FEATURE KANAGAWA UNIVERSITY Magazine Associate Professor Izumi Iwakura Laser Chemistry and Physical Organic Chemistry

Professor Tadashi Sugawara PROUD Physical Organic Chemistry

Professor Kinya Hibino BLUE High-energy cosmic ray research on the Tibetan English Plateau version 01 2016/11 Distinguished Professor Daisuke Uemura Compound Hunter

Assistant Professor Sachi Yamaguchi Mathematical Biology

Professor Nobuhiro Kihara Organic Chemistry, Bioorganic Chemistry

Professor Susumu Izumi Molecular biology, Insect physiology and biochemistry

ESSAY : SCIENCE INSIGHTS Professor Emeritus Wasuke Mori Magnetic chemistry, Functional materials chemistry, Complex chemistry 2

CONTENTS

p.04-19 FEATURE

p.04-06 p.12-13 p.18-19

Unobservable bond Chemical approach to A life mechanism breaking and bond the strategies of life hidden within

reforming steps during Distinguished Professor the silkworm, chemical reactions Daisuke Uemura glimpsed through molecular biology Associate Professor Compound Hunter Izumi Iwakura Professor Department of Chemistry, Susumu Izumi Faculty of Engineering p.14-15 Department of Laser Chemistry Biological Science, Faculty of Science and Physical Organic The mysterious sexuality Chemistry Molecular biology, of the marine organism Insect physiology and that confounded Darwin. biochemistry p.07-09 We are challenging this mystery with a p.20-23 One more theory bringing mathematical model. us closer to the mystery ESSAY : SCIENCE INSIGHTS Assistant Professor of the origin of life Sachi Yamaguchi Measuring novelty The rich behavior of the Department of Information “membrane”, clarified Systems Creation Professor Emeritus Faculty of Engineering through “artificial cells” Wasuke Mori Mathematical Biology Department of Chemistry, Professor Faculty of Science Tadashi Sugawara Magnetic chemistry, Department of Chemistry, p.16-17 Functional materials Faculty of Science chemistry, Physical Organic Chemistry Chemical reconstruction Complex chemistry of the underlying molecular concept in p.10-11 organisms

We are looking into Professor space from here Nobuhiro Kihara Department of Chemistry, Professor Faculty of Science Kinya Hibino Organic Chemistry, Department of Physics, Bioorganic Chemistry Faculty of Engineering High-energy cosmic ray research on the Tibetan Plateau PROUD BLUE 3

PROUD BLUE ISSUE:

Kanagawa University published “PROUD BLUE” in Japanese as a public relations magazine focused on our research and researchers. The title is associated with the school color, and the first issue was published in February, 2015 and the third issue in February, 2016. This English version was based on the above Japanese versions of the first and third issues. 4

FEATURE Unobservable bond breaking and bond reforming steps during chemical reactions

2H2+O2→2H2O: This is one of the most well-known chemical reactions in science textbooks. Indeed, even if you are not a scientist, you have most likely seen this chemical reaction at some point. It describes the oxidation of hydrogen, where hydrogen reacts in the presence of oxygen to produce water. The arrow symbol in this familiar chemical reaction indicates an unknown reaction mechanism, as it has so far been impossible to determine when and how the bond breaking between the hydrogen atoms and oxygen atoms, and the bond formation between the hydrogen and oxygen atoms occur during the reaction. Dr. Izumi Iwakura is a chemist who explores such unobserved reaction mechanisms using ultrashort pulse lasers.

A five-femtosecond strobe that Associate Professor reveals the reaction process

In the last 100 years, many hypotheses have at- Izumi Iwakura tempted to explain the unobserved reaction Department of Chemistry, mechanism of the Claisen Rearrangement, a Faculty of Engineering reaction originally reported by the German sci- entist, Rainer Ludwig Claisen in 1912. During Laser Chemistry the Claisen rearrangement of allyl vinyl ether (CH2CHCH2OCHCH2), the carbon-oxygen bond and Physical Organic is broken upon heating, and a new carbon-car- Chemistry bon bond is formed. Three hypotheses exist to explain the unobserved reaction mechanism and the transition state of the reaction: i) The C–O bond is broken first and then the C–C bond is formed; ii) C–C bond formation occurs first; and iii) Bond breaking and bond formation occur simultaneously. Although one can specu- late, it was considered impossible to actually observe the transition state and the structural changes taking place in this transformation. Indeed, these steps are exactly what Iwakura is attempting to visualize, which leads to the question, how exactly can she visualize this? The actual visualization of chemical reaction processes began with the pump-probe mea- surement study in 1949. The time resolution of this study was limited by a flash pulse duration of microseconds (10−6s), while in the last 50 years, the visualization of chemical reaction processes has now approached the femtosec- ond (10−15s) scale. Using a high-speed imaging camera, workers have visualized the “milk crown,” i.e., the crown-shaped structure formed when a drop of milk impacts on a thin layer of milk or any other liquid. They wondered if a chemical reaction process could be visualized using a strobe, just as a high-speed imaging camera can capture an instant snapshot that cannot be observed by PROUD BLUE 5 the naked eye. Thus, a strobe with a short flash these steps during a thermal reaction. time is required to visualize the bond breaking Chemical reactions can be generally divided and bond reforming steps during a chemical into two main groups, namely thermal reactions reaction. More specifically, the required flash and photoreactions. A thermal reaction is trig- time of the strobe would be shorter than the gered when the molecular vibrations are ex- duration of molecular vibrations. This led to cited by heat, while a photoreaction is triggered Iwakura developing the five-femtosecond pulse when the electrons are excited by light. Indeed, laser for such a purpose. thermal reactions will likely be familiar to Izumi Iwakura many. In terms of photoreactions, perhaps one The third type of chemical Izumi Iwakura graduated from the of the most well-known of these is damage to reaction that creates Department of Chemistry, Faculty DNA caused by ultraviolet irradiation, which of Science and Technology, Keio University in March 2001 and com- an observable condition can result in the formation of skin cancers. pleted her doctoral studies (science) In 2002, Takayoshi Kobayashi (a specially ap- One of the main reasons for difficulties in visu- in the same institution in September pointed professor by The University of Electro- alizing the movement of atoms in molecules is 2005. Following positions such as the Japan Society for the Promotion Communications), with whom Iwakura had a disorganized molecular vibration. The move- of Science Research Fellowship fateful encounter later on, developed a visi- ment of atoms in a disorganized manner is like and PRESTO, and the Japan ble-five-femtosecond pulse laser that allowed a large party where everyone is talking at once, Science and Technology Agency full-time researcher, she joined for the real-time spectroscopy of molecular vi- and it is difficult to hear anyone in particular. the Department of Material & Life brations. Kobayashi conducted a study to visu- Eventually, the noise takes over and the situa- Chemistry, Faculty of Engineering, alize the bond breaking and bond reforming tion cannot be understood. Kanagawa University in 2012. She later became an associate profes- steps during a photoreaction. This was followed Thus, to control the situation, Iwakura success- sor in the Department of Chemistry by Iwakura’s attempt to apply it to visualize fully developed a novel type of reaction, called at the same faculty in 2014. 6

as reactions induced by coherent molecular vi- Transition state spectroscopy of the Claisen Rearrangement bration (RCMV). This third type of chemical re- action excites the molecular vibration instantly using a five-femtosecond pulse laser. In a typical thermal reaction, molecules move )

in a disorganized manner. However, in the −1 RCMV triggered by irradiation using a five-fem- tosecond pulse laser, all molecules vibrate in 1500 unison to trigger the thermal reaction. Upon ir- radiating with a flash time of five femtoseconds, which is shorter than the molecular vibrational 1000 period, the atomic positions are measured as if in strobe light photographs, and the changes in

molecular structure (i.e. when and how bond (cm frequency vibrational Molecular 500 1500 2500 breaking and bond reforming occur) during a Reaction time (fs) reaction can be visualized as instantaneous Changes in molecular vibration molecular vibrational frequencies. accompanying the thermal This was the moment when Iwakura finally vi- calculations to simulate reaction mechanisms, Claisen Rearrangement were visualized using a five-fem- sualized this key transformation that had been and based on the results, she developed the tosecond pulse laser. The shrouded in mystery for over 100 years. novel reaction. This led to Iwakura’s desire to resulting spectrum indicated observe actual chemical reaction processes. when and how bond breaking From observing molecules to and bond reforming occurred. During her studies, she met Takayoshi creating molecules Kobayashi, who was teaching at the University Iwakura’s obsession with chemical reaction of Tokyo, and learned that she could indeed vi- Step-wise reaction mechanisms began in the synthetic organic sualize actual chemical reaction processes. As mechanism of the chemistry laboratory where she spent her un- such, she began to study the real-time spec- thermal Claisen dergraduate to graduate school years. Iwakura troscopy of molecular vibrations, including the Rearrangement

notes that while shaking flasks, she was always transition states of photoreactions. Indeed, the 0 Bis-allyl-like

