame many barriers, and ultimately achieved monumental results. This began a new page in the history of the research system in our country, and I firmly believe we have been given a glimpse of the future of the Japanese academic world.
Thereafter, research toward mass production commenced. While various types of culture media and fermentation conditions were investigated, Major Inagaki, noting that the penicillin factory from one country resembled a milking plant, acquired the assistance of Morinaga Milk Industry through his uncle and produced 100 L of bottled cultures every day at the Mishima Factory. Led by Major Inagaki’s four brains (Ken Aizawa, Hamao Umezawa, Motosaburo Masuyama, and Koichi Sato) they successfully made purified penicillin solution in one month. The purified solution was explained at the 7th Committee Meeting (December 23). At the same committee meeting, Banyu Pharmaceutical Co. Ltd., which was also engaged in the production of penicillin under the guidance of Dr. Umezawa, presented an ampule of penicillin. The principal of the Army Medical School (Army Surgeon Lieutenant General), Kenji Ibuka, proposed the following plan:
So far, the Army Medical School has been the center of the Penicillin Committee; however, these results have opened the door to operating this as a national project. Therefore, first, we should dissolve the old Penicillin Committee and continue as an army-naval joint committee. Second, in the meantime, military need should take priority over civilian need for the mass-production of penicillin. Third, as for the name “penicillin”, we cannot be positive that we have obtained the same penicillin discovered by Fleming. Therefore, it will be given the Japanese name “hekiso”.
Dr. Hamao Umezawa stated the following in his recollection on the achievements of the Penicillin Committee:
From the 2000-some strains of fungi used in the research, a strain capable of producing penicillin was selected, and in October 1944 we almost reached our goal of producing the brown amorphous penicillin. That December, the Japanese name “hekiso” was agreed upon. In November, production delegation and instructions for mass production were given to Banyu Pharmaceutical Co., Ltd., Morinaga Milk Industry, Yamagata Godo Foods (Meiji Seika and Meiji Milk Industry), and Hokkaido Kono Public Corporation. We had no choice but to rely on the surface static culture method, the traditional Japanese fermentation technique, for fermenting the fungus. Research proceeded in spite of power outages and insufficient materials for extraction and purification. The amount of specialized information we had was poor in spite of repeated trial and error. However, it became a great foundation when we received most-advanced knowledge and technological training from the US after the war. Furthermore, the principles of operation, forming an interdisciplinary committee and conducting all research reports at the committee meetings, are thought to have been inherited by the post-war penicillin production project.
Along with the end of the war, the Hekiso Committee disappeared. Following the orders of the GHQ (General Headquarters of the Allied Forces), Army Medical School Principal Ibuka and Dr. Hamao Umezawa submitted the Japanese-made penicillin together with their penicillin research results.
After the war, to improve the health of the Japanese people. The Ministry of Welfare immediately labeled the production of high-quality penicillin as a key industry, giving restart of its production top priority and allocated funding, materials, coal, and electricity. In addition, they implemented the release of the army medical supplies. Then, instructions were issued that two organizations were to be established, an association targeting cooperative connections with production industries and an organization for scientists to advise the Ministry of Welfare on comprehensive research and technical guidance. Hence, the Japan Penicillin Association (August 15 1946) and the Japan Penicillin Research Association (May 20 1947) were both founded.
The penicillin production research undertaken with the industry–government–academic project system was dramatically improved through the release of the US’s state-of-the-art scientific information, technical guidance, and supply of production strains brought by Dr. Foster, who was invited per post-war GHQ policy. Finally, while the industrial mass production and supply system were being completed, the standards were determined for penicillin’s specifications, assay, and clinical use based on studies at the Penicillin Research Association’s workshop.
In this way, penicillin research was sown as a new seed within the environment devastated by ongoing war, and within mere three or four years after the war, the penicillin production industry developed as far as to become an export industry.
