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Special New Year's Conversation between Ryoji Noyori, President of RIKEN, and Atsuko Toyama, President of the New National Theater Foundation
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| Expectations for RIKEN - RIKEN and the Universities - | |||||||||
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Noyori: We asked Ms. Atsuko Toyama, President of the New National Theater Foundation, for advice on advancing our research activities, including her expectations for RIKEN. She appointed me President of RIKEN when she was the Minister for Education, Culture, Sports, Science and Technology.Toyama: At the beginning of this year, I'm very glad to have this opportunity to talk with you, since I have great respect for you. In the fall, when I was inaugurated as Minister, you brought the good news of winning the Nobel Prize. That great deed raised the hopes of researchers in Japan. As your distinction was followed by two Japanese Nobel laureates the next year, the Japanese people's reliance and expectations for science sprang afresh. I was a lucky minister. Since the mid-1960s, I have been watching RIKEN; it is an excellent institute with numerous achievements that offers a milieu for open-hearted research, and was not available to universities in those days. RIKEN will enjoy further development under your leadership. Recently, I became aware of The Noyori Initiative*1 the five guidelines you announced after joining RIKEN. I think they are much to the point. In particular, the two precepts: "To increase contributions to society and humankind" and "RIKEN that contributes to culture" seem to suggest what had not thus far been found in RIKEN. I hope that all members of RIKEN will continue to step forward towards these goals. Noyori: Thank you very much. I joined RIKEN in October 2003, when it became an Independent Administrative Institution. Shortly after, I announced the Noyori Initiative that would serve as a management policy for the new RIKEN. Reconsidering the mission of universities and the mission of RIKEN, I realized again that education must be the first priority for universities. I think research at universities should be academic research aimed at developing our human resources. Hence, it is important for university researchers to have the confidence to work on the basis of their own free ideas. Doing this together with students will nurture young researchers, and this must be of primary concern. Research results are secondary, although hopefully they too are excellent. On the other hand, RIKEN is entrusted by society not only to excel in research by carrying out world-ranking investigations, but also to lay the foundations for scientific research in Japan. RIKEN's influence lies in its systematic strength, through which we are serving as Japan's core institute for nationwide research programs. For example, SPring-8, the Protein 3000 National Project on Protein Structural and Functional Analyses*2, bio-resources, and comprehensive analysis of SNP (single nucleotide polymorphism) which are ongoing on a large scale are unrivaled internationally, and cannot be achieved by the universities. Toyama: I too think that universities have three missions: education, the first priority, followed by research and social contributions. To date, however, too much emphasis has been placed on research, with education tending to be neglected. I would like to remind universities of the importance of education, and also to encourage them to make a social contribution. As independent academic agencies, the national universities are now enjoying the merits of deregulation to freely do what could not be done within the conventional framework. Against this background, RIKEN is expected to take new steps to adapt itself to the trends. I hope that RIKEN will undertake research that cannot be executed by individual researchers at universities. To unify research activities through the organizing ability you have just mentioned - that's RIKEN's strong point. Noyori: Although RIKEN has a number of unique research centers, they cannot cooperate with each other to open new frontiers while maintaining their independence unless we have well-thought-out research plans that accord with national policy and strategies. Toyama: I have recently felt somewhat anxious about Japan's policy on science and technology, which focuses on particular areas selected by the national government. Many of the key items are nearly the same as projects being undertaken in other countries. I strongly encourage Japanese researchers to break this stereotype and create a new paradigm. I hope that RIKEN will take a higher and broader view as an independent institute and take the lead in opening the frontiers of scientific research while watching the trends of university researchers. |
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| Increasing the Visibility of RIKEN - Science and Society - | |||||||||