3 Bis-allyl Product thinking about chemical reaction mechanisms, real-time spectroscopy developed by Kobayashi intermediate -O 4 “I preferred thinking about the reaction mecha- is now being applied to the RCMV that Iwakura nisms in a simulation using theoretical calcula- developed later on. While Kobayashi developed Aromatic-like intermediate Bond order C tions more than synthesis. I am really not good spectroscopy for photoreactions, Iwakura de- 1 0 1 at organic synthesis. I thought if I understood veloped spectroscopy for thermal reactions Reactant Bond order C1-C6 1,4-Diyl the reaction mechanisms and the best condi- using the RCMV. The C-O bond begins to break, tions about catalysts or solvents through theo- Regarding the RCMV, she said, “the RCMV takes and after going through retical calculations, even I could synthesize. place when all molecules are in synch. I am a stable aromatic-like six-membered intermediate, That’s what I was thinking back then.” wondering if I could develop a new synthetic re- the C-C bond is formed. This Indeed, a large portion of Iwakura’s doctoral action utilizing that.” three-step reaction mecha- nism was found to be different program focused on this idea. Traditionally, the- After observing the previously unseen reaction from traditional hypotheses. oretical calculations were employed after ques- mechanism, she now wishes to create something tioning what was taking place during the that no one else has ever succeeded in doing. Of reaction. In contrast, she employed theoretical course, her challenges are always novel.

SIDE STORIES The interaction of electrons is similar to soccer Interest motivates researchers “If you succeed, you are a genius. If you fail, you are an idiot.” That is a common predicament for researchers who aim to take on new chal- lenges. According to Iwakura, the driving forces that carry researchers forward are Iwakura loves to watch soccer games. But she curiosity and interest. Indeed, does not care about winning or losing. She says, these have been the driving “it is fun to watch how they pass a ball and score forces of her research since a goal,” which is similar to electron transfer. In her school days, and explains a chemical reaction, where and how to pass the why Iwakura encourages electron (ball) determines the direction of the students to “enjoy research.” reaction (i.e., whether a goal is scored or not). PROUD BLUE 7

FEATURE Human attempts to create artificial cells One more theory bringing The origin of life is still surrounded by mystery. The mainstream view is currently that the re- ductive approach used since Descartes is no us closer to the mystery longer adequate to solve the mystery of life; in- stead, a constructive approach is effective to of the origin of life understand how to fabricate systems while fo- cusing on interactions between elements. The rich behavior of the In this context, in 2001, two celebrated American professors of genetics, Szostak, “membrane”, clarified Bartell, and Luigi in Switzerland, a pioneer in chemical evolution, proposed an idea of a mini- mum cell endowed with three indispensable el- through “artificial cells” ements for life. The origin of life is still surrounded by mystery. It is still conjecture, Sugawara explains that at this time, professors but the currently accepted theory is that primitive life originated Szostak, Bartell, and Luigi listed three ele- around 3.7 to 4 billion years ago. ments fundamental to cells. “The first is a Biologists are debating whether ‘boundary’ to separate the inside from the out- life “started with RNA” (RNA side, which is essentially the cell membrane. hypothesis), or “started with The second is ‘information’, which character- protein” (protein hypothesis). izes the individuality of the cell, namely the The chemist Tadashi Sugawara genes. The third is a ‘catalyst’ required for cel- is responding to the challenge lular biological activity and reproduction. If a of the mystery of life. The clue substance prepared with these elements was he is looking at is the thin created artificially and if replication of the ‘in- “membrane” that separates an formation’ and production of the ‘boundary’ individual life from the outside (the dynamics of cell division) were generated, world. then could that not be called life? This was the assertion made by Szostak, Bartell, and Luigi. Around the same time I also started research on artificial cells based on almost the same idea, so I felt exactly the same way.” The “membrane” was the start

Professor Luigi was already interested in the self-production mechanism of the cell mem- brane, which is the ‘boundary’ separating the inside and the outside of the cell, and had pio- neered research in this field. The cell membrane structure is made up of two layers of phospholipids (see figure on the fol- lowing page). A phospholipid is an ‘amphiphilic’ substance that dissolves in both water and oil. If phospholipids are dispersed in water, hydro- phobic parts move away from water, while hy- drophilic parts face to water when they get together. Hydrophobic parts subsequently assemble together with other hydrophobic parts, while Professor hydrophilic parts assemble together with other hydrophilic parts, forming a spherical Tadashi Sugawara membrane. At this point the membrane has become a ‘boundary’ that separates the inside, Department of Chemistry, filled with water, from the outside. The pouch Faculty of Science formed by the membrane is known as a ‘vesicle’ in scientific terms. Physical Organic Chemistry “Professor Luigi reported that he observed a 8

Phospholipid bilayer research strategy. The phospholipid bilayer that Five years later, Sugawara and his colleagues forms the cell membrane. established a method that enabled DNA Hydrophilic parts that can dissolve Inside in water face the outside of the replication and amplification inside the vesicle. the cell membrane, while hydrophobic It was a method in which heat is added and the parts, which cannot dissolve in ‘PCR method’ is applied to obtain DNA water, are lined up on the inside of the membrane. replication and amplification. The ‘PCR method’ Cell membrane Hydrophilic Hydrophobic itself had been established as a biological Phospholipids experimental method, but this was the first example in which DNA was synthesized inside a vesicle large enough to be seen with an optical division phenomenon similar to that of cells microscope. with vesicles made from oleic acid. My As they adjusted conditions repeatedly, refining colleagues and I created artificial membrane the method, they discovered a compelling fact. molecules and attempted an experiment to “How was DNA amplification linked with vesicle create a vesicle reproduction system. We division? This was a major issue, but we inserted hydrophobic materials for membrane discovered that amplified DNA moves into the molecules inside the vesicle and added inner side of the vesicle membrane and serves hydrophilic materials from the outside. a role similar to an enzyme to promote Hydrophobic and hydrophilic parts inside the division.” vesicle bound together to form membrane Inside the cells of living organisms, proteins, molecules, and we successfully created a synthesized from DNA-derived information, The laboratories that are producing artificial cells system where the vesicle could reproduce play a variety of roles, and DNA amplification is are not biological laborato- itself. Under a microscope we also observed synchronized with cell division. However, ries, but organic chemistry pouches emerging from the original ones, like Sugawara claims, “it is difficult to imagine that laboratories. Several types of laboratory equipment in in cell division.” primitive life had such complex reaction organic chemistry labora- However, there was an issue with the method systems.” “Even without the complex system tories are not often seen in used at that time. Once the vesicle had mediated by proteins, DNA replication occurs in biology laboratories. reproduced a number of times, and the concert with membrane molecule reproduction material inside the vesicle ran out, division reactions and morphological changes, and stopped. However, Sugawara made fine vesicles divide with even DNA distribution. improvements and developed a method that These findings represent a clue to discover the enabled repeated divisions. That was in 2004. shape of primitive life.” The results of Sugawara’s research were Creation of the “artificial cell” – published in September 2011 in “Nature wowing the world Optical microscope, which Chemistry” and garnered significant attention captures the appearance Sugawara was excited by this outcome, thinking from around the globe. of dividing artificial cells. that he could be dealing with a primitive form It is possible to check the Passed down from mother to appearance of vesicles on of living organism. However, biologists who saw the monitor while filming a daughter, and from daughter to the video made comments like “yes, that’s very video of the process. Quite a granddaughter number of videos have been interesting, but it would be much more cell-like taken as an evidence for the if it contained informational molecules”. The “artificial cell” at this time still had issues. creation of artificial cells. Sugawara heard these opinions, consulted his The DNA material in the vesicle after division fellow researchers and designed a subsequent was depleted and the second division did not

