DOI: 10.1002/asia.201000899

One Hundred Years since the Discovery of the “” from Seaweed Broth by Kikunae Ikeda, who Transcended his Time

Eiichi Nakamura*[a] On the Occasion of the 150th Anniversary of Department of Chemistry, The University of Tokyo

In 1912, Kikunae Ikeda, Professor of Physical Chemistry Washington and New York (for the whole text, see the Sup- in the Department of Chemistry in the College of Science at porting Information), in which he referred to:[1] “A new pri- Tokyo Imperial University (Figure 1), gave a lecture at the mary taste quality. There are four well-defined taste quali- Eighth International Congress of Applied Chemistry held in ties, viz., sweet, sour, bitter, and briny. An attentive taster will find something common in the complicated taste of as- paragus, tomato, cheese, and meat, which is quite peculiar and cannot be classed under any of the above-mentioned qualities.” He continued, “The reason why we find that the glutamic taste is pleasant must be sought in the fact that glu- tamates are often present in minute quantities in nutritious matter of albuminous nature and mostly of animal origin”, and further, “The manufacture of glutamate will doubtless inaugurate a new branch of the chemical industry, that of the decomposition products of albuminous matters.”[2,3] He pointed out exactly the true nature of his own discovery. It was the moment when the discovery of the fifth taste, named the umami taste by Ikeda, was announced to the Western world, 2300 years after Aristotle described the four .[4,5] Four years earlier, in 1908, Ikeda isolated glutamate, one of the natural amino acids, from seaweed broth (Figure 2) and published a paper the following year in the Journal of the Tokyo Chemical Society,[6,7] in which he mentions that glutamate makes even a humble meal taste better, just as sodium chloride does.[8] In 1909, in collaboration with Ikeda, Figure 1. Kikunae Ikeda (1864–1936). A photo owned by the Department Saburosuke Suzuki started producing a seasoning on a com- of Chemistry of The University of Tokyo, which hangs on the wall of the mercial basis, and this product was named “”, library. meaning, quintessence of flavor. Ikeda found (and we can easily study at home) that humans can sense glutamate at a concentration as low as 0.01% in water—far lower than the detection limit of [a] Prof. Dr. E. Nakamura sodium chloride and sugar—and that it is essential for a Department of Chemistry meal to taste good. He also found that sodium glutamate The University of Tokyo and sodium chloride synergistically enhance the taste of a 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan) meal.[6] It is no wonder that Europeans add cheese and Fax : (+81)3-5800-6889 E-mail: [email protected] tomato to a soup, and Asians use seaweed broth, soy sauce, Supporting information for this article is available on the WWW or fish sauce for their meal. Parmigiano reggiano contains a under http://dx.doi.org/10.1002/asia.201000899. large amount (1.7 wt%) of glutamate, and matured

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Figure 3. Three compounds responsible for the umami taste: glutamate, dianion, and guanylic acid dianion. Data taken from Ref. [12]. Kodama found that these compounds synergistically enhanced the umami taste, which humans knew by experience.

