1. Purpose of the National Institute for Physiological Sciences
2. Mission of the National Institute for Physiological Sciences
3. Current Pillars of Research at the National Institute for Physiological Sciences
4. Collaborative Use of Resources and Research at the National Institute for Physiological Sciences
5. Fostering Young Physiologists and Students of Brain Science
6. Future Directions of the National Institute for Physiological Sciences Operation
Research into fundamental human physiology elucidates the vital activities of the human body and their underlying mechanisms. Along with giving people scientific guidance on keeping a healthy mind and body, this field of study provides information that forms a foundation for elucidating the mechanisms of the pathogenesis of diseases. The National Institute for Physiological Sciences (NIPS: SEIRIKEN in Japanese) of the National Institutes of Natural Sciences (NINS) is a unique organization, called Inter-University Research Institute, that fosters collaborations among universities in research and education into fundamental human physiology. The institute adheres to the principles of the dictum announced when it was established, to “Promote research in physiology on the molecular, cellular, organ, and individual levels, with the purpose of ultimately comprehensively elucidating the functions of the human body” (Fig. 1).
Humans can be viewed as “thinking reeds (by Blaise Pascal)” due to their well-developed brains. The human brain issues commands and makes adjustments to organs and tissues throughout the body, as well as tying together their bidirectional interrelationships and maintaining homeostasis. Therefore, basic research on the roles of the brain and nervous system in the human body and in homeostasis has a vital position in physiology. Because of this, the National Institute for Physiological Sciences currently focuses its research on the brain, nervous system, and homeostasis (Fig. 1). We intend to move this research forward, with a focus on promoting integrative studies based on general physiological (molecular and cell physiology plus biophysics) research at the molecular and cellular levels, and their significance within the human body.
As an Inter-University Research Institute which is an organization that promotes collaboration and shared utilization of resources among universities, the National Institute for Physiological Sciences has a threefold mission, and intends to continue working in these directions in the future.
To achieve its first mission, the National Institute for Physiological Sciences is promoting research on the functions of the brain and human body, and their underlying mechanisms, based on the five pillars described below (Fig. 2).
—Integrating research at levels from molecules and supermolecules to cells—
The workings (functions) of cells are supported by the actions and associations of groups of molecules. Research at the National Institute for Physiological Sciences is aiming to elucidate the details of these processes.
In particular, the structures, functions, actions and control mechanisms of channels, receptors, sensors, enzymes, and other functional proteins and complexes of these molecules (supermolecules) are being analyzed, their integration to cell functions is being carried out, and the mechanisms of pathologies and cell death are being elucidated based on their abnormalities and failures. In addition, the functional molecules related to the differentiation and migration of cells in the nervous system, the formation of brain structures and so on are being identified, and their mechanisms of action are being elucidated. Also, pathologies caused by abnormalities in these molecules are being clarified.
—Integrating research at levels from cells to tissues, organs and whole organisms, mainly using mice and rats—
Homeostasis in the living body and information processing in the brain play crucial roles in the functioning of the human body, and are inseparably linked with one another. The National Institute for Physiological Sciences is thus putting great effort into elucidating their underlying mechanisms.
In particular, analyses of the genetic foundation, the environmental dependency, and the development and adaptation (abnormalities) of homeostasis in pain-related behavior, feeding behavior, sleep and arousal, body temperature, and metabolic adjustments are being carried out. Moreover, elucidation of the plasticity of the brain (and pathologies caused by abnormalities) based on analyses of the synaptic transmission mechanism, the basic information-processing functions of the network of neural circuits, and the relationships within the neuron-glia-blood vessel network, is being carried out, mostly using mice and rats.
—Integrating research at levels from the interactions of the brain and other organs to whole organisms, mainly using the Japanese macaque—
Macaques, such as the Japanese macaque, and higher primates exhibit many brain functions that are homologous to those of humans. The National Institute for Physiological Sciences is thus putting great effort into brain research using the Japanese macaque.
In particular, research using the Japanese macaque (and other macaques) on the brain, and its interactions with other sensory organs and the motor apparatus, is indispensable for elucidating the functions of cognitive activities such as vision, hearing, smell and other senses, attention, voluntary movement, and so on. This basic research is predicted to lead to an improved understanding of Parkinson's disease and other neurological disorders, the elucidation of the recovery mechanisms following damage to the spinal cord, the cerebral cortex, and primary visual areas, and the development of basic techniques for brain-machine interfaces (BMIs).
—Integrating research at levels from brain functions to interrelations between the body and the mind, mainly in humans—
Most higher-order brain functions have only developed in humans. At the National Institute for Physiological Sciences, brain research with human subjects is being developed using non-invasive methods.