SIDE STORIES Results of artificial cell research (Publication on the Right) The results of the We will become the world’s molecular novelists research on membrane (vesicle) self-repro- Sugawara was taken by his grand- duction were published with the title “How parents to see Kabuki when he was do we understand Life Systems?” (Kyoritsu about four years old. He always Shuppan, Makoto Asashima Editor, May 2007 wanted to create a link between his issue). research and Kabuki, and recently (Publication on the Left) “Synthetic Biology achieved this goal. He created a (Introduction to current biological science Vol. scenario casting roles for mole- 9)” (Iwanami Shoten, May 2010 issue) provides cules and prepared a stage. Then, an overview of the constructive understanding unexpectedly, supporting charac- of the function of organisms at a molecular ters began to play an important level. Makoto Asashima, who worked as the role. Will “artificial life” make an aforementioned editor, is a biologist roughly appearance some day in the fiction the same age as Sugawara. His research into created by Sugawara? animal development is highly regarded. PROUD BLUE 9 occur. “RNA and proteins are both Replication Maturation Sugawara and his team introduced a too complex as molecules, DNA replication Maturation of mechanism to supply DNA from the outside to so it is difficult to believe active sites within the cell membrane the inside of vesicles using hints provided by that primitive life began substance transport mechanisms inside cells. from them. From a Then, they successfully reconstituted division chemist’s perspective, it is Division of the granddaughter artificial cell from the natural to consider that Growth and division through addition of daughter artificial cell divided from the parent simple substances such as membrane molecular precursors artificial cell. Furthermore, they observed lipids, which constitute cycles made of four stages during division of biological ‘membranes’, the primitive artificial cell. These stages looked incorporated enzymes and similar to cell cycles seen during division of information substances that Ingestion biological cells (see figure on the right). promote division into the Fusion with a vesicle In September 2015, these results were membrane pouch while enveloping a The cycle observed in the substrate published in “Nature Communications”, again drifting in the ancient seas.” artificial cell synthesized by creating massive reverberations. Sugawara also adds the Sugawara. A four-stage cycle similar to that seen in biologi- However, there was still one remaining following: “The existence of cal cells was observed, which question. bacteria that progress with illustrates the “biological like- ness” of the artificial cell. DNA provides the “information” that makes cell division using enzymes that produce the proteins inside living bodies. However, was the cell membrane without relying on the functions DNA added as genes in the artificial cells of proteins, has recently been discovered. It is created by Sugawara and his team working as debated whether this is the oldest form of cell an information molecule? division, given that the shape of these bacteria Sugawara responded to this question as is extremely similar to the vesicles we follows: “In subsequent detailed experiments reconstituted.” we ascertained that DNA was functioning as a Research on artificial cells started from the Tadashi Sugawara type of “information” in the artificial cells. The “membrane”. Life itself may have in fact Sugawara was born in Tokyo in 1946. He completed his postgraduate studies “information” was the length of the DNA, and it started from the “membrane” that separates at the School of Science, University was influencing morphology and behavior its content from the outside world. of Tokyo (Doctor of Science). He then during divisions of the vesicles.” worked as a postdoctoral researcher at the University of Minnesota and Sugawara and his team are also looking at at the University of Maryland; he experiments that will bring “information” into later became Assistant Professor at artificial cells, using a substance far simpler the Institute for Molecular Science, Okazaki National Research Institutes, than DNA. They are aiming to create an Professor at the Department of Basic artificial cell using only simple substances that Science, College of Arts and Sciences, would have existed on ancient Earth. In other University of Tokyo, Professor of Basic Science, Department of Multi- words, Sugawara is aiming to artificially Disciplinary Sciences, University of reproduce the birth of life. Tokyo Graduate School of Arts and Sciences, and is currently Professor Neither RNA nor protein at the Faculty of Science, Kanagawa University. Sugawara is also an honor- There are two main hypotheses on the origin of ary professor at the University of Tokyo. life in biology: the “RNA hypothesis” and the “protein hypothesis”. RNA is a substance that forms a bridge between DNA and proteins, when proteins are synthesized based on DNA information. The basis of the “RNA hypothesis” is that RNA can self-replicate and also play the role of an enzyme. However, the “protein hypothesis” claims that RNA and DNA appeared as specialized signal transducers, while proteins, with their various functions, underwent repeated pseudo-replications. There is also a third hypothesis, the “lipid hypothesis”. Sugawara strongly supports it as a chemist who took up the challenge of synthesizing an artificial cell. 10

FEATURE We are looking into space from here

We are able to see the spectacle of space extending far into the distance through telescopes like the Hubble Space Telescope. However, if we slightly change the visible light wavelength, space shows us a completely different face. Kinya Hibino is a ‘cosmic ray astronomer’ who is closing in on a new appearance of space by observing ultra-high-energy ‘cosmic rays’.

Professor Kinya Hibino Department of Physics, Faculty of Engineering High-energy cosmic ray research on the Tibetan Plateau

particles flying in outer space. Masatoshi The language of space as Koshiba (Honorary Doctorate from spoken by lightning Kanagawa University, Special Honorary Prof. Hibino is standing on the roof of Professor at the University of Tokyo) is an Building 6 in the Yokohama Campus of award-winning physicist who was awarded Kanagawa University with a line of “scintil- the Nobel Prize in Physics in 2002 for build- lation detectors” used for the observation ing the world’s largest Water Cherenkov of cosmic rays. A number of these scintilla- detector in 1983, the Kamiokande-II, to de- tion detectors can also observe gamma tect neutrinos that reached the Earth from Kinya Hibino rays released from lightning. Prof. Hibino the Large Magellanic Cloud (LMC), which is In 1991, he completed the Graduate School Doctoral Program in Physics says, “They have no effect on humans, but a satellite galaxy of the Milky Way. at Konan University (PhD Physics); in extremely powerful gamma rays are emit- Cosmic rays are believed to reach Earth 1991-1993, he worked at the Institute ted by lightning. We can even close in on when particles accelerate in the nucleus of for Cosmic Ray Research, University of Tokyo; in 1992, he became a fulltime the mysteries of space with this kind of the Milky Way and in supernova explosions, lecturer at Kanagawa University; in 2003, phenomena close to home.” but the actual mechanism remains one of he became an Assistant Professor in the The true character of cosmic rays is the mysteries of space. Department of Engineering, Kanagawa University; and since 2008, he has been demonstrated by high-energy particles “There are various mechanisms that can working as a Professor in the Department such as atomic nuclei and elementary accelerate particles, but, for example, of Engineering, Kanagawa University. PROUD BLUE 11 owing to the phenomenon known as a pulsar, secondary cosmic rays, and repeating the cycle particles are thought to be accelerated by pow- in a geometric progression. Thus, a vast erful electric and magnetic fields. However, it is quantity of particles rain down on Earth. The difficult to directly observe pulsars; therefore, Tibet Air Shower Observation Array takes we are studying how particles are accelerated detailed measurements of these air showers, and how gamma rays are emitted by lightning, thus enabling astronomers to ascertain the a familiar strong electric field, to elucidate the energy and the direction of arrival of cosmic Tibet Air Shower Observation Array. Scintillation detectors mechanism of acceleration of particles that rays; measuring these cosmic rays will enable are composed of approxi- originate as cosmic rays.” Hibino’s research us to investigate the activity of the sun. “The mately 800 units arranged team is composed of “cosmic ray astronomers”: sun and the moon create interference in the over approximately 3.7 ha. they observe space through cosmic rays rather measurement of cosmic rays that come to than through light and radio waves. Earth from the center of the Milky Way, and Furthermore, Hibino indicates the possibility they are detected as “shadows” in the data that lightning itself may be caused by cosmic acquired. Recently, we have started rays. Lightning is a discharge phenomenon investigating the structure of the magnetic field generated by a strong electric field born in a in the heliosphere.” cloud. Specifically, a dielectric breakdown During the “solar minimum period”, when the generates lightning in the cloud, but it is sun is not very active, cosmic rays are believed that a strong electric field does not intercepted by the sun, and the sun’s shadow is exist. What are then the “seeds of lightning”? clearly projected. Conversely, during the “solar The moon shadow’s captured with cosmic rays. The moon One theory is that cosmic rays originating in maximum period”, when the sun is very active has no magnetic field and thus space may act as triggers for lightning. and when there is reversal of the sun magnetic it appears as a clean “shadow” poles, cosmic rays are distorted by the in the data. The Sun as seen with cosmic rays magnetic field, blurring this shadow. We can The location has moved to the Yangbajing observe the sun’s activity through changes in Plateau in Tibet, located approximately 4300 m these shadows. above sea level; from here, Hibino looks up at Furthermore, Hibino and his team created a the sky. This is where the cosmic ray telescope simulation of “antiparticles” that are fired back Solar minimum period Solar maximum period 1996 (CR1910). 2001 (CR1978). Tibet Air Shower Observation Array is located from Earth towards the sun and created a The sun’s shadow captured with for astronomical observation of high-energy detailed image of the magnetic field between cosmic rays. The shadow is clear gamma rays as a Japan-China international the Earth and the sun. during solar minimum periods and not visible during solar joint research project. “When we humans will progress further into maximum periods owing to the “Air shower” is a phenomenon in which space, particularly when we will progress influence of the magnetic field. particles formed from cosmic rays rain down on beyond our own solar system, knowledge about Earth, resembling a shower. When cosmic rays the phenomenon of cosmic rays will be Cosmic ray enter the Earth atmosphere, they react with extremely useful.” “air shower” oxygen and nitrogen molecules in the air, Hibino’s “eyes” are looking from lightning destroying atomic nuclei and generating a large gamma rays, through cosmic rays, into the sun number of secondary cosmic rays. These rays magnetic field, and ultimately outside of the subsequently collide with the surrounding Milky Way. He is also casting his gaze into the atomic nuclei, increasing the number of future.

