Summary of Research Center Project*Briefly describe the general plan of your project (Compile in English within 2 pages.)

Center name: Nano Life Science Institute (NanoLSI)（Within 15 words）
Host institution: Kanazawa University
Head of host institution: Koetsu Yamazaki, President of Kanazawa University（Name, Affiliation）
Prospective Center director: Takeshi Fukuma, Professor of Kanazawa University（Name, Affiliation）
Prospective Administrative director: Seizo Morita, Professor Emeritus of Osaka University（Name,
Affiliation）
1) Overall Image of Your Center
We combine the world’s top bio-scanning probe microscopy (SPM) and supramolecular chemistry techniques to develop“nano-endoscopic techniques” that can directly image, analyze, and manipulate the nano-dynamics of proteins and nucleic
acids on the surface of or inside cells. With the developed nanoprobe technologies and multi-scale simulation techniques,
we will achieve nano-level understanding of basic cellular functions and their cancer-specific abnormalities. Based on thetechniques developed and knowledge gained, we establish a new academic field, “nano-probe life science,” where we aim
to achieve fundamental understandings on various life phenomena using advanced nanoprobe technologies.
2) Research Activities
1. Development of imaging techniques for intra- and extracellular nano-dynamics
Ando improved the speed of atomic force microscopy (AFM) by several hundred-fold to develop high-speed AFM,
enabling imaging protein dynamics at nanoscale resolution in solution. Fukuma developed liquid-environment frequency
modulation AFM, enabling true atomic-resolution imaging in liquids. Based on this technique, he also developed threedimensional AFM (3D-AFM) and achieved subnanometer-scale imaging of the 3D distribution of fluctuating water andsurface structures at solid-liquid interfaces. Korchev established the basics for scanning ion conductance microscopy(SICM), an SPM technique that utilizes a nano-pipette, and was the first to demonstrate its effectiveness in live cell imaging.
These researchers designed and fabricated their unique SPM devices from scratch, and have used them for various nanobiological measurements that were not possible using the preexisting techniques. In NanoLSI, we will foster this ability tocreate innovative nano-probe techniques. First, we will develop high-speed SICM by combining high-speed AFM and
SICM to image the nano-dynamics of cellular structures. We will also develop high-speed 3D-AFM by combining 3DAFM and high-speed AFM to image 3D distribution of signaling factors that interact with or pass through the receptors orchannel proteins on the cell surface. We will combine this technique with Korchev’s nano-fabrication technique to develop
a nano-endoscopic imaging technique, in which a long glass probe with a high aspect ratio is scanned in a 3D space (insideof a cell). The force or ion current on the probe apex is recorded to visualize various nano-dynamic events occuring inside
the cell, including rearrangement of molecular assemblies and material transportation.
2. Development of nano-endoscopic analysis and manipulation techniques
By combining the supramolecular chemistry techniques developed by Ogoshi, Maeda, Akine, and MacLachlan with theaforementioned bio-SPM techniques, we will develop nano-endoscopic analysis and manipulation techniques. We will
design and synthesize molecular sensors that undergo a structural transformation in response to changes in pH, orconcentration of oxygen species or metabolites in the liquid environment. These molecular sensors will be integrated at theapex of a nano-pipette. The nano-pipette is scanned in the intra- and extracellular spaces with high-speed 3D-AFM to

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measure the nanoscale distribution of pH and oxygen concentration at the surface of or inside the cell. Furthermore, wewill design and synthesize molecular machines that undergo structural changes in response to external stimuli such astemperature, electric potential, or light and let them act on intracellular or extracellular proteins in two ways. In the first
method, molecular machines with a recognition part for a target protein are injected by a nano-pipette. In the other method,a molecular machine is attached to the apex of an AFM probe through a linker molecule and the probe position is controlled
such that the molecular machine can act on a target protein. We will measure the dynamic responses of intracellular andextracellular molecules and cells induced by these nano-endoscopic manipulations using the nano-endoscopic imaging andanalysis techniques.
3. Fundamental understanding of basic cellular functions and their cancer-specific abnormalities
We utilize nanoendoscopic technologies for fundamental understanding of basic cellular functions. To do so, we
image, analyze and manipulate nano-dynamics of unlabeled nucleic acids, metabolites, proteins and organelles inboth normal and cancer cells. This will also allow us to understand the mechanisms of cancer-specific abnormalities.
Hirao aims to elucidate the essential nature of stem cells by precise measurement of the redox state and the
distribution of nutrients such as glucose and amino acids in normal and cancer cells. To understand cell type-specificgene expression patterns, chromatin domains will be visualized. Since global changes in the epigenetic landscape area hallmark of cancer, we will extend this approach to cancer cells. Matsumoto elucidates the structural changes ingrowth factor receptor activation involved in cell proliferation and investigates aberrant activation mechanisms of mutant
receptors found in cancer patients. Hanayama elucidates the principle mechanism of action of exosomes and develop
technique to control exosomes. Oshima investigates dynamic changes of intracellular ultrastructures at nanoscale in
the intestinal stem cells and cancer cells. Yano applies AFM to analysis of the dynamics of molecules involved inresistance signals and search for therapeutic targets. Thus, we shall build a path to the future of life science bycollaborations with experts in cell biology, cancer biology and nanotechnology.
3) Interdisciplinary Research
We combine the world’s top bio-SPM and supramolecular chemistry techniques to develop innovative nano-probe
techniques, including nano-endoscopy. With these techniques and multiscale simulations, we fundamentally understandthe mechanisms of basic cellular functions and their cancer-specific abnormalities. In this way, we combine our expertisein nanometrology, supramolecular chemistry, mathematical/computational sciences, and medical/pharmaceutical sciences
to establish a novel academic research field, “nano-probe life science.”
4) International Research Environment
Kanazawa University will locate world-class researchers as PIs and recruit young researchers by radically and flexibly
utilizing the personnel and administrative systems. The university will establish a support system so that overseas
researchers can exert their full abilities and have a comfortable stay in Kanazawa.
5) Center Management
This center will be established in the Institute for Frontier Science Initiative; it will be qualified for personal and capitalsource investment. Center Director will have the authority to decide the budget and administrative affairs of the Center.

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Research Center ProjectCenter name: Nano Life Science Institute (NanoLSI)（Within 15 words）
Host institution: Kanazawa University
Head of host institution: Koetsu Yamazaki, President of Kanazawa University（Name, Affiliation）
Prospective center director: Takeshi Fukuma, Professor of Kanazawa University（Name, Affiliation）
Appendix 1

For the prospective center director, fill in the “biographical sketch of prospective center director.”

Appendix 2

Provide a reference (recommendation) for the prospective center director (free format not subject to the 3-page limitation).

Prospective administrative director: Seizo Morita, Professor Emeritus of Osaka University（Name,
Affiliation）
Appendix 3

For the prospective administrative director, fill in the “biographical sketch of the prospective administrative director.”

1) Overall Image of Your Center* Concisely describe your institute’s identity and provide its mission statement as a WPI center.

1. Mission statement
We combine the world’s top bio-scanning probe microscopy (SPM) and supramolecular chemistry techniques todevelop “nano-endoscopic techniques” that allow us to directly image, analyze, and manipulate the nano-dynamics
of proteins and nucleic acids on the cell surface or inside the cell. Furthermore, we use these techniques and multiscale simulation techniques in a complementary fashion to elucidate the various molecular and cellular dynamics
by comparing normal and cancer cells. Based on the developed techniques and knowledge gained through thisprocess, we establish a new academic field, “nano-probe life science”, which aims to fundamentally understandand control various life phenomena, including development, disease and aging.
2. Center identity
The most salient feature of NanoLSI is our world’s top bio-SPM techniques for nanoscale live imaging ofmolecular and cellular dynamics, which offer distinctive advantages over other bio-imaging techniques. For
example, electron microscopy allows one to image the static ultrastructure of proteins in vacuum, but not to directly
image protein dynamics in solution. Live imaging by fluorescence microscopy visualizes the positions offluorescence-labeled molecules, but does not allow direct imaging of dynamic changes in the protein structure or
the positions of unlabeled molecules. To overcome these limitations, Ando developed the high-speed atomic force
microscope (AFM) and made it possible to directly image the dynamic structural changes of unlabeled protein
molecules in solution (PNAS 2001, 544 citations). In addition, Fukuma developed the liquid-environment
frequency modulation AFM (RSI 2005, 197 citations) and achieved true atomic-resolution imaging even insolution. Based on this technique, he also developed three-dimensional AFM (3D-AFM) (PRL 2010, 156 citations)and made it possible to visualize 3D distribution of water and molecular chains at subnanometer resolution. Basedon these achievements, Ando, Fukuma and their group members have led the progress in the bio-SPM research
field. Therefore, we are confident that we have gathered the world’s best members to launch a center of excellenceaiming at creating novel bio-SPM techniques for visualizing nano-dynamics of molecules and cells in solution.
To accomplish our mission, NanoLSI has attracted many world’s top class scientists with a wealth of experiencein oncology, supramolecular chemistry, and mathematical/computing science. The Cancer Research Institute ofKanazawa University, the only joint usage/research center in Japan solely focusing on cancer research, has amassed
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superb achievements in the study of cancer stem cells, tumor microenvironment, and molecularly targeted therapy,
including the identification of critical molecules involved in leukemia stem cell regulation (Hirao et al., Nature
2010, 297 citations). Kanazawa University has also garnered global attention for its advances in supramolecularchemistry, such as the development of novel pillar[n]arenes (Ogoshi et al., JACS 2008, 528 citations). Additionally,
we have collaborations with outstanding scientists at prestigious universities, including the Adam Foster’s groupat Aalto University, one of the world’s few research groups with a strong track record in AFM simulation in liquids,
and the Alexander Mikhailov’s group at Fritz Haber Institute that has made great strides in the simulation ofcomplex systems ranging from proteins to cell membranes. The contributions of these scientists will help us inbuilding an in-depth understanding of life phenomena based on the results of nanoscale experiments.
Our greatest, defining strengths are our many accomplished scientists and research achievements across all core
disciplines necessary for executing our mission—nanometrology, oncology, supramolecular chemistry, andmathematical/computational science. Another advantage that sets us apart is that the majority of our principal
investigators (PIs) are only in their forties, meaning that we can continue to lead the new science of “nano-probe
life science”.
2) Research Activities
2) -1 Research field* Write in the target research field(s)* Describe the importance of the target research field(s), including the domestic and international R&D trends in the field(s) and scientificand/or social significance.
* Describe the value of carrying out research in the field(s) as a WPI center (e.g., Japan’s advantages, global impact on science and/or
society, future prospects)* If there are other centers either in Japan or overseas advancing research in fields similar to the center’s field(s), please list them. (upto 5 organizations)* Provide a list of 10 English-written papers that are closely related to the center’s project and enclose the PDF files of those papers.
Label this bundle of documents “Appendix 8.”