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Noyori: RIKEN has been encouraged to carry out outstanding research and make use of the results to contribute to society. Furthermore, it is our major responsibility to explain to society at large about the importance of science and the potential of technology based on scientific knowledge, with the aid of our researchers.Toyama: Research has recently become increasingly specialized to the extent that makes it difficult for the general public to understand what is being investigated. The density and precision of research, and the manner of undertaking advanced research have changed significantly from those in the 20th century. Hence, it is critical to account for the meanings, effects, and influences of science. I think it is important that researchers also have a strategic approach to planning their research activities. And another apprehension I feel is about the very limited availability in Japan of "good judges" who are able to identify really valuable findings out of numerous results achieved in frontier research, and link them to industrial applications. Enhancing the interface will make the power of Japan's basic science influential in practical settings. Noyori: That's right. Japan has many players but this does not make a good orchestra. It is important to nurture not only "good judges" but also conductors who can unify and control the individual players. Another task assigned to RIKEN is to systematize research to establish a goal-oriented technical basis. And I think it will be important to design an internal system for linking our achievements to the outside world. Toyama: I agree. Doing so will lead to the accomplishment of one of the goals advocated in The Noyori Initiative: "To increase the visibility of RIKEN" |
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| In search of a new identity for science | |||||||||
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Noyori: In recent years, there have been active discussions on developments in science and technology toward society in the near future, but they err on the side of shortsightedness. We must have a longer-range view as in the title for Paul Gauguin's painting "Where Do We Come from? What Are We? and Where Are We Going?" Toyama: When the concept of "culture" was established as the basis of human intelligence around the 12th century, it comprised three main elements: first, "language," then "nature," including astronomy, arithmetic, and geometry, and lastly "music." This is very suggestive in considering your notion. Researchers are working in pursuit of a broad range of things, from the boundless universe to extremely small particles, which represents the infinite scope of science. In this situation, the very existence of human beings, or how we should live as human beings, seems to have been neglected. I'm very anxious about this trend. Hence, I would like to encourage RIKEN staff to undertake outstanding research following their own intellectual path and cultural pursuits beyond the framework of RIKEN. Noyori: Our outlooks on the universe and life have been established on the basis of findings in basic science. I think that by knowing nature systematically, human beings can understand themselves objectively, realize their identity as short-lived, tiny existences in the universe, and behave in a modest way. This is of paramount importance in our life. You mentioned culture and language a moment ago. And language, essential for dialogues with others, is the very origin of culture. I think "science" is a "language" that is needed for dialogues with nature. In this sense, the roles of natural scientists are significant. Toyama: Talking about the new roles assigned to science in this new era, I would like researchers to unify their individual results and make use of them to contribute to society, rather than to satisfy each other within a closed system. That's our wish as people not involved in advanced scientific research. Noyori: I'm also conscious about the recent strong trends towards fractionalization of researchers' interest, as you said a while ago. I think that in this sense the association between society and basic science must be the first priority. Another thing to emphasize is to make use of thus-compiled scientific knowledge to activate the national economy. Science and technology represent sources of affluence in modern society, and also the fountainhead of the competitive power of each country. The point lies in how to continue to do this. |
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| Keeping "questions" in mind | |||||||||
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Toyama: Your work has already been linked to society and the economy. You have really created one of the most advanced concepts, which is now in actual application in society.Noyori: At the beginning, my work was based on my intellectual curiosity. Through the initial investigations, I discovered a new fact and developed it into a groundbreaking concept. Then what is discovery? I place a greater emphasis on the discovery of a value than on the discovery of a fact. Although what I discovered during my early study was insignificant per se, I realized it to be of significant value and took aim at embodying its potential. The point to focus on in research into natural science resides in how to find a new problem. Unfortunately, however, Japan's current educational system fails to provide programs that enable students to find problems by themselves. The only thing they are requested to do is to find answers. Toyama: Although changes are ongoing, including revision of school programs and provision of thought-oriented lessons in compulsory education, these efforts are encountering difficulties. As the media develop, a wide variety of issues are reported every day. How should we manage the issues? The right answer cannot be found unless we have a broader vision that will serve for human beings and our planet, rather than concentrating the issues into exhaustive, specialized activities through science and technology. Noyori: Yes, I agree. Traditionally, scientific research has relied upon evidence. They have said that research is never scientific without evidence. I think, however, that