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Exploring Unknown Phenomena Involving Groups of Electrons
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| What is a strongly-correlated electron system? | |||
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"When I was a child, I wanted to be like Edison, Hideki Yukawa, and Einstein," says Dr. Furusaki, looking back on his childhood days. "I had a natural liking for science and mathematics, and when I was in the sixth grade, I happened to read an introductory book on the theory of relativity, which made me interested in black holes and cosmology." In the meantime, I studied physics at college, and when I was a junior, the superconductivity fever broke out. That led me to condensed matter physics." In 1986, a superconductor exhibiting zero electrical resistance at a temperature higher than that of any conventional superconductor was discovered, creating an explosion of interest all over the world. High-temperature superconductivity is a phenomenon caused by a special group of electrons known as a "strongly-correlated electron system." However, what is meant by a "special group of electrons"? In metals, some electrons are separated from their atoms, and positively-charged ions are arranged in an orderly manner to form a crystal lattice. Separated from their atoms, the electrons can move freely in the lattice. The phenomena caused by these independent electrons have been explained successfully by a conventional theory. Strongly-correlated electron systems are found in conductive organic materials and transition metal oxides such as copper oxides and manganese oxides. In these materials too, some electrons are separated from their atoms, but they cannot move as freely as electrons in normal metals. For example, consider a crystal lattice of positively-charged ions arranged on a grid as a basic component of a material, and a mobile electron assigned to each ion (Figure 1). When the electron moves toward an adjacent electron, the original electron is bounced back because the orbit available for electrons to move around is very narrow and a strong repulsive electric force (Coulomb repulsive force) acts between the negatively-charged electrons. "The figure on the left in Figure 1 shows the state where mobile electrons are trapped because of the repulsive forces between them. This is the state of an insulator, through which no electric current can flow. A material in this state is called a Mott insulator. When some electrons are removed from the Mott insulator, electrons in the insulator start to move gradually in cooperation with other electrons, in such a way that they keep a certain distance from each other. A group of electrons in this state is called a strongly-correlated electron system. When further electrons are removed, and the electrons are allowed to move freely, the electron system changes into the state of an ordinary metal." In considering the relationship between collective behavior of electrons and the property of a material, electron spin is as important as the electric repulsive force. In classical physics, electron spin is defined as a rotation similar to that of the earth, in which the rotating electron, because it is negatively-charged, becomes magnetized. In quantum mechanics, electron spin has two states, either upward or downward. An electron can be envisaged as a small bar magnet, with its north pole, as it were, pointing upward or downward. When two electrons come close to each other, a magnetic force is produced. When the north poles or south poles of two bar magnets are arranged in the same direction, they repel each other, whereas when they are arranged in the opposite direction, they stabilize. In the same manner, the Mott insulator in Figure 1 stabilizes when upward and downward electron spins are arranged in an alternating pattern (on left in Figure 2). However, different spin patterns can appear in strongly-correlated electron systems, when some electrons are removed. Under certain conditions, an electron system stabilizes with all the spins in the same direction. In this case, the whole structure acts as a single magnet. In this way, a special spin pattern adds a new function to a material. For example, in the mechanism of high-temperature superconductivity, which has not yet been understood, the spin pattern is considered to play an important role. The spin pattern is also related to electrical resistance. In the 1990s, Dr. Yoshinori Tokura, Professor of University of Tokyo, discovered the "colossal magneto-resistance effect," where the electrical resistance of a strongly-correlated electron system in manganese oxides decreases drastically down to less than one-millionth of the original resistance when a magnetic field applied to the system is changed slightly to arrange the spins in the same direction. Research is now actively underway to find ways to apply this phenomenon to magnetic storage devices. Dr. Tokura is said to be a strong candidate for the Nobel Prize. "In strongly-correlated electron systems, we can expect other new and unknown functions. These systems have now become one of the most popular material systems in condensed-matter physics.
