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From High-Temperature Superconductivity to Complex Electron Systems Science
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Takagi is the scientist who triggered the worldwide superconductivity fever 19 years ago by confirming the discovery of a high-temperature superconductor. Superconductivity is a phenomenon in which the electrical resistance of a substance suddenly becomes zero at a particular temperature (transition temperature). Since mercury was found to become superconducting at 4 K (-269 In 1986, Drs. J.G. Bednorz and K.A. Müller at the IBM Zurich Research Laboratory reported that a copper oxide in a layered structure became superconducting at 30 K (-243 "In those days, I was also engaged in research into superconducting oxides, and initially could not quite believe their experimental results. The superconductivity they reported that was exhibited by the poor conductor oxide at a temperature as high as 30K was unbelievable because it was out of the range of common sense in those days. I proceeded to produce this substance and measure its transition temperature using state-of-the-art equipment while raising the ambient temperature little by little from a very low level, and I was surprised to find that the superconducting state persisted even when the transition temperature exceeded the then record-high level of 23 K. I was impressed: 'This is real. Nature is amazing!' I had never been so excited in the whole of my research career!" The magnitude of the discovery of the high-temperature superconductor is clearly reflected in the fact that Drs. Bednorz and Müller received the Nobel Prize in Physics in 1987, just a year after their groundbreaking discovery. However, the mechanism behind this phenomenon remains elusive. Solving this riddle would represent a significant advance in condensed matter physics that would certainly result in a Nobel Prize, and would also provide a key to the search for more readily-available high-temperature superconductors. A wide range of high-temperature superconductors would revolutionize all types of technology that rely on electricity and magnetism. It would also make power transmission without energy loss and power storage into practical propositions, thus making a significant contribution to finding a solution to the energy issue, one of mankind's most challenging concerns.
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| Superconductivity is a phenomenon in which the electrical | |||
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In metals, some electrons exist apart from the individual atoms and positively-charged ions are arranged in order to form a crystal lattice. Electrons that are outside the atoms can move freely in the lattice. When a voltage is applied, the electrons begin moving in one direction to produce an electric current. However, the movement of discretely moving negatively-charged electrons is interfered with by the oscillation of the positively-charged ions in the crystal lattice and by impurities in the substance. This is electrical resistance. A consistent theory for the mechanism of superconductivity in metals was produced by Drs. J. Bardeen, L.N. Cooper, and J.R. Schrieffer in 1957, and for which they were awarded the 1972 Nobel Prize in physics. Their theory is now known as the BCS theory, designated as the acronym of their names. According to the BCS theory, when a metal is cooled to below a particular temperature, the discretely moving electrons bind together to form pairs (Cooper pairs). Then, all the electrons exhibit quantum-mechanical behavior by moving together like a wave, and electricity passes through the metal without interference by impurities and the like. This is superconductivity. In ordinary states, electrons electrically repel each other. Then, what is the force exerted that binds such electrons together to make pairs? When a negatively-charged electron moves, a positively-charged crystal lattice is attracted to it, resulting in the formation of a positively-charged field. Another electron is attracted to that field. Hence, an electron pair is formed, as explained by the BCS theory. "However, the formation of a pair of electrons that are weakly bound by the lattice vibration is limited to very low temperatures. The BCS theory had predicted that the transition temperature would be at most 30 K. This is because too strong a binding between the lattice and the electron makes the crystal unstable." Since 1986, however, high-temperature superconductors of copper oxide with transition temperatures much exceeding 30 K have been discovered one after the other, and the current record high is 160 K (-113 °C). The mechanism of high-temperature superconductivity cannot be explained by the BCS theory, which is based on electron-lattice interactions. Experiments have already demonstrated that electrons also form pairs in high-temperature superconductivity. What is the force behind the binding of electrons to form pairs at high temperatures exceeding 30 K? This is the biggest riddle in high-temperature superconductivity. Electrons are capable of moving outside the atom even in the copper oxide that causes high-temperature superconductivity. However, when electrons are about to move from one atom to an adjacent atom, they get too close to the electrons that already exist there and are repelled by an electrical force because of the narrow orbit available for electrons to move around in. "In this state, electrons stay in their own territories while repelling each other." Therefore, no electric current is produced even when a voltage is applied. This state produces a Mott insulator. However, if electron-deprived places (holes) are created there, the electrons gradually become able to move while staying entangled with each other. Such a group of electrons is known as a strongly-correlated electron system. In strongly-correlated electron systems, a grouping of electrons occurs like a sticky liquid. High-temperature superconductivity is a phenomenon that occurs in this group of 'sticky' electrons. As electrons are removed from a Mott insulator, it becomes a superconductor. When further electrons are removed, the insulator enters the state of an ordinary metal, in which electrons are freely to move around without resistance (Figure 2). For this reason, many researchers think that the entanglement of electrons produces high-temperature superconductivity.