predicting or forecasting power will be required. Science as is will continue to rely on evidence, but in technology, which is applied science, it is becoming very important to predict or forecast results. How should we consider the issues of the depletion of natural resources, energy, the environment, and medical care? Action should be taken before failures occur and evidence is revealed. I think it is of paramount importance to look far ahead into the future on the basis of scientific evidence. Toyama: That's right. Although politics should play an important part, I strongly encourage scientists to acquire a well-cultivated viewpoint through experience, and to prevent problems and manage the issues. Noyori: Evidence is a form of expressed knowledge. We have grown wiser and wiser by acquiring a more sophisticated form of knowledge, i.e., unexpressed knowledge, over many generations. Thinking about issues and responding to them based solely on expressed knowledge will turn out to be problematic. Toyama: I think we should be really cultured as human beings. Culture is not erudition but it does represent the volition and sagacity to create a better society and live a better life. Since scientists are good at acquiring culture, I encourage them to think about how to behave in order to live a better life and create a better society while being open-minded, capable of being impressed, and watching and enjoying good things. By doing so, the significance, value, and primary objects of research may change. Noyori: In the drama "Man of La Mancha," Don Quixote says, "Truth is an enemy of truth." It is feared that scientists may be prone to adhere to individual facts and lose sight of the universality behind them. I think we must keep in mind the questions "What are human beings? and What is nature?" Toyama: Not only information technology but also nano-technology and biotechnology are fractionalizing into DNA recombination, cloning and the like. Against this background, how should we view ethics? I think ethics is one of the major aspects of culture. This is essentially lacking, and so you and other members of the panel have just begun discussing cloning and other issues. |
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| Objects, things, minds, people | |||||||||
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Noyori: I'm in mortal fear that civilization developed through well-intentioned, sincere efforts by researchers and technicians may force the decline of the human race.I think that in the 21st century, top priority must be given to "a civilization that has respect for culture." Culture represents a spiritual characteristic that has been continually and comprehensively nurtured. We live our lives relying on culture. I think on the other hand that civilization represents a social aspect comprising a combination of culture and human technical or material properties. I believe that human society will never advance in the true sense unless both civilization and culture coexist in good balance. Toyama: From the viewpoint of culture, Japan is highly privileged. In Tunisia, where I visited recently, the heritage of the great prosperity of Carthage is no longer available as a result of the Roman Empire attacking it with fire. By contrast, Japan has a long history of continuous accumulation and a heritage of cultural multiplicity and diversity among the general public. Hence, I think that when Japanese scientists exhibit creativity, our traditions and culture should serve as a hint. I heard that Dr. Minoru Oda, ex-President of RIKEN, carried on his research using a "modulation collimator*3." He devised this unique observatory tool to analyze his findings based on an idea from Japanese culture, and discovered a black hole candidate. I remember that I thought it was a good example when I was a student. Noyori: People say that "science knows no frontiers, but all scientists have their native countries." Scientists' ideas take a deep hold upon culture. Drs. Hideki Yukawa and Shinichiro Tomonaga, both of whom were closely affiliated with RIKEN, were also great men of letters, and I'm sure that their ideas were based upon Japanese culture. Toyama: I think their ideas may have been backed by culture in its truest sense. |
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| Civilization that has respect for culture | |||||||||
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Toyama: Our New National Theatre in Tokyo stages operas, ballets, and theatrical dramas. Last fall, Wagner's opera "The Meistersinger of Nuremberg" met with great public approval. It really deserves mentioning as a great performance. Regarding such great theatrical performances, it is very clear to me that top singers, conductors, and orchestras have to get together and rehearse for many weeks to create their splendid performances. Great art cannot be created without hard training everyday, a strong desire to be top in your field, an enthusiasm for creating something good, and mutual cooperation. Noyori: That requires an outstanding director, doesn't it? Toyama: Yes, that is something I have realized from the depths of my being. I would like to encourage all researchers on RIKEN's big stage to endeavor to reach the world's highest levels in their respective areas, and also to combine their findings to create new value. And I hope that they will be proactively involved in research activities with new goals under your leadership at all costs. Noyori: I hope that RIKEN will be able to create new value by multiplying different things, rather than simply summing them up. This is my dream. 