The cosmic rays that enter the SIDE STORIES Earth atmosphere react with oxygen and other particles in Kubrick’s space odyssey The actual situation in Gazing intently at the air and rain down on Earth opened the door of interest Tibet where the space with music as a shower formed by approx- observation takes place imately 100 trillion low-energy muons, neutrinos, neutrons, The Tibet Air Shower Observation gamma rays, electrons and Array is located in the Tibetan positrons. autonomous region, approximately 80 km northwest of the central city of Lhasa. Barkhor Street in the Tibetan holy place in Lhasa is set up so that the public cannot gain Hibino always listens to access to the area without pass- music while conducting his Hibino developed an interest in space ing through security. In addition, analysis. He often listens to based on the feeling that he “liked once tourists leave Lhasa, they jazz. Since he started listen- things he could not understand by are unable to freely move around. ing to club jazz, he has taken himself”. The mysterious nature of Hibino and his team have special a liking to “FreeTEMPO”, the the movie “2001: A Space Odyssey” permits to enter the area, but they solo project of the DJ/song drew Hibino to space. are often denied access. writer Takeshi Hanzawa. 12

FEATURE Chemical approach to the strategies of life The many living things that currently thrive on Earth are based on strategies that were acquired by trial and error over a span of 3,500 million years. The natural organic compounds in organisms are the “book” in which these strategies are written. Daisuke Uemura has sought to decipher the chemical structures of these natural products, and to connect these structures with innovative drug discovery.

Ideas for solving the obesity problem inspired by marine life

Obesity has become a major public health problem in developed nations. Some patients have become so obese they can barely move and take part in social activities. All over the world, many people are waging a war against fat, with some undergoing surgery to have gastric bands fitted. Urgent measures are Distinguished needed to keep people healthy, prolong their Professor lives, and reduce burgeoning medical costs. Currently, we are attempting to develop a new Daisuke tool to battle this problem. In particular, we hope to identify an anti-obesity drug that Uemura reduces the fat that has accumulated in the cells of the body. Compound Hunter

Daisuke Uemura Daisuke Uemura received his Ph.D. from Nagoya University in 1975. In 1982, he began research as a visiting scholar at Harvard University. In 1997, he started working as a Professor at the Nagoya University Graduate School of Science, and in 2009, he was awarded the Medal with Purple Ribbon by the Government of Japan. In 2011, he began work as a Professor in the Department of Chemistry, Faculty of Science, Kanagawa University, and be- came Director of the Research Institute of Natural Drug-Leads. He was designated Professor Emeritus at Nagoya University in 2008 and a Distinguished Invited Professor at Kanagawa University in 2016. PROUD BLUE 13

Uemura and co-workers found that the conducted a great deal of research on the administration of a compound they identified, presumption that “sponges must have original SIDE STORIES ‘yoshinone A’, to mice fed a high-fat diet ideas to protect themselves”. This research led inhibited the accumulation of fat. to the discovery of the large molecule “Souvenirs Yoshinone A elevates lactic acid levels in the halichondrin B, which is a potent toxin. A large entomologiques” – Touching upon the body, which results in “a state similar to number of microorganisms coexist within H. wonders of living running”. When humans exercise, lactic acid okadai, and these microorganisms are thought things levels in the body increase. This lactic acid is to defend their host. To enable these metabolized and reverted to sugar, and energy microorganisms to coexist within their bodies, is consumed in the form of ATP (adenosine H. okadai must temporarily reduce its own vital triphosphate) molecules. When ATP is functions. The substance that mediates this consumed, fat is steadily metabolized and process is thought to be halichondrin B, which depleted. Yoshinone A creates conditions in the inhibits mitosis. body similar to those induced by exercise, and Uemura focused his attention on the function of Jean-Henri Fabre wrote that thus reduces fat in fat cells of the body. halichondrin B, and the pharmaceutical spider wasps are “master Uemura stated that “yoshinone A has no company Eisai continued this research and surgeons”. Spider wasps adverse reactions in gastrointestinal organs successfully developed the anticancer agent pierce the exoskeletons of target spiders, paralyze them such as the stomach and also does not cause Eribulin (brand name Halaven), which is used to and then lay their eggs in the fatty liver. It may truly become the ideal anti- treat breast cancer. This substance has an spider abdomens. The spiders remain paralyzed but do not obesity drug. It first should be made available extremely large molecular weight and a die until the eggs hatch, at to people struggling with extreme obesity.” complex chemical structure. Chemosynthesis which time the spiders are Current anti-obesity drugs include drugs that of this substance alone led to drug eaten by the larvae. In other words, spider wasps para- suppress the action of the satiety center, drugs development, which represents a brilliant lyze spiders to make them a that inhibit the action of fat-degrading enzymes, achievement in synthetic chemistry. It is now food source for their larvae. lipases, and glucose transporters, etc., but all approved in 64 countries worldwide and is Uemura investigated spider wasps and discovered that of these drugs can elicit adverse reactions. supporting the lives of many breast cancer they produced a narcotic Yoshinone A, which may represent a patients. protein. breakthrough in anti-obesity drugs, was Uemura tells us, “Molecules derived from discovered in the blue-green algae organisms have structures that have been Future drugs will be “Cyanobacteria”, which live in the seas around polished within the history of the organism, and discovered through Ishigaki Island of Okinawa. show a variety of biological activities and inspiration and involvements in life phenomena we would never innovative The challenge posed by “toxins” experiments expect. Elucidating these mechanisms and in cancer: the modern enemy tying them in with opportunities for drug Living organisms use various strategies to development is extremely compelling”. protect their own bodies from external attack, Uemura is now approaching the and to harmonize with their environment, to characterization of a substance from the same maintain their lives. Small molecules have black sea sponge that suppresses prostate important functions, including promoting cancer; his quest to transform ideas from Uemura embarks on a new changes in protein function and influencing the nature into valuable drugs seems to be on track experiment when he has permeability of ions. This is the world of natural to continue for a long time yet. a flash of inspiration. For organic compounds. Uemura searches for “life example, he wondered how cicada larvae acquire their ideas” from nature, identifies their chemical antibacterial properties while structure, and uses them to develop drugs for underground, and conducted humans. an experiment to discover that cicada larvae have For example, Uemura used a ‘toxin’ in the black sugars in their bodies with sea sponge Halichondria okadai to develop an antibacterial properties. This anti-cancer drug. Although sponges are sessile, is how his process of discov- ery unfolds. The photograph they have survived for 500 million years without shows a platypus, which is a being attacked by other creatures. Uemura poison-producing mammal. Molecular structure of When Uemura investigated “yoshinone A”. Potent the poison in the spurs of inhibition of the dif- male platypus, he found that Leptolyngbya, the ferentiation of cells to it could be used to anesthe- Cyanobacterium in which fat cells in the 3T3-L1 tize joints. He is now verifying yoshinone A was discovered. mouse model, which the chemical structure of the It has a diameter of approx- makes it a promising poison and searching for a imately 4 cm. The name candidate as an therapeutic agent that could yoshinone comes from the anti-obesity drug. be beneficial in patients with Yoshihara beach on Ishigaki rheumatoid arthritis. Island where Cyanobacteria were collected. 14