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| Discovery of an electron crystal is the key to high-temperature superconductivity | |||
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Researchers into high-temperature superconductivity throughout the world think that a key to elucidating the mechanism resides in a mysterious state called the "pseudogap phase," which appears just before a substance becomes a superconductor, rather than in the superconducting state with already-formed electron pairs. Postulating that electrons show some order in preparation of the onset of superconductivity, they tried various approaches to observing pseudogaps. However, all these efforts failed because direct observation of electron states at high resolution proved to be impossible; the 'hidden order of electrons' remained to be identified. Dr. Takagi and Dr. Tetsuo Hanaguri, Senior Research Scientist, began working jointly with Cornell University of the US to directly observe the electron state of the pseudogap using a scanning tunnel microscope (STM). A tunneling current is allowed to run from the probe of the STM to the sample surface, and the electron state is examined by determining the conductivity and analyzing the spectrum of the very weak light emitted from the sample surface. However, highly-accurate observations using this method cannot be achieved unless the sample surface is highly flat on the atomic scale. In those days, only one kind of high-temperature superconductor was known to meet this requirement. In addition, that substance did not permit adjustment of the number of holes to produce the pseudogap state. With this in mind, Takagi and others explored and found a high-temperature superconductor, now known as oxychloride, that can be made with such a flat surface, and succeeded in creating its monocrystals in the pseudogap state in a joint project with a team from Kyoto University. "Oxychloride is a relatively unfamiliar high-temperature superconductor. Because I have long been engaged in both material development and property research, I can select and produce the substance best suited for the measurement of the new superconductor. At present, we are the only team that can produce oxychloride in the pseudogap state." In 2004, Takagi and others thus succeeded in directly observing the electron state in pseudogaps for the first time in the world, and hence unveiled the 'hidden electron order.' They discovered that crests of high electron density occur side-by-side to form their own order like a crystal, irrespective of the positions of the crystal lattices formed by atoms (Figure 3 and Cover). "This 'melted' state of the electron crystal represents high-temperature superconductivity. However, some authors hypothesize that the crystalline state comprises regularly-arranged discrete electrons, and others believe that electrons have already made pairs in this state but remain unable to move freely and hence immobilize themselves as a crystal. Another hypothesis is that holes have made pairs, and that if the pairs become motile, the substance becomes a superconductor. However, it is not yet known which theory is right." To understand the process in which this electron crystal is formed, the inside of the substance of interest must be examined extensively using a radiation facility like SPring-8 at RIKEN's Harima Institute. "We received many proposals for joint study with radiation research groups throughout the world. However, such observation is quite difficult. Although further advances seem painstaking, I want to give shape to the dream of all condensed matter physicists by elucidating the mechanism of high-temperature superconductivity with our own efforts."
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| Creating new materials using complex electron systems science | |||
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Groups of electrons in a state like a sticky liquid can be found widely in transition metal oxides and conductive organic substances, as well as in copper oxides. "Compared to the freely-running electrons in metals, 'sticky' electrons are securely entangled with each other, so that their behavior is very complex. On the other hand however, this complexity suggests many interesting functions. The 'sticky' electrons keenly respond to minor stimulation to begin moving or to immobilize themselves like a crystal, thus exhibiting significantly altered properties. A good example is high-temperature superconductivity." Substances that exhibit such significant changes in their properties upon exposure to very small stimuli are promising for use as nanotechnology materials such as for high-performance sensors and memory. In April 2005, the Complex Electron Systems Research Group was established under the leadership of the Magnetic Materials Laboratory. "This is a joint project to explore the complex behavior of groups of 'sticky' electrons for the creation of new materials, in cooperation with other research groups specializing in oxides and organic substances, beyond the conventional boundary between the inorganic and organic fields. I want to develop new materials with innovative functions that should heighten the image of the RIKEN brand, including superconductors, thermoelectric inverting materials, substances that change their magnetism upon exposure to electrical fields, substances that change their crystalline structures, dielectric constants, or colors in magnetic fields." It is certain that Takagi's laboratory will once again be reporting sensational experimental results to the world. 
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In 1986, superconductivity fever broke out all over the world as a result of the discovery of a high-temperature superconductor, which exhibits zero electrical resistance at a temperature higher than that of any conventional superconductor. Despite the many efforts that have been made to date, however, the mechanism of high-temperature superconductivity remains unknown, posing the most challenging problem in condensed matter physics. The phenomenon of high-temperature superconductivity is caused by a strongly-correlated electron system, a group of "sticky" electrons that are entangled with each other in a solid. In 2004, Hidenori Takagi, chief scientist in the Magnetic Materials Laboratory at RIKEN's Discovery Research Institute, and other members of the Laboratory discovered an electron crystal that gives an important clue to elucidating the mechanism of high-temperature superconductivity. They conducted further experiments into high-temperature superconductivity and established the Complex Electron Systems Research Group to explore unknown functions of strongly-correlated electron systems in cooperation with other laboratories at the Institute.