In particular, research on higher-order cognitive activities such as face recognition, various types of sensory perception, integration of multiple senses, language, emotion, memory, and social cognition is being accomplished only by non-invasive methods in humans. The ties between the human mind and the body will be elucidated by this research. In addition, the period of sensibility (critical period) in the process of human psychological development is being clarified, and basic information to improve our understanding of abnormalities in brain and neural development is being provided.
—Integrating research at levels from genes and molecules to the brain and whole organisms, and visualization of their temporal-spatial transformations—
The National Institute for Physiological Sciences is a unique Inter-University Research Institute equipped with various imaging devices that can be used on the human body and brain. Efforts are being made to elucidate the functions of the brain and body, and their underlying mechanisms, based on data at the molecular level and four-dimensional (spatial plus temporal) imaging of the relationships among the processes of development and pathological change.
Hereafter, the development of specialized imaging and correlation methods to explore the workings at each hierarchical level will be indispensable for integration at a level greater than the molecular, cellular, and cerebral scales (Fig. 3). In particular, making the neural currents that carry neural information visible non-invasively over a wide area is novel territory, even though its importance has been recognized previously. New functional magnetic resonance imaging (fMRI) and “micro”-MRI (μMRI)⁄ “micro”-magnetoencephalography (μMEG) technologies, which have sub-millimeter resolutions, are close to achieving this goal. Along with this research, a multiphoton laser-scanning microscopy method that makes non-fixed unstained samples visible at the sub-micron level is being developed. Furthermore, a ultra-low-temperature phase-contrast high-voltage electron microscope (HVEM) that can give nanometer resolution to laser microscope samples without altering them is being developed in connection with this work. At the same time, as regards correlation methods connected to the human brain, an MRI molecular probe method is being developed that makes molecular imaging possible. Through integrated time recording of this three-dimensional imaging (called “four-dimensional integrated imaging”), the quantification of brain functions including mental activity, integration starting at the molecular level, and real-time visualization will be achieved.
To pursue its second mission, the National Institute for Physiological Sciences promotes the following five pillars of collaborative use and research.
The following resources will be provided for “Collaborative Use and Research (Kyodou-Riyou Kenkyu)” in Japan, and for collaborative research within the “Japan-US Brain Research Collaborative Program (Nichi-Bei Noh)”: an HVEM, which is a unique equipment specialized in biological studies with an extremely high level of performance; an MEG for use with the entire head, which has been specifically modified for brain science research; a 3 Tesla fMRI for physiological image analysis that can make measurements on humans and Japanese macaques; and other advanced large-scale imaging apparatus with superior features that are not deployed at other research institutions in Japan.
The latest imaging equipment that the National Institute for Physiological Sciences has developed on its own, such as a two-photon laser-scanning microscope capable of making the detailed morphology of the living brain visible in real time at the greatest depth available worldwide, and a ultra-low-temperature phase-contrast electron microscope that is the first to allow micro-morphological observations in unfixed unstained ice-packed samples, and peripheral technologies for these devices, are openly available to the community. Their use is implemented through public advertisements targeted at researchers nationwide in a special form of “Planned Collaborative Research (Keikaku Kyodou Kenkyu)”.
The imaging technology, facilities, and devices possessed by the National Institute for Physiological Sciences are also available broadly for “General Collaborative Research (Ippan Kyodou Kenkyu)” implemented by public advertisements targeted at researchers at national, public, and private universities, as well as research institutions nationwide. The institute intends to help to find solutions to newly discovered problems, and to foster emerging research.
Data from the leading-edge and high-level research technology, research techniques, and research software of the National Institute for Physiological Sciences are being processed within its databases. In addition, it has a database of accurate educational information about the functions of the brain and body and their mechanisms. These databases are open to the public via the institute's website, and are being provided for collaborative use.
Genetically modified (or gene-targeted) mice and rats will be produced and supplied for “Planned Collaborative Research”. Furthermore, as the core institution for the “National Bioresource (NBR) Project for the Japanese Macaque”, the institute regularly supplies Japanese macaques to researchers nationwide as experimental animals for brain science research.
The institute's various meeting rooms and lodging facilities will be available to collaborative users and researchers, so that research meetings, international workshops, and international symposia can be held via public advertisement and investigative selection for researchers at national, public, and private universities, as well as research institutions nationwide. The participation of new personnel in the fields of physiology and neuroscience is being promoted through this activity. Along with the further promotion of nationwide and international collaborative research, a contribution will be made to the establishment of new fields by researchers nationwide.