The mystery of the sexuality of marine organism ‘barnacle’. It is classified as a crustacean and is related to shrimps, lobsters, the barnacle and crabs. It is an animal, however once it It could be said that the ‘aim’ of the existence of grows past its larval stage; it drifts in the ocean, organisms is to leave behind their own descen- it attaches itself to a surface such as a rock or a dants. Unicellular organisms undergo cell divi- crab shell, and does not move once it has de- Sachi Yamaguchi sion to increase the number of individuals, while cided its habitat. It has legs like the shrimp or Yamaguchi was born in Nara pre- organisms with ‘genders’ reproduce through the crab, but these legs are not designed for fecture in 1982. She graduated male and female copulation and fertilization. walking. Its legs have segments that can filter from the Department of Physics, The human ‘gender’ is separated, with each in- plankton, which it feeds on, from the ocean. Faculty of Science, Nara Women’s University in 2005. She gained her dividual being male or female, but Yamaguchi There are several different types of barnacles. PhD (Science) from the Graduate tells us that, if we look around the world of or- The barnacles that look like Mt. Fuji are well School of Humanities and Sciences, ganisms, there is a wide spectrum in genders known, but the barnacle that Yamaguchi is ex- Nara Women’s University in 2009. She worked as a postdoctoral fellow or sexuality. “In plants, the ‘hermaphrodite’ is amining is the goose barnacle, which looks like at the Japan Agency for Marine- widely known: both the male (stamen) and the an ice-cream cone. This barnacle has a mysteri- Earth Science and Technology female (pistil) are located in a single individual. ous sexuality, which attracted Darwin’s attention. and at Kyushu University. She is currently working as a Special Even some animals, in addition to the ‘sequen- “The goose barnacle has a number of sexual Assistant Professor, Department of tial hermaphrodite’ animals, can change from systems First, during the larval stage, its sexu- Engineering, Kanagawa University. male to female or from female to male during ality is undifferentiated; the goose barnacle is In July 2014, she was awarded the Research Encouragement their lifetime.” thought to select its sexuality when it has Award by the Japanese Society for The target of Yamaguchi’s research is the grown, and has attached to a surface. The most Mathematical Biology.

Assistant Professor Sachi Yamaguchi FEATURE Department of Information Systems Creation Faculty of Engineering The mysterious Mathematical Biology sexuality of the marine organism that confounded Darwin. We are challenging this mystery with a mathematical model. Charles Darwin (1809-1882), who proposed the concept of evolution with his work “The Origin of the Species,” was interested in the sexuality of this marine organism. This mystery remained unsolved for more than 150 years until the young researcher Sachi Yamaguchi attempted to solve it. Her weapon was a mathematical model. PROUD BLUE 15 common sexuality is the hermaphrodite, which Nauplius larva Cypris larva Molting lives in the shallows of the ocean. The second Becomes hermaphrodite or female most common type is a hermaphrodite with a Hermaphrodite Becomes or female dwarf male small (dwarf) male attached, and it can also be Lifecycle of a goose barnacle. found in relatively shallow parts of the ocean. Reproduction The nauplius larva drifts in The third type is found in the ocean depths, and Growth the ocean, changes its form to cypris larva, and then looks is characterized by a female with a dwarf male for a location to attach. If that Establishes itself attached. Hermaphrodites and females are a as hermaphrodite location is either a rock or few centimeters long, while the body length of or female the surface of another living creature, then the barnacle dwarf males is less than 0.1 mm, making them increases in size and it either difficult to see with naked eye.” becomes a hermaphrodite or Hermaphrodites do not fertilize their own eggs a female, while if the larva attaches to a large barnacle it with their own sperm. The male reproductive hermaphrodite. The larger the animal body, the is thought to become a dwarf organ (penis) extends to several times the length further away it can reach to procreate with male. of the animal’s body to deliver sperm in the eggs other individuals. The deeper the ocean, the of another individual, and the eggs accept the less abundant the food sources, so fewer indi- Dwarf male sperm of other individuals. If hermaphrodites viduals can grow to a large size. It is believed are densely packed together, then they are very that to survive and produce offspring in these likely to be able to leave behind their descen- environments, some individuals become dwarf dants. However, occasionally dwarf males affix males. In even deeper parts of the ocean, the themselves to hermaphrodites or to females. number of individuals that can survive within a hermaphrodite The dwarf male always attaches immediately certain range becomes even more limited. It is Goose barnacle individual next to the egg, and although it is short-lived, it surmised that if an individual has both female where a dwarf male (small also extends its penis and reproduces. and male functions, but there are no other indi- male) is attached to a her- maphrodite. The dwarf male Darwin, who advocated the concept of ‘evolu- viduals to reproduce with, the reproductive al- is indicated by the tip of the tion’, also discovered the barnacle dwarf male. location is wasted, so that is why we see the arrow. The photo is of a speci- Why does such a small male exist? This mys- exclusive combination of female barnacles with men from the Osaka Museum of Natural History. tery attracted Darwin’s attention, but it re- dwarf males.” mained unsolved for over 150 years. In the background of the various sexualities of The big mystery of the small the barnacle is the problem of the trade-off of male how to distribute food sources from the envi- ronment for survival, growth and reproduction. Yamaguchi attempted to solve this mystery If there are large numbers of individuals in the using a mathematical model. environment, then there is also competition for “Barnacles select the optimal sexuality within food and reproduction. their own environment to maximize the off- Ten years have passed since Yamaguchi started spring they can produce in their own lifetime. researching the sexualities of barnacles in an Barnacles also live on crab Based on this hypothesis, I came up with a earnest manner. Why does the dwarf male need shells. The black spots are mathematical model. Of course, individuals do to be this small? The answer to this puzzle has locations where hermaphro- dite barnacles have taken up not consciously behave like this, so I believed still not been found, but Yamaguchi embraces a residence. Their body length that the life history we observe now had been certain concept. is only a few centimeters, but acquired through the process of evolution.” “The dwarf male is a phenomenon seen in a va- the male reproductive organ (penis) can extend several Animals need to eat to survive. If food is plenti- riety of marine organisms, not just barnacles. times their own body length, ful, they can grow large and this is beneficial In the near future I will solve the mystery of the so the penis supplies sperm for survival and reproduction. dwarf male using a mathematical model, and I to nearby hermaphrodite eggs and fertilizes them. “In the shallow parts of the ocean, where plank- want to build the field of “dwarf male science””. ton are abundant, the most effective strategy This young researcher has huge ambitions be- for increasing the offspring is to become a large yond the mystery that originally baffled Darwin.