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| Problems that appear simple sometimes turn out to be the most challenging. | |||
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In exploring unknown phenomena exhibited by groups of electrons, scientists at the Condensed Matter Theory Laboratory are trying to elucidate the theory behind strongly-correlated electron systems under various conditions. One of those conditions is known as "spin frustration." For example, when the spin of electron A on a triangle is upward, and the spin of electron B is downward, which direction can we expect for the spin of the remaining electron C (center in Figure 2)? If the direction of electron C's spin is upward, C repels A, and if the direction is downward, it repels B. "This state is called frustration, because there is no stable condition. The stable spin pattern has been theoretically clarified for the triangular lattice, the two-dimensional lattice made of triangles. However, the quantum-mechanically stable spin pattern for Kagome lattices, which are combinations of triangles and hexagons (on right in Figure 2) is too difficult to find. In this way, some problems that appear to be really simple are in fact the most difficult problems. However, that is what makes it so challenging. A continuous change in temperature or a coupling between the electron spins sometimes causes sudden changes in the spin patterns. Just as water changes into ice when the temperature is lowered, materials drastically change their properties when some conditions are changed. This is called "phase transition." Changes in spin patterns are also a kind of phase transition. "One way to explore the unknown exotic phenomena exhibited by groups of electrons is to study the kinds of spin patterns and spin phase transitions. We take it for granted that a material has a fixed spin pattern at absolute zero temperature (-273.15 degrees Celsius). However, if interactions between electron spins are strongly frustrated, an exotic state (spin-liquid) may occur where spins are fluctuating. I think it will be a great achievement if we succeed in theoretically predicting and demonstrating such special states that are beyond conventional common knowledge. |
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| Different aspects of the electron appear. | |||
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Some spin patterns can be imaged as arrangements of the directions of north poles or south poles of bar magnets, but in other cases, we observe phenomena that are completely incomprehensible according to our daily experiences. "When electrons are aligned along a straight line (one-dimensional), we can expect upward spins and downward spins to appear alternately (on left in Figure 3) along the line. However under certain conditions, each spin splits into two, and two adjacent half-spins make a pair, causing their individual magnetic fields to cancel each other out (on right in Figure 3). This is a state in which adjacent electron spins are quantum-mechanically superposed or entangled. Interestingly, a strange phenomenon is observed at both ends of the line, where a single spin with one-half the angular momentum remains." In the 1980s, a special phenomenon was discovered when a strong magnetic field is applied to a certain two-dimensional electron system at a very low temperature. Although strange, particles with a fraction of the electronic charge, for instance 1/3 or 1/5, were discovered. This phenomenon was called the "fractional quantum Hall effect." Researchers who discovered this phenomenon and Professor Robert B. Laughlin who elucidated its theory received the Nobel Prize in Physics in 1998. "I think the fractional quantum Hall effect is one of the most wonderful phenomena in the whole of condensed matter physics. Individual electrons behave as a simple electron, but when they act as a group under certain conditions, electrons can exhibit spectacular properties, including electrons with a fraction of the electronic charge. One of the examples is the phenomenon in which, when spins are aligned along a one-dimensional line, a spin with one-half the angular momentum appears at one end of the line. I am sure that other phenomena like these can be discovered. We have a strong desire to uncover new phenomena through our theoretical studies."