To address the central questions in brain research about “how the brain is formed and what is the principles of its operation”, collaboration involving researchers in many different fields is indispensable. To promote brain science research through collaborative projects across different fields, the institute is supporting a central site for cross-disciplinary collaborative research networks of brain science researchers nationwide (Fig. 4).
At present, useful examples of attempts to realize practical collaborations between different fields can be cited, including “research on and development of brain information extraction and expression” that carries out basic research vital for the development of BMIs through “medical and industrial collaboration”, and “developmental basic research on primate brains” that is promoting the development of gene-expression technology for Japanese macaque brains. Furthermore, the institute intends to form a central site for cross-disciplinary collaborative research aimed at elucidating “the interactions between the body and the mind”, such as emotions and social cognition, using an approach that “integrates the humanities and science”, as well as developing new four-dimensional brain and biomolecular imaging techniques.
In addition, the National Institute for Physiological Sciences constitutes one wing of the “Okazaki Institute for Integrative Bioscience”, and promotes collaborative research that brings together different fields for research on the analysis of membrane protein structures and functions. Furthermore, by taking responsibility for “Internal Inter-Institute Collaborations: Interdisciplinary Integrative Joint Research on Biomolecule Sensors”, work that brings together different disciplines will also be promoted in this research area.
To further its third mission, the National Institute for Physiological Sciences is promoting work in the following five areas.
Making use of the infrastructure at the disposal of the institute as a basic division of the Graduate University for Advanced Studies (SOKENDAI), and the abundance of teachers that allows one-to-one tuition, continuous 5-year graduate school education will be offered to foster international researchers in the physiological sciences and to supply personnel to the nation and the world. Furthermore, the institute will train and give guidance to graduate students entrusted to us by other universities.
To help young students of brain science and neuroscience to become familiar with a variety of fields, the institute will serve as a central site for bringing together outstanding researchers from many different fields (basic neuroscience, molecular biology and neurobiology, engineering, computational neuroscience, computational science, clinical medicine, psychology, and so on), who are based in national, public, and private universities, as well as research institutions nationwide. We will foster young researchers collaborating across different fields in a network that extends beyond the university framework, and promote programs that support brain science education for graduate students (Fig. 4). Furthermore, based on the results and evaluations of this program —and, if necessary, after adjustments based on opinions expressed at universities nationwide— the institute intends to establish “School of Brain and Neuroscience” at the Graduate University of Advanced Studies (SOKENDAI) as a continuation of this line of development.
Along with the “Physiological Science Experimental Technique Training Course” held every summer, a “Biomolecular Sensor Lecture Course” will be held. In addition, a “Brain Science Experiment Techniques for Collaboration in Different Fields Lecture Course” and a related “Training Course” will be held in the near future. Hence, the institute is working in a variety of ways to educate and foster young researchers, graduate students, and undergraduate students nationwide.
At least one postdoc of the National Institute for Physiological Sciences will be assigned to each research division, and the numbers of research associates, collaborating fellows, and other young researchers employed will be increased. Support is given to young researchers through research funds offered via annual public advertisements for collaborations, as well as travel funds for presenting papers both in Japan and overseas. Similar young researcher support is given to postdocs employed by funds from Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Society for the Promotion of Science (JSPS) and Japan Science and Technology Corporation (JST).
Collaborations with the “Class by a visiting professor called Catering Class (Demae-Jugyo)” at elementary and junior high schools in Okazaki, and the “Super Science High School” at Okazaki High School, as well as efforts heading up the “National Institute (Kokken) Seminar” targeting science teachers at elementary and junior high schools in Okazaki are being continued, and work is also being done to disseminate academic information on the physiological sciences and brain science. Furthermore, to provide support concerning “the functions of the human body and their mechanisms”, a summer school will be held for teachers involved in elementary, junior high, and high school education nationwide. In addition, collaboration with and support for partnership activities between university educators and elementary, junior high, and high school teachers is being provided nationwide as one aspect of “Inter-University Collaborative Use and Research” activity. The institute hopes to discover and develop children as future young researchers through these endeavors.
The National Institute for Physiological Sciences will take account of the following five points in future operations, in order to fulfill its mission as described above and to meet its goals.
1) In its approach to research that integrates levels from molecules to organisms, the National Institute for Physiological Sciences places importance on free thinking by individual researchers. Even in its policies of promoting research in a manner that identifies problems, carrying out collaborative research, and bringing in proposals on newly discovered themes from national, public, and private universities, and research institutions nationwide, the ultimate goal is to promote research in a “bottom-up” form.