Exploratory research on aminoglycoside antibiotic-producing micro-organisms
Following penicillin, GHQ Brigadier General Sams proposed for streptomycin (SM), which was discovered by Waksman in 1944, to be the second national project, and he brought an SM-producing actinomycete to Japan. SM displayed antibiotic activity against to which penicillin is not effective Mycobacterium tuberculosis. It is a water-soluble and basic compound that possesses a structure designated as an aminoglycoside. Dr. Waksman received the Nobel Prize in 1952 for the discovery of SM. Introduction of SM in Japan was a tremendous blessing because tuberculosis was such a plague that it was referred to as “white devil.” Dr. Hamao Umezawa took charge of the SM research project and was successful in reaching mass production of the substance.
The SM-producing Streptomyces griseus was an actinomycete, but when it was brought to Japan, none of the antibiotic researchers was acquainted with actinomycetes. Yoshirou Okami, a research scientist who joined Prof. Hamao Umezawa’s laboratory in 1947, had studied under one of the only a few of researchers having experience with actinomycetes, Hokkaido University’s Prof. Yuji Sasaki (Faculty of Agriculture, Applied Mycology Course), but he did not have an opportunity to study actinomycetes as a student. Okami began isolation and research on actinomycetes through trial and error. Then, he reached out to scientists conducting similar research in academia and pharmaceutical industries to start a group for informal discussions (ideas exchange), which became the seed for the current Society for Actinomycetes Japan.Citation2)
While this was taking place, in December 1952, Dr. Waksman stopped in Japan on his way home from receiving his Nobel Prize.Citation3) His main purpose was to attend the 100th anniversary of Shibasaburo Kitasato’s birth, for which he had accepted an invitation, but Dr. Waksman also visited antibiotic researchers all across Japan to exchange ideas and offer words of encouragement. The Kitasato Institute’s Prof. Toju Hata, who later discovered mitomycin and leucomycin from actinomycetes, accompanied Dr. Waksman. After traveling around Japan, Dr. Waksman decided to offer half of the SM patent royalties to promote Japanese research on antibiotic.Citation3) Thanks to that funding, in 1957, the Waksman Foundation of Japan Inc. was established with Prince Takahito Mikasanomiya as the Honorary President. The foundation, which is still active today, aimed at contributing to the advancement of Japan’s science and culture by supporting and promoting academic research on microbiology and medicine.Citation4) In addition, during the late 1950s, Dr. Toju Hata and Dr. Yoshiro Okami went to study under Dr. Waksman (Rutgers University, NJ, USA).
In Umezawa’s laboratory (Antibiotic Division, National Institute of Health Japan), exploratory research was conducted in earnest on antibiotics of microbial origin based on the screening system established through studies on the penicillin-producing and SM-producing micro-organisms. Finally, in 1957, a new water-soluble and basic antibiotic kanamycin (KM) made by an actinomycete was discovered. KM showed activity against SM-resistant M. tuberculosis, and it was approved as an antitubercular drug and put on the market next year. Thereafter, it was highly evaluated not only in Japan but also in the US, as The New York Academy of Sciences arranged a special symposium for it. KM obtained the status of the first international medicine of Japan origin and was used to treat tuberculosis worldwide to save countless lives.
Using the KM patent royalties, Dr. Umezawa established the Microbial Chemistry Research Foundation, built the Institute of Microbial Chemistry (IMC) in 1962, and developed world-leading antibiotic researches. For his achievements in antibiotic research, he was awarded the Order of Culture (1962, 48 years old). Over the course of his life (until he passed away at age 72 in 1986), he endeavored to elucidate resistance mechanisms of aminoglycoside antibiotic-resistant bacteria, innovate theoretical semi-synthetic aminoglycoside antibiotics such as dibekacin and arbekacin based on resistance mechanisms, and pioneer the first research in the world on antitumor antibiotics like bleomycin, antibiotic agrochemicals (kasugamycin), enzyme inhibitors, and plasmids. Dr. Umezawa was truly a charismatic leader on antibiotis for both the academic and industrial worlds. He contributed over 150 new substances, 10 pharmaceuticals/agrochemicals, and over 1000 research papers to the world through his work. Consequently, over a few years in the late 1970s, he was nominated as a candidate for the Nobel Prize in Physiology or Medicine.