tomato>2% of its dry weight (Figure 3). Aristotle must have enjoyed the taste of fish sauce (garos, then very popu- lar in Greece, or better known now as Roman garum) but did not notice that the good taste comes from glutamate. Figure 2. a) The bottle of the first sample of sodium glutamate extracted Notably, half of the amino acid content in human breast from the broth of seaweed by Kikunae Ikeda, b) the evaporating dish used for the extraction (owned by the Department of Chemistry, the Uni- milk is glutamate, and babies enjoy its taste (human amnion versity of Tokyo), and c) an autographed manuscript of his lecture for liquid also contains a large quantity of glutamate, whilst cow the 1912 meeting (owned by the Chemical Society of Japan). The bottle milk contains very little).[9,10] and the crystals were registered as “Essential Historical Material for Sci- Aristotles four tastes are the indicators of a nutritious ence and Technology” in 2009 by the National Museum of Nature and diet and of the warning against unhealthy food: sweet for Science, Tokyo. sugar, salty for sodium chloride, sour for acid, and bitter for alkaloids. Where is the indicator for the most important nu- trition, proteins and nucleic acids? It is the umami taste, dis- covered first as the glutamate ion in seaweed broth by Eiichi Nakamura received his PhD in Ikeda. Two other umami compounds were isolated later in Chemistry from the Tokyo Institute of Technology, and did his postdoctoral Japan—inosinic acid dianion (inosine monophosphate) from work at the Chemistry Department, Co- dried bonito by Kodama in 1913,[11] and guanylic acid dia- lumbia University. He returned to his nion () from dried shiitake mush- alma mater as Assistant Professor (1980– room by Kuninaka in 1956 (Figure 4).[12] Kuninaka also 1984), was promoted to Full Professor (1993), and moved to his present position found that sodium glutamate and the 5’-ribonucleotides syn- [13] at the University of Tokyo in 1995. He ergistically enhance the umami taste. Obviously, they are has served as Senior Program Officer in the degradation products of proteins and genetic materials Chemistry, JSPS (2003–2007) and that are widely present in dried and cooked meats, fish ERATO program research director, JST sauce, soy sauce, and vegetables. (2004–2010). Awards and Honors: Young Chemists Award (Chemical Society of Is it not logical that umami compounds stimulate our ap- Japan, 1984); the Japan IBM Science Prize (1993); an Elected Fellow of petite and help digestion of the meal? Humans have a gluta- the American Association for the Advancement of Science (1998); the mate-receptor protein on the surface of their tongue[14] and Chemical Society of Japan Award (2003); an Elected Foreign Fellow of stomach,[15] and when the presence of glutamate in our diet the Royal Society of Chemistry (U.K., 2005); Humboldt Research Award (2006); Honorary Foreign Member of the American Academy of Arts and is detected, a signal is generated, reaches our brain, and Sciences (2008); the Medal with Purple Ribbon, The Japanese Govern- might stimulate our appetite as well as our intestines, but ment (2009); the A. C. Cope Scholar Award, the American Chemical Soci- this biological mechanism of the function of glutamate was ety (2010). Research field: organic synthesis, physical organic chemistry, discovered only at the beginning of the 21th century. How- nano-science. ever, it took 100 years for Ikedas discovery of the umami

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Figure 4. Ripened tomato, cheese, and portini are rich in sodium gluta- mate and other umami substances, which accounts for their importance in European cuisine. In their place, the Japanese use seaweed and shi- itake mushrooms, which are also rich in umami. taste to be recognized internationally, indicating that the originality and innovative ideas of Ikeda transcended his own time. The commercialization of the umami seasoning was the first example of a successful university–industry cooperative project in Japan, which would not have been possible with- out Ikedas willingness to contribute to society through basic science.[16] Thus, Ikedas patent on the glutamate sea- soning is listed among 10 historic inventions in Japan by the Patent Office.[17] Ikeda was born in Kyoto in 1864 as the second son of a samurai family (Satsuma clan in Kyushu). As the family de- clined after the Meiji Restoration, he sold his own futon (a sleeping mattress) to raise the money to enter the Universi- Figure 5. Friedrich Wilhelm Ostwald (1853–1932) and his oil painting ty of Tokyo. His English was so good then that he is said given to Ikeda. The photo was taken from http://www.sil.si.edu/digitalcol- have lectured on Shakespeare in a private college to earn lections/hst/scientific-identity/fullsize/SIL14-O001-15a.jpg.[24] The painting his living. In 1899, Ikeda left Japan for Leipzig, Germany, to depicts a scene of the sea shore, thought to be at Marblehead, Massachu- setts (USA), and is hung in the conference hall of the Chemical Society study under Dr. Wilhelm Ostwald (Figure 5), who was of Japan (photograph reproduced courtesy of the Chemical Society of awarded the Nobel Prize in Chemistry in 1909 for his work Japan). An accompanying plate says in German: From Prof. Dr. Wilhelm on catalysis, chemical equilibria, and reaction rates.[18] Wil- Ostwald/Painted by himself in the year 1914, by the use of his self-made helm Ostwald not only reached the pinnacle of his field but dyes/—Dedicated to Prof. Dr. Kikunae— also developed the Ostwald process for the production of nitric acid. He published Die Schule der Chemie, a great textbook in a dialogue style that extensively explained the ber arguing with him and in the end being defeated almost principles of natural science. He was an established painter completely.” Ikedas discovery of the umami taste demon- (Figure 5), and worked on color theory. He was a true strated his true value as a natural philosopher. genius and a free-spirited, wisdom-loving philosopher. Ikeda After returning to Japan, Ikeda implemented Ostwalds must have hoped to fulfill Ostwalds pioneering spirit in philosophy in Japan; he improved primary education and Japan and discovered the umami taste. encouraged the application of basic science for the benefit In 1901, on his way back to Japan from Leipzig, Ikeda of society. Wishing to improve the poor nutrition of the Jap- stayed for a while in London at the same boarding house as anese people, Ikeda also decided to find a chemical that Soseki Natsume, then an English teacher of The University converts a humble supper into a delicious dinner—still a of Tokyo and afterward a renowned novelist (Figure 6). keen issue in developing countries in this century. Although Soseki, who was then suffering a nervous breakdown in winning the Russo-Japanese War in 1905 enhanced the na- London, described Ikeda later as follows:[19] “Ikeda is a nat- tions prestige, the people of Japan were in dire straits be- ural scientist but, after talking with him, I found him to be a cause of a huge national debt, and the Government encour- wise philosopher, which was a surprise to me. I still remem- aged emigration to Brazil and China. It may seem somewhat