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Developing Radical Therapeutics for Japanese Cedar Pollinosis
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| Mechanism of Japanese cedar pollinosis and the present status of treatment | |||
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When will the first radical remedy for Japanese cedar pollinosis become available? This basic question was asked at the beginning of the interview. "It will be at least five years from now at the earliest, provided everything goes well and regulatory examinations, including clinical studies, proceed smoothly," answered Yasuyuki Ishii, leader of the Research Unit for Clinical Allergy. This time span seems very short, considering the fact that it usually takes 10 years to develop a pharmaceutical product. "The prevalence of pollinosis has increased year by year, and it is now an urgent task to develop a radical remedy. We must ensure that we reach that goal as soon as possible." First, let's view the mechanism of the onset of Japanese cedar pollinosis (upper panel in Figure 1). Japanese cedar pollen contains an allergen (antigen) that causes allergies. When an allergen enters the body, antigen-presenting cells such as dendritic cells incorporate and process it and transmit signals mediated by the allergen to type 2 helper T cells (Th2 cells). Then, Th2 cells increase in number and release interleukin 4 (IL-4) to direct B cells to produce immunoglobulin E (IgE), an antibody specific to the allergen. The IgE antibody is a causative agent for allergy and binds to the surface of mast cells. When the IgE antibody captures an allergen, the mast cells release histamine, leukotriene and the like, thus causing allergic symptoms such as sneezing, nasal discharge and nasal obstruction. "Currently available Japanese cedar pollinosis remedies are based on suppressing the action of histamine, leukotriene and the like, and serve to alleviate the allergic symptoms. In some cases, however, the same symptoms recur frequently, with the severity increasing with every season that Japanese cedar pollen is dispersed in the air." Ishii's statement will ring true to many readers. As such, antihistamine drugs and the like only represent symptomatic therapies that control the allergic symptoms, and do not decrease the sufferer's predisposition to the allergy. Currently, there is only one radical therapy for Japanese cedar pollinosis, known as desensitization therapy. In this approach, Japanese cedar pollen extract is administered in ever-increasing concentrations, from a very low level, over a period of two or three years, with the expectation of increasing the resistance to the allergen and hence reducing the likelihood of the sufferer manifesting the allergic symptoms. Although a report is available stating that the method has been effective in about 60% of patients, Ishii says, "Desensitization therapy involves a long period of treatment, and the mechanism of healing with the therapy remains unknown. Furthermore, it can cause severe allergic symptoms systemically because it involves administration of the allergen as is." Ishii and others aim to develop a radical remedy that is highly effective, safe and convenient, for which the mechanism of action has been clarified. "Generally, therapeutic drugs where the mechanism of action has been clarified are approved in the shortest time after application. We have no time to waste. Another aim lies in attempting to reliably stop the onset of pollinosis as far upstream of its mechanism as possible."
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| Activating the innate immunity | |||
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Strategies for the development of therapeutic drugs for Japanese cedar pollinosis can be divided into two main approaches. The first aims at activating the innate immunity. Innate immunity is the biological system by which our body first responds to viral and bacterial infections. It is known that upon entry into the body, viruses and bacteria are incorporated by dendritic cells, and type 1 helper T cells (Th1 cells) increase in number and suppress the action of Th2 cells. On the other hand, when the Japanese cedar pollen allergen is incorporated by dendritic cells, Th2 cells increase in number and release IL-4, resulting in the onset of allergy. If the Th2 action can be suppressed by increasing the number of Th1 cells, the onset of allergy may be prevented. This is what Ishii is targeting. "CpGODN, a DNA fragment of bacterial or viral origin, is known to act to increase Th1 cells via dendritic cells. We are working to develop a therapeutic drug based on CpGODN, jointly with Masahiro Sakaguchi, team leader at the Laboratory for Vaccine Design." Solely administering CpGODN results in the suppression of all Th2 cells, which in turn can have unwanted effects. With this in mind, Cry j1 and Cry j2, the major proteins of Japanese cedar pollen allergen discovered by Sakaguchi, are administered in conjugation with CpGODN (Figure 2). Thus, it is possible to selectively suppress the action of Th2 cells that are specific to Japanese cedar pollen. A study of the administration of the CpGODN-Cry j1/j2 conjugate in mice confirmed an increase in Th1 cells and a decrease in IgE antibody production. "The CpGODN-Cry j1/j2 conjugate can be described as exhibiting a similar action to vaccines," says Ishii. The principle of vaccination resides in the prevention of infections by administering attenuated viruses or bacteria. However, allergy vaccines are significantly different from these conventional vaccines. "Conventional vaccines are administered before the onset of symptoms, whereas allergy vaccines are administered after the onset. They are both prophylactic and therapeutic. Another big difference is that the latter are based on safety-assured chemically-synthesized substances, rather than substances of viral or bacterial origin." At the Research Unit for Clinical Allergy, animal studies have been undertaken since fiscal 2004. The Unit will proceed to clinical studies in humans, jointly with medical institutions, including the National Hospital Organization Sagamihara National Hospital and the Chiba University School of Medicine. If everything goes well, their new drug will possibly gain approval five years from now at the earliest.