1. Name of the target research field: Nano-probe Life Science
We establish a novel interdisciplinary research field “nano-probe life science”, where we develop and utilize nanoprobe techniques for directly imaging, analyzing and manipulating dynamic behaviors of biomolecules and cells
at nanoscale resolution under physiological environments. This new approach will promote the fundamental
understanding of the mechanisms underlying diverse life phenomena such as diseases and aging.
2. Importance of the target research field
Domestic/global trends and key challenges in this field
To achieve our mission outlined above, we will seek to resolve the following challenges in the core disciplines ofnanometrology, supramolecular chemistry, and oncology.
(1) Challenges in nanometrology: Nanoscale imaging, analysis, and manipulation of molecular dynamics atthe periphery and inside of cells
Advances in super-resolution fluorescence microscopy have allowed nanoscale imaging dynamics of fluorescencelabeled molecules occuring in the intra-/extracellular spaces (Betzig et al., Science, 346 (2014) 439); however, thistechnique does not support direct imaging of the target molecules’ structural changes or the position of the many
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unlabeled molecules. Furthermore, fluorescent tags may interfere with biomolecular function. The microscopic
imaging of living cells with advanced atmospheric scanning electron microscopy and polymer membranes havebegun to emerge (Takaku et al., PNAS, 110 (2013) 7633), but this approach offers optimal resolution only in thetens of nanometers, and thus, is insufficient to reveal detailed molecular dynamics. Moreover, the electron beams
can damage the molecules of interest. The high-speed AFM developed by Ando at NanoLSI has been used tovisualize the nano-dynamics of aquaporins on the live bacteria having a relatively hard surface (Yamashita et al.,JMB 422 (2012) 300), but it has not yet been successfully used to measure molecular dynamics on the much softer
surfaces of eukaryotic cells. Although scanning ion-conductance microscopy (SICM) has been used to image
endocytosis and to locate ion channels and receptors on eukaryotic cell surfaces (Korchev et al., Science,
327(2010) 1653), the optimal resolution of this technique is lower than that of AFM and insufficient for imaging
the nano-dynamics of receptors and transducers. SICM has been applied in various techniques, including one thatuses a nanopipette to inject substances into specific intracellular nano-regions, as well as sample collection andanalysis (Mirkin et al., PNAS 104 (2007) 11895). However, SICM has not yet been successfully used to injectmolecular machines with high controllability for manipulating protein structures or functions, nor to map the
distributions of physical properties, such as pH and oxygen concentration, in liquids using molecular sensors. As
these advances and limitations illustrate, progress is being made in the visualization of cell-surface nano-dynamics,
but a breakthrough technology is needed for direct imaging of intracellular molecular dynamics. In addition, thedevelopment of techniques requiring the fusion of nanometrology with supramolecular chemistry, no matter it befor intracellular or cell-surface applications, is a challenge that has yet to be resolved.
(2) Challenges in supramolecular chemistry: Controlling the position and orientation of molecularsensors/machines to operate them upon nanostructures of interest
Supramolecular chemistry has developed as a field of chemistry for creating new molecular functions through thedesign of selective intramolecular interactions. Recent research attention has focused on molecular machines,
which were the subject of the 2016 Nobel Prize in Chemistry. These nanoscale devices can rotate, reciprocally
move, or perform other actions in response to external stimuli. Examples include a molecular elevator that moves
up and down in response to pH (Stoddart et al., Science 303 (2004) 1845) and molecular tweezers that open andclose in response to light (Aida et al., Nature 440 (2006) 512). However, these highly functional molecular sensors
and machines are yet to be translated into practical applications. One barrier is the lack of technology for effectively
controlling the position and orientation of these functional molecules so that they can be operated upon
nanostructures of interest. Here, SPM techniques could help by offering abilities such as the conveyance ofmolecules to specific nanoscale regions using a nanopipette, or subnanometer-scale positional control of amolecule affixed to a probe tip. The combination of SPM and supramolecular chemistry promises to pave the wayfor effectively controlling and operating functional supramolecules upon intracellular and cell-surface
nanostructures of interest.
(3) Challenges in oncology: Achieving nanoscale understanding of the cell dynamics of cancer progression
Recent progress in whole-genome sequencing of cancer cells has led to identification of driver oncogenes in many
types of cancer. Discovery of drugs that selectively inhibit function of driver gene products has established practiceand concept of molecularly targeted therapy of cancer. Despite the progress of recent medical and pharmaceuticalKanazawa University-3
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sciences, we have yet sufficiently understood mechanisms of malignant progression of cancer, such as drug
resistance and metastasis. This insufficiency is partly because there are no techniques for real-time imaging of
nano-dynamic features of non-labeled cells and molecules involved in cancer progression. For example, it is nighimpossible to understand the process leading up to drug resistance without directly imaging the changes that takeplace inside cells and their environment (e.g., pH, oxygen concentration, osmotic pressure, and amino acid andsugar distributions). The significance of interactions between cancer cells and the microenvironment mediated by
growth factors, inflammatory cytokines, and exosomes has been increasingly recognized, but without direct
imaging of the molecular and cellular dynamics, it is extremely difficult to elucidate mechanisms of adhesion,
migration, and invasion peculiar to cancer cells, through understanding of the changes in inside and surface ofcancer cells. Thus, techniques to directly image and analyze molecular cell dynamics at nanoscale resolution are
prerequisite to elucidating the unresolved mechanisms of cancer progression.
Scientific/social significanceWe seek to tackle the aforementioned challenges in nanometrology, supramolecular chemistry, and oncology
through research that expands and combines the knowledge and techniques of each of these disciplines. Instead ofjust evolving these fields, we will endeavor to pioneer a whole new discipline of “nano-probe life science” thatwill have enormous implications for the future of science. The knowledge and techniques emerging from ourresearch will pave the way to a fundamental understanding of various biological phenomena that will allow theirprecise control. Such advances hold immense social significance as they could aid in conquering cancer and otherintractable diseases, extending lifespan, and achieving other important health improvements.
3. Reasons why our research is a good match for the WPI initiative
Japan’s competitive edge
Japan’s competitive edge in this research area lies in that it hosts the world’s foremost bio-SPM techniques andthe inspired minds that created them. As noted earlier, bio-SPM is the surest path to realizing nano-endoscopic
techniques. The most fundamental and critical performance factors of bio-SPM are resolution and speed, and two
Japanese scientists from our institute, Fukuma and Ando, have led the world in the ongoing improvement of thesefactors. Having designed and built their systems from scratch, both scientists have expertise in developing SPM
techniques of top-notch resolution and speed. Having a team of scientists of such caliber at one institute is anincredibly strong advantage.
Appeal as global scientific/social challenges(1) Appeal as a scientific challenge
Origins of material properties and various phenomena can be explained in terms of nanoscale structures formed
from atomic and molecular assemblies and their dynamic behaviors. Hence, understanding and controlling
nanoscale structures would empower us to manipulate at will all sorts of physical properties and phenomena. This
represents the ultimate aim of science—to transcend the boundaries of the established disciplines of physics,
chemistry, biology, pharmacy, and medicine—and forms the core concept of nanotechnology. Ever since the
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pursuit of nanotechnological research was declared a key pillar of the US strategy by President Clinton in 2000,
enormous research as well as financial investments have been made in nanotechnological R&D worldwide. These
efforts have blazed new paths toward humankind’s understanding and control of natural phenomena at thenanoscale. In the early 2000s, the main focus was on materials and devices, but in the second half of that decade,bioscience became a greater target of exploration. Subsequently, nanoscience encompassed life sciences such as
medical and pharmaceutical sciences, evolving into one of the greatest attempts in humankind’s unending quest to
expand the borders of science and technology.
(2) Appeal as a social challenge
Initially, we will perform detailed comparisons of nanodynamics between normal and cancer cells using ourinnovative nano-probe techniques. This will lead to fundamental understanding of the mechanisms of basic cellularfunctions and their cancer-specific abnormalities. Achieving this goal will enable precision control of the various
phenomena involved in cancer, and thus make it possible to overcome this intractable disease. Clearly, our researchtarget represents a very important social challenge globally as well as specifically for Japan, where cancer kills
roughly one in every three people.
Future prospects for this field
We will endeavor to establish the foundation for nano-probe life science by building techniques for and accruing
expertise in the imaging, analysis, and manipulation of life phenomena at the nanoscale. Further in future, thosetechniques and know-how promise to deepen our understanding and control of not only cancer, but also other life
phenomena. Our research field is thus anticipated to pave the way for immense contributions to human health,including lifespan extension and conquering of intractable illnesses such as cancer, heart disease,neurodegenerative disease, and liver disease.
４．Japanese and overseas institutes focusing on similar fields① Quantitative Biology Center (QBiC), RIKEN, investigates and computationally simulates intracellularmolecular kinetics at high resolution to deepen our understanding of living systems. Although their research goals
are similar to ours, different from us, they mainly use optical microscopy to achieve them.
② Institute of Transformative Bio-molecules, Nagoya University (ITbM) develops novel functional molecules
to visualize and control living systems. Although they combine chemistry and biology to tackle issues in life
sciences as we do, their focus is on animals and plants. In addition, they use optical microscopy for imaging.
③ Janelia Research Campus, Howard Hughes Medical Institute (HHMI) focuses on basic medicine, withnovel bio-imaging techniques and neuroscience research at the core. In contrast to us, they use optical microscopy
as the main imaging technique.
④ Max Planck Institute for Biophysical Chemistry (MPI-BPC) combines knowledge in physics, chemistry,and biology to understand the mechanisms by which cells, organelles, and biomolecules express their functions.
In contrast to us, they use NMR and optical microscopy as core imaging techniques.
⑤The Center for Nanophase Materials Sciences (CNMS) in the USA researches nanotechnology in generaland is globally reputed for SPM research. However, their focus is mainly on the materials and energy fields, notKanazawa University-5
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life sciences.
As described above, while there are numerous research institutes aiming to elucidate the principles of the living
system, their main imaging tool is optical microscopy. While there are many nanotechnology research centers in
the world, none of them is solely focused on the understanding of life phenomena. We will be the first in the world
to establish a research institute for understanding living systems using advanced nano-probe techniques and tocreate the novel academic field “nano-probe life science”.
2)-2 Research objectives* Describe in a clear and easy-to-understand manner the research objectives that the project seeks to achieve by the end of its grant
period (in 10 years). In describing these objectives, the following points should be articulated in an easily understandable manner:
The kind of research area(s) you plan to cultivate by, for example, fusing various fields. In that process, what world-level scientificand/or technological issues are you seeking to solve? What will the expected impact of the scientific advances you aim to achieve beon society in the future?
* Describe concretely your research plan to achieve these objectives and any past achievements related to your proposal.

1. Exit goals (10 years from now)
Research goals
Our institute is committed to achieving the following goals by the conclusion of the ten-year period:• Develop nano-endoscopic techniques enabling direct imaging, analysis, and manipulation of the dynamic
behavior of molecules inside and on cells.
• Acquire an accurate understanding of mechanisms of basic cellular functions as well as their cancer-specificabnormalities by using the nano-endoscopic and computer simulation techniques we will develop.
• Pioneer the emerging discipline of “nano-probe life science.”
Global scientific/technological challenges and their social impact
Over the years, various techniques have been developed with the aim of gaining a fundamental understanding of
the mechanisms underlying a multitude of life phenomena, including diseases and aging, by directly visualizing
molecular and cellular dynamics; however, challenges remain. The resolution of these challenges will allow afundamental understanding and manipulation/control of the mechanisms of these phenomena. This endeavor has
immense significance for society, as it will contribute to human health by conquering intractable diseases andextend life expectancy.
２．Specific plans for research activities and related achievements to date
[Development of technique for measuring nano-dynamics on cell surface and interior](Development of nano-imaging techniques)・Measurement of the nano-dynamics of cells: Cell-membrane morphology changes continuously at the nanolevel in relation to physiological processes, including cell migration and endocytosis. Direct imaging of suchchanges using conventional techniques has been very difficult. The rapid advancements in bio-SPM indicate thatsuch imaging is on the verge of break-through. Core members of NanoLSI have played a leading role in thedevelopment of this technology. Ando increased the operation speed of AFM in solution by several hundred-fold(PNAS 98 (2001) 12468; Prog. Suf. Sci. 83 (2008) 337), enabling direct imaging of protein dynamics at the nano

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level (Figs. 1a and 1b) (Nature 468 (2010) 72; Science 333(2011) 755). Furthermore, they successfully expanded thehigh-speed AFM scan range, enabling direct imaging ofdynamic morphological changes in nerve-cell endings (Fig.
1c) (Sci. Rep. 5 (2015) 8724). However, in high-speed AFM,
the probe exerts a force on the sample, and thus, often does
not allow for nondestructive imaging of the very soft uppersurfaceofeukaryocytes.