SIDE STORIES Her heart is always in marine life Drawing sea life For Yamaguchi, marine Since she started her life is much more research, Yamaguchi also than simply a field of started drawing pictures. research. On her days The theme of her drawings is off, she enjoys going of course marine life. During to aquariums and buy- the interview, she deftly ing soft toys from the drew pictures to illustrate museum shop. the ecology of barnacles. 16

FEATURE The wondrous ‘chemical systems’ of organisms

If an amateur were to pull apart a watch finely Chemical reconstruction of assembled by a watchmaker, he would then be unable to put it back together. If those parts the underlying molecular were put into a flask, shaken, and then ob- served to return to their original form, no doubt concept in organisms everyone would gasp with surprise and think that it was magic. When we were born and every day when we eat, the interaction of diverse However, if we look at the ‘chemical system’ of molecules in the body plays a crucial role in the process of being “alive.” As our bodies, it comprises miraculous phenomena an orchestra creates a single piece of music through the assembly of the where separate parts come together to form sounds coming from vari- products as if they have a will of their own. ous musical instruments, “The construction of human body starts with the so do these molecules ‘development’ of an embryo. When the body is work together to create a taking shape within the uterus, a series of pro- single body through their teins is being made in the cells based on the in- individual small actions. formation present on the DNA. When proteins Chemically replicating the are released from a protein factory known as behavior of these assem- the ribosome, they reach their functional loca- blies is the challenge taken tion and begin to function without requiring any up by Nobuhiro Kihara. commands or impetus. Proteins constitute the human body as the parts that move to their spe- cific locations without having brains and eyes.” Indeed, we are born as if we were watches that have been automatically assembled inside a flask. From a chemistry-based viewpoint, em- bryo is a ‘reaction field’ where molecules cor- rectly arrange themselves and then progress autonomously with the reactions required for birth. From digestion to cell division, the story told by molecules Professor “This behavior occurs commonly within living creatures, so it must be able to be replicated Nobuhiro with artificial molecules.” Professor Nobuhiro Kihara’s research efforts are focused on artifi- Kihara cially facilitating ‘recognition’ and ‘response’, Department of Chemistry, which are the key functions of molecules that Faculty of Science organisms use for ‘reaction control.’ For example, let us have a look at our meals from Kihara’s perspective. When we eat food, Organic Chemistry, our digestive system degrades it and absorbs Bioorganic Chemistry the required nutritional elements. During this process, food is degraded under gentle condi- Nobuhiro Kihara tions inside the body, without the need for heat Born in Miyagi Prefecture in 1963, Kihara or light. dropped out of a PhD course in the Graduate “A variety of enzymes are at work during the di- School of Engineering, the University of Tokyo. gestion process. For example, to digest pro- He then became a Research Associate in the Research Laboratory of Resources Utilization, teins, particular enzymes recognize a specific Tokyo Institute of Technology for 4 years, linkage between amino acids through ‘intermo- and worked as a Research Associate in the lecular interactions’ and disassemble it. The Department of Polymer Chemistry in the same University for 4 years. Thereafter, he worked protein molecule is recognized and the as a Lecturer for a year, and held the position of Associate Professor in the Department of Applied Chemistry, Osaka Prefecture University for 6 years. He is now a Professor in the Department of Chemistry, Kanagawa University. PROUD BLUE 17 digestion reaction occurs as the response. and as a paint that can be peeled from the Because each reaction is very specific and surface without damaging it. functions correctly, only the ingestible mole- This new material with this unique property cules, or ‘nutrients’, are digested.” was created accidently from an unsuccessful Furthermore, the behavior of molecules during attempt to prepare a polymer of carbon dioxide. cell division is another example of a marvelous “I thought it would have been interesting if we ‘reaction control’. During cell division, a set of were able to prepare a polymer of carbon genes in the cell duplicates, and each set is dioxide. It can also be used as an explosive.” delivered to each side of the cell, before the cell An explosion occurs when a volume expands divides into two. During this process, a special faster than the speed of sound. When the reaction occurs whereby a molecule, named as decomposition of a solid polymer into gaseous a ‘molecular motor’, works to pull each set of carbon dioxide happens, the volume changes genes to the opposite directions. Kihara has rapidly, potentially causing an explosion. Such a successfully reproduced this chemistry by using material can be used as a high-energy artificial molecules for the first time. compound. “When our first ancestor was born at the “However, when we actually attempted to bottom of the sea, 4.5 billion years ago, life prepare the polymer, it decomposed and Oxidatively degradable polymer, when used as the paint, a coat can came into being with trial and error, with very disappeared as soon as it was synthesized. We be applied and removed, when few chemical ‘tools.’ However, now, we humans then attempted to prepare a similar polymer desired. A large number of biode- can use our brains and sciences as powerful using an inorganic compound, hydrazine. gradable macromolecules have been created as the so-called and goal-directing tools. If we select specific Instead of an explosive, we discovered an environmentally friendly mate- functions of a biological system, we can design oxidatively degradable polymer, with a rial, but we cannot control their artificial compounds to replicate them, even completely different potential application.” degradation. In the case of the oxidatively degradable polymer, though the flexible improvement of biological Currently, his interest is on developing a novel the timing of degradation can be system with unnatural compound is impossible polymer that degrades by blowing a special gas freely manipulated, and the prod- in organisms. This is my research.” onto it instead of using chlorine-based bleach. uct of degradation is clear and clean. This useful new material is Kihara started his research on molecular Create chemistry that changes also environmentally friendly. ‘recognition and response,’ when he was a the worldview graduate school student working on molecular Dexterity in the technique of organic synthesis ‘recognition.’ Kihara recalled, “In the biological is necessary for artificially reproducing the systems, molecular recognition triggers the functions of organisms. By using sophisticated response for the next recognition; therefore I techniques of organic chemistry, Kihara has believed that the response should be the successively created highly scarce substances research target next to the recognition.” He was such as microscopic chain-like molecule also interested with that no one had tried named “polycatenane.” researching on the chemical response, which is One day, by chance, Kihara encountered a technically more difficult than the physical unique substance, the oxidatively degradable response. polymer. The oxidatively degradable polymer is “We are undertaking the research on the a new class of material that rapidly decomposes concept ‘molecules that react in response to and disappears, when exposed to a commercial the recognition’, because it will open new Inside the laboratory, there are chlorine-based bleach. Kihara states, “we important possibilities in chemistry. New several types of equipment and reagents for the synthesis of anticipate the application of this polymer as a concept can change the ways of thinking and newly designed organic com- material that immediately degrades at any understanding the world.” pounds. Among the glassware, desired time-point.” This enables its use as an Molecular systems have the potential to some were manufactured by Kihara himself; he said, “If the adhesive that can be removed when desired change the world through chemistry. appropriate glassware is not available, you may make it.”

SIDE STORIES

The orchestra is the Reproducing the light of the reaction field of music jewel beetle with liquid crystals Kihara started playing contrabass as On the surface of the jewel beetle, there an orchestra member when he was a are extremely fine grooves at regular student. In the ‘spring concert’ held at intervals. Only light with wavelengths that the Annual Meeting of the Chemical correspond to the width of these grooves Society of Japan, he and many chem- is reflected, releasing particular colors. ists gathered from all over Japan to These principles were reproduced with play music. His favorite composers molecular recognition in liquid crystal, are Shostakovich, Wagner, and Mahler. with which own key holders are prepared. 18

Professor Susumu Izumi An insect with plant-like wisdom Susumu Izumi was born in Toyama Prefecture in 1952. He The silkworm is an insect that weaves its own Susumu Izumi completed a PhD in biology in the ‘cradle’, a cocoon made of silk thread. The Postgraduate School of Science, growth process of this insect, during which it Department of Biological Science, Tokyo Metropolitan University in Faculty of Science 1989. In the same year, he be- changes into various forms, is truly dramatic. came an assistant in the Faculty A larva that has just hatched from the egg is of Science, Tokyo Metropolitan Molecular biology, University. In 1993, he became an called a ‘first instar larva’. It repeatedly molts, Assistant Professor in the Faculty becoming a second, third and fourth instar Insect physiology and of Science, Tokyo Metropolitan larva, before finally becoming a fifth instar larva University. In 2005, he became biochemistry an Assistant Professor in the with a body length of approximately 10 to 20 Graduate School of Science and cm. At this stage, it begins to eat even more Engineering, Tokyo Metropolitan mulberry leaves, and secretes silk thread to University, and he is currently a Professor in the Faculty of create a cocoon. Inside the cocoon it molts once Science, Kanagawa University. again, becoming a hard pupa, and waits for its emergence from the cocoon. The aim of Izumi’s research is to elucidate in- sect ‘metamorphosis’ from the perspective of molecular biology, using the silkworm as a model organism. “Nature is truly interesting. For example, when a silkworm becomes a pupa inside the cocoon, its outer skin hardens and protects the body from outside physical stimuli. In fact, the en- zyme at work during this process is ‘laccase’, which performs the same activity as the en- zymes at work when lacquer, the natural paint used for lacquer-ware, hardens. So why does this insect have plant-like wisdom even though it is an animal?” Izumi has spent a significant portion of his re- search career investigating the outer skin of the silkworm. During metamorphosis of the silk- worm, the outer skin also undergoes dramatic changes. While the silkworm is a larva, its skin has elasticity, but once it becomes a pupa, it hardens to protect the silkworm body from ex- ternal stimuli. Then it once again acquires elas- ticity when the silkworm becomes a mature insect. It is as if the silkworm is changing its clothes seasonally, covering its body with an outer skin that is suitable for particular circum- FEATURE stances. However, these outer skins are all pro- duced by skillfully changing the same ‘cuticular protein’. “Regulation of gene expression, the blueprint of A life mechanism hidden life, governs all these changes.” within the silkworm, The silkworm ‘plan’ seen from gene expression glimpsed through The ‘expression’ of genes refers to the synthesis of proteins based on the genetic information in molecular biology the body. Izumi conducted research on how pro- teins in the hemolymph of silkworms correlated From larva to adult, a mysterious life process unfolds inside the silkworm cocoon. with their circumstances at a certain time. What The mystery of this small life form is explained through molecular biology. he discovered was a skillful planning of genetic Here we discovered various mechanisms that form life, including gene expression expression that shaped the life of silkworms. that skillfully plans the workings of life, and the existence of neurotransmitters “For example, after day 3 of the fifth instar lar- that are similar to those in humans. val stage, ‘30K protein’ appears in the PROUD BLUE 19 hemolymph, which was never made prior to “Research on insect neurotransmitters was Silkworm lifecycle that stage. Once that protein starts to appear, preceded by research on the fruit fly Larvae First instar larva (4 days) the silkworm begins to produce silk thread, and (Drosophila), and it was found that the insect Resting/ Molt sheds skin it can then pupate.” central nervous system was cholinergic, as Sleeping A number of these proteins that appear in sync acetylcholine was used as a neurotransmitter. Second instar larva (3 days) Resting/ with the metamorphosis have been observed in We attempted to verify if the silkworm, a Sleeping Molt sheds skin the body of the silkworm. The growth plan moves Lepidoptera insect, also had a cholinergic Third instar larva (4 days) to execution mode with planned gene expression. central nervous system.” Resting/ Several factors fulfill the role of switching on The results clearly show that acetylcholine is Sleeping Molt sheds skin gene expression, and insect hormones in the used as a neurotransmitter in the central Fourth instar body are said to participate in the synthesis of nervous system of silkworm larvae. larva (6 days)