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| Making use of the immuno-regulatory mechanism of NKT cells | |||
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Ishii says that there are great expectations for the development of the world's first radical remedy for Japanese cedar pollinosis, but the approach to activating the innate immunity is problematic. "The increase in Th1 cells is only transient and the allergy can recur. What should we do to acquire a predisposition for which the allergy never recurs? To this end, a second strategy based on the use of the immuno-regulatory mechanism may be possible." The key target is natural killer T cells (NKT cells). NKT cells, a type of lymphocytes discovered by Masaru Taniguchi, director of the RCAI Center, are responsible for immune regulation. These cells have been proven to exhibit a variety of functions, including action on dendritic cells that induce immune tolerance (lower panel in Figure 1). Immune tolerance is a phenomenon in which no immune reactions occur in response to allergens. "If NKT cells are activated artificially, it would be likely to acquire an allergy-resistant predisposition as a result of inducing immune tolerance." postulates Ishii. Then, how can NKT cells be activated? "We are planning to administer a-galactosylceramide (a-GalCer), which specifically activates NKT cells, in an artificial lipid capsule called a liposome." At the Research Unit for Clinical Allergy, it has been confirmed that  -GalCer in liposomes is efficiently incorporated by dendritic cells, where it binds to the CD-1d molecule and is transported to the cell surface (lower field on cover page; -GalCer appears in red and CD-1d-bound -GalCer in yellow). NKT cells are activated when bound to -GalCer exposed to the dendritic cell surface. A study of the administration of liposome -GalCer in mice has demonstrated the suppression of IgE antibody production (Figure 3). This is considered to reflect the induction of immune tolerance via the NKT cells."NKT cells have also been shown to induce apoptosis selectively to B cells, which produce IgE antibody (lower panel in Figure 1). NKT cells exhibit a broad range of functions for immune regulation. Controlling them successfully will provide an efficient and powerful tool in a radical therapy for allergies." The project will proceed to preparing liposome -GalCer including Cry j1/j2 capable of selectively inducing immune tolerance only against the Japanese cedar pollen allergen, and using it for further research into development of the desired therapeutic drug.
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| Reaching the goal in the shortest time | |||
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Ishii studied extreme thermophiles when he was a university student. In those days, he already wanted to do work that would help promote the welfare of mankind." And some ten years ago, he became involved in research into immunosuppression at the laboratory of Dr. Kimishige Ishizaka, now special advisor to RCAI, who discovered IgE antibody, and realized "This is exactly the thing that I have been pursuing for so long. My ultimate goal is to elucidate the mechanism of immunosuppression in the body, and to control immunity at will. It should lead to the development of new therapies for various diseases, including immunity-mediated graft rejections in organ transplant, as well as allergies." "I have learnt many things from Dr. Ishizaka," says Ishii looking back upon his past experience. "Dr. Ishizaka often mentions the phrase 'way of thinking' and encourages young scientists to 'carry out your research giving much thought to the subject.' Set a specific goal and define a strategy to accomplish it in advance. By doing so, we can make the right judgment on whether to continue the investigation by evaluating our interim results. Having no goal or strategy would lead to repeating meaningless investigations. What Dr. Ishizaka says carries weight as it reflects his long career in frontier research in the US. I think that to focus on our 'way of thinking' is the best concept to apply in strategies for the development of anti-allergy drugs."
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This year is reportedly marking a historical high for airborne levels of cryptomeria (Japan cedar) pollen dispersion, and many people are suffering from pollinosis. The prevalence of pollinosis has increased year by year, and as many as 20% of the population of Japan are affected by this condition. Unfortunately, however, the therapeutics currently available for Japanese cedar pollinosis provide no more than symptomatic treatment to alleviate allergic symptoms. The development of a radical remedy for Japanese cedar pollinosis is now one of Japan's most urgent problems. In April 2004, the Research Unit for Clinical Allergy at RIKEN's Research Center for Allergy and Immunology (RCAI) was established to help the quick transfer of the results of basic research to practical application for the radical treatment and prophylaxis of Japanese cedar pollinosis. This article reports on the revolutionary development of radical therapeutics for Japanese cedar pollinosis, the first remedy of its kind and long awaited by the people of Japan.