Therefore,scanning

ion

conductance microscopy (SICM) currently attracts attention.
In this technique, a nanopipette is scanned without touchingthesample,allowing

nondestructive

imagingofeukaryocytes (Nat. Methods, 6 (2009) 279). Korchev

Fig. 1: Nanoscale life phenomena visualized byhigh-speed AFM. (a) Myosin V walking along theactin filament. (b) Rotary catalysis of rotor-less
F1-ATPase. (c) Filopodia growth from living
nerve cell.

established the basics of SICM and were the first to demonstrate its
usefulness in live-cell imaging (Fig. 2). Takahashi of the Fukuma groupcollaborated with Korchev to combine SICM with electrochemicalmeasurement techniques, and enabled to locally measure oxygen,neurotransmitters, and ATP (ACS Nano, 10 (2016) 3214).
Furthermore, Watanabe of the Ando group developed high-speed
SICM by combining it with high-speed AFM. He developed atechnique allowing direct imaging of nanomorphological changes incells at ≥1 frame/s. In NanoLSI, the SICM techniques of the Ando,
Fukuma, and Korchev groups are combined, and with further
development, the measurement of cellular nano-dynamics will be
realized.

Fig. 3: Subnanoscale 3D distribution ofwater and surface structures of
biomolecules visualized by 3D-AFM. (a)3D-AFM. (b) Lipid/water interface. (c)GroEL/water inteface.

・ Measurement of nano-dynamics on cell surfaces: In the cell
membrane, various proteins such as receptors and channel proteins are present that allow intra/extracellularsignaling and substance transport and are often closely related to cancer development and progression.
Conventional techniques cannot satisfactorily visualize protein
dynamics on live-cell surfaces at the nano level. Exceptional
results have been obtained by Ando, who successfully used highspeed AFM to image aquaporin nano-dynamics on the live bacteria
having a relatively hard surface for a cell (JMB 422 (2012) 300).
However, high-speed AFM currently is not up to soft eucaryocyte
surfaces. While high-speed SICM allows the imaging ofeukaryocyte surface structures, its spatial resolution is not
sufficient for imaging protein dynamics at the nano level. In Fig. 2: Nanoscale structures and dynamics oncell surfaces visualized by SICM. (a) SICM
addition, to accurately understand transport phenomena, apart fromimaging. (b) Protrusions at inner hair cell. (c)the transporters, one needs to understand the distribution of water Formation of a protrusion before clathrincoated pit closure.
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molecules, ions, and small organic molecules that are transported. This distribution presumably occurs in a 3D
space of several nanometers thick near the interface. With conventional two-dimensional (2D) SPM, such
distributions cannot be captured; therefore, this study focuses on 3D-AFM. Fukuma enabled in-liquid operation of
frequency modulation AFM (FM-AFM), highest-resolution AFM technique, and enabled true atomic-resolution
FM-AFM imaging in liquids for the first time (App. Phys. Lett. 87 (2005) 034101). Based on this technique, healso developed 3D-AFM and enabled direct imaging of 3D distribution of hydration structures and flexible surface
structures of biomolecules with subnanoscale resolution (Fig. 3) (Phys. Rev. Lett. 104 (2010) 016101). Foster was
the first to succeed in reproducing a 3D-AFM measurement using atomic-level molecular dynamics simulation,
making an important step towards the full understanding of the measurement principle and quantitative calculationof hydration structures from the measured 3D-AFM data (Phys. Rev. B 92 (2015) 155412). Similar to SICM, in
3D-AFM, the probe makes hopping movements in the Z direction, enabling minimally invasive measurements.
However, the current observation speed of 1 min/frame is not adequate. By combining the high-speed scanningtechniques of Ando, 3D-AFM of Fukuma, and the simulation techniques of Foster, we aim to achieve non-invasive,high-speed 3D nano-dynamics measurements at live-cell surfaces.
・Visualization of intracellular nano-dynamics (nano-endoscopic observation): The behavior of proteins andnucleic acids on the surfaces and in the interiors of organelles such as nuclei and mitochondria plays importantroles in signal transduction through vacuoles and in physiological processes such as transportation. Direct
visualization of these phenomena at the nano level is unachievable by conventional techniques. To explore thisuncharted realm, we combine the 3D-AFM technique of Fukuma, the high-speed AFM technique of Ando, and thelong-probe fabrication technique of Korchev and create a nano-endoscopic imaging technique. In hydrationstructure measurement by 3D-AFM, the probe is scanned in a 3D space such that the probe penetrates the hydration
structure and the vertical force applied to the probe apex is recorded to visualize 3D water distribution. Similarly,
if we can penetrate the membrane at the cell surface with an acceptable perturbation to the cell activities using avery thin and long probe, we should be able to scan the probe in a 3D space including the cell interiors forvisualizing the nano-dynamics happening in the scanned region(Fig. 4a). Korchev have established fabrication technique of a
glass long probe in an effort to improve the performance of
SICM. He has succeeded in inserting it into live cells to inject
substances. In the meanwhile, Ando have established atechnique for fabricating an electron beam deposited (EBD)
carbon tip with a nanoscale asperity on an arbitrary location
under scanning electron microscope observation (Sci. Rep. 5(2015) 8724). We combine these techniques to prepare a glass
long probe with a nanoscale asperity. Using this probe withhigh-speed 3D-AFM, we achieve high-speed 3D intracellularimaging with nanoscale resolution. Preliminary experimental
results have proven its potential; we successfully imaged 3D
molecular adsorption structures showing complicated, non-Fig. 4: (a) Nano-endoscopic imaging of inside acell. (b) 3D-AFM image of molecular adsorption
structures obtained at a solid/liquid interface. (c)Glass probe attached to an AFM cantilever. (d)EBD tip fabricated on a glass probe.

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uniform distribution with subnanometer resolution (Fig. 4b). We also fabricated a glass long probe with an EBD
tip at its end (Figs. 4c and 4d) and successfully applied it to true atomic-resolution imaging in liquids. If it becomes
possible to control the probe position in cells, high-speed 2D/3D imaging of nano-dynamics at the surface oforganelles should also become possible. One result that supports this possibility is already obtained by Wong,
where he directly visualized the dynamics of the pores and proteins around them on extracted nuclei using highspeed AFM (ACS Nano (2017) in press).
(Development of nano-endoscopic analysis and manipulation techniques)
Based on the nano-endoscopic imaging technique, nano-endoscopic analysis and manipulation techniques will be
developed.
・Injection and sampling of substances using a nanopipette: If substances can be injected into specific nearsurface or intracellular nano-regions, nano-dynamics induced by the injection can be measured directly using nanoimaging techniques. To date, there are only limited number of research groups who have successfully injected
substances into intra/extracellular nano-regions using nanopipettes and examined the reactions by fluorescencemicroscopy. The Korchev group is one of the few research groups. We combine this technique with the nanoendoscopic imaging technique to enable direct visualization of nano-dynamics that cannot be imaged byfluorescence microscopy. Moreover, sampling from specific nano-regions, which will allow high-precision
analysis of the molecules and ions present, has recently become possible. Takahashi of the Fukuma group haveachieved local sampling of cell cytoplasm for mRNA analysis. The combination of these leading nanopipette andnano-imaging techniques will make nano-endoscopic analysis possible.
・Analysis of nano-distribution of physical properties using a molecular sensor: Intra/extracellular pH andoxygen concentration are closely related to not only cancer development but also the function of drugs and drugdelivery systems. The spatial resolution of conventional techniques including fluorescence sensors is notnecessarily sufficient for imaging nanoscale distributions of these physical properties. We aim to solve this problem
by combining bio-SPM and supramolecular chemistry techniques. We will develop a molecular sensor that changes
its structure in response to pH or oxygen concentration in a liquid environment using our expertise insupramolecular chemistry. By attaching the sensor to an end of a nanopipette for SICM, distributions can bedetected based on changes in the ion current passing through the pipette. By combining this nanopipette techniquewith 3D-AFM, the probe apex can be precisely positioned to a specific nano-region. Researchers at NanoLSI(Ogoshi, Maeda, Akine and MacLachlan) have successfully developed functional molecules that can change theirstructures in response to various chemical stimuli including pH and oxygen concentration changes. Combining
their expertise and the aforementioned bio-SPM techniques, we accomplish the attachment of the molecular sensor
to a nanopipette apex. While it has been a great challenge to control the orientation of a nano-sized molecularsensor and directly attach it to the nanopipette apex, there are substantial number of reports on the attachment of
nanorods at the apex of an SPM probe by scanning electron microscopy or electrophoresis. Therefore, we employ
supramolecular chemistry techniques to design and synthesize a supramolecular nanorod with a molecular sensor
integrated at its end. We further attach this nanorod to the apex of a nanopipette. This markedly increases the ability
to control the position and orientation of the molecular sensors. The methods described above will enable
Kanazawa University-9
Nano Life Science Institute (NanoLSI)

measuring the distribution of physical properties inside and outside the cells.
・Nano-manipulation using molecular machines: As mentioned above, receptors and channel proteins in thecell membrane are closely related to the mechanisms underlying cancer development and progression. Thus, adetailed understanding and precise control of their functions should contribute to overcoming cancer. So far, theeffects of drugs on the protein functions have often been investigated by the fluorescence microscopy imaging of
the cellular or molecular responses induced by the addition of drugs into the cell culture solution. However, insuch experiments, either of the methods for giving a stimulus or detecting response does not have nanoscale locality.
Thus, even when the molecules involved are known, it is difficult to know how these molecules behave in real
space and how these behaviors affect the structure and functions of the targeted protein. In NanoLSI, we detectsuch responses at the nano level using the nano-endoscopic imaging and analysis techniques. To give a stimuluswith a nanoscale locality, we use molecular machines that change their structures in response to various external
stimuli, such as changes in temperature, electric potential or light irradiation. There are two approaches to let thesemolecular machines act on specific proteins inside or outside of cells. The first is to synthesize molecular machineswith specific target-protein binding sites and inject them into specific intra/extracellular nano-regions using
nanopipette. This allows selective and local stimulation of proteins with a precision of several tens of nanometers.
For the recognition of the target proteins, we use molecular structures of the recognition part of biomolecules witha help of a library that has been established in previous studies using biochemical methodology. We can arbitrarily
control the timing of stimulation by applying an external stimulus. However, to investigate the effects of such
artificially synthesized molecules in vivo, expert knowledge of pharmacology is essential. Nakajima's group haveachieved an enhanced understanding of the factors determining drug response and toxicity as well as the underlying
mechanisms by using molecular biological approaches (Annu. Rev. Pharmacol. Toxicol. 53 (2013) 377). Moreover,the dynamics/kinetics of molecules in the body have been quantitatively analyzed, and this has been extended tofunctional analysis of factors that regulate the dynamics/kinetics of molecules. The interaction of the molecularmachines with the target proteins and the cellular response induced by their introduction into a cell are being
analyzed from the viewpoints of pharmacology and toxicity, which contributes to the optimization of the molecular
design. The second approach is to further improve the locality of the stimulation to the scale of several nanometers.
This approach, in which a molecular machine is attached to a nanorod and then to an AFM probe end, is similar tothat used for the measurements of distribution of physical properties mentioned above. Consequently, theorientation of the molecular machine in the targeted intra/extracellular site can be controlled, allowing it to act ona specific site with nano level precision. Supramolecular chemistry researchers at NanoLSI have developed
molecules that change structures in response to various
external stimuli (Fig. 5) (JACS 130 (2008) 5022; Nature
Chem. 6 (2014) 429; JACS 139 (2017) 4631). By combining
such techniques, various molecular machines that function as
molecular tweezers and scissors will be developed. NanoLSI Fig. 5: Functional supramolecular structures. (a)Cyclic compounds for molecular recognition. (b)takes full advantage of these supramolecular chemistry Dynamic structural control of helical molecules. (c)Molecular containers with caps for storing
techniques to achieve nano-endoscopic manipulation.
molecules.