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Exploring the Mechanism of Neural Circuit Formation
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| Neural cells migrate to the location where they should work | |||
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A neural cell, which is the cell that can generate electricity, extends two kinds of processes from the cell body containing the nucleus. One is a long process called an axon that transduces electrical signals to other cells, and the other is a group of intricately-arborized processes called dendrites that receive electrical signals from other cells. There are tens of billions of these neural cells in the human brain, which are correctly "wired" to each other to form precise neural circuits and fulfill various functions through exchanging electrical signals. In order for that vast number of neural cells to be correctly and efficiently "wired," various kinds of neural cells need to be arranged in their own positions where they can work properly. Furthermore, these cells need to extend their axons and dendrites in the right direction to correctly bind to their counterpart cells. Note that neural cells are not always born in the position where they work. Thus they must migrate accurately from the position where they are born to the position where they work. However, how can they find their way correctly? What is the mechanism by which they extend their axons and dendrites in the right direction to bind to their counterpart neural cells and to form the neural circuits? |
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| Neural cells making a right-angled turn | |||
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Mainly focusing on the cerebellum as a research subject, Dr. Kengaku is making efforts to figure out how neural circuits are formed. The cerebellum consists of roughly five kinds of neural cells including Purkinje cells and granule cells, and they form a three-layered structure composed of a molecular layer, a Purkinje cell layer, and a granule layer (Figure 1). In the molecular layer, the axons of granule cells called parallel fibers are located perpendicular to the fan-shaped dendrites of the Purkinje cells. The cell bodies of the Purkinje cells are arranged in the layer beneath the molecular layer, and the cell bodies of the granule cells in the layer beneath the Purkinje cell layer. "The cerebellum has the structure of a beautiful fabric," says Dr. Kengaku. When neural circuits in the cerebellum are formed, the cell body of a granule cell extends its axon from both sides, and moves in parallel in the molecular layer, thus creating a parallel fiber. After a short while the cell body bends at a right angle and descends down to the granule layer through the Purkinje cell layer (Figure 2). Dr. Kengaku and her team members studied the phenomenon in which granule cells bend at right angles. "When newly-born granule cells are taken and cultivated in a Petri dish, the granule cells extend their axons and bend at right angles. Thus it is reasonable to conclude that the granule cells have a built-in genetic mechanism that enables the cells to bend at right angles. To figure out the mechanism, we tried to look for proteins that are not expressed in the granule cells before making the right-angled turn, but are expressed immediately after the turn." In 2002, Dr. Kengaku and her team members succeeded in finding the protein "DNER." However, subsequent studies revealed that DNER is highly expressed in Purkinje cells rather than granule cells. DNER is not the protein that is necessary to make granule cells bend at right angles, but the protein does seem to play some important role in the Purkinje cells. DNER is a membrane protein embedded in a cell membrane, and part of it protrudes outward through the membrane surface. From the molecular structure of the protruding part, it is estimated that DNER can bind to Notch proteins. Notch is also a membrane protein and is known to play an important role as a receptor that receives information from outside of the cells when the body of any animal, including insects and vertebrates, is created. Notch is expressed in the neural stem cells that generate neural cells. When neural cells are generated by the neural stem cells, a kind of protein protrudes from their cell membranes, which in turn binds to Notch of the surrounding neural stem cells to convey information, enabling the stem cells to differentiate into glia cells instead of neural cells. Glia cell is a generic term for the cells that are not neural cells, but which form brain and neural systems. They are supportive of the functions of the neural cells. It is estimated that the human brain contains up to about 10 times more glia cells than neural cells. "Early differentiation of cells into neural cells affects the Notch in the surrounding neural stem cells, issuing a directive for them to change into glia cells because sufficient numbers of neural cells have been produced. Thus the numbers of neural and glia cells are balanced. It is known through gene manipulation experiments with insects and mice that when the functions of Notch are inhibited, they will die early in development."
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| DNER prompts the growth of glia cells | |||
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It is after the differentiation from neural stem cells into neural and glia cells is completed that DNER is expressed. Then how does DNER function? Dr. Kengaku and her team members have found out that DNER in Purkinje cells binds to Notch of the surrounding glia cells called Bergmann glia, and conveys information (Figure 3). Furthermore they confirmed that processes of the Bergmann glia cells are poorly grown in DNER-deficient mice, and that the neural circuits in the cerebellum are remarkably underdeveloped. Purkinje cells extend their dendrites into the molecular layer to receive information from the parallel fibers. At that time, the Purkinje cells produce DNER in abundance, which binds to the Notch of Bergmann glia cells to convey information and prompts their growth and process formation. It is considered that the Purkinje cells extend their dendrites into the molecular layer based on the processes of the Bergmann glia cells. Furthermore it seems that the processes of the Bergmann glia cells also serve as a basis for movement activities when granule cells bend at right angles and descend down into the granule layer. "The genetic program in the cell that determines what kind of processes the individual neural cell extends, has already been implemented according to the kind of cell, such as a granule cell or Purkinje cell. However, external information is necessary for the cell to decide in which direction it should move or should extend its processes. The cell is either drawn to or repels proteins secreted by surrounding cells or remote cells, thus changing direction." However, note that the brain is compactly filled with neural cells and processes of glia cells. Generation of neural cells needs some kind of interaction by which some cells fight for a space or yield their space to other cells, or some cells assist of other cells to extend their processes. Here, the communication at cell-to-cell contact points between neighboring cells, such as DNER and Notch, is also considered very important. "So far, DNER is found only in vertebrates. As brain cells voluminously increased in kind, it is very likely that they needed the communication at cell-to-cell contact points between neighboring cells, as is observed with DNER when it finely adjusts process patterns." Two communication methods are used between the cells in the cerebellum. One is the secretory type in which information is widely transmitted, and the other is the contact type in which detailed directives are issued to neighboring cells. The cells use these methods in combination to communicate and form high-performance neural circuits. DNER expression is also observed in the neural cells in the cerebral cortex. Dr. Kengaku and her team members are pursuing their studies to determine whether DNER is also adjusting process formation in the cerebral cortex.