2) Essentially, physiology is not a discrete subject area, but rather a scholarly field that should be renewed moment-by-moment through exchanges with many different disciplines. In fact, most previous research that has been awarded the “Nobel Prize for Physiology or Medicine” has been achieved through collaborations between different fields, and by introducing research and experimental techniques from other areas. Therefore, the road to future developments for physiology and for the National Institute for Physiological Sciences is expected to open up new areas through exchanges with other fields. Hereafter, a national network for collaboration across disciplines will be constructed, and the institute intends to be its core site (Fig. 4). As a point of contact in collaborations across different fields, the institute intends to promote cross-disciplinary collaborative research not only at the molecular level, such as “membrane protein research” and “biomolecular sensor research”, but also in the field of imaging science through “four-dimensional brain and biomolecular imaging method development”, and more broadly through the “elucidation of the formation of the brain and its operating principles”. In particular, this includes “basic research for BMI development”, “development of Japanese macaque brain gene expression techniques”, and “basic research on the neurology of social cognition”. Furthermore, the institute intends to promote progress in brain research in marmosets, for which gene modification is possible, in order to help solve the problems raised by research on Japanese macaques.
3) To non-invasively study the human brain, the National Institute for Physiological Sciences has introduced and deployed devices for advanced imaging by MEG, fMRI, near-infrared spectroscopy (NIRS), and so on. In addition, a ultra-low-temperature phase-contrast electron microscope technique has been successfully developed, and further progress is being made to develop a ultra-low-temperature phase-contrast HVEM technique. Technology has also been developed that allows brain imaging in a living body at the greatest depth possible worldwide, using two-photon laser-scanning microscopy. This technique is also being developed further. Additionally, progress is being made on a new multiphoton laser-scanning microscope capable of imaging any tissue or organ inside the human body. Hereafter, the institute intends to develop an MRI molecular probe to allow non-invasive imaging inside the bodies of humans and animals, as well as new fMRI and MEG techniques that can measure brain and neural circuit activity with a sub-millimeter resolution. Through these developments, and the deployment and collaborative use of various devices and techniques, the National Institute for Physiological Sciences intends to establish itself as a large national center for molecular imaging in the living brain and body (Fig. 3).
4) Much effort is being made to disseminate academic information and the implementation of the three missions of the National Institute for Physiological Sciences as well as to carry out public relations activities, mainly through the “Public Relations Promotion Office”, so that there is transparency both for the community and for the public. The initial target of this activity is the research community, followed by graduate students and young researchers (including those in other fields), then university students studying physiology, teachers of science, health and physical education at elementary, junior high, and high schools (in order to foster future scientists), and finally the public taxpayers. The institute's website provides information at multiple levels to target these groups, and the institute intends to disseminate academic information on the workings of the human body and brain, and their underlying mechanisms, which is up-to-date, accurate, and easy to understand. To make these publications more effective and visually appealing, the institute is moving forward with work to create databases containing various types of research, educational, and technical information, which is centered on the activities of the “Technical Division” and the “Office for Inspection and Collaborative Materials”. Furthermore, the institute aims to construct four-dimensional images of the human body in which a time axis is added to the spatial axis as a step towards this goal, through work that centers on the “Technical Division”, the “Office for Inspection and Collaborative Materials”, and the “Public Relations Promotion Office”.
5) The National Institute for Physiological Sciences is supported by a community of researchers across a wide range of physiological science, brain science, and neurological science fields. The operations of the institute will continue to be carried out based on the ideas of this community. Furthermore, even in future academic research, and in the establishment of projects and the development of new methods for obtaining research funds according to this community of researchers, the National Institute for Physiological Sciences intends to play a role as a place and platform for consensus forming, as well as acting as the hub organization.
The mission of the National Institute for Physiological Sciences is not achieved by researchers alone, but rather by collaborations among the many staff members that make up the institute, including those working in technical and office support roles, graduate students, and so. The institute intends to operate openly through a wide community of researchers, creating an active and satisfying work environment in which there is collaboration among members, each of whom has awareness and pride in his or her job.
In the 30 years since the establishment of the National Institute for Physiological Sciences, steady development has been made and superior results have been achieved through the multifaceted and strong support of many senior associates and all within the community of researchers. As a result, the institute has been highly rated internationally, as illustrated by the following congratulatory words from Professor Erwin Neher (1991 Nobel Prize winner for Physiology or Medicine; Fig. 5): “A National Institute of Physiology — that is what many physiologists worldwide are dreaming of. Let me congratulate the Colleagues in Japan on the occasion of the 30th anniversary of SEIRIKEN. You have achieved that dream a long time ago and have managed over 30 years to turn it into an excellent and internationally shining research institution.” With this legacy and these results as a foundation, we are spurred on to continue to steadily develop the National Institute for Physiological Sciences as a place of research that will shine a light on the world in the future.