Kanazawa University-10
Nano Life Science Institute (NanoLSI)[Nano-level understanding of the mechanisms of basic cellular functions using expertise in cancer research](Understanding measurement principles of newly-developed nano-probe techniques and life phenomena bymeans of mathematical/computational sciences)
・ Verifying and understanding the principles of nano-probe measurement techniques: In general, theaccuracy and reliability of a newly-developed measurement method should be verified before it is used for practicalapplications. Such verifications typically involve comparison with results obtained by an existing method and/or
measurement of model samples with known properties. However, both of these approaches are often difficult for
an atomic- or molecular-scale measurement technique. As an alternative solution, simulation techniques are
becoming increasingly important owing to rapid advances in mathematical/computational sciences. However, very
few research groups have experience in reproducing SPM measurements at the atomic/molecular level in silico
and verifying the principles behind them. The Foster group is one of these few groups and has many experiencesin joint research with SPM researchers from all over the world (Nat. Commun. 7 (2016) 12711; Nat. Commun. 7(2016) 11559; Nat. Commun. 6 (2015) 8098). So far, he reproduced the 3D hydration-structure measurements
reported by Fukuma using the atomic-level molecular dynamics simulation, making an important step towards thefull understanding of the measurement principle (Phys. Rev. B 92 (2015) 155412). At NanoLSI, we reproduce
nano-endoscopic imaging in 3D spaces, including the cell surface and interior, using computer simulation, andstudy the principles in detail. In particular, we clarify the effect of the probe on the measurement, the relationshipbetween relaxation time and scanning speed, and the optimal measurement conditions for accurate measurementof life phenomena.
・Understanding life phenomena: Regardless of the measurement technique, we obtain information on the
structure and properties of targets through probe–target interaction. Therefore, unless we fully understand thenature of the probe and interaction, even a clear atomic-resolution AFM image may not provide a complete
understanding of the structure of the target. Simulation techniques help in bridging this gap between the measured
data and the real-space model. For example, Fukuma recently developed high-speed FM-AFM and visualized
calcite dissolution processes with true atomic resolution yet these images alone were not sufficient to fully
understand the atomistic model of the dissolution process. In cooperation with Foster, they performed density
functional theory and molecular dynamics calculations for numerous possible models and finally determined aunique atomistic model that is consistent with the experimental results. Similarly, at NanoLSI, we use suchatomistic simulation techniques for reproducing the measurements of 3D distribution of water, ions and local
surface structures. However, simulating the dynamics of an entire protein, organelle, or cell using this method is
not practical because of the high computational cost. This problem will be solved by the coarse-grained modelingapproach, where certain number of amino acids or molecules are treated as a cluster. Mikhailov, an expert in thesimulation of complex systems (Nat. Phys. 6 (2010) 544; Science 264 (1994) 223), will use various mathematical
approaches for modeling the formation and other collective behaviors of complex systems from simple elements
and element–element interactions, and reproduce measured nano-dynamics of proteins, organelles and cells to
elucidate the underlying mechanisms.
(Nano-level understanding of basic cellular functions using expertise in cancer research and innovative
nano-probe techniques）
Kanazawa University-11
Nano Life Science Institute (NanoLSI)At NanoLSI, we will image, analyze and manipulate nano-dynamics of unlabeled nucleic acids, metabolites,
proteins and organelles in normal and cancer cells using nanoendoscopic technologies. This will allow us tounderstand the mechanisms of basic cellular functions and their cancer-specific abnormalities.
Stem cells are defined as cells that have the ability to perpetuate undifferentiated status through self-renewal, anddevelop into mature cells through differentiation. The group of Hirao aims to elucidate the essential nature of stem
cells, and has identified that inhibition of cell cycle transition, the removable of reactive oxygen species, and theactivation of a nutrient starvation signals are important for regulation of the stemness and self-renewal ofhematopoietic and leukemia stem cells (Nat. Med. 12 (2006) 446; Cell Stem Cell, 1 (2007) 101; Nature 463 (2010)676). Therefore, precise measurement of the redox state and the distribution of nutrients such as glucose and aminoacids in cells will enable us to elucidate the essence of the stem cell properties. Use of molecular probes that detect
pH and nutrient distribution, and real-time imaging of the dynamics of molecules in normal stem and mature cellsby high-speed/high-resolution SPM will pave the way to novel stem-cell control systems. In addition, comparative
analyses between normal and cancer stem cells would lead to identification of cancer stem cell specific metabolic
abnormality.
Molecular modifications to either DNA or histones affect the structure and function of chromatin in nuclei,
leading to change of gene expressions. Inside nuclei, chromatins are considered to be separated by insulator
molecules, making up different domains. In this project, we will visualize chromatin domains by nanoendoscopic
technology to understand how cell type-specific gene expression patterns are controlled. Furthermore, since globalchanges in the epigenetic landscape are a hallmark of cancer, we will extend this approach to cancer cells. We will
understand mechanisms how malignant properties are acquired in a process of tumorigenesis in aspect of chromatinarchitecture.
Growth factors play important roles in cell proliferationand development of normal tissues and organs.
Matsumoto has played a pioneering role in physiology,
drug discovery and medical application of hepatocyte
growth factor (HGF) (Cell 67 (1991) 901; J. Gastroentel.
Hepatol. 26 (2011) 188; Nat. Commun. 6 (2015) 6737).
Recently, his group succeeded in visualization of the
dynamic structural change for HGF receptor activation
by high-speed AFM. This is the first to capture thedynamics of receptor activation, and the structures are
unexpected. His group will verify: (1) structuraldynamics and a new mechanism for transmembrane

Fig. 6: Comprehensive research on cancer progression
using nano-endoscopic techniques.

growth factor receptor activation, (2) aberrant molecular dynamics and activation mechanisms of mutant receptors
found in cancer patients, and (3) structure-based peptide drug discovery by artificial regulation of the receptor
activation.
Exosomes released by cells are small (30–100-nm diameter) vesicles containing lipids, proteins, RNAs, etc. andparticipate in cell-cell communications, which contribute to variety of cellular functions and phenomena.
Kanazawa University-12
Nano Life Science Institute (NanoLSI)

Hanayama has performed outstanding works on molecular mechanisms for the association between apoptosis andautoimmune disease, and has identified molecules involved in the formation, release, encapsulation, and uptake of
exosomes (Nature 417 (2002) 182; Science 305 (2004) 1147; Cell 140 (2010) 619). In this project, by visualizing
and analyzing the function and dynamics of exosomes at the single-particle level using SPM, Hanayama’s groupwill elucidate the principle mechanism of action of exosomes and develop technique to control exosomes. As
cancer cell-derived exosomes contain molecules closely involved in angiogenesis, immune-evasion, and metastasis,
thereby participate in the formation of microenvironment promotive for cancer progression, these research willcontribute to elucidate the detailed mechanisms of cancer progression mediated by exosomes.
For the development and regeneration of the normal epithelial organs, appropriate control of proliferation of
normal stem cell is critical. Although the possible molecular mechanism for morphogenesis and regeneration has
been elucidated by genome-wide analyses, precise morphological changes at nano-scale has not been investigated.
It has been shown that the molecular processes of morphogenesis/regeneration are similar to that of cancer
progression, and Oshima has developed various cancer models (Cell 87 (1996) 803; Cell 92 (1998) 645; EMBO J.
27 (2008) 1671). Oshima’s group will examine dynamic changes of intracellular ultrastructures at nano scale in
the intestinal stem cells during the above process with using cancer cells as references. Based on this project, we
expect that dynamic change at nano-level in morphogenesis as well as tumorigenesis will be understood.
Molecular-targeted cancer therapy has changed the concepts and practice of cancer treatment. However, evenwhen molecular-targeted therapies yield a favorable response, relapse due to drug resistance is a major problem.
Yano has analyzed the mechanism of the resistance in lung cancer, and showed that growth factor-induced receptor
activation leads to resistance against molecular-targeted drugs (Cancer Res. 68 (2008) 9479; Nat. Commun. 6(2015) 8792; Cancer Discovery 7 (2016) 754). Yano’s group will apply AFM to analysis of the dynamics ofmolecules involved in resistance signals and search for therapeutic targets. Using SPM techniques for patientderived unlabeled molecules and cells, aberrant signal characteristics, sensitivity, and resistant responses areanalyzed. The nano-manipulation technique to overcome resistance will be tested.
Thus, by collaborations with experts in cell biology, cancer biology and nanotechnology, we shall build a pathto the future of life science and a new era of cancer biology.
2)-3 Project management* Describe the center’s research organization (including its research, support and administrative components) and your concept forbuilding and staffing the organization.
* Describe your concrete plan for achieving the center’s final staffing goal, including steps and timetables.
* If the center will form linkage with other institutions, domestic and/or foreign, by establishing satellite functions, provide the name(s)of the partner institution(s), and describe their roles, personnel composition and structure, and collaborative framework with thecenter project (e.g., contracts to be concluded, schemes for resource transfer).

Kanazawa University-13
Nano Life Science Institute (NanoLSI)

* If the center will form linkage with other institutions, domestic and/or foreign, without establishing satellite functions, provide thenames of the partner institutions and describe
their roles and linkages within the center project.
* List in Appendix 4 the principal investigators whoare expected to join the center. If it there are anychanges from the list you submitted for the firstscreening, please state the changes and give yourreasons for them.
* Provide a biographical sketch for each principal
investigator using Appendix 5.
* List in the Appendix 6 the personnel making up
center, including researchers and other center
staffs, satellites, partner institutions. Use Excel
format when preparing the list.
* Regarding the researchers invited from abroad orfrom other Japanese institutions, attach a letterfrom each of them indicating their intent to join
the center project (free format). Label this bundleof documents “Appendix 7.”

Fig. 7: Organization of NanoLSI[The concept for NanoLSI]The center will be comprised of a 77-person Department of Research, a 25-person Department of Administration,
and a 25-person Department of Research Support.
At the time the center is established, 16 principal investigators will be appointed. These PIs will engage in research
activities alongside the faculty at Kanazawa University, thereby bringing the total number of research department
staff at the outset to 50. Furthermore, 20 administrative and Research Support staff will also be transferred to thecenter at the outset. Within 3 years, the center will reach its final staffing level of 127 persons.
Satellite Research Centers will be promptly established in Europe (the UK) and North America (Canada) in orderto accelerate international joint research, train human resources through exchanges of young scientists, andimprove international visibility.
i.

Center in Europe: Imperial College London, London, UK: Professor Korchev as PI

ii.