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| Contribution to treatment for malignant nerve system diseases | |||
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"The first thing we investigated, when we found DNER, was whether or not the gene that produces this protein is a causative gene for neurological diseases. Unfortunately no relevance was found, but some studies on neural circuit formation can contribute to finding the causative genes for incurable neurological diseases, the causes of which are still unknown and the treatments for which have not yet been found. It is known that mental retardation, epilepsy, and disorder of movement occur due to migration defects of the neural cells causing unsuccessful formation of the laminar structure. Furthermore, failed dendrite formation may be a cause of malignant nerve system diseases. Finding the causative genes for these diseases will pave the way to a permanent cure. Studies on neural circuit formation are also expected to contribute to regeneration medicine for the brain. These days, studies on tissue regeneration are being actively conducted. Some examples are the transplantation of neural stem cells into non-functioning brain or spinal cord tissue. "In some cases, mere transplantation of neural stem cells contributes to a partial functional recovery. However, full functional recovery requires the regeneration of neural circuits. We are sure that our studies can contribute to providing the basic knowledge for this." |
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| The age of rediscovery of phenomena | |||
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How will Dr. Kengaku and her team members try to clear up their original question about the mechanism with which the granule cells in the cerebellum bend at right angles? "We are going back to observing the phenomena. Granule cells may become round and grope for the direction to proceed before they bend at right angles, or suddenly make a turn by extending a long process in a certain direction. Observation of these phenomena enables us to figure out to some degree the mechanism of the right-angled turn." Dr. Kengaku goes on, "We are in the age of the rediscovery of phenomena." "In the past, we have observed the traces of movement of dead cells in a slice of brain tissue fixed by chemicals. However, advanced microscopic techniques have allowed us to observe a thick slice of brain tissue in culture, directly observe the surface layer of a living animals's brain, and to obtain highly-magnified views of cells moving in the tissue. Many questions about neural circuit formation have been clarified, but we do not have enough knowledge about how the cells move dynamically. We will be able to find out many interesting phenomena and come up with new questions through detailed observation of cell behavior in the brain tissue. This will surely serve to clarify the whole picture of neural circuit formation." Live as if you were to die tomorrow. Learn as if you were to live forever-Dr. Kengaku adheres to this creed. "I discovered this quote from Mahatma Gandhi when I was at graduate school. Neural circuits are really beautiful when observed under a microscope. Furthermore the beauty is significant because it must be based on the ultimate form of the neural circuit to fulfill the function. We want to explore this beautiful magic. So far we have been successful in making some small discoveries, but we definitely do not feel we have reached the goal. There is no end to learning, and our time for research is limited. We are pursuing our studies with the desire to get even one step closer to our goal each day." 
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"The brain's neural circuits are really beautiful and impressive when observed under a microscope. How have such beautiful things been created? We want to know what the mechanism is," says Dr. Mineko Kengaku, Laboratory Head. When a brain is created, tens of billions of nerve cells of various kinds are born, which then migrate to the location where they should work, extend their dendrites and axons in the right direction, and bond to other nerve cells to form nerve circuits. The Laboratory for Neural Cell Polarity is exploring the mechanism of neural circuit formation, mainly focusing on the cerebellum as its research subject. Their study results are expected to contribute to therapeutic neurology, in which cells are transplanted to repair neural circuits, and to contribute to cause analysis and treatment of incurable neurological diseases.