I was a member of Dr. Umezawa’s Research Institute, Institute of Microbial Chenistry (IMC) for 13 years (1972–1985) and conducted actinomycetes research in Prof. Okami’s laboratory. Therefore I want to mention three things that left a deep impression on me. First, although Dr. Umezawa was a basic medical scientist, he possessed extensive knowledge and insight about chemistry and other subjects. Every Sunday in IMC’s library, he would glance over all of the new journal editions. If he found a paper of interest, he would tag it and send it to the scientists researching related topics, encouraging them to read it promptly and report the details. It was quite an effective habit for educating ourselves. Second, emphasizing the importance of the invariance of compounds, he persisted with “isolate and purify the substance, then determine its chemical structure.” Third, as he continued to understand more about the fuzziness of biology, he was very much aware of its exclusion and occasionally announced bold hypotheses on theories about plasmid encodes antibiotic-biosynthesis genes. At an international meeting held one year after Prof. Umezawa passed away (1987), a scientist from a pharmaceutical company said the following at the beginning of his lecture: “About 10 years ago, Hamao Umezawa visited our company and lectured on plasmids being involved in antibiotic production. His talk inspired me to begin research on the genetics of antibiotical-producing microorganisms.” Sitting in the audience, I could not help but be deeply impressed by the immensity of Prof. Umezawa’s influence.
Thoughts on the progression of Prof. Ōmura’s research
By focusing his research on macrolides stemming from leucomycin research rather than β-lactams like penicillin or aminoglycosides like SM, Prof. Ōmura realized many scientific achievements. These efforts finally lead to the development of the antiparasitic agent ivermectin, a monumental contribution to the human race. I acted as a member of the preparatory committee formed in 1985 in preparation for the 7th International Symposium on Biology of Actinomycetes (ISBA ’88) hosted by the Society for Actinomycetes Japan, where I became acquainted with Prof. Ōmura who had assumed the chairman of the fund-raising committee. Since then, I have received his guidance in every possible matter for 30 years. A few years ago, I was presented with a piece of art that was made by etching an electron micrograph of the avermectin-producing actinomycete, the origin of ivermectin development. It now hangs in our meeting room. This is to always remind us of Prof. Ōmuras attitude toward life.
Assuming suitable people are being requested to talk about Prof. Ōmura’s achievements, I would like to share one of Prof. Ōmura’s magazine interviews from 1990 when he was promoted to the Director of the Kitasato Institute and was awarded the Japan Academy Prize. It was printed in Cell Science, a Japanese journal, and also appeared in a compilation book.Citation5) Later, it also had the privilege to appear in Prof. Ōmura’s own writing, Rhododendoron no Saku Machi (Rhodoendoron-blooming Town).
The interview session comprised a Q&A concerning the topics Prof. Ōmura had touched on during his Japan Academy Prize acceptance speech. A picture from his earliest days as a scientist, the efforts to use avermectin to eradicate onchocerciasis in Africa and his way of thinking and philosophy showing a certain ukiyo-e painting. Then, i as the interviewer inquired about, a compound named lactacystin that exhibits the same activity as NGF to PC12 cells from rats. I personally thought lactacystin hinted at the future of antibiotic substances. As the interview progressed, Prof. Ōmura also talked about many topics—his resolve to follow in Prof. Toju Hata’s laboratory when he started up his own laboratory (1973, age 38), his reason for foregoing research on β-lactams and aminoglycosides, building the necessary infrastructure to drive research, the importance of carrying one’s research to the top as if climbing a tall mountain step by step, his philosophy for cultivating young scientists, and the importance of a sense of mission toward one’s research.