Center in North America: University of British Columbia, Vancouver, Canada: Professor MacLachlan as PIa) Principal investigators (full professors, associate professors or other researchers of comparable
standing)* Paste on table a) of Appendix 6

Final goal

At beginningof projectAt end of FY
2017(Date: Mar.,2021)

Researchers from within the host institution

12

12

12

Foreign researchers invited from abroad

4

5

7

Researchers invited from other Japanese institutions

0

2

4

Total principal investigators

16

19

23

b) Total members* Paste on table b) of Appendix 6

Kanazawa University-14
Nano Life Science Institute (NanoLSI)At beginning of
project
Number of％
persons
Researchers

At end of FY2017
Number of
persons

48
Overseas
researchers
Femaleresearchers％

65

Final goal
(Date: Mar.,2021)
Number of％
persons
77

9

18.8

19

28.1

25

32.5

5

10.4

12

18.5

16

20.8

Principal investigators

16

Overseas PIs

5

31.3

6

27.8

8

31.8

Female PIs

1

6.3

1

5.3

2

8.7

Other researchers

19

32

23

46

54

Overseas
researchers
Femaleresearchers
Research support staffs

15

15

25

Administrative staffs

5

17

25

Total number of people who form the"core" of the research center

68

97

127

4

12.5

13

28.3

17

31.5

4

12.5

11

23.9

14

25.9

2)-4 Securing research funding
Past record* Give the total amount of research funding (e.g., competitive funding) secured by the principal investigators who will join the center
project. Itemize by fiscal year (FY2012-2016).

FY
Amount

2012
572

2013
594

2014
668

2015
749

2016
708

(Million Yen)

Prospects after establishment of the center* Based on the past record, describe the concrete prospects for securing resources that match or exceed the WPI project grant.
* Calculate the total amount of research funding (e.g. competitive funding) based on the percentage of time that the researchers will
devote to research activities at the center vis-à-vis the total time they spend on research activities (“Effort” in Appendix 5). Be surethat the prospects (FY2017-2021) are realistically based on the past record.

Within the first two years, the 16 PIs will have collectively secured an average of 650 million yen per year (after
effort conversion) for external research funding;furthermore, by adding in the funds secured by other scientists
who plan to participate in the center’s research, the total figure would amount to 770 million yen. Further fundingis anticipated with the addition of six junior PIs with high potential immediately after the center is established, as
well as the appointment of staff specializing in fundraising support. In addition, the host institution will provide
the equivalent of 540 million yen per year in research project expenses, usage of facilities and equipment, among
others.

Overall, the center secure 1.31 billion yen in FY2017-2018 and 1.41 billion yen in FY2019 -2020. This

exceeds the project grant being requested.
3) Interdisciplinary Research* Describe why interdisciplinary research is necessary and important in the target field(s) and what new field(s) can be expected to becreated by way of this project. Describe your concrete strategy for advancing such interdisciplinary research.

1. Necessity and significance of interdisciplinary research

Kanazawa University-15
Nano Life Science Institute (NanoLSI)We aim to gain a fundamental understanding of the mechanisms of basic cellular functions at the atomic or
submolecular levels by comparing nanodynamics inside normal and cancer cells. To this end, we will expand andcombine our world’s top bio-SPM and supramolecular chemistry techniques to take a dramatic technological leap
toward the creation of nano-endoscopic techniques for direct imaging, analysis, and manipulation of nanodynamics of proteins, nucleic acids, and other molecules inside and on the surface of cells, as well as nanodistributions of pH and oxygen concentration. Naturally, this work will require collaborations with oncology
specialists in the medical and pharmaceutical sciences. Moreover, partnering with simulation experts will beessentialforaccurately

understanding

atomic and molecular dynamics fromexperimental results. As this illustrates, thepath toward our goal will require an all-out
effort that draws upon the techniques andknowledge of bio-SPM, supramolecularchemistry, medical and pharmaceuticalsciences,andmathematicalandcomputational sciences. This work will leadtotheestablishment

of

the

new

interdisciplinary science field of “nanoFig. 8: Strategy for interdisciplinary research at NanoLSI.

probe life science”.
2. Strategy for interdisciplinary research

In our research, there are two key challenges that are tackled with by combining expertise in multiple disciplines.
The strategies for achieving this goal are outlined below.
[Development of nano-endoscopic techniques through combination of bio-SPM and supramolecularchemistry techniques]
We will realize nano-endoscopic analysis for visualizing the nano-distribution of pH, oxygen concentration, andother properties that significantly influence molecular and cellular dynamics, using SPM probes fitted with highly
environmental-responsive molecular sensors. Simultaneously, we seek to achieve nano-endoscopic manipulationof nano-structures using probes fitted with molecular machines (molecular tweezers, scissors, etc.) offering highlevel control functionality. Furthermore, we will develop a mode of combined measurement whereby molecularmachines are injected into nano-regions with a nanopipette and a nano-probe will be used for live imaging of themolecular and cellular dynamics induced by stimuli from the molecular machines. In this way, we combine theexpertise in the two disciplines, nanometrology and supramolecular chemistry.
[Understanding of mechanisms of basic cellular functions and their cancer-specific abnormalities using
nano-endoscopic and simulation techniques]
The success of nanometrology depends on not only the performance of the instruments, but also the operatingskills of their users and sample preparation conditions. In NanoLSI, SPM researchers will work on the optimizationof the operating conditions while medical/pharmaceutical researchers will optimize the sample preparation
Kanazawa University-16
Nano Life Science Institute (NanoLSI)

procedures. In the meanwhile, simulations necessary for proper interpretation of the measured results are
performed by the following two researchers having different expertise in mathematical/computational sciences;
Foster, specialized in the atomistic simulation of molecular dynamics and in ab initio calculation (Phys. Rev. Lett.
102 (2009) 126807; Phys. Rev. Lett. 93 (2004) 187202), and Mikhailov, focusing on simulation of complicatedsystems using coarse-grained modeling (Nat. Phys. 6 (2010) 544; Science 264 (1994) 223). The comparative
examination of our experimental/simulation results and development of a nanoscale understanding of cancer-relate
phenomena

will

involvepoolingtheknowledge

of

SPM,

medical/pharmaceuticalscience,andmathematical/computational science researchers and repeated discussions.
[Formation of international alliance for “nanoprobe life science”]
We will establish an international alliance for the new research field “nanoprobe life science” to achieve thefollowing three goals.
(Complementary use of various bio-imaging techniques)
Although nanoprobe technology is unique and powerful, it is not the only tool for bio-imaging. There are manyother technologies and they are developing very rapidly. The complementary use of these different technologies
will be a key to achieve fundamental understandings of various life phenomena. To achieve this goal, we will form
an international alliance with other life science institutes having world-leading bio-imaging technologies. Tight
collaborations through this alliance network will also allow us to keep monitoring the progress of other bio-imaging
technologies and to adjust the plan for the development of our nanoprobe technologies. In this way, we will ensurethat our technologies always stay at the frontier of bio-imaging.
(Complementary use of various expertise in molecular cell biology)
At NanoLSI, we have gathered various experts in each important cancer research area as well as in basic medical
and pharmaceutical science. However, fundamental understanding of basic cellular functions requires broad rangeof expertise so that we may need to expand the range of our expertise. To this end, we will flexibly expand theinternational alliance network and, for a particularly important research area, we may recruit a talented researcher
to join us as a Junior PI or a PI. The formation of international alliance should help us to meet and find a right
person to join our research team.
(Widespread use of nanoprobe technologies for life science research)
Ultimate goal of our institute is to achieve nano-level understandings on various life phenomena using advanced
nanoprobe technologies. Considering the wide variety of life phenomena, this goal cannot be achieved only by our
institute. Thus, we aim to open our nanoprobe technologies to all life science researchers in the world. However,
newly developed methods and instruments are not necessarily usable by non-experts and often need improvements
in usability and applicability. Thus, we initially open our technologies to the limited members in the international
alliance so that we can obtained detailed reports from them. Based on the feedback, we will improve ourtechnologies to establish them as common tools for nanoprobe life science research.

4) International Research Environment4)-1 System for advancing international research* Describe your concrete plan for building an international research center including the makeup of its foreign researchers,
establishment of oversea satellites, and provision of researcher exchanges. Please include a timetable for this plan.

Kanazawa University-17
Nano Life Science Institute (NanoLSI)

* Describe concretely your strategy for staffing foreign researchers (e.g., postdoc positions) through open international solicitations.
Describe the procedures you will use to do so.

1. Concrete plan for building an international research center
2017

2018

2019

NanoLSI-Employ 64 researchers forstart-up(16 PIs incl. 5 from overseas, 2Junior PIs, 46 other researchersincl. 13 from overseas)-Hosting a symposium in Tokyo-Holding 3 seminars-Holding 12 seminars-Employ newly 2 Junior PIs incl. 1
from overseas; 4 Junior PIs incl. 1
from overseas in all-Employ newly 5 other researchersincl. 3 from overseas; 51 otherresearchers incl. 16 from overseas inall-Holding 12 seminars-Employ newly 2 Junior PIs incl.
1 from overseas; 6 Junior PIs incl.
2 from overseas in all-Employ newly 3 other researchersincl. 1 from overseas; 54 otherresearchers incl. 17 from overseas
in allSatellite
research
centers-Agreement with Imperial
College London-Employ 2 Postdoc-Agreement with University of British
Columbia-Exchange of young scientists-Hosting an international symposiumin Europe-Exchange of young scientists-Hosting an international
symposium in North America

Sixteen PIs will be hired when the center is established. During open recruitment for these positions, these positions
will be advertised widely using a range of methods. This procedure will be repeated in FY2019 and thereafter inorder to bring the center to full operation, with the recruitment drive occurring earlier than scheduled when possible.
４) -2 Establishment of international research environment* Describe your concrete strategy for establishing an international research environment and administration system, and the support
system to be provided for researchers from overseas.
* Describe your strategy, procedure and timing for periodically holding international research conferences or symposiums (at least oncea year).
* Describe your measures to ensure that top-caliber researchers from around the world can work comfortably in carrying out theirresearch within a competitive international environment.

1. Establishment of an International research center and administrative system, and provision of support
for overseas researchers[Establishment of an international research environment by radicalizing existing systems for university
reform] Kanazawa University is working toward creating an international research environment and strengthening
its research support system. Its unique Research Professor System and Center of Excellence system (Chozen
Project) provide resources for building such research environment, while its Cross-appointment System enables
flexible utilization of human resources. These unique systems enable the establishment of a world-class research
environment, and through them, the university is able to engage 6 world-class scientists from abroad, including a
Nobel laureate in chemistry. The new research center will further intensify these systems, which have alreadyachieved excellent results, and will implement the following measures in order to allow the introduction of fresh
blood from outside, and to enhance dynamic collaboration with other institutions.
•

Launch other unique COE for enhancing transdisciplinary and trans-institutional research.

•

Provide a competitive salary for all researchers and staff in NanoLSI.

•

Provide funding for the employment of post-doctoral researchers, technical staff, and research lab
secretaries.

•

Employ university research administrators (URAs) who, as assistants to the center director, will supportscientist recruitment and research funding acquisition.

• Utilize the excellent research networks of research professors invited from overseas to send
Kanazawa University-18
Nano Life Science Institute (NanoLSI)

young scientists and students to overseas research centers, thereby creating an environmentthat supports the cultivation of pioneering international scientists and enhances thevisibility of the center’s research.
•Through international recruitment, hire young scientists who represent the next generation of leaders intheir field as junior PIs, and use the tenure-track system to train and retain them as core staff who will leadthe center in the future.