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| Nano-scale electron world | |||
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Alongside strongly-correlated electron systems, quantum dots (a confined system of electrons in a semiconductor nanostructure) or nano-scale material systems such as the carbon nanotube, an extremely thin carbon tube, are promising targets as one stage in the exploration of unknown quantum phenomena. "For example, we are investigating situations in which electrons only move in one direction in the same way as in a semiconductor quantum wire or the carbon nanotube. At very low temperatures, electrons try to line themselves up at regular intervals due to the repulsive forces between them, and then move around as a group. An electron system of this kind is also a kind of strongly-correlated electron system. We have determined theoretically that when a point of restriction is introduced into an electron system through which electrons have slight difficulty in passing, the electrons completely stop running at absolute temperature. This is a phenomenon that was not expected from conventional common knowledge. I was so excited when I found this phenomenon through theoretical calculations. When electrons move independently, individual electrons can pass through the point of restriction one after another. However, when they try to line up at regular intervals and move as a group, even a slight difficulty is a large obstacle for the group of electrons as a whole, causing this kind of unfamiliar phenomenon." This theoretical prediction by Dr. Furusaki was proved to be true by experiments using semiconductor quantum wires and carbon nanotubes. |
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| Infinite possibilities latent in a group of electrons | |||
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"The theory that explains how individual electrons act is now complete. Nothing is left that cannot be explained from basic principles. However, when many electrons form a group and move as a group in relation to each other, some unknown phenomena can occur. Some scientists compare these phenomena to the game of Go or to Japanese chess. The rules of the games are already decided. However, various excellent moves have been derived from them. In the same way, unexpected phenomena may appear because infinite possibilities are latent in a group of electrons. " In 2005, Complex Electron Systems Research Group was established at Riken's Discovery Research Institute to explore unknown phenomena involving strongly-correlated electron systems and to create materials with new functions. This group includes experimental laboratories such as the Magnetic Materials Laboratory, and the Condensed Matter Theory Laboratory. "In cooperation with the experimentalists, we will advance our research by theoretically clarifying the properties of materials created by the experimentalists." Theoretical studies are underway, in collaboration with the Magnetic Materials Laboratory, on magnetic properties of a strongly-correlated electron system in materials which have the frustrated lattice structure called "pyrochlore" (upper panel on cover page). "We do not intend to become mere theoreticians who just try to explain specific experimental data. We also conduct studies on abstract theoretical models. With theoretical models we can predict and discover new and universal phenomena, and then apply the model to various materials." Unknown phenomena waiting to be discovered in the Condensed Matter Theory Laboratory may significantly affect our societies in the future. 
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New materials with new properties have the potential to change society in the same way as the discovery of semiconductors has led to today's information society. Properties of materials depend significantly on the electron states inside the materials themselves. "In general, many electrons in metals move in random order. However, under certain conditions, electrons act as a group, causing quantum-mechanical, exotic phenomena." We aim to explore new phenomena exhibited by groups of electrons and to establish the theoretical principles that govern those phenomena," says Dr. Akira Furusaki, Chief Scientist. Furusaki's Laboratory, started in 2002, was the first condensed matter theory laboratory ever established throughout the more than 80-year-long history of Riken. What kinds of phenomena are the young theoreticians in the Laboratory trying to explore under Dr. Furusaki's leadership?
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From Cytokine Signals to Zinc Signals
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| What are cytokines? | |||
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"Probing into one theme dedicatedly will lead to striking a wide and rich vein of ore that extends laterally to the general principle of life science. That's my way of research." As reflected in his words, Hirano has been engaged in research into interleukin-6 (IL-6), a kind of cytokine, for more than two decades. Cytokines generically refer to a class of proteins responsible for intercellular signaling. Hirano did discover IL-6 as a factor that stimulates lymphocyte B cells to produce antibodies in 1982, and determined the base sequence of its gene in 1986. First, a brief explanation is given of how cytokines act in, for example, the onset of allergies (Figure 1). When an allergen (antigen) such as pollen enters the body, dendritic cells incorporate and process the antigen, and expose its portion as a MHC-peptide complex to the cell surface (antigen presentation) to transmit antigen signals to helper T cells. Upon receipt of the antigen signals, the helper T cells release a wide variety of cytokines. For example, IL-4, IL-5, and IL-6 are released to transmit the signals to B cells to direct them to turn into antibody-producing cells to produce immunoglobulin E (IgE) and to produce and release IgE. The released IgE binds to the mast cell surface. When capturing pollen or the like, the mast cells release histamine and other chemical substances, thus causing allergic symptoms such as nasal discharge. Cytokines have been shown to mediate not only in these events in the immune system, but also in inflammatory reactions and the hematological, endocrine, and nervous systems, so as to play key roles not only in body defense but also in development, keeping homeostasis of the body. "Cytokines transmit signals between cells by binding to receptors on the cell surface. When a cytokine binds to its receptor, a variety of molecules respond to cause biochemical reactions in sequence and transmit signals in the cell. The fate of the cell, including growth, differentiation, and migration, is eventually determined. The mechanism of intracellular signaling is quite complex. What is occurring in the cell? I have been working steadily to understand the mechanism with a focus on IL-6, which I myself discovered more than twenty years ago."