Resting/ 30K protein. In the body of the silkworm larva, “The expression level of acetylcholine increases Sleeping Molt sheds skin the ‘juvenile hormone’ is secreted to maintain even further in the mature insect. I want to Fifth instar larva the silkworm in its larval state until it becomes continue with more research, to look into how (8 days) a fifth instar larva. However, once it becomes a the nervous system is reorganized during the fifth instar larva, the secretion of that hormone process of metamorphosis, and how the use of is inhibited. Then the protein 30K is synthesized, neurotransmitters changes at a molecular level.” Cocoon Produces silk the cocoon is made, and the silkworm becomes Humans also use acetylcholine for a mature insect. neurotransmission. Human muscles contract

“I wanted to research and clarify insect upon secretion of acetylcholine. The Pupation Pupa metamorphosis, which is replete with mystery, acetylcholine degrading enzyme at the gene expression level. I have had this acetylcholinesterase acts upon contracted wish for a long time.” muscles to relax them, which is how we The cuticle that forms the exoskeleton of the normally control our skeletal muscles. Emergence insect binds to various cuticular proteins If acetylcholinesterase is inhibited, muscles Mature insect expressed during the process of molting and remain contracted and this produces symptoms metamorphosis to ‘chitin nanofibers’, enabling such as breathing difficulty and seizures. Larvae the cuticle to become either softer or harder. Incidentally, the nerve gas ‘sarin’ that was used The life cycle of the silkworm is skillfully by the Japanese religious group Aum Shinrikyo controlled by regulation of gene expression. in terrorist attacks, was a potent inhibitor of acetylcholinesterase. The common language of Neurotransmitters are a ‘common language’, neurotransmission spoken and there is no significant difference between by the silkworm molecules that act as neurotransmitters in Furthermore, Izumi conducted research to humans or insects. These discoveries in investigate the central nervous system of silkworms may be deployed to other areas of insects using the silkworm as a model. This research. research is on the key neurotransmitter “Observation is everything to natural scientists. ‘acetylcholine’, which is related to the If they have any doubts about something, they cholinergic nerve of the silkworm. Acetylcholine will discover many interesting things if they performs a variety of actions, but it is present in look closer. My life as a researcher has been vertebrates, including humans, and is mainly like that from the beginning until today.” involved in the contraction of muscles mediated Izumi is starting his next journey to seek out by the motor neuron. the mysteries of the silkworm.

SIDE STORIES Observant eye for nature - Creating a high-class gentle breeze High-performance Olympus Pen The laboratory specialty product, The film camera Izumi received as The silkworm is a domesti- a present when he was in middle cated insect, and since it is the silk fan school - Olympus Pen D3 (camera easy to rear, it makes a supe- Making use of the silkworm behavior, on the left). At that time, Izumi rior subject for experiments. It we created a silk fan that bestows a used a closet as a dark room and lies quietly on the palm of the high-class cooling sensation when developed photographs himself. hand and does not run away. fanning one’s face. For the silk over Influenced by his father, who loved the ‘bones’ of the fan, we used a cameras, photography remains a number of fifth instar larvae that had favorite hobby of Izumi’s to this day. started producing silk. If the silk- The nature surrounding the Shonan worms are kept horizontal, they do not Hiratsuka campus is the main sub- make cocoons, instead they created ject of his photographs. The camera enough silk to cover the entire fan. on the right is an Olympus Pen F. 20 ESSAY : SCIENCE INSIGHTS

Measuring novelty We herein present a mysterious metal complex that stores a large amount of gas, and discuss its potential for practical use in gas storage, moving toward a hydrogen society. After its discovery by Wasuke Mori, this material and concept was further developed by many brilliant researchers and has grown to be a field that attracts international attention. Its beginning was not particularly inspirational, nor was it discovered in an ideal experimental environment, but rather, a small accident was responsible. We therefore ask, what is required for science to create novelty? We herein present you with a series about a great scientific drama surrounding a mysterious metal complex.

Professor Emeritus

conduction, a small amount nitrogen gas Creating novelty Wasuke Mori that is about 1/50 of atmospheric pressure Department of Chemistry, Creating novelty is an important role of sci- was added. In addition, since weaker inter- Faculty of Science ence, but the key question is, what is re- actions can be measured more clearly at quired for novelty to be born? Could it be lower temperatures, the sample was Magnetic chemistry, good conditions for experiments and mea- cooled externally using liquid nitrogen at Functional materials surements? We’re not so sure. Although 77 K (Figure 1). chemistry, modern experimental facilities are breath- When the measurement was performed taking, conditions may actually be too good, under standard conditions, mysteriously, Complex chemistry and could actually hinder creating novelty the balance tipped immediately and at times. stopped moving, suggesting that the sam- Firstly, to recognize novelty, something ple became too heavy for the balance to must be measured. Previously, it was nec- measure. As the apparatus set-up did not essary to build our own devices to perform allow us to observe what was occurring in- measurements. For example, my expertise side, we had no choice but to remove the is in magnetic chemistry, a science that liquid nitrogen Dewar from the outside. At approaches subjects through magnetism. I that point, the sample spurted out of the Wasuke Mori previously used a magnetic balance that I cell and covered the interior of the mag- Born in Aichi Prefecture in 1941, built myself to examine magnetic interac- netic balance. I panicked. As the magnetic Wasuke Mori left the Chemistry tions between various atoms and mole- balance is an extremely sensitive instru- Program of the Graduate School of Science, Nagoya University in 1968, cules on a daily basis. But one day, an ment, my concern was that if it was con- and took up positions as assistant, accident occurred, due to a metal complex taminated inside, it may never be usable lecturer, and associate professor at known as copper(II) terephthalate. again. I quickly disassembled the magnetic the Liberal Arts Department, later moving to the Faculty of Science As the name implies, the magnetic balance balance and carefully cleaned the inside. at Osaka University. In 1996, he was composed of a balance and a magnet, Thankfully, I was able to rebuild it and it became a professor in the Faculty of Science, Kanagawa University. and the samples to be measured were worked fine; it must have been a rather After serving in the positions of placed in a container called a cell. A glass well-built balance! vice president and executive di- tube was used to cover the cell from above, However, the problem was that I didn’t rector at Kanagawa University, he became an honorary professor, a and the inside of the container was sealed learn my lesson the first time. To try to de- title which he currently holds. to create a vacuum. To improve heat termine what had happened, I repeated PROUD BLUE 21