• At all times, assign 20 young staff to the department of administration, in order to introduce international
administrative systems and staff culture in NanoLSI to the host institution as a whole through its staff
rotation.
[Establishment of international research support system] In order to establish a world-class research support
system that is capable of quickly implementing the center director’s principles and vision, Kanazawa University
will employ an administrative director with experience in international research and management of large-scale
research projects. the university will also relocate administrative staff from Kanazawa University who are
proficient in English and administrative tasks, and will enhance staffing through international recruitment in orderto establish an all-English work environment.
In addition to the administrative department, the university will establish a research support department staffedwith personnel (URAs and technical staff) who are highly skilled in specialized fields as well as proficient inEnglish. After the WPI program ends, this department will be succeeded by International Research Support Center,
which continues to offer high skilled technical and research supports.
[Establishment of a family support system] Spouses will be given priority in the hiring of positions within theuniversity that match their qualifications. In addition, the university will work with the existing school affiliatedwith the university—an unusual program on the national level which offers a comprehensive preschool throughhigh school education—to develop a special educational program for the children of the center’s staff.
2. International research conferences[Lightening scientist workloads and connecting with business networks through regular conferences
organized by specialized support staff] A large-scale international symposium will be hosted once a year,
revolving around the main research center and the satellite centers in Europe and North America. A kick-off
symposium will be held in Tokyo in March 2018. Monthly international seminars will also be held with the aim ofsharing research findings between fields and further promoting interdisciplinary research. Administrative staff
specializing in public relations and event planning will handle all aspects of these events (including those hosted
internationally) from planning to logistics, with guidance from the center director and PIs.
5) Center Management5) -1 Operational management* Describe the role of the center director.
* Describe the role of the administrative director.
* Concretely describe your concept for establishing an administrative organization.
* Concretely describe the center’s decision-making system.
* Concretely describe how authority is allocated between the center director and the host institution.
* Concretely describe how the center will adopt a rigorous system for evaluating research and will introduce a system for merit-based
compensation (e.g. annual salary scheme). Please describe your procedures and timing for operationalizing these systems.

Kanazawa University-19
Nano Life Science Institute (NanoLSI)

1. Roles of the center and administrative directors[Role of Center Director: Creating a new field of academic research] The aim of the center is to create a newinterdisciplinary research field called Nanoprobe Life Science, which integrates nanometrology, cancer research,supramolecular chemistry, and computational science in order to elucidate the mechanisms behind a variety ofvital phenomena. To achieve this goal, the center director will draw on his own background as a leader in various
research fields to develop a vision for this interdisciplinary research. The center director will have authority todetermine strategies and all other matters necessary for achieving this vision as well as deciding on the center’s
direction.
[Role of the administrative director: Achieving the vision] Based on the center director’s strong initiative, theadministrative director will work to realize the center director’s vision, and will develope a research environmentthat enables the achievement of this vision in the most appropriate way. Kanazawa University will invite Osaka
University Professor Seizo Morita to server as administrative director because of his deep understanding of theresearch areas this center will focus on as well as his abilities to succeed in a competitive international environment
and to manage large-scale research projects.
2. Concept for establishing an administrative organization[Basic concept] Kanazawa University’s top priority in establishing an administrative department is to create aneffective, prompt, and flexible support system so that scientists can focus on their research activities. To that end,
the University will establish a separate research support department staffed with highly specialized personnel. This
support system will be continuously reevaluated and improved in order to provide scientists with optimal support.
Furthermore, to ensure effective operation, the administrative and research support departments will coordinate
extensively with the university’s administrative headquarters and departmental administrative offices, thereby
drawing on the knowledge and knowhow of the entire university.
[Appointment of a current trustee as deputy administrative director: Building close ties with the university’s
executive office] A current trustee in the university’s executive office will be appointed as deputy administrative
director, serving directly under the administrative director. While always prioritizing the center director’s visionand the administrative director’s approach to managing the center, the deputy will build close ties with the hostinstitution’s current executive office, thus enabling various issues to be addressed and ensuring that the center runs
smoothly.
3. Decision-making system[Establishment of a steering meeting] the center director will have authority over all aspects of the center’s
operation, with the exception of his own dismissal and salary. However, in order to ensure optimal cooperation
with the administrative director and PIs and appropriate operation of the center, the center director will establish asteering meeting consisting of the Center Director, Administrative Director, Deputy Administrative Director, URA
Unit Leader, technical support unit leader, and other staff appointed by the center director. The steering meeting
will have jurisdiction over research, personnel affairs, budgets, and self-assessments. The establishment of just
one such meeting ensures that information will be centralized, the center director will be able to implement topdown management, and the number of meetings will be minimized, thereby ensuring that research activities areprioritized
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Nano Life Science Institute (NanoLSI)

[Establishment of an advisory board] The Center Director will establish an advisory board consisting of thepresident of Kanazawa University, leading international scientists in related fields, and world-class research center
managers. The center director will be able to request advisory support and receive advice from this board at any
time regarding interdisciplinary research and operation of the center.
4. Allocation of authority between the center director and the host institution
The center director will have complete authority over decisions related to the center’s research strategy, as well as
the acquisition and allocation of budgetary resources, personnel, space, and other research resources as well as allother matters. To this end, Kanazawa University will conform to its Commitment, and will proactively reassess
existing regulations and develop new systems. Furthermore, to provide foundational support for the center’s
initiatives, the university will have the authority and responsibility to allocate part of its budget to the center. It
will also review and audit the management of the center.
5. Research Evaluation system and flexibly salary system
An annual salary system will be applied to all center personnel, including faculty, administrative department staff,
and research support department staff. Their pay scale will be higher than that of other university personnel. At
the time of hiring, researchers will present a five-year research plan, and their progress will be evaluated yearly on
the basis of this plan. The center director will appoint an evaluation working group to each researcher, consistingof 2 PIs or Junior PIs, 1 researcher working in a related field at Kanazawa University or elsewhere, and otherindividuals, as deemed necessary. The center management will be evaluated biennially by an external Evaluation
Committee that comprises at least 10 world-class scientists. This evaluation committee will assess initiatives toincrease interdisciplinary and international research, the level of research achievements, center management, theperformance and treatment of staff scientists, and the screening of Junior PIs for tenure positions. The results ofthese evaluations will be used to improve the center’s management.
5) -2 Research environment* Concretely describe how equipment and facilities, including laboratory space, will be provided in a manner appropriate for a top worldlevel research center. Include your procedure and timing.
* Concretely describe how the center will provide an environment in which researchers can work comfortably on their research by being
exempted from duties other than research and related educational activities, and how they will be provided adequate staff support tohandle paperwork and other administrative functions. Include your procedure and timing.
* Concretely describe how the center will arrange for its researchers to participate in the education of graduate students.

1. Provision of research facilities and equipment
The center will be part of the Institute for Frontier Science Initiative, which occupies a research building with
2,100 square meters of total floor space. This research building features open laboratories and common spaces thatencourage intellectual cross-pollination, thereby promoting interdisciplinary research. 12 PIs at Kanazawa
University currently have approximately 2,850 square meters of research space at their disposal; and in addition,
the university has prioritized the center in its facilities and equipment plan, which will provide a new researchbuilding with 7,190 square meters of total floor space.
2. Streamlining of procedures and strengthening of support staff[Streamlining of procedures and allocation of outstanding staff: Freeing scientists from administrative
duties] In order To quickly achieve the center director’s vision, cumbersome procedures will be eliminated, andKanazawa University-21
Nano Life Science Institute (NanoLSI)

administrative staff will be granted extensive discretionary powers. In addition, staff will be allocated to provide“one-stop support” for all procedures and paperwork related to employment and daily life. To further enable thecenter director and PIs to focus on research, an adequate number of secretaries with appropriate skills will betransferred to the center. These measures will be implemented by the end of FY2018 in order to release researchers
from administrative duties as quickly as possible.
[Establishment of Department of Research Support: Support from specialized staff] In addition to theadministrative department, the university will establish a research support department staffed by personnel withhighly specialized skills. This department will include URA and technical support units. The URA unit will provide
support in attaining international grants, recruiting scientists, promoting relationships with industries and otherentities, and facilitating interdisciplinary research. The Technical Support Unit will handle research measurement
and analysis requiring advanced technical skills and provide technical guidance to young scientists and graduate
students.
3. Participation in graduate student education
A new “WPI Education Program (temporary name)” will be established to allow PIs and Junior PIs to participate
in graduate student education.
5) -3 Establishing the center in sync with organizational restructuring* Concretely describe the host institution’s organizational reform that will be synchronized with the establishment of the center.
* Describe measures that will be taken by the host institution to sustain the center’s operation after the WPI funding ends. Also describe
how the host institution will promote the centers autonomy after WPI funding ends and how it will over the mid-to-long term
restructure its existing organization in ways that give the center a permanent place within its organization.

1. Integration of the research center with an existing organization and measures to sustain independent
operation after WPI funding ends
As described in section 2 of the Host Institution’s Commitment, the goal of the Institute for Frontier Science
Initiative is to strategically advance interdisciplinary research. The institute, which has led the university’s
strategic organizational reforms, is a permanent organization. Placing the new research center within the Institutefor Frontier Science Initiative likewise situates it clearly as a permanent organization.
2. Plan for restructuring the existing organization over the mid-to-long term
NanoLSI will develop new systems and management methods in order to build an international research
environment and flexible management system. The most successful of these initiatives will be incorporated into
mid-to-long-term goals and plans, and will be adopted by the host institution as a whole. This will contribute
greatly to the reform of Japan’s university conventional system overall.

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Nano Life Science Institute (NanoLSI)Director’s Vision
Continuous advances in science and technology have enabled humans to explore diverse realms. We have traveled
across the Earth’s surface, atmosphere, and neighboring regions of space and amassed knowledge of various
phenomena, gaining insights that paved the way for today’s prosperity. Yet, there still are many worlds that we have
only begun to explore—the deep sea, the Earth’s interior, the vast reaches of outer space, and, at the other end of thespectrum, the microscopic universe. Optical microscopy, electron microscopy, scanning probe microscopy (SPM),
and other tools have allowed us to peer into domains invisible to unaided human eye. Our observations of
microorganisms, cells, molecules, and atoms have revealed various phenomena and elucidated their origins andphysical properties. Today, we are even able to characterize phenomena based on knowledge of configurations andinteractions among the smallest units of matter—atoms and molecules. Nevertheless, many corners of the nano world
remain uncharted; science and technology are currently unable to provide an accurate portrait of nanoscale structuresand dynamics. This limitation represents a significant barrier to the further advancement of science and technology.
In the life sciences, determining the behavior of proteins, nucleic acids, and other cellular components—basic
building blocks of the human body—is a key step toward fundamentally understanding and controlling the mechanismsof complex biological phenomena, such as development, disease and aging. However, we lack a detailed grasp of these
dynamics. For example, fluorescence microscopy allows us to visualize specific molecules tagged with fluorescentlabels, but we are unable to determine the position or structural changes of the many unlabeled molecules. Electron
microscopy can be used to examine the static ultrastructure of cells and molecules in a vacuum, but not to observe
nanoscale behavior in physiological solutions. At present, SPM is the only available technology for the direct imagingof the position and structural changes of protein molecules in solution, and thus is promising for approaching challenges
in the life sciences. However, SPM does not yet enable the direct observation of the intracellular protein behavior.
Accordingly, many nanoscale properties of intra/extracellular space have yet to be mapped out, limiting our ability tofundamentally understand biological phenomena, such as disease and aging.
Our institute (NanoLSI: Nano Life Science Institute) will explore
these uncharted realms with the aim of elucidating the mechanisms of
biological phenomena at the atomic and molecular levels (≈nanoscale). To advance this mission, we will create innovativetechnologies for direct imaging, analysis, and manipulation of
intracellular and cell-surface nanodynamics. First, we will develop atool for “nanoendoscopic imaging” that, similar to endoscopic
imaging of the stomach cavity, will enable direct video imaging of
intracellular nanodynamics. This tool will visualize on the nanoscale
not only the dynamics of proteins, nucleic acids, and other molecules,
but also the distribution of chemical properties, such as the pH andoxygen concentration, using highly environmentally responsive molecular sensors. We will seek to achieve on thecellular level something akin to therapeutic endoscopy, which includes endoscopic sampling/analysis of foreign
matter in the body and drug injection. Our “nanoendoscopic manipulation” technology will make it possible toKanazawa University-1