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| Mouse model of rheumatoid arthritis | |||
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Hirano took note of gp130, a subunit of the receptor to which IL-6 binds, and achieved a groundbreaking discovery in 2002. "Symptoms that are very similar to those of human rheumatoid arthritis developed in a knockin mouse with only one amino acid, tyrosine 759 of pg130 being replaced artificially with phenylalanine. This was the first mouse in the world to develop rheumatoid arthritis due to a cytokine signal abnormality." Rheumatoid arthritis, a disease characterized by joint deformation and collapse due to inflammation, reportedly affects nearly one percent of the Japanese population. It is classified as an autoimmune disease, in which the self is attacked by the immune system, which otherwise attacks foreign matter only, and much remains unknown about the mechanism of its onset. The mouse model exhibits dendritic cell abnormalities and has increased memory cells. Research into this model is expected to contribute to the elucidation of the mechanism of the onset of rheumatoid arthritis. Hirano has a unique approach to elucidating the mechanism of the onset of rheumatoid arthritis. "I employ ENU mutagenesis, which can be performed only at RIKEN." ENU mutagenesis is a technique for randomly introducing point mutations to a gene with a chemical agent called ethyl nitrosourea (ENU), followed by comprehensive identification of the resulting mutants. The RIKEN Genomic Sciences Center (GSC) boasts levels of technology and equipment for ENU mutagenesis that lead the world. Jointly with GSC, a number of research groups and teams at the Research Center for Allergy and Immunology (RCAI) are working to find mice with abnormalities in the immune system using ENU mutagenesis, and identify the causative genes. As such, the Laboratory for Cytokine Signaling is engaged in an advanced level of ENU mutagenesis. "ENU mutagenesis is performed on knockin mice that develop rheumatoid arthritis. Mice that are more likely to develop the disease and those that no longer develop the disease are selected, and the causative genes are identified. Thus, a large number of genes associated with the onset of rheumatoid arthritis are detected, and their relations are clarified. Without doing this, the universal mechanism of the onset of rheumatoid arthritis, and even of autoimmune diseases, cannot be approached. We are the only people in the world who can achieve this." |
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| Mechanism of mast cell degranulation signaling | |||
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IL-6 signals are transmitted via two pathways (Figure 2): one mediated by STAT3 and one mediated by both SHP2 and GAB. At the Laboratory for Cytokine Signaling, researchers are working to explore the actions of STAT3 and GAB with a focus on their presumed importance in the IL-6 signaling mechanism. Below is a summary of the most recent achievements. The first thing demonstrated by the GAB study was the signaling mechanism for degranulation in mast cells. When IgE bound to the mast cell surface captures an allergen, chemical substances such as histamine and leukotriene are released by the mast cells, causing allergic symptoms such as nasal discharge and sneezing. These chemical substances are contained in the granules that are present in the mast cells, and are released outside the cells upon degranulation (Figure 1). "Degranulation cannot occur unless the granule membrane and the mast cell plasma membrane fuse together. The process of cell membrane fusion has been well investigated, and calcium is known to be essential. We showed for the first time in the world that translocation of granules to the cell membrane is important, in addition to this pathway. And we demonstrated that the pathway does not require calcium but must be mediated by the microtubule (Figure 3). Furthermore, we demonstrated that Gab2 plays a key role in this process." Hirano thinks that the same signaling mechanism as the presently revealed one also serves in the degranulation process in immune cells other than mast cells and in nerve cells. Additionally, the process of translocation of granules to the cell membrane is promising as a new target for the development of allergy therapeutics.