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ited for a long time in the United States.[20] Umetaro Suzuki (Professor at the College of Agriculture) discovered the first vitamin, Vitamin B1, in 1910 (elucidating the cause of beri- beri).[21] The credit for the first discovery of a vitamin, how- ever, went to Dutch and British researchers who received the Nobel Prize in Physiology or Medicine in 1929. San- ichiro Mizushima of the Department of Chemistry discov- ered a new conformation of 1,2-dichloroethane[22] and named it the gauche conformation in 1941—at the time, only the anti conformation was known.[23] The importance of this discovery was not widely appreciated, perhaps because of World War II. In response to Ikedas question “How to discover geni- uses in their youth?”, Ostwald later wrote as follows: “I in- sisted to students that unexpected results are much more valuable than the expected one. Just like a new branch starts to grow from a part with bumps and dips on a tree stem, a new field of science emerges from such places.”[24] Ikeda was exactly such a researcher who opened a new world in science and industry through the manifestation of his unconventional free spirit.

Figure 6. Soseki Natsume (1867–1916). Taken from http://commons. wikimedia.org/wiki/File:Natsume_Soseki_photo.jpg?uselang= ja. Acknowledgements quixotic that Ikeda chose a research subject that was outside The author thanks the Department of Chemistry for giving him this op- portunity to summarize the achievements of Prof. Ikeda on the occasion his specialty, kinetics and equilibria, but pursuing his re- of the 150th anniversary of the Department, and also for provision of search as he wished was exactly what he did. Prof. Ikedas picture, and the Chemical Society of Japan for access to the However, oddly enough, Ikeda stated after resigning from Ostwalds painting. He also thanks Dr. Ei-ichiro Suzuki and Dr. Koji the University before the retirement age: “I regret that, al- Harano for provision of reference data, Dr. Joerg Heber for valuable comments and the Ajinomoto Company for the provision of pictures though I was in the position of a university professor who (Figure 2 and 4). should have focused his efforts on academic pursuits and made achievements in his academic field, I failed to do so. The discovery of Ajinomoto is one of my disappointments [1] “On the taste of the salt of ”: K. Ikeda, Proceedings of in that sense. I wish to be more-closely involved in academi- the 9th International Congress in Applied Chemistry, Section VIII c: Bromatology, 1912, Vol. 38, p. 147, as cited in reference 4. The publi- cally focused research in future. I would like to recommend cation list of Prof. Ikeda in reference 5 describes this presentation that those who teach science not engage in research whose as: “On the taste of the salt of glutamic acid” Original Communica- primary objective is to make money.” tions Eighth International Congress of Applied Chemistry, 1912, 22, Ikeda, who proved the existence of the fifth taste that 157. human beings can detect, is a pioneer of what is now called [2] Taken from the hand-written copy of his talk, kept by the Chemical Society of Japan. chemical biology. He reached a milestone achievement that [3] Glutamic acid, first isolated from seaweed, was first produced indus- was worthy of the Nobel Prize, as well as contributing to so- trially by acid hydrolysis of gluten, and, since the 1950s, it has been ciety by creating a new industry unique to Japan. Why did produced by amino acid fermentation by the use of bacteria that se- this man make such a sarcastic comment? Had he lost his lectively produce glutamic acid. [4] B. P. Halpern, Chem. Senses 2002, 27, 845 –846. confidence in the importance of his discovery after receiving [5] “Ikeda Kikunae Hakase Tsuioku Roku” (Memory of Dr. Kikunae criticism in Japan? Was it a warning for narrow-sighted sci- Ikeda), (Ed.: Masao Katayama), Ikeda Kikunae Hakase Tsuioku entists? After making this comment, Ikeda left Japan and Kai, October 1956, in the book collection of the Department of continued his research on the production of sodium gluta- Chemistry, the University of Tokyo. mate in Leipzig. [6] For the original paper, see: K. Ikeda, J. Tokyo Chem. Soc. 1909, 30, 820– 836. English translation: K. Ikeda, Chem. Senses 2002, 27, 847 – At the beginning of the 20th century, the University of 849. Tokyo produced great scientists who made pioneering ach- [7] The Tokyo Chemical Society was established in 1878 by the mem- ievements in chemistry. However, these achievements were bers of the Department of Chemistry of the University of Tokyo often not well recognized in the world, or in Japan either. and later became the Chemical Society of Japan. The “Journal Club” in the Department was started in Ikedas time and has held Jokichi Takamine (the discoverer of “Takadiastase”, who 1373 seminars up till now (as of November 2010). left Japan and lived in the United States) succeeded in iso- [8] For those living in developed countries, Ikedas intention to enhance lating adrenaline in 1900, the structure of which was discred- appetite by food additives may sound antisocial. However, it was ab-