Figure 2 Copper(II) terephthalate100g This compound has a nanopore struc- ture exhibiting a large number of holes

Benzene(C H ) 6 6 This structure Copper atom : can store benzene molecule ratio = 1:0.5 30 Xenon of either nitrogenl Copper atom : or oxygen xenon molecule ratio = 1:1 Nitrogen The “nanopore” structure containing fine Copper atom : nitrogen molecule holes stores the gas ratio = 1:2 The figure shows models presenting how much gas (e.g., benzene (C6H6) vapor, xenon, or nitrogen) can be stored in the copper(II) terephthalate nanopore structure. Due to its excel- lent storage abilities, this structure this “accident” three times, each time with became clear that the copper(II) tere- may be suitable for application in hydrogen storage technologies. the same consequences, and I still was no phthalate structure contained a large num- wiser as to what caused it. ber of pores, and that oxygen and / or Other professors and researchers joined nitrogen could be stored in these holes me in contemplating this issue, and we (Figure 2). Figure 1 came up with the idea that the small This accounted for sample sputtering Electronic balance amount of nitrogen gas present in the during the measurement, as removal of magnetic balance used to improve heat the Dewar increased the temperature of Vacuum pump conduction may have been adsorbed by the the cell, and the nitrogen gas stored inside Weight sample. This would result in the mass of the sample at low temperatures exited the the sample increasing and the magnetic structure rapidly. balance being overwhelmed. It was a sim- I presented this mysterious phenomenon Sample ple hypothesis. in 1972 at the Chemical Society of Japan, To confirm this idea, we carried out the but it was not well received. It took 20 Electromagnet (S) Electromagnet (N) same measurement using a vacuum inside years before it was accepted when I pre- the magnetic balance. In this case, the bal- sented the same idea overseas. After many ance moved normally, and the measure- years, that mysterious metallic complex ment was performed without any problems. that I had discovered finally became a We therefore concluded that the excessive novelty. The high performance weight of the sample was caused by the Current research environments are ex- creation: A magnetic balance that measures adsorption of nitrogen gas by copper(II) tremely suitable for young researchers. novelty terephthalate at very low temperatures. However, if the conditions are too good, the This device consists of a balance results of experiments are obtained A large number and a magnet, and measures small quickly, and as young researchers do not of holes store the gas magnetic interactions between atoms have much time to consider what they are and molecules. A cell containing the sample (cooled using liquid nitrogen) At that point, there was nothing to stop my discovering, a new opportunity may be is hung between electromagnets that curiosity. We discovered that 100 g of cop- overlooked. As novelty comes from unex- create a strong magnetic field for per(II) terephthalate could occlude almost pected potentials and probabilities, scien- measurement. Due to the preciseness of this balance, many students have 30 L of either oxygen or nitrogen. When tists should try to value the concept of visited Mori’s laboratory to use it for considering the mechanism of occlusion, it novelty. their measurements. 22 ESSAY : SCIENCE INSIGHTS

In the spring of 1968, when I took up a po- Attracting researchers Chemistry sition in the Liberal Arts Department at worldwide Osaka University, I was measuring the that mesmerizes magnetic interactions between atoms and Since 1993, I have been conducting re- the world molecules for various metallic complexes search into the application of copper(II) under the supervision of Professor terephthalate in the storage of natural Michihiko Kishita, using the magnetic bal- gas, in cooperation with Osaka Gas. Our ance that I designed. However, one of the objective was the practical use of this compounds I was studying displayed an complex in natural gas storage through interesting phenomenon during its mea- increasing its storage capacity. surement. The balance swung all the way In this case, natural gas is stored under over, indicating that the sample was pressure with copper(II) terephthalate in a heavier than what the balance could mea- storage container (gas cylinder). This is sure. This led to the discovery of the possible due to the lattice structure of unique characteristic exhibited by cop- copper(II) terephthalate, which contains per(II) terephthalate, namely, its ability to numerous pores (nanopores) that can store gases. store gas molecules. Thus, we studied a Following much research worldwide, it number of ways to increase the size of appears that this compound is likely to these pores to increase the storage ca- play an important role in achieving a “hy- pacity. Indeed, we confirmed methods of drogen society.” In particular, it is receiv- increasing the pore size while maintaining ing increasing attention for its ability to the strength of the material through the store gases, to store and separate a large use of a carboxylic acid longer than tere- amount of hydrogen gas, and to contribute phthalic acid, along with pyrazine as a to the basic technology of hydrogen pro- bridging ligand. duction in its role as a catalyst. Indeed, In 2000, it was selected as a NEDO (New this metal complex appears to have im- Energy and Industrial Technology measurable potential. Development Organization) project, and we conducted research and development in cooperation with a number of PROUD BLUE 23

A hydrogen society achieved using a metal complex

Fuel cell H2

Gas turbine power generation Providing electric power to society including each household

Hydrogen generation A metal complex is used as a photocatalyst in order to Hydrogen cars synthesize hydrogen from Energy source to support water using sunlight transportation infrastructure Using a metal complex, hydrogen is stored

companies and universities, including What is certain is that although hydrogen By the simple action of exposing plants to Kyoto University and Osaka Gas. We suc- is generally stored under high pressure sunlight, starch can be synthesized from cessfully achieved the low pressure stor- (e.g., 900 atm), if metal complexes such water and CO2. Of course, I was awestruck age (20–30 times atmospheric pressure) as copper(II) terephthalate are employed, by this amazing ability exhibited by plants. of natural gas. At low pressures, the force hydrogen storage can be achieved at sig- Previously, it was considered impossible on the container was lower, increasing the nificantly lower pressures. As such, this to decompose water into hydrogen and choice of containers available for the sys- technology has the potential to greatly im- oxygen using sunlight alone, but we are tem. Ultimately, we employed a thin and prove the storage method for a future hy- actually relatively close to achieving this. flat rectangular container instead of a drogen society. Indeed, I believe that the society in which conventional sturdy cylindrical high pres- Currently, research is ongoing worldwide hydrogen can be manufactured, sepa- sure container (200 atm). Thus, we in- to establish hydrogen storage technolo- rated, and stored in a controlled manner creased the storage capacity while using a gies that function at normal or ambient without putting a burden on the environ- more compact container. temperatures. ment is just around the corner. In addi- With this technology, we were able to effi- tion, the establishment of this technology Hydrogen synthesis using a ciently install a fuel tank on either the roof could lead the way to solving a range of metal complex or the undercarriage of natural gas cars global issues, such as food shortages and as desired, which saved space. As the In addition to its hydrogen storage proper- the energy crisis. storage capacity increased, the driving ties, the use of copper(II) terephthalate as However, to achieve this, we need young distance was increased to 500 or 600 km, a photocatalyst could lead to hydrogen researchers. In science, fresh ideas are which is equivalent to that of a conven- production. abundant until a researcher reaches their tional gasoline-powered car. At present, the results of experiments 30s. I therefore hope that young research- Hydrogen storage studies were also con- employing metal complexes of rare met- ers will not only focus on achieving re- ducted by major automobile companies. als such as ruthenium and rhodium as sults, but will also look at their infinite However, although copper(II) terephthal- photocatalysts are quite favorable. We potential and future. ate can theoretically store a large amount hope to obtain similar good results with of hydrogen, storage temperature is an more typical metals such as iron, and to issue. Hydrogen is extremely light, and challenge reactions such as photosynthe- has a low boiling point. As such, unless sis, which involve the use of CO2 gas. the temperature is extremely low (90 K, These wonderful results remind me of my approx. −183 °C), it would not be stable. childhood when I admired photosynthesis. Publisher/Research Support Department, Kanagawa University

CD / Haruka Tamefusa (Tosho Printing Company, Limited) Kanako Kurosawa (Tosho Printing Company, Limited) AD / Mitsunobu Hosoyamada (Hosoyamada Design Office) D / Christian Gusukuma (Hosoyamada Design Office) Takumi Kawaguchi (Hosoyamada Design Office) TEXT/Akihiko Mori Masatsugu Kayahara PH/Takahiro Okamura PD/Noriko Nagahama (Tosho Printing Company, Limited)

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