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| Linkage of cytokine signals and zinc signals | |||
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The study of STAT3 has led to a noteworthy new finding of 'zinc signals.' "STAT3 is a transcription factor that binds to other genes to regulate their expression. We searched for the target gene for STAT3, and identified it as LIV1. LIV1 was then found to be a zinc transporter that imports zinc into cells (lower panel on front cover). Another fact we revealed was that cells depart from adjoining cells to acquire motility and become capable of migration as a result of zinc signal-mediated regulation of the nuclear localization of the Snail transcription factor," explains Hirano. This was achieved by extensively exploring gastrulation, the process of highly integrated cell and tissue movements to establish the multilayered body plan of the organisms operating in early embryogenesis, using fertilized eggs of the zebrafish. Epithelial cells are in close contact with adjoining cells via adhesion molecules such as E cadherin (upper right, ower panel on front cover). During gastrulation, E cadherin expression is suppressed to weaken intercellular adhesion, resulting in the migration of discrete mesenchymal cells (upper left, lower panel on front cover). When the cells have arrived at predetermined positions, E cadherin is expressed again to allow the cells to come in contact with each other and restore the identity of epithelial cells. This process is known as epithelial-mesenchymal transition. Although the Snail gene had been known to suppress E cadherin expression, there had been no information about how Snail is activated. Hirano says that he was also astonished by the present discovery of evidence for the control of Snail activity by zinc signals. Why? He explains the reason as follows: "Zinc is an essential nutrient, and its deficiency has long been known to cause growth retardation and immune deficiency. In addition, there are many zinc-requiring enzymes and transcription factors, which cannot maintain their structural integrity without zinc bound to them. Among such entities is Snail (bottom, lower panel on front cover, shown in fluorescence). The importance of zinc has been well recognized and relevant investigations from structural viewpoints have been available. However, absolutely no studies had been linked with zinc signals." Epithelial-mesenchymal transition is a phenomenon universally found in a broad range of biological events such as organogenesis and wound healing. This process also occurs in cancer cell metastasis. "The present discovery will lead to cancer metastasis prevention and regeneration medicine. Because zinc deficiency results in immune deficiency, zinc signals must also be associated with the immune system. In this sense as well, the discovery of the linkage of cytokine signals and zinc signals is groundbreaking. We have already begun studying to determine how zinc influences immune responses and allergic reactions, and very interesting data are emerging," says Hirano. "Only a few researchers are working on zinc signals worldwide. All remain to be explored. 'From cytokine signals to the world of zinc signals.' I am excited over the future prospects for my work. In the 20th century, calcium signals were highlighted. In this 21st century, zinc signals may move into the limelight." The final question concerns what output Hirano aims at in his work. "It is the RCAI's mission to clarify the immune mechanisms, and eventually to control allergies and autoimmune diseases. This agrees with my own hopes. I very much want to discover a more universal principle that governs various biological phenomena through research into cytokine signals and zinc signals. I also hope that my achievements will eventually find medical applications."
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Elucidating the mechanism behind immune reactions would open a way to the development of streamlined vaccination and the treatment of cancer, as well as to the treatment of allergic diseases and autoimmune diseases. What is required to achieve this? Immune reactions are caused by interactions of cells such as T cells, B cells, and dendritic cells. "Basically, it is necessary to understand thoroughly what is occurring between input from outside and output from inside in each cell. Then it is necessary to understand how individual cells interact with each other, and hence how immune reactions are controlled," says Toshio Hirano, Group Director of the Laboratory for Cytokine Signaling at RIKEN's Research Center for Allergy and Immunology. At his laboratory, researchers are working to elucidate the mechanism of intracellular signal transduction (signaling) with a focus on interleukin-6. Hirano recently clarified the mechanism behind the release from mast cells of chemical substances that cause allergic symptoms, and made the groundbreaking discovery of linkage between cytokine signals and zinc signals.