Nano Life Science Institute (NanoLSI)

sample/analyze specific nanoscale substances in cells and to control the function of receptors and other biomolecules
via molecular machines with high-level control functions.
Bringing such innovative technologies to reality will be a major challenge, but is not unrealistic. SPM is promising
for the development of nanoendoscopic technologies. SPM visualizes, at the nanoscale, surface topography and the
distribution of physical properties by scanning with a fine-tipped probe. In addition, the probe can be used to apply
stimuli and for structural manipulations with nanoscale precision. Kanazawa University’s achievements in this field
make it a world leader in technological development and applied research in bio-SPM operable in solutions. I
developed the first method for in-solution nanoscale imaging of the water density and surface potential distributions,and Ando was the first in the world to create an SPM technology for the direct nanoscale visualization of protein
dynamics. These technologies form the foundation for nanoendoscopic observations of the behaviors of proteins,
nucleic acids, water molecules, and ions. Moreover, one of NanoLSI’s members, Korchev, established the basis forscanning ion-conductance microscopy, which makes it possible to inject or sample substances in specific nanoscaleregions inside or outside of cells using a nanoscale pipette. Combined, our technologies provide a platform forrealizing nanoendoscopic manipulation. By leveraging these world-leading bio-SPM technologies and collaborations
among the outstanding researchers who pioneered them, NanoLSI will strive to develop nanoendoscopic
imaging/manipulation technologies.
Capitalizing on our innovative technologies for nanoscale imaging, analysis, and manipulation, NanoLSI willseek to establish a fundamental understanding of the mechanisms of basic cellular functions and their cancer-specificabnormalities. This focus on cancer has clear significance, as overcoming intractable diseases is a major goal insociety, and has considerable research implications. Cancer involves many different types of molecular dynamics,
including stemness (i.e., the ability of cells to proliferate by self-renewal and to differentiate), intra/extracellularsignaling, and genome dynamics, and the elucidation of these dynamics on the nanoscale will provide a fundamental
basis for understanding a wide range of biological phenomena. Furthermore, cancer research proceeds from a model
defining normal and abnormal cells; this comparison can be used to determine the relationship between cellular-level
abnormalities and abnormalities in the underlying molecular dynamics. Since cancer has a long research history, a
relatively deep understanding of the determinants of the onset of cancer has been established. Nevertheless, cancer
has yet to be conquered and accounts for one in three Japanese deaths. This suggests that current technologies are
insufficient for fully understanding the underlying molecules and processes. Our proposed nanoendoscopic
technology could provide insight into these elusive factors, and in so doing could lead to significant breakthroughsin the fight against cancer.
This goal cannot be achieved solely by nanometrological researchers. Naturally, medical/pharmaceuticalscientists specializing in oncology, supramolecular chemists with expertise in molecular sensor-based nanoanalyses
and nanomanipulation, and mathematical/computational scientists who can perform multiscale simulations areneeded. NanoLSI will strive to achieve the aforementioned goals through collaborations among researchers withworld-class track records in various fields. Kanazawa University, endowed with the Bio-AFM Frontier ResearchCenter and the Cancer Research Institute, is known worldwide as a leading institute of nanobio research and cancer
research. We will further build upon and expand this foundation to pioneer unexplored nanoscale realms and thus
evolve into a one-of-a-kind research institute, without parallel anywhere else in the world.
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Host Institution’s Commitment
Date

June 1st, 2017

To MEXTName of host institution
Kanazawa University
Name and title of head of host institution
Koetsu Yamazaki, President of Kanazawa University
Signature

I confirm that the measures listed below will be carried out faithfully regarding “Nano Life Science Institute”
adopted under the World Premier International Research Center Initiative.
<Provision in host institution’s mid-to-long-term plan>・Describe clearly the host institution’s mid-to-long-term plan and how it will position the center within that plan.

Kanazawa University aims to establish a world-class research center as a part of its mid-to-long-term plan,and is now advancing valuable original research in a systematic and focused way under the auspices of the Chozen
Project (Center of Excellence in Kanazawa University) in the following areas: nanometrology with strongemphasis on atomic force microscopy, medical and pharmaceutical research on cancer, and supramolecularchemistry for producing innovative materials. These research fields will play major roles in the interdisciplinary
research in the Nano Life Science Institute (NanoLSI).
On the president’s initiative, the university also plan to amass research projects valuable to the university in
the Institute for Frontier Science Initiative (a.k.a. “InFiniti,” established in FY2015 to promote interdisciplinary
research), and systematically and strategically develop its research programs with InFiniti taking center stage.
The Institute for Frontier Science Initiative’s overall plan includes the establishment of NanoLSI as a center forinterdisciplinary research in FY2018, the university specifies that in “Working Papers on Budget Request
FY2017.”
Furthermore, Kanazawa University lays also down “YAMAZAKI PLAN 2016” to autonomously develop
enhancing function and reforming systems looking ahead after twenty years. In this plan, the university aims to“form a research network with strong international competitiveness” (vision 6), and specifies “making research
networks with the world-class universities” and “inviting world-class researchers and exchange researchers from
Kanazawa University.”This center aims to realize the projects noted above, and intends to integrate the four branches of research:nanometrology with strong emphasis on atomic force microscopy, medical and pharmaceutical research on cancer,
supramolecular chemistry for producing innovative materials, and mathematical and computational science. It
will be established as an interdisciplinary center within the Institute for Frontier Science Initiative. Kanazawa
University has been planning to establish this center since the start of the Chozen Project in FY2014. It alreadyhas an explicit place in the university’s mid-to-long-term-plan. After the award, we will specify our target in mid-Kanazawa University-1
Nano Life Science Institute (NanoLSI)

to-long-term-plan and the entire university will support their execution.
<Concrete Measures>・Describe the concrete measures that the host institution will take to satisfy the following requirements.

1) How the host institution will support the center’s operation and research activities inaccordance with the Application Guidelines, section “6. Host institution’s commitment.”

This NanoLSI-project is a proposal to establish a center for the interdisciplinary research based on theexisting institute, the Institute for Frontier Science Initiative (InFiniti), which was funded with the aid of an
official operating expenses grant for national university corporations (for strengthening the function of national
universities). InFiniti is the organization taking the lead in university reform at Kanazawa University.
To support InFiniti’s operations, Kanazawa University has comprehensively improved various systems,
and it has already established the flexible personnel and administrative systems. In the establishment of the
NanoLSI, Kanazawa University will provide the world-class, pioneering, and international research
environment by further intensifying these organizational systems of Kanazawa University and the Institute for
Frontier Science Initiative. To achieve that, Kanazawa University is committed to financially supporting the
research in this center in amounts equal to or greater than the WPI grant.
Specifically, Kanazawa University continually supports the financing of this center’s annual budget 600
million yen to employ Principal Investigators (PI), 60 million yen to conduct research, and 80 million yen forthe location fee of the interdisciplinary research. In addition, plans to improve the environment of this center are
a top priority in Kanazawa University’s development project, therefore, the university would establish a new
project building for the cooperation of NanoLSI and the other institutes and organizations.
The research group presided by the sixteen PIs of this center acquired its average research funds of 770
million yen from FY2013 to 2016, with 850 million yen over the last two years. In regards to the future,
Kanazawa University will employ six young scientists as “Junior PI” who will work in this center’s next
generation research fields, and also arrange full-time staff who will give support for the acquiring of externalfunds. Therefore, NanoLSI will be able to acquire further funds and secure research funds equivalent or higher
than that of the WPI grant.
2) How the host institution will establish a basic policy for the mid-to-long term direction of its
organization and operation, one that restructures its existing organization in ways that givethe center a permanent place within its organization. Please provide a concrete schedule forcarrying out this organizational restructuring.

Kanazawa University will establish NanoLSI for interdisciplinary research as an internal center of theInstitute for Frontier Science Initiative. The university has already placed “Research Cancer Core,” grounded in
the Cancer Research Institute of Kanazawa University, within the Institute for Frontier Science Initiative.
Likewise, the university will consider this center as an independent organization. Besides securing its
independence in this way, the university also clearly positions it as a permanent organization by establishing it
within the Institute for Frontier Science Initiative.
The Institute for Frontier Science Initiative is the organization leading our strategic and systematic

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Nano Life Science Institute (NanoLSI)

reformation at Kanazawa University. In founding this institute, Kanazawa University rearranged twelve
positions from each department. In addition to this, the university secured twelve tenure track positions, andemployed five assistant professors through the Grant of University Reform Action Plan of MEXT. The
university also allocates a special budget and selected main research projects of NanoLSI as Chozen Project:nanometrology with strong emphasis on atomic force microscopy, medical and pharmaceutical research on
cancer, and supramolecular chemistry for producing innovative materials. Each area of research has an annual
research budget of approximately twenty million yen financed by Kanazawa University, i.e. centralized
additional distribution from the university.
This center will be established in the Institute of Frontier Science Initiative; therefore, it will have systems
I place to support for research costs through Chozen Project, receive research resources such as faculty position
and research spaces, and get research support from University Research Administrators (URAs) who are highlevel research support specialists. After the WPI period, Kanazawa University will also maintain these systems,
and regard this center as a permanent organization.
3) Ways in which the host institution will provide support to sustain the center as a world
premier international research center after the WPI grant period ends.

As mentioned above, NanoLSI will be established within the permanent organization, the Institute of
Frontier Science Initiative. Therefore, this center has been already defined as a permanent organization.
1. Maintaining the world-class research environment: Research Professor System and the Cross-appointment
SystemThe Institute of Frontier Science Initiative determines the direction of research in Kanazawa University.
To develop a suitable research environment for the Institute of Frontier Science Initiative, the university has
introduced a variety of new systems, and improved existing systems. In particular, the Research Professor (RP)
System, which is an original strategy of Kanazawa University, maintains continuous research of world-classresearchers from overseas by generous provision of costs for research start-up activities. Additionally, thissystem secures compensation and HR transparency that meet international standards through rigorous
performance evaluations and an annual salary system, and provides an environment where researchers canconcentrate on research by releasing them from managerial, administrative, and undergraduate teaching duties.
By the combined use of the RP-System and the Cross-appointment system, Kanazawa University has invited
six world-class researchers, including a winner of the Nobel Prize 2016 in Chemistry (his research field connectswith this center’s research on supramolecular, and he has the world authority on the design and synthesis ofmolecular machines): The university is already well on its way to establishing a top-level research environment
according to international standard. The Institute of Frontier Science Initiative has mechanisms in place to becontinually invested with resources: both research capital through the Chozen Project, and human resources
through the redistribution of university posts as described in detail above. Consequently, the university will
enable to maintain this center’s research environment as “World Premier International Research Center” after
the WPI grant period ends.
Kanazawa University will support world-class researchers from overseas who participate as a PI via the

Kanazawa University-3
Nano Life Science Institute (NanoLSI)RP system, in order that the PIs can continue the further cooperation between Kanazawa University and overseas
institutions as RPs after WPI grant period, as well as cultivating outstanding young researchers throughinternational intellectual exchange and leading the further development of this center. The six Junior PIs
employed through international recruitment will be further screened after the grant period ends, and those whomeet university standards will be employed in the tenure-track positions.
2. Fostering the next generation through the WPI Education Program
In FY2018, Kanazawa University and Japan Advanced Institute of Science and Technology will coestablish the Graduate School of Frontier Science Initiative Division of Transdisciplinary Science as atransdisciplinary sciences course within the Institute for Frontier Science Initiative. Some of NanoLSI’s PIs willtrain students in this course. We will also establish the “WPI Education Program (temporary name)” for selectedstudents in the Institute for Frontier Science Initiative’s Higher Education Department (an organization for theeducation of the graduate students in high grades). In this program, PIs and Junior PIs will instruct students bydeveloping the internationality, comprehensiveness, and interdisciplinarity of young researchers. NanoLSI will
maintain its position as a “World Premier International Research Center” by continually fostering excellent
young scientists taught by world-class researchers in a world-class research environment. To this end, theprogram will conduct interdisciplinary research by laboratory rotation, pay all students a research assistantallowance, support domestic and international employment, and give students priority admission into our
Kanazawa University Student/International Student Dormitory “SAKIGAKE.”
4) How will a system be instituted under which the center’s director is able to makesubstantive personnel and budget allocation decisions necessary to implementing the center
project—a system, which in practice, will allow the center director autonomy in making
decisions regarding the center’s operation.