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solutely necessary in Japan in those days, and it still is in developing [16] K. Hirota, Kagakusha Ikeda Kikunae—Soseki, Umami, and Doitsu, countries today. Tokyo Kagaku Dojin, Tokyo, 1994. [9] Although adverse effects of glutamate were suggested by an Ameri- [17] http://www.jpo.go.jp/seido/rekishi/judai.htm (in Japanese). can researcher in the 1960s, extensive studies afterwards by world [18] R. Zott, Angew. Chem. 2003, 115, 4120– 4126; Angew. Chem. Int. authorities including FDA, JECFA, EU, USFDA, etc., did not sup- Ed. 2003, 42, 3990–3995. http://nobelprize.org/nobel_prizes/ port this claim. medicine/laureates/1929/. [10] G. Sarwar, H. G. Botting, T. A. Davis, P. Darling, P. B. Pencharz, [19] Natsume Soseki, Shojosaku Tsuikaidan 1908, reproduced in Nat- British Journal of Nutrition 1998, 79, 129 –131. sume Soseki Zenshu Vol. 10, Chikuma Shobo, Tokyo, 1972. [11] “On a procedure for separating inosinic acid”: S. Kodama, J. Tokyo [20] Adrenalin controversy: J. K. Aronson, BMJ 2000, 320, 506 –509. Chem. Soc. 1913, 34, 751. [21] U. Suzuki, T. Shimamura, J. Tokyo Chem. Soc. 1911, 32, 4 –17, fol- [12] a) “Studies on taste of ribonucleic acid derivatives”: A. Kuninaka, J. lowing his presentation in December 13, 1910 to the Tokyo Chemi- Agric. Chem. Soc. Jpn. 1960, 34, 487– 492; b) “The Nucleotides, a cal Society. Rationale of Research on Flavor Potentiation”: A. Kuninaka, Sym- [22] S. Mizushima, Y. Morino, S. Noziri, Sci. Pap. Inst. Phys. Chem. Res. 29 posium on Flavor Potentiation, Arthur D. Little, Cambridge, MA, 1936, , 68. [23] S. Mizushima, Y. Morino, M. Takeda, J. Chem. Phys. 1941, 9, 826. 1964, pp.4–9. [24] Ref. [5] mentions this statement as a citation from: W. Ostwald, [13] S. Yamaguchi, K. Ninomiya, J. Nutr. 2000, 130, 921S–926S. “Lebenslinien, eine Selbstbiographie” Bnde, Berlin, 1926, and W. [14] G. Nelson, J. Chandrashekar, M. A. Hoon, Nature 2002, 416, 199 – Ostwald, “Grosse Mnner: Studien zur Biologie des Genies” Leip- 202. zig, 1909. [15] H. Uneyama, A. Niijima, A. San Gabriel, K. Torii, Am. J. Physiol. Received: December 14, 2010 Gastrointest. Liver Physiol. 2006, 291, G1163– G1170. Published online: April 5, 2011

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