Everything Prof. Ōmura talked about then matches what he talked about upon being awarded the Nobel Prize. I was deeply impressed by his steadfast spirit consistent from the beginning. Prof. Ōmura authored many essay books such as Rhododendoron no Saku Machi (Rhodoendoron-blooming Town), Shiba-Shirokane Sanko-cho (name of a district in Tokyo), Yugure (Twilight), and Shokurin (Allorestation), all of which are highly educational for a holistic worldview. I recommend that everyone read them. Furthermore, I strongly felt the nature and sentiments of Prof. Ōmura conveyed through the first book he presented me, Rosajin to Kage no Meiko Toko Matsushima Hiroaki no Shogai (Rosanjin and a hidden craftsman–The life of a potter, Hiroaki Matsushima) written by Fumino Kagawa.Citation6)
Prof. Ōmura’s way of life embodied the pioneering spirit and challenging ambition of a scientist, the importance of regarding practical science and internationality as paramount, holistic education, and the desire for peace. All while never losing his passion for innovation, every one of those attributes was the pride of his dignified and virtuous way of life. I am forever thankful for my good fortune of being able to come in contact with and learn from such an exemplary researcher.
Concluding remarks
Research conducted under the mid-war (1944) Penicillin Committee led by Army Major Katsuhiko Inagaki and Prof. Hamao Umezawa was the inception of antibiotical research in Japan. At that time, Ōmura was a mere boy of 8 years, running about the fields and hills of Yamanashi prefecture. Dr. Ōmura initiated antibiotic research at the Kitasato Institute in the mid-1960s, and around the time when he established his laboratory in 1973, anticipation that Prof. Umezawa would be awarded a Nobel Prize was growing. Unfortunately, Prof. Umezawa was not honored with that glory. However, over 40 years later, to the immense joy of the actinomycetes community and other academic societies, an actinomycete scientist, Prof. Ōmura, received the award.
Figure is a superficial depiction of the milestones of antibiotic research development described above. It focuses on the key events in time that link Fleming, Waksman, Hamao Umezawa, and Prof. Ōmura. Prof. Umezawa led penicillin research after its development in Japan, and the foundations of the research fields necessary for antimicrobial development fell into place. However, after Prof. Umezawa passed away, the torch was handed to Prof. Ōmura, who worked to develop the research even further.
Fig. 1. Key contributors to develop antibiotic researches in Japan.
From their 30s, Prof. Umezawa and Prof. Ōmura both held distinct philosophies, beliefs, and senses of mission. They also fulfilled their leadership roles by exercising wisdom, forming plans, and forging on without hesitation to apply and industrialize findings from fundamental research. I strongly believe they both kept the torch of innovation burning. Hence, they are paragons to be followed.
Author contributions
Professor Satoshi Ōmura was awarded the 2015 Nobel Prize in Physiology or Medicine. He is the third to win the award for research on antibiotic, following Fleming’ (U.K., 1945, discovery of penicillin) and Waksman (USA, 1952, discovery of streptomycin), and the second person after Waksman to receive the award for research on actinomycetes. By focusing his research on macrolides stemming from leucomycin research rather than β-lactams like penicillin or aminoglycosides like streptomycin, Prof. Ōmura realized many scientific achievements. These efforts finally led to the discovery of avermectin and its semi-synthetic derivative, ivermectin, considered a monumental contribution to the human race. In this manuscript, I will outline the milestones of the epoch-making antibiotic exploratory researches preceding Prof. Ōmura.
Disclosure statement
No potential conflict of interest was reported by the author.
Notes
† This work is a translation of an original work in Japanese in the Japan Society for Bioscience, Biotechnology, and Agrochemistry http://doi.10.1271/kagakutoseibutsu.54.27.
References
- Hotta K. A historical story of the Japanese antibiotics world-development of penicillin. Jpn J Antibiot. 2010;63:179–204.
- The Society for Actinomycetes Japan [Living with Actinomycetes] [in Japanese]. Tokyo: Mimizuku-sha; 2011.
- Iijima M, translator. Selman Waksman’s autobiography My life with the Microbes. Tokyo: Shinhyoron Publishing Inc.; 1955.
- http://www.waksman.or.jp/
- Nagai K, editor. Seimei ni Miserareta Kenkyushatachi [Researchers Attracted by Life] [in Japanese]. Tokyo: Igaku Shuppan Center; 1995. p. 16–29.
- Kagawa F. Rosajin to Kage no MeikoToko Matsushima Hiroaki Shogai [Rosanjin and a Hidden Craftsman-The Life of a Potter, Hiroaki Matsushima] [in Japanese]. Tokyo: Oscarart; 1990.