Kanazawa University has already placed the “Cancer Research Core,” grounded in Cancer ResearchInstitute of Kanazawa University, within the Frontier Science Initiative. Likewise, the university will treat
NanoLSI as an independent department. The university will give the Center Director complete authority over
NanoLSI, including research subjects, budgets, and personnel affairs, so that this center can be operated flexibly
and expeditiously according to the strong initiative of the Center Director.
Kanazawa University will employ an Administrative Director who has international research as well as
management experience in large-scale research projects to enact the Center Director’s vision. Additionally, theuniversity will assign the active Trustee from the headquarters of Kanazawa University as Deputy
Administrative Director. Through the Deputy Administrative Director, the university will closely cooperate with
the Center Director and Administrative Director, promptly taking measures to support the center as needed while
guaranteeing the Center Director’s decision-making authority.
Additionally, Kanazawa University will make use of the experience and knowledge of the university as awhole by relocating full-time, manager-level staff with excellent management ability to the center to support its
operation in terms of personnel affairs, budget, and all other matters. Measures such as this full-time personnel
allocation will also be decided in consultation with the Center Director and Administrative Director through the

Kanazawa University-4
Nano Life Science Institute (NanoLSI)

Deputy Administrative Director as the university supports NanoLSI’s operations.
5) Support that will be provided to the center director in coordinating with other departments
within the host institution when recruiting researchers for the center, while giving
reasonable regard to the educational and research activities of those departments.

Regarding the Kanazawa University researchers who participate in NanoLSI, the university will devise
measures to prevent their participation from hindering the educational activities of their respective departments.
The Deputy Administrative Director will aid the Center Director by proactively making adjustments to support
each department as needed, including securing substitute faculty.
6) Flexibility that will be given in applying, revising, or outfitting the host institution’s internal
systems as needed for the center to effectively implement new management methods (e.g.
English-language environment, merit-based pay, top-down decision making, cooperation in
graduate education) unfettered by conventional modes of operation.

Kanazawa University will actively make flexible use of its existing systems, improve them and lay down
new rules, according to needs of NanoLSI in order to operate NanoLSI according to the best methods without
being bound to the methods of the past. Examples of such measures include the following: creating anenvironment suitable to carrying out all duties in English, adopting a salary system appropriate to the abilitiesof all researchers and staff, developing a powerful and flexible decision-making system under the Center
Director and a close cooperative relationship with Kanazawa University, and establishing an education
partnership with the graduate school.
7) The accommodation that will be given the center’s infrastructural requirements (forfacilities, e.g., laboratory space; equipment; land, etc.).

Kanazawa University provided a research building (three-story, total floor space: 2,100 square meters) in
April FY2015 to the Institute for Frontier Science Initiative, where the university planes to establish NanoLSI.
Open laboratories and common spaces will allow for intellectual cross-pollination to step up interdisciplinary
research. The twelve PIs at Kanazawa University already have 2,850 square meters of research space at theirdisposal utilizing the resources of Chozen Project, and the university’s facilities development project willprioritize in providing more, including a project building in the Natural Science and Technology Hall 3 Building(total floor space: 7,190 square meters) to promote interdisciplinary cooperation between NanoLSI and otherinstitutes and organizations. In these research facilities, the Department of Research Support’s TechnicalSupport Unit will provide total support via staff members with mastery of the equipment and ability to support
it in English. The university will duly carry out all these measures to support NanoLSI’s operations.
8) Other types of assistance that will be provided to give maximum support to the center inachieving its concepts and objectives and in becoming a world premier international
research center in both name and deed.

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Nano Life Science Institute (NanoLSI)

1. Establishment of the international employment system
NanoLSI will allocate a page especially for international recruitment on our website and update it with thelatest information as needed. We will also advertise our position openings in top-level journals, for example
Nature and Science, both in print and online, post them on the international recruitment site EURAXESS, andmake announcements in conferences and academic organizations related to this center’s research field.
Moreover, Kanazawa University will assign URAs with doctorates in related fields to NanoLSI’s Center
Director as advisers, and recruit young scientists utilizing research networks of the Center Director and PIs.
During recruitment, the university will provide information about its research and employment environment inadvance, which is in accordance with the recruitment methods of research institutions outside Japan. As forselection, the university will set up a Selection Committee consisting of the Center Director, Administrative
Director, Deputy Administrative Director, one or more PIs appointed by the Center Director, and one or more
external experts. This committee will screen applicants based on the vision and strategy of the center. One
external expert will come from the Evaluation Committee of this center. To execute these procedures, theuniversity will speed up the hiring process by reviewing current overly complicated processes and utilizing thesystems more flexibly.
2. Enhancing the research visibility of the Nano Life Science InstituteKanazawa University will widely advertise this center’s research and educational activities in and outside
Japan to increase its presence as a world-class research center. Public Relations Office and Organization of
Frontier Science and Innovation of Kanazawa University, in cooperation with NanoLSI’s public relation officers,
will conduct active outreach initiatives. Specifically, they will construct a website with careful attention tousability in a broad range of environments. In addition, a large international symposium will be hosted once a
year, revolving between in NanoLSI and the satellite centers in Europe and North America, which will further
increase NanoLSI’s international visibility (the kick-off symposium is scheduled March 2018 in Tokyo).
Monthly international seminars will also be held in this center, in order to share research results in acrossdifferent research fields, and enhance interdisciplinarity. These international events will be an appeal to thosein charge of new business at start-ups as well as big companies, supporting the continuation of the center after
the WPI grant project is completed. With these things in mind, Kanazawa University will fully support these
events by investing human and financial resources.
3. High-level research support System: The Department of Research Support (URA Unit and Technical Support
Unit)
Kanazawa University will support world-class PIs and Junior PIs by the establishment of an excellent
research support system. Concretely, the university will establish the Department of Research Support mannedby a highly specialized research support staff. This department will consist of the URA Unit and the TechnicalSupport Unit. The university will appoint researchers with backgrounds in fields close to the research of thiscenter as URAs and place them directly under the Center Director as advisers. They will provide support ininternational grant applications, recruitment of top-level researchers, development cooperation with companies,
and integration of research fields. In addition, the Center Director may request to be assigned other advisers
besides URAs as needed. The university will reallocate staff from the “General Technical Department”

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Nano Life Science Institute (NanoLSI)

(centralized management of the university’s technicians and technical/specialist staff, and the first independently
organized department of its type in Japan) to this center to form the Technical Support Unit. This unit will takecharge of measurements and analyses that require advanced skills as well as introducing these skill to young
scientists and graduate school students, thus contributing to research and cultivating the next generation. In thesecond half of the WPI period, Department of Research Support will gradually be incorporated into the Institutefor Frontier Science Initiative’s existing research support department, and after WPI period, it will be a divisionof the Institute for Frontier Science Initiative and function as a highly skilled international support divisionassisting the endeavors of the university as a whole.
Including the supports described above, Kanazawa University will take whatever measures needed to fully
support NanoLSI as a world-class research center.
9) How the host institution will self-evaluate the good results of the system reforms achievedby the center and take the initiative in extending them to departments throughout its
organization.

Kanazawa University understands that one of WPI program’s key priorities is to contribute to the systems
reform of universities in Japan, for example the development of international research environments andestablishment of flexible management systems. Any of NanoLSI’s undertakings in this vein, which produce
high quality results, will be actively rolled out across the university as a whole. We will document this in our
mid-to-long-term plan.
10) If the host institution has already established a WPI center, it should be fully supporting
the maintenance and further development of the existing center and be capable, at thesame time, of fully supporting the new center.

Not Applicable.

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List of Principal Investigators
・If the number of principal investigators exceeds 10, add columns as appropriate.
・Place an asterisk(*) by the name of the investigators who are considered to be ranked among the world’s top researchers.
・Give age as of 1 April 2017.
・For investigators who cannot participate in the center project from its beginning, indicate the time that their participation will start in the “Notes” column.
・ Include principal investigators affiliated with satellite institutions. Give the name of their satellite institutions in the “Notes” column.

Name

Age

Current affiliation(Institution, department, specialization)

Faculty of Electrical and Computer
Engineering, Institute of Science and
40 Engineering, Kanazawa University/ Bio-AFM
Frontier Research Center, Kanazawa
University
Bio-AFM Frontier Research Center, Kanazawa
66
University

Academic degree

Ph.D.(Doctor ofEngineering)

1

Takeshi Fukuma*

2

Toshio Ando*

3

Shigehisa Akine*

44

Faculty of Chemistry, Institute of Science and Ph.D.(Doctor ofEngineering, Kanazawa University
Science)

4

Tomoki Ogoshi*

40

Faculty of Chemistry, Institute of Science and Ph.D.(Doctor ofEngineering, Kanazawa University
Engineering)5

Katsuhiro Maeda*

46

Faculty of Chemistry, Institute of Science and Ph.D.(Doctor ofEngineering, Kanazawa University
Engineering)

6

Rikinari
Hanayama*

Faculty of Medicine, Institute of Medical,
42 Pharmaceutical and Health Sciences,
Kanazawa University

7

Masanobu
Oshima*55

8

Atsushi Hirao*

53

9

Kunio Matsumoto*10

Seiji Yano*

11

Miki Nakajima*

12

Richard W. Wong*

13

Adam S. Foster*

14

Alexander S.
Mikhailov*

15

Mark J.
MacLachlan*

16

Yuri E. Korchev*

17(To be selected)

Cancer Research Institute, Kanazawa
University

Cancer Research Institute, Kanazawa
University
Cancer Research Institute, Kanazawa
58 University/ Institute for Frontier Science
Initiative, Kanazawa University
Cancer Research Institute, Kanazawa
51
University
Faculty of Pharmacy, Institute of Medical,
47 Pharmaceutical and Health Sciences,
Kanazawa University
42

Institute for Frontier Science Initiative,
Kanazawa University

Ph.D.(Doctor of
Science)

Ph.D.(Doctor of
Medicine)
Ph.D.(Doctor of
Vaterinary
Medicine)
Ph.D.(Doctor of
Medicine)
Ph.D.(Doctor of
Science)
Ph.D.(Doctor of
Medicine)
Ph.D.(Doctor of
Pharmaceutical
Sciences)
Ph.D.(Doctor of
Medicine)

Department of Applied Physics, School of
41 Science, Aalto University/ Bio-AFM Frontier
Ph.D.
Research Center, Kanazawa University
Department of Physical Chemistry, Complex
67 Systems Group, Fritz Haber Institute of the Ph.D.
Max Planck Society
Department of Chemistry, Faculty of Science,
The University of British Columbia/ InstitutePh.D.
43
for Frontier Science Initiative, Kanazawa
University
56

Department of Medicine, Imperial College
London

Notes

Ph.D.

The University of
British Columbia
Satellite
Imperial College
London Satellite
basic cell biologist

Kanazawa University - 1

Nano Life Science Institute (NanoLSI)